Types and chemical composition of intrahepatic stones.
The calcium bilirubinate stone is the typical gallstone found in patients with hepatolithiasis; a series of studies on the formation of stones have been performed by Maki [1966, 1982]. Results of chemical analysis and clinical factors lend support to Maki's bacterial beta-glucuronidase theory [Maki, 1966]. However, besides calcium bilirubinate these stones also contain other components such as fatty acids and free bile acids. The presence of these components indicates bacterial involvement, which is proved by the decomposition of the lecithine in bile to fatty acids by phospholipase A and the formation of free bile acids by deconjugation of the conjugated bile acids. In the formation of calcium bilirubinate stones, it is believed that diet [Matsushiro et al, 1977] and bacterial infections accompanying biliary stasis are important inducing elements. Since these stones are formed mainly in the bile ducts and recurrence rates are likely to be high, it is important from the therapeutic viewpoint to remove these inducing factors. However, it is still uncertain whether bacterial infection accompanying biliary stasis should be considered as an inducing factor in the development of fatty acid-calcium stones. More than 90% of all cholesterol and black stones are found in the gallbladder. However, when these stones are found in the intrahepatic bile ducts, it is still not clear whether they are expelled from the gallbladder or formed initially in the intrahepatic bile ducts. In patients who have cholesterol stones filling the entire biliary tract, it is difficult to conceive that these gallstones are first expelled from the gallbladder. In addition, in patients with black stones, the stones are located only in the dilated bile ducts, and stenosis of the bile duct is often recognized in the excisional stump of the liver at lateral segmentectomy. In these cases, the expulsion of stones from the gallbladder seems rather improbable. Different types of gallstones show a tendency to occur in certain regions; however, gallstones may be formed in almost any part of the biliary system if conditions are favorable. It can be concluded that the pathogenesis of hepatolithiasis may not be clarified only by analysis of the intrahepatic gallstones. In addition, an understanding of the formation of different types of gallstones may contribute to elucidation of the pathogenesis of hepatolithiasis.


Gender Differences in Functional Health and Mortality Among the Chinese Elderly: Testing an Exposure Versus Vulnerability Hypothesis.
In this study, the authors focused on older adults in Beijing with three objectives: to examine gender differences in functional health and mortality at the end of a five-year study period, controlling for initial functional health; to determine the extent to which these differences were a function of exposure versus vulnerability to risk factors; and to analyze the relative importance of social, economic, and psychological risk factors in explaining gender differences. The results show that women were more likely to survive and to be functionally dependent at follow-up compared with men among those functionally independent at baseline. No significant differences among those who were initially dependent were apparent. Differential vulnerability to risk factors, more so than exposure, explained the variation in health outcomes across gender. Smoking, a lack of formal education, a lack of health insurance, a low sense of control, stressful events, and rural living played large roles in explaining the differences.


Affinity maturation of human growth hormone by monovalent phage display.
We describe a selection procedure for construction of very high affinity variants of human growth hormone (hGH) for binding to the extra cellular domain of its receptor (called the hGHbp). Five different libraries of mutated hGH genes (each containing approximately 2 x 10(5) protein variants) were created by randomly mutating four different codons at residues that were shown to be important for receptor binding by structural or functional criteria. Mutated proteins were displayed as single copies from their respective filamentous phagemid particles and sorted in vitro for binding to the immobilized hGHbp. Phagemid particles that bound the immobilized hGHbp were eluted and propagated. After three to seven rounds of binding enrichments, hGH variants were isolated that contained 2 to 4 mutations and exhibited three- to sixfold improvements in binding affinity. Because of the limits of DNA transfection efficiency in creating the library we could not sample thoroughly mutations at more than four codons at once. Nonetheless, the free energy effects for these mutations acted cumulatively. Thus, by combining affinity enhanced mutants from libraries independently sorted we created an hGH variant with 15 substitutions that bound approximately 400-fold more tightly to the hGHbp than wild-type hGH. The affinity enhancements occurred predominantly by slowing the off-rate of the hormone (> 60-fold), and partly through increasing the on-rate (up to 4-fold). Residues that were shown to be important for binding by alanine-scanning were most highly conserved after binding selection, and interestingly many of them could be further improved. Thus, we found it most effective to randomly mutate the residues that were shown to modulate affinity by alanine-scanning, and to combine the selectants from separate libraries that exhibit the highest affinities. The selection procedure and mutagenesis strategy provides a framework for affinity maturation of protein-protein complexes.


Beyond the 10-m time: a pilot study of timed walks in lower limb amputees.
To investigate in a pilot study the use of extended walking times as an objective method of distinguishing differences in outcome in lower limb amputees. Sixteen lower limb amputees attending the prosthetic clinic. Patients were asked to walk 100 m, turning every 20 m, using their usual walking aids and prostheses at their chosen walking speed. Demographic details and modified Stanmore/Harold Wood mobility grades, walking aids used and discomfort were recorded. Time to walk each 20 m up to 100 m was recorded. Statistical analysis was carried out using the Spearman rank order correlation coefficient. There was a wide age range and differing causes of amputation. Five out of 16 subjects failed to complete 100 m and these had the slowest 20- and 40-m times. The mean time to walk 40 m was 41 seconds for those who were able to complete 100 m and 144 seconds for those who could not complete 100 m. All those with modified Stanmore/Harold Wood mobility grades less than four failed to complete 100 m. There was a high correlation between 20-, 40-, 60-, 80- and 100-m times and mobility grades, which was statistically significant, and between 20-, 40-, 60-, 80- and 100-m times. Forty-metre walking time can differentiate between those of mobility grades 4b-6 and those with lower mobility grades who are unable to walk significantly outside.


[Efficacy of interventions aimed at the main carers of dependent individuals aged more than 65 years old. A systematic review].
In our environment, care of the dependent elderly is usually provided by family members, thereby ensuring autonomy and avoiding institutionalization of the dependent adult. Thirty-three percent of Spanish caregivers have acknowledged the importance of acquiring the knowledge and skills necessary for daily care. Consequently, several interventions have been developed by health professionals from distinct disciplines. The purpose of this study was to systematically review and evaluate the efficacy of published interventions for the caregivers of dependent elderly individuals. We conducted a systematic review of the literature on interventions in the caregivers of the dependent elderly (older than 65 years old) published between 1996 and 2006. The inclusion criteria included controlled clinical trials with outcome measures related to effectiveness in reducing caregiver burden, anxiety and depression. Our search yielded 15 reports. The interventions produced statistically significant reductions in burden (40%), anxiety (50%) and depression (90%). Interventions requiring active participation by caregivers and those based on cognitive-behavioral therapy were more effective than those focused on knowledge acquisition. Due to the heterogeneity of caregiving interventions, evaluation of both the clinical and statistical significance of these interventions is essential. Reducing the chronic stress experienced by caregivers is difficult to achieve. Consequently, future experimental designs should take into account the needs reported by caregivers as well as promote active participation.


Investigations on uterine fatty lesions.
The aim of the study was to determine the occurrence of UFLs and the dynamics of their development, as well as to evaluate the histopathology and relationship with regressive stromal changes. 3750 uterine specimens were reviewed during the period between 1984 and 2003. In the examined series of 3750 uteruses removed due to tumors or prolapse, 50 cases with four types of changes were chosen: adipocytic metaplasia of primary uterine leiomyomas (70% of cases), adipocytic metaplasia of interlobular stroma of primary uterine tumors (16%), adipocytic aggregates in the uterine muscle (8%), and pure lipomas (6%). Additionally, the cases were divided into three groups depending on the extent of fatty changes. Group 1 (48% of cases) consisted of cases in which less than 25% of the changes were present in the examined material. In group 2 (28% of cases) the fatty changes were between 25 and 50%. In group 3 (16% of cases) fatty changes constituted more than 50% of the examined specimen. The extent of adipocytic changes was connected with patient age, being significant between groups 1 and 3 (p < 0.01). Regressive stromal changes in leiomyomas occurred more often in middle-aged patients, with stage 2 lipomatosis than in other subgroups. Among 46 cases of UFLs two patients were diagnosed with a coexisting malignant uterine neoplasm (4.35%). In four patients with muscular lipomatosis, two were diagnosed with a coexisting malignant uterine tumor too (50%). 1. Uterine fatty lesions are rarely diagnosed, although they occur more often than previously thought. 2. Mixed tumors predominate over pure lipomas. 3. The histogenesis of these lesions seems to be multi-factorial, considering the different types of UFLs. 4. The extent of uterine fatty metaplasia positively correlated with the age of operated women. 5. The coexistence of UFLs with other malignant uterine neoplasms is accidental.


Platinum complexes with NH groups on the carrier ligand and with only one guanine or hypoxanthine derivative. Informative models for assessing relative nucleobase and nucleotide hydrogen-bond interactions with amine ligands in solution.
Complexes of the type syn-(R,S)-Me(3)dienPtL (Me(3)dien = N,N',N' '-trimethyldiethylenetriamine; L = guanine or hypoxanthine derivative) have two rotamers, a feature useful for assessing hydrogen-bond interactions between a Me(3)dien NH group and either the O6 or the phosphate group of the coordinated L. The two rotamers are defined as endo and exo for the rotamer with the six-membered ring of the purine on the same side and on the opposite side, respectively, of the coordination plane as the N-Me's. For L = 5'-GMP and 5'-IMP the endo rotamer is the exclusive form (at neutral and basic pH) or is present at 90% and more (low pH where 5'-phosphate group is protonated). A 5'-phosphate group can be positioned to form a direct H-bond with a Me(3)dien NH group only in the endo form; such an H-bond explains this high endo preference. Such a direct phosphate-NH H-bond is not possible for other complexes used in this study because either L has no phosphate group (9-EtG, Guo) or the phosphate is at the 3'-position (3'-GMP and 3'-IMP), too far for H-bonding. Nevertheless, a preference for the endo rotamer was observed for these L also. This result is opposite to that expected both from potential steric repulsion of the L O6 with the N-Me groups and also from the lack of a potential favorable H-bond interaction between L O6 and a Me(3)dien NH. For the 9-EtG adduct, the temperature dependence of the endo/exo equilibrium and the activation parameters for endo/exo interconversion suggest that the preference for the endo rotamer arises from the hydration of the Me(3)dien NH groups; such hydration is favorable in the endo rotamer. At basic pH, N1H deprotonation increases the H-bond capacity of O6, and the exo rotamer increases in stability, becoming the dominant rotamer for the 9-EtG and Guo adducts. For L = 3'-GMP and 3'-IMP, stabilization of the endo form upon phosphate deprotonation at neutral pH was observed. This result is attributed to an H-bonding network involving water, the 3'-phosphate, and the Me(3)dien NH groups.


