Enhancing the radiation efficiency of dye doped whispering gallery mode microresonators.
We present a novel form of a Whispering Gallery Mode (WGM) sensor that exploits dye doped polystyrene microspheres, as active resonators, positioned onto the tip of a Microstructured Optical Fiber (MOF) as a means of overcoming the limited Q-factors for small resonators. We show that it is possible to substantially enhance the fluorescence emission of selected WGMs of the microspheres, resulting in an increase of the signal-to-noise ratio of the modes and of the effective Q-factor. This is done by positioning the resonator into one of the holes of a suspended core MOF and matching the resonator diameter with the hole diameter where it sits, effectively breaking the symmetry of the environment surrounding the sphere. Furthermore we demonstrate that using this experimental configuration, the lasing efficiency of the dye-doped microspheres is also significantly enhanced, which also contributes to an enhancement in the observed Q-factor.


Body Mass Index Does Not Impact Clinical Efficacy of Ustekinumab in Crohn's Disease: A Post Hoc Analysis of the IM-UNITI Trial.
This post hoc analysis aimed to evaluate the impact of BMI on the efficacy of ustekinumab in the IM-UNITI study. The relationship between body mass index (BMI) and efficacy of ustekinumab was evaluated using data from a 44-week maintenance study of ustekinumab in Crohn's disease (IM-UNITI, NCT01369355, YODA #2019-4105). The primary endpoints of interest were clinical remission (CR), defined as Crohn's disease activity index <150 and corticosteroid-free CR at week 44. Patients were stratified into the following subgroups according to their BMI at study entry: underweight <18.5 kg/m2, normal 18.5 to 25 kg/m2, overweight 25 to <30 kg/m2, and obese ≥30 kg/m2. The χ 2 test of linear trend was conducted for comparisons of frequencies between the 3 cohorts. Multivariate regression analyses evaluated possible association between BMI and efficacy outcomes of CR and corticosteroid-free CR, with adjustment for variables found significant on univariate analyses. Results are presented as odds ratios with 95% confidence intervals. Data were analyzed using Stata/IC 15. A total of 254 patients treated with ustekinumab were included in this analysis. At week 44 of IM-UNITI, rates of CR did not differ among those whose BMI was underweight (67.9%%; 19 of 28 patients), normal (51.3%; 60 of 117), overweight (45.1%; 32 of 71), or obese (55.3%; 21 of 38; P = 0.89). Multivariate logistic analysis did not find BMI to be a significant predictor of CR when adjusted for covariates. Ustekinumab drug level at week 44 was significantly lower in obese patients (median level 2.98 mcg/mL; interquartile range [IQR], 2.86) compared with patients who were overweight (4.84 mcg/mL; IQR, 3.51; P = 0.021) or had underweight or normal BMI (4.43 mcg/m;, IQR, 2.82; P = 0.014). Although BMI impacts ustekinumab drug levels, there was no impact of BMI on clinical efficacy. Further studies of the pharmacodynamic effects of ustekinumab in patients with high BMI are needed.


Interactions between HIV-1 Gag and Viral RNA Genome Enhance Virion Assembly.
Most HIV-1 virions contain two copies of full-length viral RNA, indicating that genome packaging is efficient and tightly regulated. However, the structural protein Gag is the only component required for the assembly of noninfectious viruslike particles, and the viral RNA is dispensable in this process. The mechanism that allows HIV-1 to achieve such high efficiency of genome packaging when a packageable viral RNA is not required for virus assembly is currently unknown. In this report, we examined the role of HIV-1 RNA in virus assembly and found that packageable HIV-1 RNA enhances particle production when Gag is expressed at levels similar to those in cells containing one provirus. However, such enhancement is diminished when Gag is overexpressed, suggesting that the effects of viral RNA can be replaced by increased Gag concentration in cells. We also showed that the specific interactions between Gag and viral RNA are required for the enhancement of particle production. Taken together, these studies are consistent with our previous hypothesis that specific dimeric viral RNA-Gag interactions are the nucleation event of infectious virion assembly, ensuring that one RNA dimer is packaged into each nascent virion. These studies shed light on the mechanism by which HIV-1 achieves efficient genome packaging during virus assembly.IMPORTANCE Retrovirus assembly is a well-choreographed event, during which many viral and cellular components come together to generate infectious virions. The viral RNA genome carries the genetic information to new host cells, providing instructions to generate new virions, and therefore is essential for virion infectivity. In this report, we show that the specific interaction of the viral RNA genome with the structural protein Gag facilitates virion assembly and particle production. These findings resolve the conundrum that HIV-1 RNA is selectively packaged into virions with high efficiency despite being dispensable for virion assembly. Understanding the mechanism used by HIV-1 to ensure genome packaging provides significant insights into viral assembly and replication.


Pharmaceutical applications of cyclotides.
Cyclotides are cyclic peptides, present in several plant families, that show diverse biological properties. Structurally, cyclotides share a distinctive head-to-tail circular knotted topology of three disulfide bonds. This framework provides cyclotides with extraordinary resistance to thermal and chemical denaturation. There is increasing interest in the therapeutic potential of cyclotides, which combine several promising pharmaceutical properties, including binding affinity, target selectivity, and low toxicity towards healthy mammalian cells. Recently, cyclotides have been reported to be orally bioavailable and have proved to be amenable to modifications. Here, we provide an overview of the structure, properties, and pharmaceutical applications of cyclotides.


Evolution and functional significance of derived sternal ossification patterns in ornithothoracine birds.
The midline pattern of sternal ossification characteristic of the Cretaceous enantiornithine birds is unique among the Ornithodira, the group containing birds, nonavian dinosaurs and pterosaurs. This has been suggested to indicate that Enantiornithes is not the sister group of Ornithuromorpha, the clade that includes living birds and their close relatives, which would imply rampant convergence in many nonsternal features between enantiornithines and ornithuromorphs. However, detailed comparisons reveal greater similarity between neornithine (i.e. crown group bird) and enantiornithine modes of sternal ossification than previously recognized. Furthermore, a new subadult enantiornithine specimen demonstrates that sternal ossification followed a more typically ornithodiran pattern in basal members of the clade. This new specimen, referable to the Pengornithidae, indicates that the unique ossification pattern observed in other juvenile enantiornithines is derived within Enantiornithes. A similar but clearly distinct pattern appears to have evolved in parallel in the ornithuromorph lineage. The atypical mode of sternal ossification in some derived enantiornithines should be regarded as an autapomorphic condition rather than an indication that enantiornithines are not close relatives of ornithuromorphs. Based on what is known about molecular mechanisms for morphogenesis and the possible selective advantages, the parallel shifts to midline ossification that took place in derived enantiornithines and living neognathous birds appear to have been related to the development of a large ventral keel, which is only present in ornithuromorphs and enantiornithines. Midline ossification can serve to medially reinforce the sternum at a relatively early ontogenetic stage, which would have been especially beneficial during the protracted development of the superprecocial Cretaceous enantiornithines.


Comparative analysis of S haplotypes with very similar SLG alleles in Brassica rapa and Brassica oleracea.
Self-incompatibility in Brassica is controlled by a single multi-allelic locus (the S locus) which harbors at least two highly polymorphic genes, SLG and SRK. SRK is a putative transmembrane receptor kinase and its amino acid sequence of the extracellular domain of SRK (the S domain) exhibits high homology to that of SLG. The amino acid sequences of the SLGs of S8 and S46 haplotypes of B. rapa are very similar and those of S23 and S29 haplotypes of B. oleracea were also found to be almost identical. In both cases, SLG and the S domain of SRK of the same haplotype were less similar. This seems to contradict the idea that SLG and SRK of the same haplotype have the same self-recognition specificity. In the transmembrane-kinase domain, the SRK alleles of the S8 and S46 haplotypes had almost identical nucleotide sequences in spite of their lower homology in the S domain. Such a cluster of nucleotide substitutions is probably due to recombination or related events, although recombination in the S locus is thought to be suppressed. Based on our observations, the recognition mechanism and the evolution of self-incompatibility in Brassica are discussed.


Extracellular stimulation of mammalian neurons through repetitive activation of Na+ channels by weak capacitive currents on a silicon chip.
Reliable extracellular stimulation of neuronal activity is the prerequisite for electrical interfacing of cultured networks and brain slices, as well as for neural implants. Safe stimulation must be achieved without damage to the cells. With respect to a future application of highly integrated semiconductor chips, we present an electrophysiological study of capacitive stimulation of mammalian cells in the geometry of adhesion on an insulated titanium dioxide/silicon electrode. We used HEK293 cells with overexpressed Na(V)1.4 channels and neurons from rat hippocampus. Weak biphasic stimuli of falling and rising voltage ramps were applied in the absence of Faradaic current and electroporation. We recorded the response of the intra- and extracellular voltage and evaluated the concomitant polarization of the attached and free cell membranes. Falling ramps efficiently depolarized the central area of the attached membrane. A transient sodium inward current was activated that gave rise to a weak depolarization of the cell on the order of 1 mV. The depolarization could be enhanced step by step by a train of biphasic stimuli until self-excitation of sodium channels set in. We applied the same protocol to cultured rat neurons and found that pulse trains of weak capacitive stimuli were able to elicit action potentials. Our results provide a basis for safe extracellular stimulation not only for cultured neurons on insulated semiconductor electrodes, but also more generally for metal electrodes in cell culture and brain tissue.


Consumer reporting of adverse events following immunization (AEFI): identifying predictors of reporting an AEFI.
Passive reporting of adverse events following immunization (AEFI) by consumers or healthcare professionals is the primary mechanism for post-marketing surveillance of vaccine safety. Although recent initiatives have promoted consumer reporting, there is a lack of research concerning consumer reporters. Computer assisted telephone interviews (CATI) were conducted in 2011 of a cross-sectional, random, general population sample of 191 South Australian parents who stated that their children had previously experienced an AEFI. We compared awareness of surveillance, vaccine safety opinions, and demographics of parents reporting an AEFI to either healthcare professionals or surveillance authorities with those who did not report their children's AEFI. Multivariate regression analyses measured: the association between reporting and safety views; and demographic predictors of reporting an AEFI. Reporting an AEFI to a healthcare professional or a surveillance authority was not significantly associated with awareness of a surveillance system. AEFI reporters, when compared with non-reporters, were more likely to be Australian-born (OR = 4.58, [1.64, 12.78], P = 0.004); were associated with the perception that a serious reaction was more likely to occur at their children's last immunization (OR = 2.54 [95%CI 1.22, 5.30], P = 0.013); and were less accepting of the risk of febrile convulsion, (OR = 3.59 [95%CI 1.50, 8.57], P = 0.004). Although reporting an AEFI was not associated with awareness of surveillance or most socio-demographics, the results suggest some difference in safety opinions. Further studies are required to ascertain if these differences pre-date the occurrence of an AEFI or are a consequence of the AEFI and how consumers can contribute further to vaccine safety surveillance.