Increased risk for depression persists for years among women treated for gynecological cancers - a register-based cohort study with up to 19 years of follow-up.
Little is known about long-term risk of depression in women treated for gynecological cancers. We aim to investigate risk for depression among these women compared to women without a history of cancer. We followed 16,833 women diagnosed with gynecological cancers between 1998 and 2013 and 138,888 reference women in nationwide registers for up to 19 years. Women with a history of severe psychiatric disorders, and those who had redeemed a prescription for antidepressants three years before study entry were excluded from analyses. Regression analyses were applied to compare the risk for antidepressant use among patients compared to reference women, and to investigate associations between socio-demographic as well as clinical risk factors and use of antidepressants. We found an increased risk for antidepressant use among women treated for ovarian (HR 4.14, 95% CI 3.74-4.59), endometrial (HR 2.19, 95% CI 1.97-2.45), and cervical cancer (HR 3.14, 95% CI 2.74-3.61) one year after diagnosis. This increased risk persisted years after diagnosis in all three groups, with the longest (up to eight years) found for ovarian cancer. Advanced disease was strongly associated with antidepressant use followed by short education, and comorbidity. Women diagnosed with gynecological cancer have an increased risk for depression compared to reference women. The risk remains increased for years after diagnosis throughout and beyond standard oncological follow-up care. Advanced disease, short education, and comorbidity are factors associated with antidepressant use in this patient group.


Uncovering the molecular identity of cardiosphere-derived cells (CDCs) by single-cell RNA sequencing.
Cardiosphere-derived cells (CDCs) generated from human cardiac biopsies have been shown to have disease-modifying bioactivity in clinical trials. Paradoxically, CDCs' cellular origin in the heart remains elusive. We studied the molecular identity of CDCs using single-cell RNA sequencing (sc-RNAseq) in comparison to cardiac non-myocyte and non-hematopoietic cells (cardiac fibroblasts/CFs, smooth muscle cells/SMCs and endothelial cells/ECs). We identified CDCs as a distinct and mitochondria-rich cell type that shared biological similarities with non-myocyte cells but not with cardiac progenitor cells derived from human-induced pluripotent stem cells. CXCL6 emerged as a new specific marker for CDCs. By analysis of sc-RNAseq data from human right atrial biopsies in comparison with CDCs we uncovered transcriptomic similarities between CDCs and CFs. By direct comparison of infant and adult CDC sc-RNAseq data, infant CDCs revealed GO-terms associated with cardiac development. To analyze the beneficial effects of CDCs (pro-angiogenic, anti-fibrotic, anti-apoptotic), we performed functional in vitro assays with CDC-derived extracellular vesicles (EVs). CDC EVs augmented in vitro angiogenesis and did not stimulate scarring. They also reduced the expression of pro-apoptotic Bax in NRCMs. In conclusion, CDCs were disclosed as mitochondria-rich cells with unique properties but also with similarities to right atrial CFs. CDCs displayed highly proliferative, secretory and immunomodulatory properties, characteristics that can also be found in activated or inflammatory cell types. By special culture conditions, CDCs earn some bioactivities, including angiogenic potential, which might modify disease in certain disorders.


Biomedical Grade Stainless Steel Coating of Polycaffeic Acid via Combined Oxidative and Ultraviolet Light-Assisted Polymerization Process for Bioactive Implant Application.
Stainless steel as a biomedical implant material has been studied in various fields and in various forms, such as vascular stents, bone plates, dental screws, and artificial hip and bone material. In this study, we used polycaffeic acid (PCA), a natural phenolic compound, to coat the surface of medical grade stainless steel to provide added potential medicinal effects by virtue of its inherent anti-inflammatory, antiviral, antifibrosis, antithrombosis, and antihypertensive characteristics. We did this via UV irradiation under an alkaline state to solve the cost and time problems of other existing coating methods. The physicochemical properties of the samples were investigated through field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), contact angle, FTIR, and X-ray photoelectron spectroscopy (XPS). Surface bioactivity using NIH-3T3 cell lines were observed in vitro. We expect that the proposed methodology may contribute to the field of study of implantable metallic devices.


Aberrant nuclear trafficking of La protein leads to disordered processing of associated precursor tRNAs.
Eukaryotic precursor tRNAs undergo extensive processing prior to nuclear export. The first of multiple factors to interact with pre-tRNAs and other nascent transcripts is the La protein. Using suppressor and wild-type tRNAs, we demonstrate that the normal distribution of cellular end-processed and spliced tRNA species is disordered by La proteins that lack a conserved nuclear retention element. Fission yeast or human La mutants that lack this element enter nuclei and stabilize nascent pre-tRNA but are aberrantly exported and fail to support normal tRNA processing. Instead, anomalous 5' and 3' end-containing, spliced tRNAs accumulate, complexed with the mutant La protein. Thus, appropriate nuclear trafficking by La affects the normal order of pre-tRNA processing.


Delayed cytotoxicity of 6-mercaptopurine is compatible with mitotic death caused by DNA damage due to incorporation of 6-thioguanine into DNA as 6-thioguanine nucleotide.
Many protocol studies have shown that low dose 6-mercaptopurine (6MP) in maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL) can be utilized to cure the disease. Mitotic or reproductive cell death has been recognized after G2 arrest when cells are treated with antitumor agents. The precise mechanism of mode of action of 6MP still remains unclear. We found delayed cytotoxic effect of 6MP in P388 murine leukemic cells. Morphological study showed that 6MP induced delayed death was characterized by an enlargement of cell size and multinucleated nuclei. Agarose gel electrophoresis of fragmented DNA from cells treated with 6MP showed the typical ladder pattern. These findings were compatible with mitotic death. Our results make us hypothesize that the delayed cytotoxicity of 6MP is one of the drug induced mitotic deaths caused by DNA damage due to incorporation of 6-thioguanine (6TG) into DNA as thioguanine nucleotide (TGN). Mitotic death may be a mechanism for killing the cycling cells from residual leukemic cells in G0 or long G1 phases in the treatment of childhood ALL.


A MRI rotary phased array head coil.
A new rotary phased array (RPA) head coil that can provide homogenous brain images comparable to volumetric radiofrequency coils is proposed for magnetic resonance brain imaging applications. The design of the RPA head coil is a departure from conventional circumferential array design method, as coil elements of the RPA head coil have a "paddle-like" structure consisting of a pair of main conductors located on opposite sides, inserted equi-angularly around and over the head. A prototype 2T receive-only 4-element RPA head coil was constructed and experimentally tested against a conventional receive-only 4-element phased array head coil and a commercial receive-only quadrature birdcage head coil. Homogenous phantom images acquired by the RPA head coil show that signal intensity deep at the center of the phantom was improved as compared to the conventional phased array head coil and this improvement allow the RPA head coil to acquire homogenous brain images similar to brain images acquired with the birdcage head coil. In addition, partial parallel imaging was used in conjunction with the RPA head coil to enable rapid imaging.


Perception of everyday odors--correlation between intensity, familiarity and strength of hedonic judgement.
In this study, 40 Japanese, 44 German and 39 Mexican women were presented with 18 everyday odorants. They were asked to rate them for intensity on a six-point scale from not detectable to very strong, for pleasantness on an 11-point scale from -5, to neutral at 0, to +5, and for familiarity on a six-point scale from completely unknown to extremely familiar. Consistent positive correlations were found between paired rating scores for the three measures, and although they were not particularly strong (r(s) range, 0.19-0.60), for most odorants all three correlations were significant. Similar results were obtained whether the data were analyzed on an individual or a national basis. Most notable were the consistent positive correlations between perceived intensity and ratings of familiarity and hedonic strength. It is suggested that the perceived intensity of the odorants depended not only on stimulus concentration but probably also on experience-dependent factors.


[Age-related macular degeneration].
Age-related macular degeneration (AMD) is the commonest overall cause of irreversible blindness in patients aged 50 or over in the western world. It is a spectrum of related diseases that have in common the progressive decline of vision as a consequence of dysfunction of the central retina and its underlying supporting elements, principally the retinal pigment epithelium and choroid in older adults. The disease has been traditionally classified into early and late stages with its dry and wet forms. Patients with age-related maculopathy should consider taking a dietary supplement such as that used in AREDS. There is no effective treatment for geographic atrophy. The exudative AMD is approached depending on the type and localisation of choroidal new vessels. Laser photocoagulation has only been shown to be beneficial for extra and juxtafoveal well defined lesions. PDT with verteporfin is effective in the management of patients with subfoveal predominantly classic lesions. A variety of molecules such as bevacizumab, pegaptanib sodium and ranibizumab, specifically targeted to different pathologic pathways in AMD, have been identified to their therapeutic potential. Research is actively being pursued in preclinical models both in academic laboratories and in the pharmaceutical industry, including multiple early stage clinical trials. There is no strong evidence to support benefits of submacular surgery in the management of neovascular AMD.


CRISPR/Cas9 gene-editing: Research technologies, clinical applications and ethical considerations.
Gene therapy carries the potential to treat more than 10,000 human monogenic diseases and benefit an even greater number of complex polygenic conditions. The repurposing of CRISPR/Cas9, an ancient bacterial immune defense system, into a gene-editing technology has armed researchers with a revolutionary tool for gene therapy. However, as the breadth of research and clinical applications of this technology continues to expand, outstanding technical challenges and ethical considerations will need to be addressed before clinical applications become commonplace. Here, we review CRISPR/Cas9 technology and discuss its benefits and limitations in research and the clinical context, as well as ethical considerations surrounding the use of CRISPR gene editing.