Optimal differential energy watermarking of DCT encoded images and video.
This paper proposes the differential energy watermarking (DEW) algorithm for JPEG/MPEG streams. The DEW algorithm embeds label bits by selectively discarding high frequency discrete cosine transform (DCT) coefficients in certain image regions. The performance of the proposed watermarking algorithm is evaluated by the robustness of the watermark, the size of the watermark, and the visual degradation the watermark introduces. These performance factors are controlled by three parameters, namely the maximal coarseness of the quantizer used in pre-encoding, the number of DCT blocks used to embed a single watermark bit, and the lowest DCT coefficient that we permit to be discarded. We follow a rigorous approach to optimizing the performance and choosing the correct parameter settings by developing a statistical model for the watermarking algorithm. Using this model, we can derive the probability that a label bit cannot be embedded. The resulting model can be used, for instance, for maximizing the robustness against re-encoding and for selecting adequate error correcting codes for the label bit string.


DeepSP: A Deep Learning Framework for Spatial Proteomics.
The study of protein subcellular localization (PSL) is a fundamental step toward understanding the mechanism of protein function. The recent development of mass spectrometry (MS)-based spatial proteomics to quantify the distribution of proteins across subcellular fractions provides us a high-throughput approach to predict unknown PSLs based on known PSLs. However, the accuracy of PSL annotations in spatial proteomics is limited by the performance of existing PSL predictors based on traditional machine learning algorithms. In this study, we present a novel deep learning framework named DeepSP for PSL prediction of an MS-based spatial proteomics data set. DeepSP constructs the new feature map of a difference matrix by capturing detailed changes between different subcellular fractions of protein occupancy profiles and uses the convolutional block attention module to improve the prediction performance of PSL. DeepSP achieved significant improvement in accuracy and robustness for PSL prediction in independent test sets and unknown PSL prediction compared to current state-of-the-art machine learning predictors. As an efficient and robust framework for PSL prediction, DeepSP is expected to facilitate spatial proteomics studies and contributes to the elucidation of protein functions and the regulation of biological processes.


Acrylamide produces a direct, dose-dependent and specific inhibition of oxidative metabolism in motoneurons.
The mechanism of action of acrylamide (ACR) in producing a central-peripheral distal axonopathy is unknown. We have tested the hypothesis that ACR inhibition of enzymes of oxidative metabolism is responsible for compromise of the energy supply, thereby producing the neuropathy. A single 50 mg/kg i.p. dose of ACR resulted in a 33.4% decrease in NADH-tetrazolium reductase (NADH-TR) (indicative of oxidative metabolism) activity in rat soleus motoneurons within one hour of injection. Methylene bis ACR (Mb-ACR), a non-neurotoxic analogue, produced a much smaller (6.7%) decrease in NADH-TR activity. Restoration of normal NADH-TR activity following that single injection occurred in 3 days. In vitro histochemical assays demonstrated a dose-dependent inhibition of motoneuron NADH-TR activity (10-54%) by 1-10mM ACR. Equimolar Mb-ACR produced significantly less inhibition. The rapid, dose-dependent and specific inhibition of this oxidative enzyme activity by ACR provides evidence in support of the energy hypothesis of ACR-induced neuropathy and more specifically suggests that oxidative enzyme inhibitions are a critical site of ACR action.


TGFbeta signalling: a complex web in cancer progression.
The distortion of growth factor signalling is the most important prerequisite in tumour progression. Transforming growth factor-beta (TGFbeta) signalling regulates tumour progression by a tumour cell-autonomous mechanism or through tumour-stroma interaction, and has either a tumour-suppressing or tumour-promoting function depending on cellular context. Such inherent complexity of TGFbeta signalling results in arduous, but promising, assignments for developing therapeutic strategies against malignant tumours. As numerous cellular context-dependent factors tightly maintain the balance of TGFbeta signalling and contribute to the regulation of TGFbeta-induced cell responses, in this Review we discuss how they maintain the balance of TGFbeta signalling and how their collapse leads to tumour progression.


Early decades of Madras Medical College: Apothecaries.
The Government at Fort St George determined that a school for instructing and training candidates towards the titles of 'apothecary' was necessary to improve medical help to people in the 1830s. This led to the establishment of the medical school in Madras (presently Chennai) in 1835. The school got renamed as the Madras Medical College in 1850. From 1835, the Madras Medical School offered formal training to personnel to be called either 'apothecaries' or 'dressers' under the superintendence of William Mortimer, who was assisted by George Harding in teaching at the school. Apothecary D'Beaux and Dresser P. S. Muthuswami Mudaliar were subordinate assistants. These apothecaries were recruited essentially under the Subordinate Medical Service of Madras, which was established in 1812 and included non-commissioned medical servants. The Madras apothecaries launched the Madras Apothecaries Society in 1864, which aimed at promoting and advancing medical science and knowledge. This society existed until 1871. Formal training of apothecaries ceased in Madras by the later decades of the 19th century, although informal training continued, especially for army cadets and women. Establishment of medical schools in Royapuram (which developed as the Stanley Medical College and Hospital), Tanjavur and Madurai, in the early decades of the 20th century and the 'branch' of Madras Medical College in Calicut during the Second World War changed the complexion of training of medical personnel immensely in pre- 1947 Madras Presidency. The Royapuram and other Medical Schools in Madras trained medical practitioners granting the title 'Licensed Medical Practitioner' (LMP). Whether the apothecary-dresser training at the 'old' Madras Medical College had a role to play in these developments remains to be verified.


Conceptual and operational considerations in identifying socioenvironmental factors associated with disability among community-dwelling adults.
Disability is conceived as a person-context interaction. Physical and social environments are identified as intervention targets for improving social participation and independence. In comparison to the body of research on place and health, relatively few reports have been published on residential environments and disability in the health sciences literature. We reviewed studies evaluating the socioenvironmental correlates of disability. Searches were conducted in Medline, Embase and CINAHL databases for peer-reviewed articles published between 1997 and 2014. We found many environmental factors to be associated with disability, particularly area-level socioeconomic status and rurality. However, diversity in conceptual and methodological approaches to such research yields a limited basis for comparing studies. Conceptual inconsistencies in operational measures of disability and conceptual disagreement between studies potentially affect understanding of socioenvironmental influences. Similarly, greater precision in socioenvironmental measures and in study designs are likely to improve inference. Consistent and generalisable support for socioenvironmental influences on disability in the general adult population is scarce.


Evidence for distinct alterations in the FGF axis in prostate cancer progression to an aggressive clinical phenotype.
Multiple fibroblast growth factor (FGF) axis alterations are known to occur in prostate cancer. Here we simultaneously profiled key components of this axis to determine their relevance in disease progression. An optimized immunohistochemistry protocol was used in expression analysis of FGF2, FGF8, FGFR1, FGFR4, and Sef (similar expression to FGF) in a single TMA of prostate cancer. FGF ligands and receptors were overexpressed in cancers compared to benign samples (p < 0.0001), while Sef expression was reduced (p < 0.0001). There was a positive association between higher grades and increased FGFR4 (p = 0.02), FGF2, and FGF8 (p = 0.002 and p < 0.0001). Sef expression was progressively lower with increasing grade (p = 0.005). Clinical stage was positively associated with FGF2, FGF8, and FGFR4 expression (p = 0.005, 0.03, and 0.012) but not with FGFR1 or Sef expression. Only reduced Sef was associated with bone metastasis (p = 0.02) and was also predictive of subsequent metastasis in initially localized tumours (p = 0.004). Down-regulation of Sef and increased FGFR4 were also the only independent variables associated with disease-specific survival (HR 1.73, p = 0.04 and HR 0.56, p = 0.01). In in vitro studies, silencing Sef enhanced the cell response to FGFs (p < 0.001) and substantially mitigated the effectiveness of an FGFR1 inhibitor. Conversely, increased Sef blocked the response to FGFs and had a comparable suppressive effect to the inhibitor. This study demonstrates that increased FGFR4 and reduced Sef may be critical FGF alterations associated with prostate cancer progression. Sef may also have a role in the tumour response to FGFR inhibition and warrants further investigation in this context.


Imaging markers of multiple sclerosis prognosis.
Studies of large longitudinal cohorts of patients with multiple sclerosis (MS) have emphasized the prognostic value of conventional MRI markers, at least during early stages. Advanced imaging metrics derived from quantitative MRI and PET provide relevant information about microstructural damage within and outside visible lesions that may be more sensitive to predict long-term disability. Here, we summarize the most recent findings regarding the prognostic value of imaging markers throughout MS stages. In clinically isolated syndrome, the presence of at least one brain or spinal cord T2 lesion strongly increases the risk of conversion to clinically definite MS (hazard ratio ranging from 5 to 11). Similarly, the occurrence of new white matter lesions is strongly predictive of subsequent relapse rate and response to current disease modifying therapies. Beyond white matter lesions, volumetric changes in the grey matter and normal-appearing tissue damage are more sensitive prognostic markers for physical and cognitive disability, especially in progressive MS. Although white matter lesion number and volume still remains the imaging metric used in daily clinical practice, further development of advanced imaging predictors of long-term disability should allow a better stratification of patients in future clinical trials aimed at promoting repair or neuroprotection.


Assessing oral malignancies.
Oral cancers account for approximately 3 percent of all cases of cancer in the United States. An estimated 30,000 people will be diagnosed with oral cancer this year, and about one half of them will eventually die of the disease. The most common type of oral cancer is squamous cell carcinoma. Sixty percent of oral cancers are well advanced by the time they are detected, even though physicians and dentists frequently examine the oral cavity. The two most important risk factors for oral cancer are tobacco use and heavy alcohol consumption. The keys to reducing mortality are prevention and control. The earlier any intraoral or extraoral abnormalities or lesions are detected and biopsied, the more lives can be saved. Controversy exists whether screening programs effectively reduce the mortality rate. Specific step-by-step guidelines should be followed to perform an adequate examination of the head and neck.


Elastin-like recombinamers in collagen-based tubular gels improve cell-mediated remodeling and viscoelastic properties.
Natural polymers are commonly used as scaffolds for vascular tissue engineering. The recognized biological properties of this class of materials are often counterbalanced by their low mechanical performance. In this work, recombinant elastin-like polypeptides (or elastin-like recombinamers, ELRs) were mixed with collagen gel and cells to produce cellularized tubular constructs in an attempt to recapitulate the mechanical behavior of the vascular extracellular matrix (ECM). The presence of the elastic protein influenced cell-mediated remodeling evaluated in terms of construct compaction, cell proliferation and ECM (collagen, elastin and fibrillin-1) gene expression. The partial substitution of collagen with ELR and the observed differences in cellular behavior synergistically contributed to the superior viscoelastic properties of the constructs containing 30% ELR and 70% of collagen (in mass). This led to the improvement of 40% in the initial elastic modulus, 50% in the equilibrium elastic modulus, and 37% in the tensile strength at break without compromising the strain at break, when compared to a pure collagen scaffold. Suggestions for future research include modifications in the crosslinking technology, ELR composition, polymer concentration, cell seeding density and dynamic stimulation, which have the potential to further improve the mechanical performance of the constructs towards physiological values.


Investigation of Factors Determining the Enhanced Permeability and Retention Effect in Subcutaneous Xenografts.
Liposomal chemotherapy offers several advantages over conventional therapies, including high intratumoral drug delivery, reduced side effects, prolonged circulation time, and the possibility to dose higher. The efficient delivery of liposomal chemotherapeutics relies, however, on the enhanced permeability and retention (EPR) effect, which refers to the ability of macromolecules to extravasate leaky tumor vessels and accumulate in the tumor tissue. Using a panel of human xenograft tumors, we evaluated the influence of the EPR effect on liposomal distribution in vivo by injection of pegylated liposomes radiolabeled with (111)In. Liposomal accumulation in tumors and organs was followed over time by SPECT/CT imaging. We observed that fast-growing xenografts, which may be less representative of tumor development in patients, showed higher liposomal accumulation than slow-growing xenografts. Additionally, several other parameters known to influence the EPR effect were evaluated, such as blood and lymphatic vessel density, intratumoral hypoxia, and the presence of infiltrating macrophages. The investigation of various parameters showed a few correlations. Although hypoxia, proliferation, and macrophage presence were associated with tumor growth, no hard conclusions or predictions could be made regarding the EPR effect or liposomal uptake. However, liposomal uptake was significantly correlated with tumor growth, with fast-growing tumors showing a higher uptake, although no biological determinants could be elucidated to explain this correlation.


Resolving the Dance: A Case Study on Non-Ketotic Hyperglycemic Hemichorea-Hemiballismus in a Patient with Long-Standing Type 2 Diabetes.
BACKGROUND Non-ketotic hyperglycemic hemichorea-hemiballism (HCHB) is a rare complication of diabetes, which is mainly described in case reports. This condition occurs more commonly in older women and is known to be associated with T1 hyperintensity basal ganglia lesions on magnetic resonance imaging (MRI). The pathophysiology of non-ketotic hyperglycemic HCHB is not well defined, although a combination of regional metabolic failure and ischemia due to hyperglycemia is suspected to occur. Treatment entails tight blood glucose control, although antipsychotic medications such as risperidone may be helpful in refractory cases. CASE REPORT We describe a case of a middle-aged man with long-standing type 2 diabetes who experienced 3 weeks of progressive unilateral arm, leg, and face choreiform movements. Laboratory testing performed just prior to symptom onset was notable for a hemoglobin A1C of >15% and a serum blood glucose of 566 mg/dl. MRI revealed diffuse T1 hyperintensity in the left lentiform nucleus. Our patient's insulin regimen was adjusted, resulting in improvement in average serum glucose (A1C of 9.4%). However, his symptoms did not improve significantly. A trial of benzodiazepine was attempted, without success. When risperidone was started, the patient experienced resolution of symptoms. Recurrence of non-ketotic hyperglycemic HCHB while off risperidone has not occurred to date. CONCLUSIONS Non-ketotic hyperglycemic HCHB is a rare but important diagnosis to consider in patients with hyperglycemia and new-onset choreiform movements. Patients with long-standing type 2 diabetes may be affected, especially when glycemic control worsens. When tight blood glucose control does not resolve symptoms, a short course of antipsychotic agents may provide relief.


Fabrication of submicron-diameter silica fibers using electric strip heater.
In nonlinear optical frequency conversion process, it is desirable to maximize the product of the intensity of pump laser and the interaction length in order to achieve maximum conversion efficiency. In this paper, long and unbroken submicron-diameter optical fibers with low optical loss about 0.1dB/cm were fabricated with a new drawing process by heating the conventional single mode fiber using a designed electric strip heater. Pumped by a 532 nm mode-locked pico-second laser, enhanced SRS phenomena can be observed in the submicron-diameter fibers with relative low pump power.


Stimulated Brillouin scattering and its dependences on strain and temperature in a high-delta optical fiber with F-doped depressed inner cladding.
Stimulated Brillouin scattering (SBS) in a high-delta fiber with F-doped depressed inner cladding is studied through considering the interaction of acoustic and optical modes in the fiber. It is found that the number of acoustic modes in the fiber is reduced and the frequency spacing between neighboring modes is enlarged because of the F doping. The dependences of SBS on strain and temperature are measured and compared for each acoustic mode to investigate the feasibility of discriminative sensing of strain and temperature by use of the fiber.


Effects of medical interventions on suicidal behavior. Summary and conclusions.
An international symposium evaluated current knowledge of the epidemiology, psychobiology, and effects of medical treatment on suicidal behavior. Moderators summarized the main findings and conclusions of the participants on the basis of presentations and consensus statements at the meeting. Despite striking advances in the medical treatment of mood disorders in the past half-century, rates of suicidal acts have changed little in the general population. Evidence of reduction of long-term rates of suicidal acts in specific at-risk populations remains very limited, particularly persons with major affective illnesses and other common, primary or comorbid psychiatric and substance use disorders. It is plausible that reduction of psychiatric morbidity should limit suicidal risk, but very little is known about specific effects of most psychiatric treatments or other interventions aimed at suicide prevention. An exception is substantial evidence of lower suicidal risk during long-term lithium treatment that was not equaled with carbamazepine. However, diagnosis and timely therapeutic interventions reach only a minority of psychiatrically ill persons at risk for suicide. Renewed efforts are strongly urged to: (1) improve public and professional awareness of risk factors for suicide, (2) enhance earlier access to appropriate clinical assessment and increasingly safe and effective treatments for affective and psychotic disorders, and (3) encourage and support research to clarify specific benefits and risks of medical treatments and social interventions aimed at preventing suicide.


Probing the reactivity of ZnO and Au/ZnO nanoparticles by methanol adsorption: a TPD and DRIFTS study.
The adsorption of methanol on pure ZnO and Au-decorated ZnO nanoparticles and its thermal decomposition monitored by temperature-programmed desorption (TPD) experiments and by diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), both applied under continuous flow conditions in fixed bed reactors, is reported. Two distinguishable methoxy species are formed during methanol adsorption on ZnO differing in the C-O stretching bands. During the subsequent TPD experiments two different H(2) peaks are observed, indicating the conversion of methoxy into formate species. By applying different heating rates, activation energies of 109 kJ mol(-1) and 127 kJ mol(-1) for the selective oxidation of the two methoxy species are derived. Correspondingly, the methoxy decomposition results in two distinguishable formate species, which are identified by the asymmetric and symmetric OCO stretching bands on pure ZnO and Au/ZnO. Based on the decreased intensities of the OH bands during methanol adsorption, which are specific for the various ZnO single crystal surfaces, on the different reactivities of these surfaces, and on the formate FTIR bands observed on ZnO single crystal surfaces, the two methoxy and the corresponding formate species are identified to be adsorbed on the exposed less reactive non-polar ZnO(10 10) surface and on the highly reactive polar ZnO(000 1) surface. The simultaneous formation of H(2), CO, and CO(2) at about 550-600 K during the TPD experiments indicate the decomposition of adsorbed formate species. The CO/CO(2) ratio decreases with increasing Au loading, and a broad band due to electronic transitions from donor sites to the conduction band is observed in the DRIFT spectra for the Au-decorated ZnO nanoparticles. Thus, the presence of the Au nanoparticles results in an enhanced reducibility of ZnO facilitating the generation of oxygen vacancies.


The Lidcombe Program of early stuttering intervention for Malaysian families: Four case studies.
This study investigated the outcomes of implementing the Lidcombe Program, an evidence-based early intervention for stuttering, with four preschool children in Malaysia. Early stuttering intervention is currently underdeveloped in Malaysia, where stuttering treatment is often more assertion-based than evidence-based. Therefore, introducing an evidence-based early stuttering intervention is an important milestone for Malaysian preschoolers who stutter. The participants ranged from 3 years 3 months to 4 years 9 months at the start of the study. Beyond-clinic speech samples were obtained at 1 month and 1 week pretreatment and immediately post-Stage 1, and at 1 month, 3 months, 6 months and 12 months post-Stage 1. Two participants, who were bilingual, achieved near-zero levels of stuttering at 12 months posttreatment. Near zero levels of stuttering were also present in their untreated languages. One participant withdrew due to reasons not connected with the research or treatment. The remaining participant, who presented with severe stuttering, completed Stage 1 but had some relapse in Stage 2 and demonstrated mild stuttering 12 months post-Stage 1. The outcomes were achieved without the need to significantly adapt Lidcombe Program procedures to Malaysian culture. Further research to continue evaluation of the Lidcombe Program with Malaysian families and to estimate proportion of those who will respond is warranted.