Preparation, characterization and bioactivities of nano anhydrous calcium phosphate added gelatin-chitosan scaffolds for bone tissue engineering.
Gelatin, chitosan and nano calcium phosphate based composite scaffold with tailored architectures and properties has great potential for bone regeneration. Herein, we aimed to improve the physico chemical, mechanical and osteogenic properties of 3D porous scaffold by incorporation of dihydrogen calcium phosphate anhydrous (DCPA) nanoparticles into biopolymer matrix with variation in composition in the prepared scaffolds. Scaffolds were prepared from the slurry containing gelatin, chitosan and synthesized nano DCPA particle using lyophilization technique. DCPA nano particles were synthesized using calcium carbonate and phosphoric acid in water-ethanol medium. XRD pattern showed phase pure DCPA in synthesized nanopowder. Scaffolds were prepared by addition of DCPA nanoparticles to the extent of 5-10 wt% of total polymer into gelatin-chitosan solution with solid loading varying between 2.5 and 2.75 wt%. The prepared scaffold showed interconnected porosity with pore size varying between 110 and 200 micrometer. With addition of DCPA nanoparticles, average pore size of the prepared scaffolds decreased. With increase in nano ceramic phase content from 5 wt% to 10 wt% of total polymer, the compressive strength of the scaffold increased. Scaffold containing 10 wt% DCPA showed the highest average compressive strength of 2.2 MPa. Higher cellular activities were observed in DCPA containing scaffolds as compared to pure gelatin chitosan scaffold suggesting the fact that nano DCPA addition into the scaffold promoted better osteoblast adhesion and proliferation as evident from MTT assay and scanning electron microscopic (SEM) investigation of osteoblast cultured scaffolds. A higher degree of lamellopodia and filopodia extensions and better spreading behavior of osteoblasts were observed in FESEM micrographs of MG 63 cultured DCPA containing scaffold. The results demonstrated that both mechanical strength and osteogenic properties of gelatin-chitosan scaffold could be improved by addition of anhydrous dihydrogen calcium phosphate nanoparticles into it.


Transluminal extraction atherectomy for aortosaphenous vein graft stent restenosis.
The optimal strategy to manage in-stent saphenous vein graft (SVG) restenosis has not been studied. We present two cases in which transluminal extraction atherectomy (TEC) was used successfully for the treatment of SVG stent restenosis. TEC atherectomy may provide an alternative to conventional balloon angioplasty for such patients.


Personality and transformational and transactional leadership: a meta-analysis.
This study was a meta-analysis of the relationship between personality and ratings of transformational and transactional leadership behaviors. Using the 5-factor model of personality as an organizing framework, the authors accumulated 384 correlations from 26 independent studies. Personality traits were related to 3 dimensions of transformational leadership--idealized influence-inspirational motivation (charisma), intellectual stimulation, and individualized consideration--and 3 dimensions of transactional leadership--contingent reward, management by exception-active, and passive leadership. Extraversion was the strongest and most consistent correlate of transformational leadership. Although results provided some support for the dispositional basis of transformational leadership--especially with respect to the charisma dimension--generally, weak associations suggested the importance of future research to focus on both narrower personality traits and nondispositional determinants of transformational and transactional leadership.


Linkage and the limits to natural selection.
The probability of fixation of a favorable mutation is reduced if selection at other loci causes inherited variation in fitness. A general method for calculating the fixation probability of an allele that can find itself in a variety of genetic backgrounds is applied to find the effect of substitutions, fluctuating polymorphisms, and deleterious mutations in a large population. With loose linkage, r, the effects depend on the additive genetic variance in relative fitness, var(W), and act by reducing effective population size by (N/Ne) = 1 + var(W)/2r2. However, tightly linked loci can have a substantial effect not predictable from Ne. Linked deleterious mutations reduce the fixation probability of weakly favored alleles by exp (-2U/R), where U is the total mutation rate and R is the map length in Morgans. Substitutions can cause a greater reduction: an allele with advantage s < scrit = (pi 2/6) loge (S/s) [var(W)/R] is very unlikely to be fixed. (S is the advantage of the substitution impeding fixation.) Fluctuating polymorphisms at many (n) linked loci can also have a substantial effect, reducing fixation probability by exp [square root of 2Kn var(W)/R] [K = -1/E((u-u)2/uv) depending on the frequencies (u,v) at the selected polymorphisms]. Hitchhiking due to all three kinds of selection may substantially impede adaptation that depends on weakly favored alleles.


Posttranslational ISGylation of NLRP3 by HERC enzymes facilitates inflammasome activation in models of inflammation.
The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a crucial component of the innate immune system that initiates inflammatory responses. Posttranslational modifications (PTMs) of NLRP3, including ubiquitination and phosphorylation, control inflammasome activation and determine the intensity of inflammation. However, the role of other PTMs in controlling NLRP3 inflammasome activation remains unclear. This study found that TLR priming induced NLRP3 ISGylation (a type of PTM in which ISG15 covalently binds to the target protein) to stabilize the NLRP3 protein. Viral infection, represented by SARS-COV-2 infection, and type I IFNs induced expression of ISG15 and the predominant E3 ISGylation ligases HECT domain- and RCC1-like domain-containing proteins (HERCs; HERC5 in humans and HERC6 in mice). HERCs promoted NLRP3 ISGylation and inhibited K48-linked ubiquitination and proteasomal degradation, resulting in the enhancement of NLRP3 inflammasome activation. Concordantly, Herc6 deficiency ameliorated NLRP3-dependent inflammation as well as hyperinflammation caused by viral infection. The results illustrate the mechanism by which type I IFNs responses control inflammasome activation and viral infection-induced aberrant NLRP3 activation. This work identifies ISGylation as a PTM of NLRP3, revealing a priming target that modulates NLRP3-dependent immunopathology.


Simian virus 40 detection in human mesothelioma: reliability and significance of the available molecular evidence.
Simian virus 40 was discovered as a contaminant of early poliovirus vaccines that were inadvertently administered to millions of people in Europe and the United States between 1955 and 1963. Although SV40 was proven to be oncogenic in rodents and capable of transforming human and animal cells in vitro, its role in human cancer could not be proven epidemiologically. The matter was forgotten until 1993 when SV40 was accidentally found to cause mesotheliomas in hamsters injected intra-cardially. Subsequently, DNA sequences associated with its powerful oncogenic principal, the large T antigen, were found with high frequency in human pleural mesothelioma using the polymerase chain reaction (PCR). Since then many laboratories have confirmed the human findings. However, a few laboratories have failed to reproduce these data and the authors of the studies have claimed that the detection of SV40 DNA may simply represent PCR contamination artefacts. The controversy raised by this viewpoint is reviewed in this article together with a critical appraisal of the reliability of the molecular techniques used to detect SV40 DNA, in order to evaluate the potential aetiopathogenic role of SV40 in human mesothelioma.


Function of the rat carotid body chemoreceptors in ageing.
Some age-related deficits in the ventilatory responses have been attributed to a decline in the functionality of the carotid body (CB) arterial chemoreceptors, but a systematic study of the CB function in ageing is lacking. In rats aged 3-24 months, we have performed quantitative morphometry on specific chemoreceptor tissue, assessed the function of chemoreceptor cells by measuring the content, synthesis and release of catecholamines (a chemoreceptor cell neurotransmitter) in normoxia and hypoxia, and determined the functional activity of the intact organ by measuring chemosensory activity in the carotid sinus nerve (CSN) in normoxia, hypoxia and hypercapnic acidosis. We found that with age CBs enlarge, but at the same time there is a concomitant decrease in the percentage of chemoreceptor tissue. CB content and turnover time for their catecholamines increase with age. Hypoxic stimulation of chemoreceptor cells elicits a smaller release of catecholamines in rats after 12 months of age, but a non-specific depolarizing stimulus elicits a comparable release at all ages. In parallel, there was a marked decrease in the responsiveness to hypoxia, but not to an acidic-hypercapnic stimulus, assessed as chemosensory activity in the CSN. We conclude that in aged mammals chemoreceptor cells become hypofunctional, leading to a decreased peripheral drive of ventilation.


Effect of low glyphosate doses on flowering and seed germination of glyphosate-resistant and -susceptible Digitaria insularis.
Herbicide hormesis is characterized by stimulation of various growth and developmental parameters, such as biomass and height, at low herbicide doses. Other possible hormetic effects are earlier flowering, higher seed weight, more seeds, and a shorter plant life cycle, which could favor the propagation of the species. This study tested the early flowering in glyphosate-resistant and -susceptible Digitaria insularis biotypes under treatment with low glyphosate doses. Hormesis caused by low glyphosate doses occurred in all experiments. The hormetic effects were a decrease in time necessary for the formation of inflorescences and increased seed weight and germination speed. Higher glyphosate doses were required for the hormetic effect in the glyphosate-resistant than the -susceptible D. insularis biotype. Hormesis caused by low glyphosate doses in D. insularis may provide an advantage for the dissemination of this species, helping to alter the weed flora. As the doses that cause stimulation in glyphosate-resistant biotypes are higher than in glyphosate-susceptible biotypes, the selection of resistant biotypes may be favored in glyphosate-sprayed fields, increasing the rate of infestation of glyphosate-resistant biotypes.


The effects of hypoxia on catecholamine dynamics in the rat carotid body.
The catecholamine content of the rat carotid body was assayed using high performance liquid chromatography with electrochemical detection. The concentration of dopamine (DA) was found to predominate over that of norepinephrine (NE) by a small margin (31 pmol/carotid body pair DA; 23 pmol/carotid body pair NE). The turnover rates of carotid body DA and NE were determined from the time-dependent decline in their concentrations following the blockade of synthesis with alpha-methyl-p-tyrosine. Values were obtained (DA t 1/2 = 1.9 h; NE t 1/2 = 2.3 h) which suggested a rapid turnover of carotid body catecholamines. Exposure of rats to conditions of severe hypoxia (5% O2-95% N2) failed to significantly alter either the content or turnover of carotid body catecholamines. By contrast, the concentration of carotid body DOPAC, a reflection of DA utilization, was significantly elevated following hypoxic conditions. Further, in vivo tyrosine hydroxylase activity was assessed by measuring the accumulation of carotid body DOPA after inhibiting L-aromatic amino acid decarboxylase with NSD-1015. Basal tyrosine hydroxylase activity (approximately 14-16 pmol/carotid body pair/h) also was significantly increased by acute hypoxic exposure. These results, in part, suggest that rat carotid body DA may act as a neurotransmitter whose synthesis and release are coupled to stimulus demand.


Pneumomediastinum in COVID-19: a phenotype of severe COVID-19 pneumonitis? The results of the United Kingdom (POETIC) survey.
There is an emerging understanding that coronavirus disease 2019 (COVID-19) is associated with increased incidence of pneumomediastinum. We aimed to determine its incidence among patients hospitalised with COVID-19 in the United Kingdom and describe factors associated with outcome. A structured survey of pneumomediastinum and its incidence was conducted from September 2020 to February 2021. United Kingdom-wide participation was solicited via respiratory research networks. Identified patients had SARS-CoV-2 infection and radiologically proven pneumomediastinum. The primary outcomes were to determine incidence of pneumomediastinum in COVID-19 and to investigate risk factors associated with patient mortality. 377 cases of pneumomediastinum in COVID-19 were identified from 58 484 inpatients with COVID-19 at 53 hospitals during the study period, giving an incidence of 0.64%. Overall 120-day mortality in COVID-19 pneumomediastinum was 195/377 (51.7%). Pneumomediastinum in COVID-19 was associated with high rates of mechanical ventilation. 172/377 patients (45.6%) were mechanically ventilated at the point of diagnosis. Mechanical ventilation was the most important predictor of mortality in COVID-19 pneumomediastinum at the time of diagnosis and thereafter (p<0.001) along with increasing age (p<0.01) and diabetes mellitus (p=0.08). Switching patients from continuous positive airways pressure support to oxygen or high flow nasal oxygen after the diagnosis of pneumomediastinum was not associated with difference in mortality. Pneumomediastinum appears to be a marker of severe COVID-19 pneumonitis. The majority of patients in whom pneumomediastinum was identified had not been mechanically ventilated at the point of diagnosis.