[Small pelvic MRI on "Ellipse" low-adz tomograph made in Russia].
The paper presents the authors' experience in using small pelvic MRI on an Ellipse low-field apparatus made in Russia. A total of 74 patients were examined. Abnormal formations in the small pelvic organs were visualized in 72 patients. The potentialities and limitations of MRI in visualizing small pelvic organs and their pathology are shown. The technique is compared with CT and ultrasound study.


Criteria in radioisotope detection of venous thrombosis.
Forty-one patients out of a larger series undergoing elective surgery were examined for the presence of venous thrombosis in the legs by means of the (125)I-fibrinogen technique. The radioisotope data were analysed by three different methods. The percentage uptake was calculated and, by the generally accepted difference of 15%, 22 patients had evidence of thrombosis. The statistical index, which takes account of the errors due to radioactivity counting inherent in the percentage uptake calculation, indicated thrombosis in 36 patients. The relative uptake index, which allows for the errors due to unequal distribution of radioactivity throughout the normal limb as well as the errors due to radioactivity counting, provided evidence of thrombosis in a total of 34 patients, compared with only 22 patients when assessed by the "15%" criterion.


Association between sexually transmitted disease and church membership. A retrospective cohort study of two Danish religious minorities.
Studies comprising Danish Seventh-day Adventists (SDAs) and Danish Baptists found that members have a lower risk of chronic diseases including cancer. Explanations have pointed to differences in lifestyle, but detailed aetiology has only been sparsely examined. Our objective was to investigate the incidence of sexually transmitted diseases (STDs) among Danish SDAs and Baptists as a proxy for cancers related to sexual behaviour. We followed the Danish Cohort of Religious Societies from 1977 to 2009, and linked it with national registers of all inpatient and outpatient care contacts using the National Patient Register. We compared the incidence of syphilis, gonorrhoea and chlamydia among members of the cohort with the general population. The cohort comprised 3119 SDA females, 1856 SDA males, 2056 Baptist females and 1467 Baptist males. For the entire cohort, we expected a total of 32.4 events of STD, and observed only 9. Female SDAs and Baptists aged 20-39 years had significant lower incidence of chlamydia (both p<0.001). Male SDAs and Baptists aged 20-39 years also had significant lower incidence of chlamydia (p<0.01 and p<0.05, respectively). No SDA members were diagnosed with gonorrhoea, when 3.4 events were expected, which, according to Hanley's 'rule of three', is a significant difference. No SDA or Baptist was diagnosed with syphilis. The cohort shows significant lower incidence of STD, most likely including human papillomavirus, which may partly explain the lower incidence of cancers of the cervix, rectum, anus, head and neck.


Perceived racism and discrimination and youth substance use in the United States - Intersections with sex and ethnicity.
This study sought to examine associations between U.S. adolescents' perceived racism and discrimination (PRD) at school and current substance use. Data were drawn from the Adolescent Behaviors and Experiences Survey (ABES), a probability sample of U.S. high school students in 2021 (n = 7705). Multivariable regression models were conducted to examine associations of PRD with current (past 30-day) use of tobacco products, marijuana, alcohol, and prescription opioid misuse. Interaction effects of PRD and demographic factors were tested. Among participants in the 2021 ABES, PRD was associated with higher odds of current use of tobacco (AOR = 1.3, p = 0.03), marijuana (AOR = 1.3, p = 0.03), alcohol (AOR = 1.2, p = 0.03), and misuse of prescription opioids (AOR = 1.6, p = 0.004). The effects of PRD on current tobacco and alcohol use differed by Hispanic and non-Hispanic adolescents (interaction effect = 0.007 and 0.01, respectively) with higher odds among Hispanic youth than among non-Hispanic counterparts. The associations of PRD and current tobacco use, marijuana use, alcohol use, and misuse of prescription opioids were moderated by sex with more pronounced effects on males than females. Efforts to promote awareness and create support environments that value diversity and inclusivity at school are needed to mitigate adolescent exposure to racism and discrimination.


Effect of dietary benzylselenocyanate on azoxymethane-induced colon carcinogenesis in male F344 rats.
The effect of dietary benzylselenocyanate (BSC) and its analogue, benzylthiocyanate (BTC), and sodium selenite during the initiation and postinitiation phases of azoxymethane (AOM)-induced intestinal carcinogenesis was studied in male F344 rats. Animals intended for initiation study were fed the high-fat (23.5% corn oil) diets containing 25, 50, and 100 ppm BSC (10, 20, and 40 ppm selenium, respectively) and 100 ppm BTC and 4 ppm selenium (as sodium selenite in drinking water); those intended for postinitiation study were fed the high-fat control diet. Two weeks later, all animals were injected subcutaneously with AOM (15 mg/kg body wt) once weekly for two weeks. Three days after the last AOM injection, animals in the initiation and postinitiation studies were transferred respectively to the high-fat diet and high-fat diets containing BSC and BTC and sodium selenite in drinking water. This regimen was continued until 36 weeks post-AOM injection. BSC inhibited the small intestinal and colon adenocarcinoma incidence and multiplicity of colon adenocarcinomas when fed during the postinitiation phase. Sodium selenite inhibited the incidence and multiplicity of colon adenocarcinomas only during the postinitiation phase. BTC had no inhibitory effect when fed during the initiation and postinitiation phases. The colonic mucosal ornithine decarboxylase activity was significantly inhibited by the administration of all three compounds, BSC (78%), BTC (62%), and sodium selenite (44%). It is concluded that the BSC has an inhibitory effect on the intestinal carcinogenesis in animals fed the high-fat diet.


Case Report: Grade 2 Metastatic Pancreatic Neuroendocrine Tumor With Progression of One Metastasis After Pregnancy to Grade 3 Large-Cell Neuroendocrine Carcinoma: One Case Cured by Resection With Genomic Characterization of the Two Components.
Temporal and spatial tumor heterogeneity can be observed in pancreatic neuroendocrine tumor. We report the case of a young woman with long term stabilization of a G2 metastatic pancreatic NET that, after pregnancy, suddenly progressed into one single liver metastasis corresponding to a transformation into G3 large-cell neuroendocrine cancer. The patient underwent liver resection (the progressive and one dormant metastasis). With a 45 months follow-up the patient is without evolutive disease. Exome sequencing of the two metastases revealed completely different genomic signatures and gene alterations: the dormant metastasis was MSS without any gene alteration; the poorly differentiated tumor was MSI, with gain of many mutations including MEN1, BCL2, MLH1 and TP53 corresponding to a mutational signature 11. Could temozolomide play a role in this transformation?


Relationship between the Uncompensated Price Elasticity and the Income Elasticity of Demand under Conditions of Additive Preferences.
Income and price elasticity of demand quantify the responsiveness of markets to changes in income and in prices, respectively. Under the assumptions of utility maximization and preference independence (additive preferences), mathematical relationships between income elasticity values and the uncompensated own and cross price elasticity of demand are here derived using the differential approach to demand analysis. Key parameters are: the elasticity of the marginal utility of income, and the average budget share. The proposed method can be used to forecast the direct and indirect impact of price changes and of financial instruments of policy using available estimates of the income elasticity of demand.


An assessment of the fibrinolytic system in hemophilia A.
The fibrinolytic system was assessed in 28 hemophiliacs using the chromogenic substrate H-D-Val-Leu-Lys-pNA. To determine whether a state of hyperfibrinolysis might be associated with Factor VIII replacement therapy, 14 patients with severe disease who were intensively treated with Factor VIII concentrates were compared with 14 patients with mild disease who were receiving infrequent transfusions with cryoprecipitate or fresh frozen plasma. Seventeen normal males served as controls. With the exception of an elevated level of plasminogen activator and a decreased level of immediate antiplasmin in the mild group only, no evidence of enhanced fibrinolysis was found. Other components of the fibrinolytic system were either normal (plasmin) or increased (progressive antiplasmin containing both alpha 2PI and alpha 2M, and plasminogen). The elevated plasminogen levels were found only in the severe intensively transfused group. The elevated progressive antiplasmin levels were found in both groups of patients and did not appear to be related to transfusions. These findings do not support the concept of enhanced fibrinolysis associated with intensive Factor VIII replacement therapy.


The dental pathology of southern sea otters (Enhydra lutris nereis).
Skulls (n = 1,205) of southern sea otters were examined macroscopically according to defined criteria. The museum specimens, acquired from strandings, varied in age from juvenile to adult, with an equal sex distribution. The results from all young adult and adult specimens were pooled according to tooth type. Ninety-two percent of teeth were available for examination, with 6.5% artifactually absent, 0.6% deemed absent due to acquired tooth loss and 0.03% deemed congenitally absent. All teeth were normal in morphology, except for three pairs of fused teeth, including two instances of fused maxillary first incisor teeth. Supernumerary teeth were associated with 97 normal teeth (most commonly maxillary canine teeth) in 68 specimens. At least one persistent deciduous tooth was present in six skulls, two of which were from adults. The majority (94.6%) of alveoli, either with or without teeth, were not associated with bony changes consistent with periodontitis; however, the majority (74.4%) of specimens did have at least one tooth associated with mild periodontitis. The mesial root of the mandibular third premolar tooth was the most common location at which periodontal hard tissue lesions were observed (56.6%). Ten sea otters had lesions consistent with focal enamel hypoplasia. Approximately half of the teeth (52.0%) were abraded; almost all adult specimens (98.1%) contained at least one abraded tooth, while fewer young adults were affected (76.4%). Tooth fractures were uncommon, affecting 1,343 teeth (4.5%). Periapical lesions were associated with 409 teeth (1.3%) in a total of 176 specimens, and these would likely have caused considerable morbidity while the animals were alive.


Permutation entropy of finite-length white-noise time series.
Permutation entropy (PE) is commonly used to discriminate complex structure from white noise in a time series. While the PE of white noise is well understood in the long time-series limit, analysis in the general case is currently lacking. Here the expectation value and variance of white-noise PE are derived as functions of the number of ordinal pattern trials, N, and the embedding dimension, D. It is demonstrated that the probability distribution of the white-noise PE converges to a χ^{2} distribution with D!-1 degrees of freedom as N becomes large. It is further demonstrated that the PE variance for an arbitrary time series can be estimated as the variance of a related metric, the Kullback-Leibler entropy (KLE), allowing the qualitative N≫D! condition to be recast as a quantitative estimate of the N required to achieve a desired PE calculation precision. Application of this theory to statistical inference is demonstrated in the case of an experimentally obtained noise series, where the probability of obtaining the observed PE value was calculated assuming a white-noise time series. Standard statistical inference can be used to draw conclusions whether the white-noise null hypothesis can be accepted or rejected. This methodology can be applied to other null hypotheses, such as discriminating whether two time series are generated from different complex system states.


Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial.
Purpose To report the final results on treatment outcomes of a randomized trial comparing conventional and hypofractionated radiotherapy in high-risk, organ-confined prostate cancer (PCa). Patients and Methods This single-institution, randomized clinical trial, conducted from January 2003 to December 2007, enrolled 168 patients with high-risk PCa who were randomly assigned in a 1:1 ratio to conventional (80 Gy in 40 fractions in 8 weeks) or hypofractionated radiotherapy (62 Gy in 20 fractions in 5 weeks) to prostate and seminal vesicles. The primary outcome measure was late toxicity. Additional outcomes were freedom from biochemical failure (FFBF), prostate cancer-specific survival (PCaSS), and overall survival (OS), evaluated on an intention-to-treat basis. Results A total of 85 patients were assigned to conventional and 83 to hypofractionated radiotherapy. At a median follow-up of 9 years (interquartile range, 7.5 to 10.1 years), no differences was observed in physician-assessed late gastro intestinal and genitourinary toxicity greater than or equal to grade 2 ( P = .68 and .57, respectively) were found between the two arms. The 10-year FFBF rate was 72% in the hypofractionation group and 65% in the conventional fractionation group ( P = .148). Ten-year OS rates were 75% in the hypofractionation group and 64% in the conventional group, respectively ( P = .22). The same features for 10-year PCaSS were 95% and 88%, respectively ( P = .066). Hypofractionation, pretreatment prostate-specific antigen level, Gleason score, and clinical tumor stage for FFBF, and hypofractionation and Gleason score for PCaSS were significant prognostic variables on the multivariate analysis. Conclusion Long-term findings showed that hypofractionated radiotherapy failed the intent of either reducing physician-assessed late toxicity or maintaining the same efficacy. A postrandomization analysis, however, revealed that hypofractionation was a significant prognostic factor for FFBF and PCaSS, when adjusted for clinical prognostic variables.


Evidence that SecB enhances the activity of SecA.
In Escherichia coli, SecA is a critical component of the protein transport machinery which powers the translocation process by hydrolyzing ATP and recognizing signal peptides which are the earmark of secretory proteins. In contrast, SecB is utilized by only a subset of preproteins to prevent their premature folding and chaperone them to membrane-bound SecA. Using purified components and synthetic signal peptides, we have studied the interaction of SecB with SecA and with SecA-signal peptide complexes in vitro. Using a chemical cross-linking approach, we find that the formation of SecA-SecB complexes is accompanied by a decrease in the level of cross-linking of SecA dimers, suggesting that SecB induces a conformational change in SecA. Furthermore, functional signal peptides, but not dysfunctional ones, promote the formation of SecA-SecB complexes. SecB is also shown to directly enhance the ATPase activity of SecA in a concentration-dependent and saturable manner. To determine the biological consequence of this finding, the influence of SecB on the signal peptide-stimulated SecA/lipid ATPase was studied using synthetic peptides of varying hydrophobicity. Interestingly, the presence of SecB can sufficiently boost the response of signal peptides with moderate hydrophobicity such that it is comparable to the activity generated by a more hydrophobic peptide in the absence of SecB. The results suggest that SecB directly enhances the activity of SecA and provide a biochemical basis for the enhanced transport efficiency of preproteins in the presence of SecB in vivo.


[Comparative analysis of results of gastric banding and gastric shunting operations].
Gastric banding and gastric shunting constitute the most frequently used methods of operations for treatment of morbid obesity, they owe certain advantages and disadvantages. The indications for choice of these operations are discussed. The comparative analysis of gastric banding and gastric shunting operations was conducted.


Abnormal synaptic vesicle biogenesis in Drosophila synaptogyrin mutants.
Sustained neuronal communication relies on the coordinated activity of multiple proteins that regulate synaptic vesicle biogenesis and cycling within the presynaptic terminal. Synaptogyrin and synaptophysin are conserved MARVEL domain-containing transmembrane proteins that are among the most abundant synaptic vesicle constituents, although their role in the synaptic vesicle cycle has remained elusive. To further investigate the function of these proteins, we generated and characterized a synaptogyrin (gyr)-null mutant in Drosophila, whose genome encodes a single synaptogyrin isoform and lacks a synaptophysin homolog. We demonstrate that Drosophila synaptogyrin plays a modulatory role in synaptic vesicle biogenesis at larval neuromuscular junctions. Drosophila lacking synaptogyrin are viable and fertile and have no overt deficits in motor function. However, ultrastructural analysis of gyr larvae revealed increased synaptic vesicle diameter and enhanced variability in the size of synaptic vesicles. In addition, the resolution of endocytic cisternae into synaptic vesicles in response to strong stimulation is defective in gyr mutants. Electrophysiological analysis demonstrated an increase in quantal size and a concomitant decrease in quantal content, suggesting functional consequences for transmission caused by the loss of synaptogyrin. Furthermore, high-frequency stimulation resulted in increased facilitation and a delay in recovery from synaptic depression, indicating that synaptic vesicle exo-endocytosis is abnormally regulated during intense stimulation conditions. These results suggest that synaptogyrin modulates the synaptic vesicle exo-endocytic cycle and is required for the proper biogenesis of synaptic vesicles at nerve terminals.


Tactile-emotion synesthesia.
We discuss experiments on two individuals in whom specific textures (e.g., denim, wax, sandpaper, silk, etc.) evoked equally distinct emotions (e.g., depression, embarrassment, relief, and contentment, respectively). The test/retest consistency after 8 months was 100%. A video camera recorded subjects' facial expressions and skin conductance responses (SCR) were monitored as they palpated different textures. Evaluators' ratings significantly correlated with the valence of synesthetes' subjective reports, and SCR was significantly enhanced for negative synesthetic emotions. We suggest this effect arises from increased cross-activation between somatosensory cortex and insula for 'basic' emotions and fronto-limbic hyperactivation for more subtle emotions. It may represent an enhancement of pre-existing evolutionarily primitive interactions between touch and emotions.


Effect of high salt intake on local renin-angiotensin system and ventricular dysfunction following myocardial infarction in rats.
1. This study was performed to evaluate the effect of chronic high salt intake on local cardiac and renal components of the renin-angiotensin system (RAS) and its impact on cardiac remodelling and function after myocardial infarction (MI). 2. Rats submitted to coronary artery ligation to produce MI or sham operation (SO) were randomized to receive 1% NaCl solution or tap water as drinking water for 4 weeks. Plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) activity were quantified. Tissue angiotensin (Ang) II and ACE activity were determined by ELISA and a fluorimetric assay, respectively. Renal and cardiac AT(1) and AT(2) receptor protein levels were quantified by western blot. 3. Independent of the lower PRA levels, MI promoted a significant increase in the left ventricular/bodyweight ratio and impaired cardiac function. The cardiac RAS was activated after MI with a significant increase in ACE activity, AngII and AT(1) receptor levels. The RAS was slightly attenuated under high-salt conditions. 4. Interestingly, high salt intake increased the expression of the AT(2) receptor by approximately twofold in the kidney of MI rats compared with the SO control group. Because of its natriuretic effect, the AT(2) receptor may counterbalance the salt overload and prevent the additional impairment of cardiac function. 5. The present study indicates that 4 weeks after MI, high salt intake did not further increase cardiac hypertrophy or further impair cardiac function in MI rats. A chronic increase in salt intake significantly suppressed PRA, but did not prevent activation of the local RAS or the progression of cardiac remodelling and left ventricular dysfunction caused by MI. 6. The present results show that inhibition of systemic renin production with salt overload does not affect ventricular remodelling after MI in rats. This suggests that local activation of the RAS in the heart, which was not suppressed by salt overload, exerts a predominant role for local adaptations of the heart after MI.


HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1.
In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer.


Effect of different dietary omega-3/omega-6 fatty acid ratios on reproduction in male rats.
Beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on the reproduction of male animals are widely described in the literature. However, there is little information about the effect of n-3/n-6 PUFA ratios on male health and reproduction. The aim of this study was to investigate the effects of diets with different n-3/n-6 PUFA ratios on the reproductive performance of male rats. Eighty male Sprague Dawley (SD) rats were supplemented with diets containing different n-3/n-6 PUFA ratios (0.13, 0.40, 0.85, 1.52 and 2.85) for 60 days. Half of the rats in each group were sacrificed on day 60, and the other half were chosen to mate with female mice to assess the effects of n-3/n-6 ratios on reproductive performance. Sperm density and sperm motility of the 1.52 group were higher than other groups (P < .05), and the development of testis and the morphological structure of sperm in the 1.52 group were better than other groups. Furthermore, a higher litter size and birth weights of offspring were observed in the 1.52 group. Additionally, serum reproductive hormone levels were significantly affected by the n-3/n-6 ratios. These findings demonstrated that a balanced n-3/n-6 ratio was important in male rat reproduction. Therefore there is a necessity to determine an appropriate n-3/n-6 PUFA ratio in man and different male animals in the future.


Targeting the Opioid Receptors: A Promising Therapeutic Avenue for Treatment in "Heavy Drinking Smokers".
Despite a general decline in tobacco use in the last decades, the prevalence of tobacco smoking in individuals with alcohol use disorder (AUD) remains substantial (45-50%). Importantly, the co-use of both substances potentiates the adverse effects, making it a significant public health problem. Substantial evidence suggests that AUD and Tobacco use disorder (TUD) may share common mechanisms. Targeting these mechanisms may therefore provide more effective therapy. Numerous studies describe a potential role of the endogenous opioid system in both AUD and TUD. Reviewing this literature, we aim to evaluate the efficacy of molecules that target the opioid system as promising therapeutic interventions for treating alcohol and tobacco co-use disorders. We provide a synthesis of the current epidemiological knowledge of alcohol and tobacco co-use disorders. We evaluate clinical and preclinical research that focuses on the regulation of the endogenous opioid system in alcohol, nicotine, and their interactions. The epidemiological data confirm that smoking stimulates heavy drinking and facilitates alcohol craving. Pharmacological findings suggest that treatments that are efficacious in the dual addiction provide a beneficial treatment outcome in comorbid AUD and TUD. In this regard, MOP, DOP and NOP-receptor antagonists show promising results, while the findings prompt caution when considering KOP-receptor antagonists as a treatment option in alcohol and tobacco co-use disorders. Existing literature suggests a role of the opioid system in sustaining the high comorbidity rates of AUD and TUD. Molecules targeting opioid receptors may therefore represent promising therapeutic interventions in 'heavy drinking smokers.'


Evaluation of skeletal tissue repair, part 1: assessment of novel growth-factor-releasing hydrogels in an ex vivo chick femur defect model.
Current clinical treatments for skeletal conditions resulting in large-scale bone loss include autograft or allograft, both of which have limited effectiveness. In seeking to address bone regeneration, several tissue engineering strategies have come to the fore, including the development of growth factor releasing technologies and appropriate animal models to evaluate repair. Ex vivo models represent a promising alternative to simple in vitro systems or complex, ethically challenging in vivo models. We have developed an ex vivo culture system of whole embryonic chick femora, adapted in this study as a critical size defect model to investigate the effects of novel bone extracellular matrix (bECM) hydrogel scaffolds containing spatio-temporal growth factor-releasing microparticles and skeletal stem cells on bone regeneration, to develop a viable alternative treatment for skeletal degeneration. Alginate/bECM hydrogels combined with poly (d,l-lactic-co-glycolic acid) (PDLLGA)/triblock copolymer (10-30% PDLLGA-PEG-PDLLGA) microparticles releasing VEGF, TGF-β3 or BMP-2 were placed, with human adult Stro-1+ bone marrow stromal cells, into 2mm central segmental defects in embryonic chick femurs. Alginate/bECM hydrogels loaded with HSA/VEGF or HSA/TGF-β3 demonstrated a cartilage-like phenotype, with minimal collagen I deposition, comparable to HSA-only control hydrogels. The addition of BMP-2 releasing microparticles resulted in enhanced structured bone matrix formation, evidenced by increased Sirius red-stained matrix and collagen expression within hydrogels. This study demonstrates delivery of bioactive growth factors from a novel alginate/bECM hydrogel to augment skeletal tissue formation and the use of an organotypic chick femur defect culture system as a high-throughput test model for scaffold/cell/growth factor therapies for regenerative medicine.


Association of FGF-2 Concentrations with Atheroma Progression in Chronic Kidney Disease Patients.
Atherosclerosis is highly prevalent in CKD. The rate of progression of atherosclerosis is associated with cardiovascular events. Fibroblast growth factor 2 (FGF-2) is a member of the FGF family with potentially both protective and deleterious effects in the development of atherosclerosis. The role of circulating FGF-2 levels in the progression of atherosclerosis in CKD is unknown. We used a multicenter, prospective, observational cohorts study of 481 patients with CKD. We determined the presence of atheroma plaque in ten arterial territories by carotid and femoral ultrasounds. Progression of atheromatosis was defined as an increase in the number of territories with plaque after 24 months. Plasma levels of FGF-2 were measured by multiplex analysis. A multivariable logistic regression analysis was performed to determine whether plasma FGF-2 levels were associated with atheromatosis progression. Average age of the population was 61 years. The percentage of patients in each CKD stage was 51% in stage 3, 41% in stages 4-5, and 8% in dialysis. A total of 335 patients (70%) showed plaque at baseline. Atheromatosis progressed in 289 patients (67%). FGF-2 levels were similar between patients with or without plaque at baseline (79 versus 88 pg/ml), but lower in patients with atheromatosis progression after 2 years (78 versus 98 pg/ml; P<0.01). In adjusted analyses, higher plasma FGF-2 was associated with lower risk of atheromatosis progression (odds ratio [OR], 0.86; 95% confidence interval [95% CI], 0.76 to 0.96; per 50 pg/ml increment). Analysis of FGF-2 in tertiles showed that atheroma progression was observed for 102 participants in the lowest tertile of FGF-2 (reference group), 86 participants in the middle tertile of FGF-2 (adjusted OR, 0.70; 95% CI, 0.40 to 1.20), and 74 participants in the lowest tertile of FGF-2 (adjusted OR, 0.48; 95% CI, 0.28 to 0.82). Low FGF-2 levels are independently associated with atheromatosis progression in CKD.


Development of a movement quality measurement tool for children.
Pediatric physical therapists assess the quantity and quality of children's motor skills. Several quantitative motor tests are currently available, but a concise measurement tool of observable movement quality (OMQ) is lacking. The purpose of this study was to develop an OMQ measurement tool for children from the perspective of pediatric physical therapists. A qualitative, 3-phase study involving pediatric physical therapists was conducted. The first phase consisted of 7 semistructured interviews. The second phase comprised a structured meeting using a nominal group technique, with the interviewees required to identify the most relevant OMQ aspects. The third phase comprised a Delphi technique involving 61 pediatric physical therapy experts with the aim of achieving at least 80% agreement on relevance, terminology, and definitions of OMQ aspects. Across all 3 phases, 32 aspects based on different theoretical constructs were considered. Fifteen aspects were included in the measurement. The pediatric physical therapy experts achieved at least 80% agreement on the definitions of 14 OMQ aspects: automated movements, asymmetry in movements, variation in movements, appropriate gross motor movements, fluency of movements, reduced muscle tone, increased muscle tone, involuntary movements, accuracy, slow/delayed movements, accelerated/abrupt movements, tremors, strength regulation, and stereotyped movements. The definition of appropriate fine motor movements achieved 75% agreement. This aspect was included because gross and fine motor movements are complementary. The aspects were scored using a 5-point Likert scale, with a total score ranging from 15 to 75 and with a higher score indicating a better OMQ. The OMQ scale, a concise measurement tool with 15 defined aspects, was developed. Content validity was obtained, but before the OMQ scale can be used in clinical practice, studies on reliability, construct validity, and responsiveness are needed.


The regulation of diaminopimelate decarboxylase activity in Escherichia coli strain w.
Activity of diaminopimelate decarboxylase in Escherichia coli strain W, growing in an aerated fermenter, was only slightly (14%) repressed by 2 mM-lysine when approximately equimolar diaminopimelate was present in the medium. Lysine alone caused 78% repression. Diaminopimelate did not interfere with uptake of lysine by growing organisms. Organisms grown in medium containing diaminopimelate, without lysine, had a decarboxylase activity 24% higher than organisms from minimal medium. The extent of repression by pyridoxine (56% when added to minimal medium) was decreased (to 31%) when diaminopimelate was also present in the medium. A diaminopimelate-requiring mutant, with limited ability to take up diaminopimelate, formed almost three times less diaminopimelate decarboxylase than did a diaminopimelate-requiring second-stage mutant that had an increased rate of transport of this amino acid. The internal concentration of diaminopimelate thus probably regulates the activity of the decarboxylase by induction. Lysine might not directly repress the enzyme but might give an apparent repression by restricting the biosynthesis of diaminopimelate. This restriction is probably not caused only by inhibition or repression of aspartokinase. Lysine and threonine together, though not singly, almost completely inhibited aspartokinase in vitro but caused less apparent repression of diaminopimelate decarboxylase than did lysine alone. Lysine plus diaminopimelate strongly repressed the lysine-sensitive aspartokinase (85%) without much affecting diaminopimelate decarboxylase formation, and pyridoxine repressed the decarboxylase without affecting aspartokinase.


Chloroquine and Hydroxychloroquine for the Prevention and Treatment of COVID-19: A Fiction, Hope or Hype? An Updated Review.
In December 2019, the novel coronavirus disease pandemic (COVID-19) that began in China had infected so far more than 109,217,366 million individuals worldwide and accounted for more than 2,413,912 fatalities. With the dawn of this novel coronavirus (SARS-CoV-2), there was a requirement to select potential therapies that might effectively kill the virus, accelerate the recovery, or decrease the case fatality rate. Besides the currently available antiviral medications for human immunodeficiency virus (HIV) and hepatitis C virus (HCV), the chloroquine/hydroxychloroquine (CQ/HCQ) regimen with or without azithromycin has been repurposed in China and was recommended by the National Health Commission, China in mid-February 2020. By this time, the selection of this regimen was based on its efficacy against the previous SARS-CoV-1 virus and its potential to inhibit viral replication of the SARS-CoV-2 in vitro. There was a shortage of robust clinical proof about the effectiveness of this regimen against the novel SARS-CoV-2. Therefore, extensive research effort has been made by several researchers worldwide to investigate whether this regimen is safe and effective for the management of COVID-19. In this review, we provided a comprehensive overview of the CQ/HCQ regimen, summarizing data from in vitro studies and clinical trials for the protection against or the treatment of SARS-CoV-2. Despite the initial promising results from the in vitro studies and the widespread use of CQ/HCQ in clinical settings during the 1st wave of COVID-19, current data from well-designed randomized controlled trials showed no evidence of benefit from CQ/HCQ supplementation for the treatment or prophylaxis against SARS-CoV-2 infection. Particularly, the two largest randomized controlled trials to date (RECOVERY and WHO SOLIDARITY trials), both confirmed that CQ/HCQ regimen does not provide any clinical benefit for COVID-19 patients. Therefore, we do not recommend the use of this regimen in COVID-19 patients outside the context of clinical trials.