Atmospheric Pressure Drift Tube Ion Mobility-Orbitrap Mass Spectrometry: Initial Performance Characterization.
Atmospheric pressure drift tube ion mobility spectrometry (AP-DTIMS) was coupled with Fourier transform Orbitrap mass spectrometry. The performance capabilities of this versatile new arrangement were demonstrated for different DTIMS ion gating operation modes and Orbitrap mass spectrometer parameters with regard to sensitivity and resolving power. Showcasing the optimized AP-DTIMS-Orbitrap MS system, isobaric peptide and sugar isomers were successfully resolved and the identities of separated species validated by high-energy collision dissociation experiments.


Double-blind comparison of cabergoline and bromocriptine in Parkinson's disease patients with motor fluctuations.
In the present study we compared the efficacy and safety of the new dopamine agonist cabergoline (CBG) with bromocriptine (BCR) in Parkinson's disease (PD). CBG has a very long half-life and can be administered as a single daily dose. Forty-four PD patients with uncontrolled motor fluctuations participated in the study. Patients were randomly and blindly assigned to equivalent doses of either CBG or BCR in addition to preexisting levodopa. Dosage was titrated to optimal, using up to 6 mg of CBG or 40 mg of BCR daily. CBG was given as a single morning dose whereas BCR was administered tid. Sixteen patients were followed for 1 year and 16 additional patients for 6 months. The mean follow-up duration was 9 +/- 5 months. The main effect of both drugs was observed on motor UPDRS scores, rigidity, bradykinesia items, and the percentage of awake hours spent during "on" and "off". In general, the effect of CBG was similar to that of BCR. The percentage of awake hours spent during "on" was higher with CBG as compared with BCR. Adverse events included dyskinesias, orthostatism, confusion, edema, and paresthesias in limbs. These effects were seen at similar frequencies with both drugs. The study shows that CBG given as a single morning dose is at least as efficacious as BCR given tid. CBG is a promising dopamine agonist for the treatment of motor fluctuations in PD.


Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression.
Vitamin D has been shown to have immunomodulatory function, but the molecular basis for it has not been well understood. In this study, we found that vitamin D receptor expression was induced in a CD4+ effector T cell lineage, Th17 cells, which required the transcription factors, RORα, RORγt, and STAT3. Treatment of mice with an active ligand of vitamin D receptor (VDR), 1,25-dihydroxyvitamin D(3) (1,25D3), ameliorated experimental autoimmune encephalomyelitis, accompanied with reduced IL-17 and IL-17F expression. In vitro, treatment of CD4+ T cells with the physiological doses of 1,25D3 preferentially inhibited cytokine production by Th17 cells, in a VDR-dependent manner, without affecting the expression of transcription factors or surface molecules. Moreover, at these concentrations, cytokine expression was suppressed only at protein but not at mRNA levels. Stimulation of Th17 cells with 1,25D3, in a concentration-dependent manner, induced the expression of C/EBP homologous protein (CHOP), a molecule involved in endoplasmic reticulum stress and translational inhibition. In addition, overexpression of CHOP in developing Th17 cells suppressed their cytokine production. Our results suggest a novel, post-transcriptional mechanism whereby Th17 cytokines are inhibited by VDR, which may underscore future therapeutic usage of vitamin D in treatment of autoimmune diseases.


A single nucleotide deletion resulting in a premature stop codon is associated with marked reduction of transcripts from a goat beta-casein null allele.
A null beta-casein allele (CSN2O) was investigated in Creole and Pyrenean goats producing milk devoid of beta-casein (CSN2). Northern blot analyses of total mammary RNA showed much lower amounts of CSN2 transcripts that were similar in size to the wild-type counterpart. The amount of CSN2O mRNA was roughly 5% of the amount of mRNA obtained at the same age and stage of lactation from CSN2A/A goats. Comparative sequence analyses of full-length CSN2O and CSN2A cDNAs showed that both alleles were of similar size, but allele CSN2O had a one-nucleotide deletion in the 5' end of exon 7, which introduces a premature stop codon. The open reading frame of allele CSN2O encodes a shortened polypeptide of 72 amino acids, compared to 223 amino acids for caprine pre beta-casein A. Comparative analyses of RT-PCR products suggested that alleles CSN2O and CSN2A might also differ in the amount and relative ratio of minor deleted CSN2 transcripts. The lower amount of CSN2O mRNA was associated with the occurrence of the premature stop codon which may mediate a rapid decay of CSN2O mRNA and promote skipping of nucleotide stretches containing premature nonsense triplets.


Between-days intra-rater reliability with a hand held myotonometer to quantify muscle tone in the acute stroke population.
A myotonometer can objectively quantify changes in muscle tone. The between-days intra-rater reliability in a ward setting for the acute stroke population remains unknown. This study aimed to investigate the device's between-days intra-rater reliability when used in a ward setting for acute stroke participants. Muscle tone of biceps brachii, brachioradialis, rectus femoris, and tibialis anterior was recorded in the ward at bedside by one physiotherapist on two consecutive days. This study included participants who were within 1 month of their first stroke occurrence. Participants who were medically unstable or who suffered from brain stem injury were excluded. Reliability was assessed by the intraclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), and the Bland-Altman limits of agreement. The results indicated excellent between-days intra-rater reliability (ICC > 0.75). SEM and SRD show small differences between measurements. The Bland-Altman analysis indicated a tendency of overestimation of the rectus femoris. MyotonPRO demonstrated acceptable reliability when used in a ward setting in those patients with acute stroke. However, results should be interpreted with caution, due to the limitations of the study and the varying level of consistency observed between different muscles.


Reducing Racial and Ethnic Disparities in Access to Care: Has the Affordable Care Act Made a Difference?
ISSUE: Prior to the Affordable Care Act (ACA), blacks and Hispanics were more likely than whites to face barriers in access to health care. GOAL: Assess the effect of the ACA's major coverage expansions on disparities in access to care among adults. METHODS: Analysis of nationally representative data from the American Community Survey and the Behavioral Risk Factor Surveillance System. FINDINGS AND CONCLUSIONS: Between 2013 and 2015, disparities with whites narrowed for blacks and Hispanics on three key access indicators: the percentage of uninsured working-age adults, the percentage who skipped care because of costs, and the percentage who lacked a usual care provider. Disparities were narrower, and the average rate on each of the three indicators for whites, blacks, and Hispanics was lower in both 2013 and 2015 in states that expanded Medicaid under the ACA than in states that did not expand. Among Hispanics, disparities tended to narrow more between 2013 and 2015 in expansion states than nonexpansion states. The ACA's coverage expansions were associated with increased access to care and reduced racial and ethnic disparities in access to care, with generally greater improvements in Medicaid expansion states.


Ileal endogenous nitrogen recovery is increased and its amino acid pattern is altered in pigs fed quebracho extract.
Ileal endogenous nitrogen recovery (ENR) in pigs (9 +/- 0.6 kg body weight) was estimated simultaneously using the (15)N-isotope dilution technique ((15)N-IDT) and the peptide alimentation ultrafiltration (UF) method. Diets were cornstarch, enzyme-hydrolyzed casein with no (control) or high (4%) content of quebracho extract (Schinopsis spp.) rich in condensed tannins. The amino acid (AA) pattern of the ENR was also determined. The ENR of pigs fed the quebracho diet was higher (P = 0.0001) than that of pigs fed the control diet [6.00 vs. 1.95 g/kg dry matter intake (DMI) for the (15)N-IDT and 5.18 vs. 1.49 g/kg DMI for the UF method, respectively]. With the (15)N-IDT, ENR values were 0.44-0.79 g/kg DMI (24%) higher (control P = 0.0032, quebracho P = 0.0002) than for the UF method. Apparent nitrogen digestibility depended on diet (69.0% quebracho vs. 86.0% control, P = 0.0001). Real nitrogen digestibility (RD-N) determined by the UF method was higher (P = 0.0001) for the control than for the quebracho diet (91.4 vs. 88.2%). Corresponding values for the (15)N-IDT did not differ (P = 0.0569) between diets (92.8 vs. 91.4%). The (15)N-IDT gave higher values for RD-N of both diets (control P = 0.0030, quebracho P = 0.0002) compared with the UF method. Endogenous AA recoveries (g/kg DMI) were increased 300% (P = 0.0001) and the AA-pattern of ENR was changed (P from 0.0001 to 0.7530 for different AA) by the quebracho diet. A constant AA-pattern of ENR cannot be assumed. Despite limitations of both techniques, the (15)N-IDT and the UF method gave similar results with respect to ENR.


Modulation of GDP release from transducin by the conserved Glu134-Arg135 sequence in rhodopsin.
A superfamily of seven-transmembrane helix receptors catalyzes GDP release from heterotrimeric guanine nucleotide-binding proteins (G proteins) to initiate the intracellular signaling cascade. The photoreceptor rhodopsin is a prototypical member of the superfamily that activates the retinal G protein transducin (Gt). The cytoplasmic domain of rhodopsin binds and activates Gt, but residues that stimulate GDP release from Gt have not been identified until now. We show here that the abnormal signal transduction phenotypes of several different mutations affecting the highly conserved Glu134-Arg135 charge pair result from alteration of the GDP release step in the Gt activation cascade. We propose that Glu134 and Arg135 constitute the site that directly provides the signal from rhodopsin to activate GDP release from Gt. Because the Glu/Asp-Arg sequence occurs at a topologically identical location in most of the seven-transmembrane helix receptors, we propose that these residues constitute a switch for signal transfer.