Authenticity Testing and Detection of Eurycoma longifolia in Commercial Herbal Products Using Bar-High Resolution Melting Analysis.
The present study demonstrated High Resolution Melting (HRM) analysis combined with DNA barcode (Bar-HRM) as a fast and highly sensitive technique for detecting adulterants in Eurycoma longifolia commercial herbal products. Targeting the DNA barcoding of the chloroplastic region-ribulose biphosphate carboxylase large chain (rbcL) and the nuclear ribosomal region- internal transcribed spacer 2 (ITS2), PCR amplification and HRM analysis using saturated Eva green dye as the source of fluorescence signals, was accomplished by employing a real-time cycler. The results were further validated by sequencing to identify unknown sequence from Genbank database and to generate phylogenetic tree using neighbour joint (NJ) analysis. Both of the DNA markers exhibited a distinguishable melting temperature and shape of the normalised curve between the reference and the adulterants. In the case of species identification, ITS2 was more successful in differentiating between species. Additionally, detection of admixture sample containing small traces of targeted E. longifolia DNA (w/v) can be detected as low as 5% for rbcL and less than 1% for ITS2, proving the sensitivity and versatility of the HRM analysis. In conclusion, the Bar-HRM analysis is a fast and reliable technique that can effectively detect adulterants in herbal products. Therefore, this will be beneficial for regulatory agencies in order to regulate food safety issues.


Deep Learning Networks for Breast Lesion Classification in Ultrasound Images: A Comparative Study.
Accurate lesion classification as benign or malignant in breast ultrasound (BUS) images is a critical task that requires experienced radiologists and has many challenges, such as poor image quality, artifacts, and high lesion variability. Thus, automatic lesion classification may aid professionals in breast cancer diagnosis. In this scope, computer-aided diagnosis systems have been proposed to assist in medical image interpretation, outperforming the intra and inter-observer variability. Recently, such systems using convolutional neural networks have demonstrated impressive results in medical image classification tasks. However, the lack of public benchmarks and a standardized evaluation method hampers the performance comparison of networks. This work is a benchmark for lesion classification in BUS images comparing six state-of-the-art networks: GoogLeNet, InceptionV3, ResNet, DenseNet, MobileNetV2, and EfficientNet. For each network, five input data variations that include segmentation information were tested to compare their impact on the final performance. The methods were trained on a multi-center BUS dataset (BUSI and UDIAT) and evaluated using the following metrics: precision, sensitivity, F1-score, accuracy, and area under the curve (AUC). Overall, the lesion with a thin border of background provides the best performance. For this input data, EfficientNet obtained the best results: an accuracy of 97.65% and an AUC of 96.30%.Clinical Relevance- This study showed the potential of deep neural networks to be used in clinical practice for breast lesion classification, also suggesting the best model choices.


[Substitution treatment of drug addicts during pregnancy: consequences for the children?].
Substitution treatment of opioid-dependent addicts was introduced in Norway in 1998. During the last 10 years, approximately 150 infants have been born to mothers taking part in this programme. 10 mothers, who took part in the substitution treatment programme, gave birth to 15 infants at Haukeland University Hospital in the period 1999-2005. The infants were observed and monitored at the Department of Pediatrics, Haukeland University Hospital. During pregnancy, six of the infants were only exposed to opiates, i.e methadone or buprenorphine. Eight infants were also exposed to heroine, benzodiazepines or cannabis. As a group, these infants had lower birth weight than the national average. 14 of the 15 children developed neonatal abstinence syndrome (NAS), 10 needed treatment and two children died from sudden infant death syndrome (SIDS). Long-term follow-up showed that six of 13 children had normal psychomotor development, five had various degrees of delayed psychomotor development and two children had symptoms indicating a hyperkinetic disorder. Five children were in foster care. Infants of women included in substitution treatment programmes for drug addicts are at high risk compared to infants of women without such addiction. For the newborn, NAS was a frequent complication. The study also showed that symptoms of hyperkinetic disorder and delayed psychomotor development were common. Children who had been exposed to opiates in combination with additional drugs seemed to have a high risk of delayed development and behaviour disorders. As they get older many were placed in foster care, despite well-coordinated, multidisciplinary treatment for the mother.


Opioid Growth Factor and its Derivatives as Potential Non-toxic Multifunctional Anticancer and Analgesic Compounds.
Despite significant research progress on the pathogenesis, molecular biology, diagnosis, treatment, and prevention of cancer, its morbidity and mortality are still high around the world. The emerging resistance of cancer cells to anticancer drugs remains still a significant problem in oncology today. Furthermore, an important challenge is the inability of anticancer drugs to selectively target tumor cells thus sparing healthy cells. One of the new potential options for efficient and safe therapy can be provided by opioid growth factor (OGF), chemically termed Met-enkephalin. It is an endogenous pentapeptide (Tyr-Gly-Gly-Phe-Met) with antitumor, analgesic, and immune-boosting properties. Clinical trials have demonstrated that OGF therapy alone, as well as in combination with standard chemotherapies, is a safe, non-toxic anticancer agent that reduces tumor size. In this paper, we review the structure-activity relationship of OGF and its analogues. We highlight also OGF derivatives with analgesic, immunomodulatory activity and the ability to penetrate the blood-brain barrier and may be used as safe agents enhancing chemotherapy efficacy and improving quality of life in cancer patients. The reviewed papers indicate that Met-enkephalin and its analogues are interesting candidates for the development of novel, non-toxic, and endowed with an analgesic activity anticancer drugs. More preclinical and clinical studies are needed to explore these opportunities.


Physical strain during activities of daily living of patients with coronary artery disease.
The purpose of this study was to determine the physical strain of activities of daily living (ADL) in patients with coronary artery disease (CAD) compared with healthy controls. Seventeen patients with CAD and 15 controls performed a graded exercise bicycle test and 5 ADL tasks: walking with/without load, vacuum cleaning, undressing, and walking stairs. Peak heart rate (HRpeak) and peak oxygen uptake (VO(2) peak) were determined during the bicycle test. Heart rate (HR) and oxygen uptake (VO(2)) were continuously measured during all ADL tasks. Physical strain during ADL tasks was calculated using HR and VO(2) response, expressed relative to individual HR and VO(2) reserves (%HRR, %VO(2) R, respectively). Perceived strain was measured using the Rating of Perceived Exertion (RPE) scale. HRpeak and VO(2) peak were lower (P<0·001) in patients. Patients performed the ADL tasks slower and with lower absolute VO(2), except for undressing. HR was only higher in patients during stair climbing. No differences in RPE scores were found between both groups, except for undressing. However, physical strain was significantly higher in patients (mean %VO(2) R ranged from 43% to 51%; mean %HRR ranged from 38% to 47%) compared with controls (mean %VO(2) R: 14% to 30%; mean %HRR: 14% to 29%) for all ADL tasks. In general, ADL tasks were performed slower and with higher physical strain in patients with CAD compared with controls.


Attempted transfer of antibiotic resistance between Bacteroides and Escherichia coli.
Transfer of antibiotic resistance between Bacteroides organisms and E. coli in mixed culture under optimal anaerobic conditions was attempted. Donor strains used were E. coli with R factors of a number of compatibility groups and Bacteroides with unusually high antibiotic resistance. Recipient strains included E. coli strains with characteristics favouring conjugal transfer. Although control experiments verified that conjugal transfer of derepressed R factors could occur at a high frequency between E. coli in an anaerobic environment, transfer of antibiotic resistance between E. coli and Bacteroides was never demonstrated.


Zika virus infection in the genital tract of non-pregnant females: a systematic review.
This review provides a general overview on the positivity and persistence of Zika virus (ZIKV) in female genital tract (FGT) of non-pregnant women and animals, as well as in cell cultures, and its influence on FGT health. We performed a systematic review based on the PRISMA statement to identify studies focused on "Zika virus" and "non-pregnant female" in PubMed, Embase, Scopus Scholar and Web of Knowledge databases of full-text papers and abstracts published in English, with no restrictions regarding the initial date of publication, up to August 2019. Our search terms yielded 625 records, that were 108 after removal of duplicates, leaving 517 items for title and abstract reviews. Of these, 475 did not meet the inclusion criteria, leaving 42 records for full-text review and resulting in the exclusion of 6 additional records. The remaining 36 met our inclusion criteria. Variations were observed regarding the presence and persistence of ZIKV in lower and upper genital samples. However, the FGT was the place in which ZIKV RNA has been detected, sometimes for relatively long periods, even after the clearance from blood and urine. In addition to the vagina and cervix, the endometrium, uterus and ovary (oocytes and follicles) could also be involved in persistent ZIKV infections. Further prospective studies are needed to assess the effect of ZIKV on FGT health.


Reanalysis of the DEMS nested case-control study of lung cancer and diesel exhaust: suitability for quantitative risk assessment.
The International Agency for Research on Cancer (IARC) in 2012 upgraded its hazard characterization of diesel engine exhaust (DEE) to "carcinogenic to humans." The Diesel Exhaust in Miners Study (DEMS) cohort and nested case-control studies of lung cancer mortality in eight U.S. nonmetal mines were influential in IARC's determination. We conducted a reanalysis of the DEMS case-control data to evaluate its suitability for quantitative risk assessment (QRA). Our reanalysis used conditional logistic regression and adjusted for cigarette smoking in a manner similar to the original DEMS analysis. However, we included additional estimates of DEE exposure and adjustment for radon exposure. In addition to applying three DEE exposure estimates developed by DEMS, we applied six alternative estimates. Without adjusting for radon, our results were similar to those in the original DEMS analysis: all but one of the nine DEE exposure estimates showed evidence of an association between DEE exposure and lung cancer mortality, with trend slopes differing only by about a factor of two. When exposure to radon was adjusted, the evidence for a DEE effect was greatly diminished, but was still present in some analyses that utilized the three original DEMS DEE exposure estimates. A DEE effect was not observed when the six alternative DEE exposure estimates were utilized and radon was adjusted. No consistent evidence of a DEE effect was found among miners who worked only underground. This article highlights some issues that should be addressed in any use of the DEMS data in developing a QRA for DEE.


Principle and mechanism of direct porphyrin metalation: joint experimental and theoretical investigation.
The direct metalation of tetraphenylporphyrin with bare metal atoms (Co and Zn) was studied with X-ray photoelectron spectroscopy, scanning tunneling microscopy, and temperature-programmed reaction measurements on ordered monolayer films of the molecules adsorbed on a Ag(111) surface. The mechanism of this novel type of surface reaction was investigated using density functional theory (DFT) calculations for the related gas-phase reactions of the unsubstituted porphyrin with the metals Fe, Co, Ni, Cu, and Zn. The reaction starts with the formation of an initial complex, in which the metal atom is coordinated by the intact unreduced porphyrin. This complex resembles the sitting-atop complex proposed for porphyrin metalation with metal ions in solution. In two subsequent steps, the pyrrolic hydrogen atoms are transferred to the metal atom, forming H2, which is eventually released. The activation barriers of the H-transfer steps vary for the different metal atoms. DFT calculations suggest that metalations with Fe, Co, and Ni show two-state reactivity, while those with Cu and Zn proceed on a single potential energy surface. For metalation with Zn, we calculated a barrier of the first hydrogen transfer step of 32.6 kcal mol(-1), in good agreement with the overall experimental activation energy of 31 kcal mol(-1).


Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats.
Growing evidence suggests that oxytocin plays an important role in the regulation of energy balance and that central oxytocin administration induces weight loss in diet-induced obese (DIO) animals. To gain a better understanding of how oxytocin mediates these effects, we examined feeding and neuronal responses to oxytocin in animals rendered obese following exposure to either a high-fat (HFD) or low-fat diet (LFD). Our findings demonstrate that peripheral administration of oxytocin dose-dependently reduces food intake and body weight to a similar extent in rats maintained on either diet. Moreover, the effect of oxytocin to induce weight loss remained intact in leptin receptor-deficient Koletsky (fa(k)/fa(k)) rats relative to their lean littermates. To determine whether systemically administered oxytocin activates hindbrain areas that regulate meal size, we measured neuronal c-Fos induction in the nucleus of the solitary tract (NTS) and area postrema (AP). We observed a robust neuronal response to oxytocin in these hindbrain areas that was unexpectedly increased in rats rendered obese on a HFD relative to lean, LFD-fed controls. Finally, we report that repeated daily peripheral administration of oxytocin in DIO animals elicited a sustained reduction of food intake and body weight while preventing the reduction of energy expenditure characteristic of weight-reduced animals. These findings extend recent evidence suggesting that oxytocin circumvents leptin resistance and induces weight-loss in DIO animals through a mechanism involving activation of neurons in the NTS and AP, key hindbrain areas for processing satiety-related inputs.


Regionality in vector control: effect of fluctuating temperature in the susceptibility of Aedes aegypti (Diptera: Culicidae) larvae to Pyriproxyfen.
Using Pyriproxyfen in controlling Aedes aegypti shows great potential considering its high competence in low dosages. As an endocrine disruptor, temperature can interfere with its efficiency, related to a decrease in larval emergence inhibition in hotter environments. However, previous studies have been performed at constant temperatures in the laboratory, which may not precisely reflect the environmental conditions in the field. The aim of this study was to assess the effect of the fluctuating temperatures in Pyriproxyfen efficiency on controlling Aedes aegypti larvae. We selected maximum and minimum temperatures from the Brazilian Meteorological Institute database from September to April for cities grouped by five regions. Five fluctuating temperatures (17-26; 20-28.5; 23-32.5; 23-30.5; 19.5-31 °C) were applied to bioassays assessing Pyriproxyfen efficiency in preventing adult emergence in Aedes aegypti larvae in five concentrations. In the lowest temperatures, the most diluted Pyriproxyfen treatment (0.0025 mg/L) was efficient in preventing the emergence of almost thrice the larvae than in the hottest temperatures (61% and 21%, respectively, p value = 0.00015). The concentration that inhibits the emergence of 50% of the population was lower than that preconized by the World Health Organization (0.01 mg/L) in all treatments, except for the hottest temperatures, for which we estimated 0.010 mg/L. We concluded that fluctuating temperatures in laboratory bioassays can provide a more realistic result to integrate the strategies in vector surveillance. For a country with continental proportions such as Brazil, considering regionalities is crucial to the rational use of insecticides.


Selective mRNA degradation by antisense oligonucleotide-2,5A chimeras: involvement of RNase H and RNase L.
Antisense oligonucleotides (ON) allow the specific control of gene expression and phosphorothioate derivatives are currently being evaluated for possible clinical applications. Numerous second generation ON analogues with improved pharmacological properties have been described. Most of them, however, do not recruit RNase H, which is known to increase ON potency by eliciting the specific degradation of the target RNA. Silverman, Torrence and colleagues have conjugated 2,5A to natural antisense ON and demonstrated the preferential cleavage of a target RNA in cell-free and intact cell experiments. We have established for the first time that RNase H-incompetent ON, viz. alpha-anomeric ON analogues, can be converted into sequence-specific nucleases upon conjugation to 2,5A. The use of alpha-ON- and beta-ON-2,5A chimeras has allowed us to delineate the part played by RNase H and RNase L in target RNA degradation and translation arrest. Finally, the present studies have revealed limitations which are encountered in the choice of a suitable target for such ON-2,5A chimeras.


A quantum laser pointer.
The measurement sensitivity of the pointing direction of a laser beam is ultimately limited by the quantum nature of light. To reduce this limit, we have experimentally produced a quantum laser pointer, a beam of light whose direction is measured with a precision greater than that possible for a usual laser beam. The laser pointer is generated by combining three different beams in three orthogonal transverse modes, two of them in a squeezed-vacuum state and one in an intense coherent field. The result provides a demonstration of multichannel spatial squeezing, along with its application to the improvement of beam positioning sensitivity and, more generally, to imaging.


Adaptation of the [13C]urea breath test as a noninvasive method for detection of Helicobacter pylori infection in squirrel monkeys (Saimiri spp.).
The [13C]urea breath test was adapted for use in squirrel monkeys (Saimiri spp.) for identification of experimentally induced infection with Helicobacter pylori, the bacterium causing gastric ulcer in humans. A canine anesthesia inhalation mask was modified with a volume-reducing insert allowing sufficient breath collection from these small primates within 30 sec. Fourteen milligrams of [13C urea per kilogram of body weight was adequate for clear distinction between experimentally infected and noninfected animals. Initial infection of five squirrel monkeys resulted in increased 13CO2 in breath within 3 days after inoculation with H. pylori. Additional inoculation with H. pylori superimposed on an existing gastric population caused a transient increase in breath 13CO2 values, which gradually declined over the following 15 days. Breath test results indicating H. pylori infection were confirmed by high [13C] concentration in blood, by urease-positive culture, modified Steiner stain reaction, and Western blot analysis. This modified [13C]urea breath test provides a rapid, reproducible, noninvasive method for screening small primates used as nonhuman models for the study of gastric infection with H. pylori.


Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab11.
Two endosome populations involved in recycling of membranes and receptors to the plasma membrane have been described, the early and the recycling endosome. However, this distinction is mainly based on the flow of cargo molecules and the spatial distribution of these membranes within the cell. To get insights into the membrane organization of the recycling pathway, we have studied Rab4, Rab5, and Rab11, three regulatory components of the transport machinery. Following transferrin as cargo molecule and GFP-tagged Rab proteins we could show that cargo moves through distinct domains on endosomes. These domains are occupied by different Rab proteins, revealing compartmentalization within the same continuous membrane. Endosomes are comprised of multiple combinations of Rab4, Rab5, and Rab11 domains that are dynamic but do not significantly intermix over time. Three major populations were observed: one that contains only Rab5, a second with Rab4 and Rab5, and a third containing Rab4 and Rab11. These membrane domains display differential pharmacological sensitivity, reflecting their biochemical and functional diversity. We propose that endosomes are organized as a mosaic of different Rab domains created through the recruitment of specific effector proteins, which cooperatively act to generate a restricted environment on the membrane.


Inappropriate Indexing of Case Reports to the "Papilledema" Subject Heading: A Systematic Review.
Papilledema must be managed distinctly from other causes of optic disc edema (ODE) due to its basis in raised intracranial pressure (ICP). However, evidence indicates that the term "papilledema" is widely misused across specialties to describe ODE without raised ICP. Sources of this misconception remain undiscerned. Because all physicians consult medical databases, our objective was to evaluate whether nonspecific "papilledema" subject heading definitions misleadingly associate articles on other conditions with papilledema proper. Systematic review of case reports, prospectively registered on PROSPERO (CRD42022363651). MEDLINE and Embase were searched to July 2022 for any full-length case report indexed to the "papilledema" subject heading. Studies were graded for incorrect indexing, defined as cases lacking evidence for raised ICP. Nonpapilledema diagnoses were assigned to a predefined set of diseases and pathophysiological mechanisms for subsequent comparison. Incorrect indexing occurred in 40.67% of 949 included reports. Embase-derived studies were misindexed significantly less than MEDLINE-derived studies ( P < 0.01). There was also significant heterogeneity in incorrect indexing among specific diseases ( P = 0.0015) and mechanisms ( P = 0.0003). The most commonly misindexed diseases were uveitis (21.24% of errors), optic neuritis (13.47%), and instances with no mention of ODE (13.99%). The most commonly misindexed mechanisms were inflammation (34.97%), other mechanism (e.g., genetic; 25.91%), and ischemia (20.47%). Database subject headings, especially from MEDLINE, do not adequately distinguish between true papilledema and other causes of ODE. Inflammatory diseases were most often incorrectly indexed among other diseases and mechanisms. Current "papilledema" subject headings should be revised to reduce the probability of misinformation.


Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication.
Interstitial deletions of 3q29 have been recently described as a microdeletion syndrome mediated by nonallelic homologous recombination between low-copy repeats resulting in an ~1.6 Mb common-sized deletion. Given the molecular mechanism causing the deletion, the reciprocal duplication is anticipated to occur with equal frequency, although only one family with this duplication has been reported. In this study we describe 14 individuals with microdeletions of 3q29, including one family with a mildly affected mother and two affected children, identified among 14,698 individuals with idiopathic mental retardation who were analyzed by array CGH. Eleven individuals had typical 1.6-Mb deletions. Three individuals had deletions that flank, span, or partially overlap the commonly deleted region. Although the clinical presentations of individuals with typical-sized deletions varied, several features were present in multiple individuals, including mental retardation and microcephaly. We also identified 19 individuals with duplications of 3q29, five of which appear to be the reciprocal duplication product of the 3q29 microdeletion and 14 of which flank, span, or partially overlap the common deletion region. The clinical features of individuals with microduplications of 3q29 also varied with few common features. De novo and inherited abnormalities were found in both the microdeletion and microduplication cohorts illustrating the need for parental samples to fully characterize these abnormalities. Our report demonstrates that array CGH is especially suited to identify chromosome abnormalities with unclear or variable presentations.