Profiling mouse cochlear cell maturation using 10× Genomics single-cell transcriptomics.
Juvenile and mature mouse cochleae contain various low-abundant, vulnerable sensory epithelial cells embedded in the calcified temporal bone, making it challenging to profile the dynamic transcriptome changes of these cells during maturation at the single-cell level. Here we performed the 10x Genomics single-cell RNA sequencing (scRNA-seq) of mouse cochleae at postnatal days 14 (P14) and 28. We attained the transcriptomes of multiple cell types, including hair cells, supporting cells, spiral ganglia, stria fibrocytes, and immune cells. Our hair cell scRNA-seq datasets are consistent with published transcripts from bulk RNA-seq. We also mapped known deafness genes to corresponding cochlear cell types. Importantly, pseudotime trajectory analysis revealed that inner hair cell maturation peaks at P14 while outer hair cells continue development until P28. We further identified and confirmed a long non-coding RNA gene Miat to be expressed during maturation in cochlear hair cells and spiral ganglia neurons, and Pcp4 to be expressed during maturation in cochlear hair cells. Our transcriptomes of juvenile and mature mouse cochlear cells provide the sequel to those previously published at late embryonic and early postnatal ages and will be valuable resources to investigate cochlear maturation at the single-cell resolution.


MyoRing Implantation with and without Corneal Collagen Crosslinking for the Management of Keratoconus.
To evaluate the safety and efficacy of femtosecond laser-assisted MyoRing implantation with concurrent corneal collagen crosslinking (CXL) compared to MyoRing alone for the treatment of progressive keratoconus. A total of 60 patients were enrolled in this randomized controlled trial. The patients were randomly allocated into two groups. In the first group, MyoRing was implanted, while in the second, it was inserted in the corneal stroma using the same technique, along with simultaneous CXL. Visual, refractive, topographic, and abberometric outcomes were measured preoperatively and at every postoperative visit. Data of 47 patients were available at the end of the study; 28 in the MyoRing group and 19 in the MyoRing + CXL group. The mean uncorrected distance visual acuity (UDVA) improved from 0.79 ± 0.39 logMAR to 0.52 ± 0.31 logMAR (P < 0.05) in the MyoRing + CXL group and from 0.65 ± 0.38 logMAR to 0.62 ± 0.23 logMAR (P = 0.70) in the MyoRing group. CDVA changed from 0.33 ± 0.19 logMAR to 0.25 ± 0.16 logMAR (P = 0.10) in the MyoRing + CXL group and 0.32 ± 0.22 logMAR to 0.33 ± 0.17 logMAR (P > 0.50) in the MyoRing group. The mean keratometry (Km) decreased from 47.5 ± 2.7 D to 43.8 ± 3.2 D (P < 0.001) in the MyoRing group and 49.3 ± 3.4 D to 45.1 ± 3.0 D (P < 0.001) in the MyoRing + CXL group. Besides, horizontal coma was significantly lower in the MyoRing + CXL group (P = 0.022). MyoRing insertion combined with CXL is a safe and effective method for the treatment of keratoconus. The visual and topographic outcomes were comparable to that for MyoRing insertion after 10 months; however, horizontal coma was significantly lower in the MyoRing + CXL group.


Clinic based transfer of the N(D,W)(60Co) calibration coefficient using a linear accelerator.
Ionization chambers used for reference dosimetry require a local secondary standard ionization chamber with a 60Co absorbed dose to water calibration coefficient N(D,W)(60Co) traceable to a national primary standards dosimetry laboratory or an accredited secondary dosimetry calibration laboratory. Clinic based (in-house) transfer of this coefficient to tertiary reference ionization chambers has traditionally been accomplished with chamber cross calibration in water using a 60Co beam; however, access to 60Co teletherapy machines has become increasingly limited for clinic based physicists. In this work, the accuracy of alternative methods of transferring the N(D,W)(60Co) calibration coefficient using 6 and 18 MV photon beams from a linear accelerator in lieu of 60Co has been investigated for five different setups and four commonly used chamber types.


Emerging contaminants and antibiotic resistance in the different environmental matrices of Latin America.
This review aims to gather and summarize information about the occurrence of emerging contaminants and antibiotic resistance genes in environmental matrices in Latin America. We aim to contribute to future research by compiling a list of priority pollutants adjusted to the needs and characteristics of Latin America, according to the data presented in this study. In order to perform a comprehensive research and secure a representative and unbiased amount of quality data concerning emerging contaminants in Latin America, the research was performed within the Scopus® database in a time frame from 2000 to July 2019. The countries with higher numbers of published articles were Brazil and México, while most studies were performed in the surroundings of Mexico City and in Southern and Southeastern Brazil. The main investigated environmental matrices were drinking water and surface water. The presence of antibiotic resistance was frequently reported, mainly in Brazil. Monitoring efforts should be performed in other countries in Latin America, as well as in other regions of Brazil and México. The suggested priority list for monitoring of emerging contaminants in Latin America covers: di(2-ethylhexyl) phthalate (DEHP), bisphenol-A (BP-A), 4-nonylphenol (4-NP), triclosan (TCS), estrone (E1), estradiol (E2), ethinylestradiol (EE2), tetracycline (TC), amoxicillin (AMOX), norfloxacin (NOR), ampicillin (AMP) and imipenem (IMP). We hope this list serves as a basis for the orientation of the future research and monitoring projects to better understand the distribution and concentration of the listed emerging substances.


Amyloid Protein-Biofunctionalized Polydopamine Nanoparticles Demonstrate Minimal Plasma Protein Fouling and Efficient Photothermal Therapy.
Polydopamine (PDA) shows great application potential in photothermal therapy (PTT) of tumors due to its excellent photothermal performance. However, PDA rich in a large number of catechin structures, with strong adhesion, can readily attach to plasma proteins in blood to form protein corona, which greatly hinders the transfer efficiency to tumors and reduces the bioavailability. In this paper, a simple, rapid phase-transitioned albumin biomimetic nanocorona (TBSA) is used for the surface camouflage of PDA nanoparticles for minimal plasma protein fouling and efficient PTT. TBSA coating is formed by the BSA-derived amyloid through the hydrophobic aggregation near the isoelectric point and the rupture of disulfide bonds by tris(2-carboxyethyl) phosphine. The stable PDA@TBSA complexes are formed by camouflaging TBSA onto the surface of PDA through hydrophobic, electrostatic, and covalent binding between TBSA and PDA, which showed excellent anti-plasma protein adsorption properties profited from the surface charge of PDA@TBSA approaching equilibrium and the surface passivation of BSA. The plasma protein thickness of the PDA@TBSA surface is 6 times lower than that of PDA at adsorption saturation. In vitro and in vivo experiments have revealed that PDA@TBSA has an excellent photothermal antitumor effect compared to PDA. Both PDA and PDA@TBSA treatment plus 808 nm laser irradiation result in more than 70% inhibition on tumor cell proliferation. In addition, PDA@TBSA does not cause a significant inflammatory response and tissue damage. Taken together, the TBSA coating endows PDA with low-fouling functions in blood and improves the residence time of PDA in blood and enrichment in the tumor tissue. This work offers a novel and efficient strategy for the design of functional nanosystems exploiting the speciality of the biomolecular corona formation around nanomaterials.


The cardiovascular, metabolic, fetal and neonatal effects of CPAP use in pregnant women: a systematic review.
Continuous positive airway pressure (CPAP) is the standard treatment for obstructive sleep apnea (OSA), but its outcomes for the pregnant are still undefined. This study aims to review current CPAP intervention during pregnancy, discuss published trials, and propose relevant issues that have yet to be addressed satisfactorily about the cardiovascular, metabolic, fetal, and neonatal effects of CPAP treatment during gestation. Two authors independently conducted a systematic review until March 28th, 2021 on PubMed, BVS, and Cochrane Library, using PRISMA guidelines, and risk of bias. Discrepancies were reconciled by a third reviewer. Of 59 identified citations, eight original trials have submitted a total of 90 pregnant women to polysomnography and CPAP therapy. Four studies performed in samples with hypertension or preeclampsia presented blood pressure decrease or maintained the antihypertensive drug dose in the CPAP group. After CPAP utilization, one trial registered cardiac output and stroke volume increase with heart rate and peripheral vascular resistance decrease, which were correlated with birth weight increment. Others documented a higher Apgar in the CPAP group and more fetal movements during CPAP use. There was a reduction in serum uric acid and tumor necrosis factor-alpha in the CPAP groups whose blood pressure decreased. However, two weeks of CPAP use in women with gestational diabetes and OSA did not improve glucose levels but raised the insulin secretion in those adherents to CPAP. Despite these positive results without adverse effects, randomized controlled trials with standardized follow-up in larger populations are required to determine CPAP therapy recommendations in pregnancy.


The nucleus raphe interpositus in the Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy).
As the integrity of the omnipause neurons located in the nucleus raphe interpositus is a prerequisite of normal ocular motility, cell and neurofibrillary tangle densities were determined in 13 Steele-Richardson-Olszewski syndrome (SROS) cases [eight with supranuclear gaze palsy (SGP) and five without] and six controls. Compared with normal controls, cases with SGP were associated with approximately 50% nerve cell loss (P < 0.001), whereas data from cases without SGP were not significantly different (P = 0.18). Furthermore, cases with SGP had lower neuronal cell (P = 0.016) and higher neurofibrillary tangle densities than those without (P = 0.011). These results indicate that the involvement of the omnipause neurons, which are glycinergic, contributes to abnormal eye motility in SROS. Involvement of these glycinergic nerve cells suggests that the degeneration of brainstem structures in SROS affects neurochemically diverse systems; so far other brainstem nuclei concerned with eye motility; and known to be affected in SROS, are cholinergic. The results of this study provide evidence that clinically distinct subgroups of SROS may be differentiated histologically when adequate morphometric techniques are applied.


Periodontal inflammatory and cystlike lesions in BDF1 and B6C3F1 mice.
Periodontal inflammatory and cystlike lesions were detected in aged BDF1 and B6C3F1 mice. Lesions were unilateral, single, and located in the labial region of the incisor teeth. The largest cystlike lesion deformed the skull. Histologically, the cystlike lesions were classified into three types: predominantly an inflammatory reaction, predominantly a cyst formation, and a mixed lesion. These periodontal inflammatory and cystlike lesions were pathogenetically similar and were considered sequential changes; the lesions showing both cyst formation and inflammatory reaction seemed to be intermediate along a path toward formation of large cysts. The cysts probably were derived from periodontal tissue and developed as a result of inflammatory reaction to foreign bodies, including hair. The term "murine periodontal cyst" is proposed for this lesion. Detailed pathogenetic studies on murine odontogenic cystic lesions may be warranted.


Comparison of genomic DNA and cDNA for detection of residual disease after treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation.
To test whether patients in remission after allogeneic bone marrow transplantation (BMT) possess a pool of chronic myeloid leukemia (CML) cells that do not express BCR-ABL mRNA, we have compared the results and sensitivity of amplification of BCR-ABL from genomic DNA with conventional reverse transcription-polymerase chain reaction (RT-PCR). Bubble PCR was used to amplify the genomic BCR-ABL translocation breakpoints from chronic-phase DNA of 10 patients with CML who subsequently underwent BMT. After cloning and sequencing of the amplification products, patient-specific ABL primers were synthesized and tested for both specificity and sensitivity in nested or heminested combinations with a variety of primers derived from the major breakpoint cluster region of the BCR gene. In all cases, combinations of primers were selected that enabled the detection of chronic-phase DNA from a specific patient at up to a 10(5)x dilution into DNA from a normal individual. Patterns of residual disease obtained by serial RT-PCR and DNA-PCR analyses of blood and bone marrow samples obtained after BMT were similar for most patients, including one treated for relapse by infusion of donor leukocytes. Of the 24 samples for direct comparison of RT-PCR and DNA-PCR, results were concordant in 19 (79%) cases. Five results were discordant. In two instances, RT-PCR was positive, while PCR from genomic DNA was negative; this discrepancy might have arisen due to the slightly greater sensitivity of RT-PCR compared with DNA-PCR. In three samples from three patients, two of whom had been transplanted in the accelerated phase, PCR from genomic DNA was positive while RT-PCR was negative; this could mean that some CML cells in these samples had a reduced or absent capacity to express BCR-ABL mRNA post-transplant. Of these three patients, one subsequently relapsed; and two are in remission at 21 and 24 months after the discordant result. Thus, the finding of a single DNA-PCR- positive, RT-PCR-negative results does not necessarily predict relapse. Because the great majority of samples (79%) gave concordant results with the two assays, we believe that patients in remission do not generally harbor a substantial pool of CML cells that do not express BCR-ABL mRNA.


An examination of 'unidentified' Prevotella (formerly PINLO) using RAPD-PCR and partial 16S rRNA gene sequencing.
Prevotella intermedia- and Prevotella nigrescens-like organisms (PINLO) have been described as organisms which are phenotypically and biochemically similar to P. intermedia and P. nigrescens and the species P. pallens was created to include some of them. Other PINLO groups which do not fit the definition of P. pallens exist, and in this study these 'unidentified' Prevotella sp. were compared with P. corporis, P. intermedia, P. nigrescens and P. pallens using commercial identification kits, GLC, RAPD-PCR and partial 16S rRNA gene sequencing. The Rapid ID 32 A and the RapID ANA II system both identified all 'unidentified' Prevotella as P. intermedia. Similarly they gave this identification to all the species tested (with the exception of P. corporis using the RapID ANA II system) clearly demonstrating biochemical similarities. Gas liquid chromatography (GLC) analysis of the volatile end-products of fermentation could not distinguish between strains. RAPD-PCR using arbitrary primer L10 demonstrated intra-species homogeneity within PINLO strains with amplification profiles which differed from other Prevotella species tested. Cluster analysis of the amplification profiles confirmed species divisions and yielded a distinct 'unidentified' Prevotella cluster. Comparison of partial 16S rDNA sequences displayed 98% sequence similarity between the 'unidentified' Prevotella strains, although 2 strains, HST 1156 and HST 2160 displayed 100% identity. The highest similarity between groups was seen between 'unidentified' Prevotella strains and P. corporis (approximately 94% similarity). The DNA techniques used here confirm that 'unidentified' Prevotella strains are distinct from the other species of Prevotella tested, including P. pallens. Partial 16S rDNA sequence comparisons suggested a close relationship with P. corporis.


Giant Cross Section for Molecular Ion Formation in Ultracold Rydberg Gases.
We have studied the associative ionization of a Rydberg atom and a ground-state atom in an ultracold Rydberg gas. The measured scattering cross section is 3 orders of magnitude larger than the geometrical size of the produced molecule. This giant enhancement of the reaction kinetics is due to an efficient directed mass transport which is accelerated by the Rydberg electron. We also find that the total inelastic scattering cross section is given by the geometrical size of the Rydberg electron's wave function.


Antimicrobial use at the end of life among hospitalized patients with advanced cancer.
We sought to evaluate antimicrobial use among patients with advanced cancer. Retrospective review of patients experiencing cancer-related death while hospitalized. Among 145 patients, 126 (86.9%) received antimicrobials for a mean of 12.5 ± 12.9 days. 88 (69.8%) of 126 had clinical findings suggestive of infection. Sixty-one patients (48.4%) had positive cultures, the remaining were treated empirically. "Comfort care" was ultimately pursued in 99 (78.5%) of 126; 35 (35.4%) of 99 continued to receive antimicrobials after a transition to comfort care for an average of 1.6 ± 1.1 days. On average, antimicrobials were discontinued <1day prior to death. Antimicrobial use was common among patients with advanced cancer. Even after transition to comfort care, more than one third of patients remained on antimicrobials. The risks and burdens of antimicrobials should be carefully examined when comfort is the stated goal.


Tourette syndrome, co-morbidities and quality of life.
Tourette syndrome is often associated with attention deficit hyperactivity disorder, obsessive compulsive disorder and other co-morbidities, the presence of which can reduce health-related quality of life. The relationship between the number and type of co-morbidities and tic severity upon health-related quality of life has been insufficiently examined in Tourette syndrome populations and not at all in the Australian context. We hypothesised that an increased number of co-morbid diagnoses would be inversely related to health-related quality of life and that the presence of attention deficit hyperactivity disorder and obsessive compulsive disorder in particular would negatively impact health-related quality of life. In all, 83 people with a previously established diagnosis of Tourette syndrome, who responded to a letter of invitation sent to the Tourette Syndrome Association of Australia past-member database, formed the study sample. Participants completed the Gilles de la Tourette Syndrome-Quality of Life Scale and a short form of the National Hospital Interview Schedule to assess tics and related behaviours. Participants with pure-Tourette syndrome had significantly better health-related quality of life than those with Tourette syndrome and three or more co-morbid diagnoses. Few differences were observed between the pure-Tourette syndrome and Tourette syndrome and one or two co-morbid diagnoses groups. Analysis of the impact of individual co-morbid disorders and Tourette syndrome symptoms on health-related quality of life indicated that attention deficit hyperactivity disorder exerted a significant negative effect, as did the presence of complex tics, especially coprolalia and copropraxia. When these variables were examined in multiple regression analysis, number of co-morbidities and the presence of coprophenomena emerged as significant predictors of health-related quality of life. While tics are the defining feature of Tourette syndrome, it appears to be the presence of co-morbidities, attention deficit hyperactivity disorder, in particular, and coprophenomena that have the greater impact on health-related quality of life. This has implications for symptom-targeting in the treatment of Tourette syndrome since all available treatments are symptomatic and not disease modifying.


Expression and characterization of Xenopus laevis SRY-related cDNAs, xSox17alpha1, xSox17alpha2, xSox18alpha and xSox18beta.
Sox is a large family of genes related to the sex-determining region Y gene (designated as the SRY gene). Sox genes encoding DNA-binding transcriptional factors are found in many animals and are involved in developmental events. In this study, we newly isolated and sequenced novel Sox cDNAs from African clawed frog (Xenopus laevis). Five clones isolated here were classified into four distinct Sox genes designated as xSox17alpha1, xSox17alpha2, xSox18alpha and xSox18beta. All four belong to a subtype of SOX family, type F. The cDNA xSox17alpha1 contains essentially the same nucleotide sequence as that identified as Sox17alpha in a previous work (Cell 91 (1997) 397), whereas xSox17alpha2 is a distinct gene with high homology to xSox17alpha1. The clones, xSox18alpha and xSox18beta, are highly homologous to each other over the entire nucleotide sequences. The xSox18alpha and xSox18beta genes encode 363 and 361 amino acids, respectively. Genomic Southern hybridization analysis showed the existence of two copies of the xSox18. Northern analysis indicated that the xSox18 gene was expressed in the spleen and kidney and the size of the transcript was estimated to be 2.4 knt. Electrophoretic mobility shift assays indicated that recombinant xSox18 polypeptide was capable of binding to the HMG consensus nucleotide sequence, AACAAT.


Results of microsurgical treatment of nerve injuries of the wrist.
A retrospective study was made of 62 patients with sharp, total transection of the ulnar and/or median nerves, operated on with use of microsurgical techniques. The results were evaluated in 44 patients. Following primary repair of the median nerve, eight patients achieved a reasonable result (8/25, 32%) and 13 a good result (13/25, 52%). In contrast, after secondary nerve grafting in six patients, only one patient achieved a reasonable result (1/6, 17%) and three a good result (3/6, 50%). After primary repair of the ulnar nerve, four patients (4/10, 40%) achieved a reasonable result, and five a good result (5/10, 50%). In contrast, after secondary nerve grafting in five patients, four achieved a reasonable result (4/5, 80%) and none a good result. The age of the patients appeared to determine the quality of recovery; in all patients younger than 20 years reasonable or good function of the nerve returned.


Absence of determinism in El Niño Southern Oscillation.
We perform two direct determinism tests on the El Niño Southern Oscillation index monthly average series. The results indicate that, for timescales over 1 month, the series does not exhibit determinism, an essential feature of chaos.


An element in the bovine papillomavirus late 3' untranslated region reduces polyadenylated cytoplasmic RNA levels.
Expression of the two bovine papillomavirus type 1 (BPV-1) late genes, L1 and L2, coding for the two capsid proteins, is limited to terminally differentiated keratinocytes in bovine fibropapillomas. This pattern of expression is determined both by the activity of the late promoter and by the inhibition of late region expression in less well differentiated cells. Inhibition of L1 and L2 mRNA production in nonpermissive cells must occur since the late region potentially could be transcribed from early region promoters. Nuclear runoff analysis of the late region has demonstrated that up to 95% of transcripts which are initiated in the early region in nonpermissive cells terminate within the late region upstream of the late polyadenylation site (C. C. Baker and J. Noe, J. Virol. 63:3529-3534, 1989). However, very few of the primary transcripts which include the late polyadenylation site are processed into mRNA. In this study, we have used expression vectors to characterize an inhibitory element active in nonpermissive cells which is located in the late 3' untranslated region (3'UTR). While the late polyadenylation site is functional in these cells, a 53-bp element in the late 3'UTR reduces levels of polyadenylated cytoplasmic RNA. This element inhibited chloramphenicol acetyltransferase (CAT) expression 6- to 10-fold when cloned in the sense orientation into the 3'UTR of a CAT expression vector. No block to expression was seen when the fragment was cloned immediately downstream of the poly(A) site, in an intron upstream of the CAT coding sequence, or in an antisense orientation in the 3'UTR. When the same fragment was deleted from a BPV-1 L1 expression vector, a sixfold increase in mRNA levels was seen. Actinomycin D chase experiments using BPV-1 L1 expression vectors indicated that the element does not destabilize cytoplasmic polyadenylated RNA. Therefore, the element must act before the mature mRNA reaches the cytoplasm. The data presented are consistent with effects on nuclear stability and/or inhibition of polyadenylation or nuclear transport.


Fine mapping of a gene for non-pollen type thermosensitive genic male sterility in rice (Oryza sativa L.).
The thermo-sensitive genic male sterility (TGMS) lines play a crucial role in two-line hybrid rice production. For a practical TGMS line, the stability of male sterility is one of the most important technical indicators. In this study, XianS, a spontaneous mutant with stable male sterility from an indica rice cultivar Xianhuangzhan, was classified as a non-pollen type TGMS line. The critical non-pollen sterility point temperature of XianS was determined as 27 degrees C. Genetic analysis demonstrated that the non-pollen sterility in XianS was controlled by a single recessive gene. Using SSR markers and bulked segregant analysis, the TGMS gene in XianS was fine mapped to a 183 kb interval between RMAN81 and RMX21 on chromosome 2. Two markers, 4039-1 and RMX14 completely cosegregated with this gene. Allelism test indicated that the non-pollen phenotype in seven non-pollen type TGMS lines from different sources, XianS, AnnongS-1, Q523S, Q524S, N28S, G421S, and Q527S is caused by the same TGMS gene. Although the location of TGMS gene in XianS is close to the gene OsNAC6, a previously identified candidate gene of tms5 in AnnongS-1, the sequence of OsNAC6 and its promoter region was identical in TGMS line XianS, AnnongS-1, and wild-type Xianhuangzhan. These results suggest that the non-pollen type TGMS trait probably be controlled by the same TGMS gene in different TGMS rice lines, but its real candidate gene still need to be further studied and identified.


A comparative analysis of Medicare home care cost savings for the terminally ill.
Claims histories of 1,148 Medicare beneficiaries who died of cancer were examined to determine if traditional home care, compared to hospice home care and conventional oncological care, achieved substantial cost savings. Using analysis of variance and the test for the difference between percentages, the study indicated that although traditional home care beneficiaries were about one-third more costly during the last 24 weeks of life than either the hospice home care or conventional care patients, there appeared to be some cost savings during the last 4 weeks of life. The analysis clearly showed that the substitution of home care visits for hospital days occurred much more readily in hospice home care than in traditional home care. As a consequence, the cost savings potential of hospice home care was substantially greater. The study did not show a tendency for daily hospital costs to decline among the hospice or traditional home care patients as death approached. Thus, the hypothesis that home care services achieve cost savings by reducing the daily cost of hospital inpatient care was not supported.


Hidden Topological Structure of Flow Network Functionality.
The ability to reroute and control flow is vital to the function of venation networks across a wide range of organisms. By modifying individual edges in these networks, either by adjusting edge conductances or creating and destroying edges, organisms robustly control the propagation of inputs to perform specific tasks. However, a fundamental disconnect exists between the structure and function: networks with different local architectures can perform the same functions. Here, we answer the question of how changes at the level of individual edges collectively create functionality at the scale of an entire network. Using persistent homology, we analyze networks tuned to perform complex tasks. We find that the responses of such networks encode a hidden topological structure composed of sectors of nearly uniform pressure. Although these sectors are not apparent in the underlying network structure, they correlate strongly with the tuned function. The connectivity of these sectors, rather than that of individual nodes, provides a quantitative relationship between structure and function in flow networks.


Comprehensive study on clinical responses and socioeconomic characteristics of COVID-19 patients during outbreak.
The severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2) causes coronavirus disease 2019 (COVID-19) and emerged as a new public health crisis. This RNA virus, which has an origin in bats, is phenotypically and genotypically diverse. The source of transmission is by direct inhalation or contact with infected droplets or indirect through fomites. The disease shows an average incubation period of 2 to 14 days. The general symptoms include fever, cough, sore throat, breathlessness, fatigue, and malaise, although in a few it is found to be asymptomatic. The immune response shows variation from individual to individual, which varies from pneumonia, chest pain, acute respiratory distress syndrome, and multiorgan failure leading to death. The cytokine and chemokine responses play a major role in the severity of the infection. Laboratory diagnosis is done by molecular investigations. The socioeconomic conditions of individuals also play a role in disease manifestation. Treatment is supportive with symptomatic management. Preventive measures include social distancing, use of face masks, and contact tracing. This review will present a general overview of coronavirus and describe the clinical and socioeconomic features of the COVID-19 patients. It will also introduce comprehensive data of symptomatic and asymptomatic patients among different Asian and Western countries during the current pandemic. Furthermore, it also focuses on the most up-to-date information on effective management and prevention of COVID-19.


Characteristics of healthcare services associated with adherence to tuberculosis treatment.
To analyze characteristics related to adherence to tuberculosis treatment in tuberculosis outpatient clinics. An ecological study was conducted in outpatient clinics for the treatment of tuberculosis cases in the sanitary districts of Salvador, Northeastern Brazil, in 2006. The sample was composed of the municipal health units that assisted 67.2% of the 2,283 tuberculosis cases that were reported during the year. The following variables were analyzed: cure, dropout, tests, health team and benefits offered to the patients. Chi-square test or Fisher's exact test was used to verify the association between variables, and associations with p<0.05 were considered to be statistically significant. Of the studied cases, 78.4% resulted in cure, 8.6% in dropout, 2.2% in death and 8.1% in transference. Adherence rates per health unit varied between 66.7% and 98.1%. The variables cure and dropout showed a statistically significant association with adherence in the comparison of proportions. All the units with high adherence rates had complete health teams. Adherence was an important factor for the outcomes cure and dropout, but the index of units that achieved the cure goals was low. The presence of a complete multidisciplinary team in the tuberculosis program may help the patient understand his/her illness and contribute to adherence to treatment.


New route for the activation of poly(ADP-ribose) polymerase-1: a passage that links poly(ADP-ribose) polymerase-1 to lipotoxicity?
In this issue of Biochemical Journal, Chen and colleagues characterize an interaction between ACBD3 (acyl-CoA-binding domain-containing 3) protein and PARP [poly(ADP-ribose) polymerase]-1 through the activation of ERKs (extracellular-signal-regulated kinases). This study envisages a pathway through which ABCD3 translates enhanced fatty acid levels to ERK and consequently PARP-1 activation. The consequences of PARP-1 activation lead to cellular and tissue damage, implying that the ACBD3/PARP-1 pathway is an important pathway in lipotoxicity events.


A Brief Review of the Biophysical Hallmarks of Metastatic Cancer Cells.
A hallmark of metastatic cancer cells is their invasion through the basal membrane and endothelial layer, which requires a highly elastic cytoskeleton and nucleus. Therefore, cellular deformability can serve as a universal biophysical marker for detecting a tumor's propensity for invasion, migration, and metastasis. In this review, we define the importance of the biophysical features of cancer cells in tumor metastasis and summarize the state-of-the-art technology for the study of cell biomechanics. This review will serve as a brief introduction to the interdisciplinary character of cancer cell biophysics for cancer biologists, physicists, and engineers.


Clinical and psychometric evaluation of two doses of loprazolam and placebo in geriatric patients.
A double-blind, parallel group, randomized trial was carried out to compare the hypnotic efficacy, tolerance and psychometric effects of two doses of loprazolam and placebo in 89 elderly hospital in-patients. All had disturbed sleep patterns, which were not the result of serious psychiatric or physical illness and, after a 1 or 2 day single-blind placebo baseline period, they received either 0.5 mg or 1.0 mg loprazolam or placebo administered double-blind for 5 days. The sleep of patients in all three treatment groups, as measured by patient self-rating scales, substantially improved during the study, with loprazolam being superior to placebo for measures of sleep latency, satisfaction with sleep, number of nocturnal awakenings and feeling refreshed on waking. Differences in hypnotic efficacy between the 0.5 mg and 1.0 mg loprazolam groups were not significant. The incidence of side-effects was low and, although there was a significant relationship with loprazolam treatment, this was not dose-related. Performance tests for residual effects (critical flicker fusion threshold and choice reaction time) showed no difference between the placebo and active treatment groups, suggesting that loprazolam, even in a dose of 1.0 mg, is unlikely to produce hangover effects. It is concluded that the findings confirm that loprazolam is an effective and well-tolerated hypnotic in the elderly and that a 0.5 mg dose would be an appropriate initial dose for older patients.


Aeromonas hydrophilia Infection in an Immunocompromised Host.
Aeromonas hydrophila is an anaerobic, gram-negative rod-shaped bacterium that is commonly found in aquatic environments. This organism can cause a wide range of infections in humans, including gastroenteritis, septicemia, and skin and soft tissue infections. We herein describe a case of bacteremia due to Aeromonas hydrophila secondary to a soft tissue infection of the fingers that resulted in osteomyelitis in an immunocompromised patient.


Balance, gait and dizziness in adult cochlear implant users: A cross sectional study.
Objective: Cochlear implantation is associated with vestibular impairment due to the close proximity of the structures. The aim of the study was to quantify dizziness/vertigo, gaze instability, balance and gait problems in a sample of adult cochlear implant (CI) users.Methods: An observational, cross sectional study evaluated subjective dizziness (Vestibular Rehabilitation Benefit Questionnaire (VRBQ)), balance confidence (Activities Specific Balance Questionnaire (ABC)), gait (Functional Gait Assessment (FGA) and 10m walk test), balance (Equitest Sensory Organisation Test (SOT)), and computerised dynamic visual acuity (DVA). The Dix Hallpike test was performed to test for benign paroxysmal positional vertigo (BPPV).Results: Twenty participants (n=10F), 2.8(±2.7) years post implantation, with mean age 59.3(±15.8) years were assessed. Subjective dizziness (VRBQ) was low (15.0% (±15.5)) and balance confidence was high (ABC: 82.1%±14.9). FGA scores (25.1 ± 4.4) and gait speed (1.8 (±0.3) m/sec) were below normal. Dx Hallpike was positive in 3. Gaze instability was found in 50% (DVA loss, 0.29 (± 0.16) LogMAR), while 79% demonstrated balance impairment (mean SOT score, 57.8%±14.5), with 42% falling on SOT condition 5.Discussion: Evidence of vestibular dysfunction was identified in these adult CI users.Conclusion: Access to vestibular function assessment and rehabilitation is required in adult CI users.


Population Health: Identifying Skill Sets and Education Alignment for HIM Professionals.
The COVID-19 pandemic has increased the emphasis on population health, therefore potentially amplifying demand for healthcare workforce professionals in this area. There is an urgent need to explore and define the roles of health information management (HIM) professionals in the population health workforce. This study sought to identify the skill sets and qualifications needed, and HIM education alignment with skills necessary for HIM professionals entering the population health workforce. An intentionally broad internet search of job postings was conducted to determine skills in population health. Population health-related job descriptions and qualification requirements were abstracted and analyzed using ATLAS.ti. Three common job categories were identified: management, analytics, and coding. Skill set requirements included soft skills, problem solving, project management, research, and data analysis. The study results identified HIM educational alignment and found that HIM professionals are generally a good fit to meet the increased need in the population health workforce.


Clinical dental adhesive application: the influence on composite-enamel interface morphology.
Although the adhesion phenomenon is crucial in achieving and maintaining a composite building on dental structure, this phenomenon is not completely understood. On the other hand, adhesion is dependent on the interface quality (the interface between enamel and adhesive). In this study, the authors approached the subject of the influence of adhesive clinical application on the composite-enamel interface, which was less investigated by the scientists. On intact extracted human teeth were prepared enamel areas, and then filled with light-curing composite. The teeth were sectioned and prepared for microscopic investigation, at 10×, 100× and 200× magnifications.


An isoform of retinoid-related orphan receptor β directs differentiation of retinal amacrine and horizontal interneurons.
Amacrine and horizontal interneurons integrate visual information as it is relayed through the retina from the photoreceptors to the ganglion cells. The early steps that generate these interneuron networks remain unclear. Here we show that a distinct retinoid-related orphan nuclear receptor β1 (RORβ1) isoform encoded by the retinoid-related orphan nuclear receptor β gene (Rorb) is critical for both amacrine and horizontal cell differentiation in mice. A fluorescent protein cassette targeted into Rorb revealed RORβ1 as a novel marker of immature amacrine and horizontal cells and of undifferentiated, dividing progenitor cells. RORβ1-deficient mice lose expression of pancreas-specific transcription factor 1a (Ptf1a) but retain forkhead box n4 factor (Foxn4), two early-acting factors necessary for amacrine and horizontal cell generation. RORβ1 and Foxn4 synergistically induce Ptf1a expression, suggesting a central role for RORβ1 in a transcriptional hierarchy that directs this interneuron differentiation pathway. Moreover, ectopic RORβ1 expression in neonatal retina promotes amacrine cell differentiation.


Effect of Calcium Chloride as a Coagulant on the Properties of ESBR/Silica Wet Masterbatch Compound.
When designing rubber compounds for high-performance tires, increasing the silica content can improve the wet traction performance but decreases the fuel efficiency. This trade-off relation makes it difficult to improve the two factors simultaneously. One approach is the development of silica wet masterbatch (WMB) technology for producing compounds containing a high silica content with good dispersion. The technology involves a step to mix surface-modified silica and rubber latex. The technique requires a coagulant to break up the micelles of the rubber latex and cause the surface-modified silica and the rubber molecules to co-coagulate due to van der Waals forces. In this study, the effect of coagulant type on the characteristics of silica surface, and the mechanical properties of the emulsion styrene-butadiene rubber (ESBR)/silica WMB compounds was investigated, as well as the abrasion properties and the viscoelastic properties of the vulcanizates.


Efficacy of tracheal gas insufflation in spontaneously breathing sheep with lung injury.
Tracheal gas insufflation (TGI) decreases dead space (V D) and can be combined with continuous positive airway pressure (CPAP) to decrease minute volume (VE) and effort of breathing. In 11 anesthetized sheep, we induced acute lung injury (ALI) through oleic acid (OA) infusion and studied the effects of TGI combined with CPAP (CPAP-TGI) at different TGI flows and with catheters of different designs. Sheep were randomized to two groups: Group A (n = 7) was placed on CPAP and CPAP-TGI at 10 and 15 L/min of insufflation flow delivered through a reverse thrust catheter (RTC). Group B (n = 4) was placed on CPAP and CPAP-TGI at a flow of 10 L/min delivered through a RTC, and through a straight flow catheter (SFC). Compared with CPAP alone, CPAP-TGI resulted in significantly lower VD, VE, pressure time product, and work of breathing. We found no additional benefit from TGI flow of 15 L/min, compared with 10 L/min, and no statistically significant difference between the SFC and the RTC. In conclusion, TGI can be combined with CPAP in this model of ALI to reduce ventilation and effort of breathing.


N1 Magnitude of Auditory Evoked Potentials and Spontaneous Functional Connectivity Between Bilateral Heschl's Gyrus Are Coupled at Interindividual Level.
N1 component of auditory evoked potentials is extensively used to investigate the propagation and processing of auditory inputs. However, the substantial interindividual variability of N1 could be a possible confounding factor when comparing different individuals or groups. Therefore, identifying the neuronal mechanism and origin of the interindividual variability of N1 is crucial in basic research and clinical applications. This study is aimed to use simultaneously recorded electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data to investigate the coupling between N1 and spontaneous functional connectivity (FC). EEG and fMRI data were simultaneously collected from a group of healthy individuals during a pure-tone listening task. Spontaneous FC was estimated from spontaneous blood oxygenation level-dependent (BOLD) signals that were isolated by regressing out task evoked BOLD signals from raw BOLD signals and then was correlated to N1 magnitude across individuals. It was observed that spontaneous FC between bilateral Heschl's gyrus was significantly and positively correlated with N1 magnitude across individuals (Spearman's R = 0.829, p < 0.001). The specificity of this observation was further confirmed by two whole-brain voxelwise analyses (voxel-mirrored homotopic connectivity analysis and seed-based connectivity analysis). These results enriched our understanding of the functional significance of the coupling between event-related brain responses and spontaneous brain connectivity, and hold the potential to increase the applicability of brain responses as a probe to the mechanism underlying pathophysiological conditions.


Electrical resistances of corn root segments.
Longitudinal electrical resistances have been measured on 2-centimeter segments of corn (Zea mays L.) roots, cut at varying distances from the root apex. The segment resistances vary from 400 to 100 kilohms per centimeter along the root length (apex to 18 cm), with the maximum occurring in the 2- to 4-centimeter segment, and decreasing thereafter toward the root base. Measurements of isolated root cortical sleeves and steles show that the pathway of least resistance is in the cortex, which has a greater cross-sectional area; the specific resistance of the older stele is less than that of the cortex. The anatomical state of the xylem cannot be inferred from electrical resistance determinations.


Age patterns of mortality for older women: an analysis using the age-specific rate of mortality change with age.
"In this paper we propose a mortality measure that seems useful in analyzing age patterns of death rates. The measure, which will be denoted by k(x), indicates the proportional increase or decrease with age in the risk of death at a given age x, and is called the age-specific rate of mortality change with age." Estimations are presented for women in 10 countries. "Eight of the selected sets of data are for developed nations in the 1960s and 1970s, and the other two sets of data, for Taiwan, 1931-35, and for Germany, 1910-11, represent relatively high mortality. For France and West Germany, three different periods are included for an investigation of cohort effects on the observed age patterns." Other mathematical models of age-specific mortality rates are discussed and compared. (SUMMARY IN FRE)


N4-methylation of cytosine drastically favors the formation of (6-4) photoproducts in a TCG context.
Methylation of cytosine is a common biological process both in prokaryotic and eukaryotic cells. In addition to 5-methylcytosine (5mC), some bacterial species contain in their genome N(4) -methylcytosine (N4mC). Methylation at C5 has been shown to enhance the formation of pyrimidine dimeric photoproducts but nothing is known of the effect of N4 methylation on UV-induced DNA damage. In the present work, we compared the yield and the nature of bipyrimidine photoproducts induced in a series of trinucleotides exhibiting a TXG sequence where X is either T, C, 5mC or N4mC. HPLC associated to tandem mass spectrometry was used to quantify cyclobutane pyrimidine dimers (CPD), (6-4) photoproducts (64PP) and their Dewar valence isomer. Methylation at position N4 was found to drastically increase the reactivity of C upon exposure to both UVC and UVB and to favor the formation of 64PP. In contrast methylation at C5 increased the yield of CPD at the expense of 64PP. In addition, enhancement of photoreactivity by C5 methylation was much higher in the UVB than in the UVC range. These results show the drastic effect of the methylation site on the photochemistry of cytosine.


Vasoactive properties of procyanidins from Hypericum perforatum L. in isolated porcine coronary arteries.
Procanidin fractions (PC) were isolated from Hypericum perforatum L. (Guttiferae). Characterization of the main components of each fraction was performed by UV- and mass spectroscopy. Their biological activity was tested in porcine isolated coronary arteries. All PC fractions antagonized histamine- or prostaglandin F2 alpha-induced arterial contractions. In contrast, vasorelaxation was insignificant in KCl-precontracted coronary arteries except with the higher oligomeric PC fraction 3. Vasoactive properties of the PC seem to be dependent on their relative molecular mass. An inhibition of cellular phosphodiesterase might be involved in the underlying mechanism of action.


A Sleeve-Based, Micromotion Avoiding, Retractable and Tear-Opening (SMART) Insertion Tool for Cochlear Implantation.
In conventional cochlear implantation, the insertion of the electrode array is strongly affected by the local anatomy and human kinematics. Herein, we present a concept for an insertion tool that allows to optimize the insertion trajectory beyond anatomical constraints and stabilizes the electrode array in manual implantation. A novel sleeve-based design allows the instrument to be compliant and potentially protective to intracochlear structures, while a tear-open mechanism allows it to be removed after insertion by simply retracting the tool. Conventional and tool-guided manual insertions were performed by expert cochlear implant surgeons in an analog temporal bone model that allows to simultaneously record intracochlear pressure, insertion forces and electrode array deformation. Comparison between conventional and tool-guided insertions demonstrate a substantial reduction of maximum insertion forces, force variations, transverse intracochlear electrode array movement, and pressure transients. The presented tool can be utilized in manual cochlear implantation and significantly improves key metrics associated with intracochlear trauma. The instrument may ultimately help improve hearing outcomes in cochlear implantation. The versatile design may be used in both manual cochlear implantation and motorized and robotic insertion, as well as image-guided surgery.