The titanium tris-anilide cation [Ti(N[(t)Bu]Ar)3](+) stabilized as its perfluoro-tetra-phenylborate salt: structural characterization and synthesis in connection with redox activity of 4,4'-bipyridine dititanium complexes.
This work explores the reduction of 4,4'-bipyridine using two equivalents of the titanium(iii) complex Ti(N[(t)Bu]Ar)3 resulting in formation of a black, crystalline complex, (4,4'-bipy){Ti(N[(t)Bu]Ar)3}2, for which an X-ray structure determination is reported. The neutral, black, 4,4'-bipyridine-bridged bimetallic was found to be redox active, with mono- and di-anions being accessible electrochemically, and with the mono- and di-cations also being accessible chemically, and isolable, at least when using the weakly coordinating anion [B(C6F5)4](-) as the counter-ion. It proved possible to crystallize the salt [(4,4'-bipy){Ti(N[(t)Bu]Ar)3}2][B(C6F5)4]2 for a single-crystal X-ray structure investigation; in this instance it was revealed that the aromaticity of the 4,4'-bipyridine ligand, that had been disrupted upon reduction, had been regained. A rare cationic d(0) metal tris-amide complex, shown by X-ray crystallography to contain an intriguing pyramidal TiN3 core geometry, namely {Ti(N[(t)Bu]Ar)3}(+), could also be isolated when using [B(C6F5)4] as the essentially non-interacting counter-ion. This highly reactive cation should be considered as a potential intermediate in the plethora of reactions wherein Ti(N[(t)Bu]Ar)3 has been shown to effect the reduction of substrates including halogenated organic molecules, carbonyl compounds, organic nitriles, and metal complexes.


Improving outcomes in high-risk prostate cancer with radiotherapy.
There have been significant improvements in the radiotherapeutic management of patients with high risk prostate cancer. Randomized trials have clearly demonstrated improved outcomes with the combination of radiotherapy in conjunction with androgen deprivation. While these trials have utilized low doses of radiotherapy in the range of 70 Gy, recent studies have suggested that significant benefits of combined androgen deprivation therapy with dose escalated radiotherapy are also observed. The use of high radiation dose levels in the setting of high risk prostate cancer is important, and strategies which combine external beam radiotherapy with a brachytherapy boost may provide an opportunity for even greater intensification of the radiation dose to the prostate target. Systemic therapies, second generation anti-androgen therapy and novel targeted agents integrated with radiotherapy will open up new vistas and challenges for further improved outcomes in patients with high-risk disease.


Parents' Willingness to Invest in Primary Oral Health Prevention for Their Preschool Children.
There is growing evidence for the beneficial effects of starting oral health prevention early in life. Preventing dental caries in very young children requires considerable investment from parents. Therefore, this cross-sectional study aimed to explore parents' willingness to pay (WTP) and willingness to invest in time (WTIT) for primary oral health prevention in preschool children and describe whether these are related to the parents' demographic, socio-economic and behavioural characteristics. In a convenience sample of parents of preschool children aged six months to four years (n = 142), data were collected with questionnaires. On average, parents were willing to pay EUR15.84 per month, invest time for 1.9 dental visits per year, and spend 2.4 min per day brushing their child's teeth. A higher education level of the mother and having a child older than two were associated with a higher WTIT in brushing minutes per day (p = 0.03). In addition, parents who brushed their child's teeth more frequently were also more willing to invest in brushing minutes (p < 0.01) and money (p < 0.01). Findings emphasise the importance of early oral health interventions and the need to increase awareness of primary prevention's importance in maintaining healthy teeth and reducing possibly oral health inequalities.


Challenges and pitfalls in the management of phenylketonuria.
Despite recent advances in the management of phenylketonuria and hyperphenylalaninemia, important questions on the management of this disorder remain unanswered. Consensus exists on the need for neonatal screening and early treatment, yet disagreement persists over threshold levels of blood phenylalanine for starting treatment, target blood phenylalanine levels, and the management of older patient groups. The mainstay of treatment is a phenylalanine-restricted diet, but its application varies between and within countries. Beyond diet treatment, there is a lack of consensus on the use of newer treatments such as tetrahydrobiopterin. Although neonatal screening and early treatment has meant that most well-treated children grow up with near-normal IQ scores, the effect of relaxing metabolic control on cognitive and executive function later in life is still not fully understood. Although it is clear from the available literature that the active control of blood phenylalanine levels is of vital importance, there are other treatment-related factors that affect outcome. A uniform and firmly evidence-based approach to the management of phenylketonuria is required.


Hemophagocytic lymphohistiocytosis mimicking surgical symptoms and complications: lessons learned from four cases.
Hemophagocytic lymphohistiocytosis (HLH) is a severe immunological disorder that leads to a massive inflammatory reaction that may prove rapidly fatal. We show that HLH may present by masquerading as surgical disease or as a postoperative complication leading to delays in diagnosis and treatment. A case series of four children with acute surgical presentation and prolonged unexplained postoperative sepsis, who were diagnosed with HLH. Four children with different clinical presentations (1. neonatal abdominal distension, 2. ileostomy closure and Hirschsprung's disease, 3. iatrogenic sigmoid perforation and Crohn's disease, and 4. streptococcal toxic shock syndrome with primary peritonitis) were diagnosed with HLH at our regional pediatric surgical centre in the last two years. All developed signs of prolonged postoperative sepsis with hepatosplenomegaly and pancytopenia, requiring intensive care support. In the absence of explanation for their symptoms and deteriorating clinical condition, a total of six 'negative' exploratory laparotomies were performed. Eventually, HLH was diagnosed with bone marrow aspiration after an average of 23 days (range 17-40), following the finding of significantly elevated ferritin (up to 293150 ng/ml) and triglyceride levels. All children improved with initiation of high-dose steroid treatment followed by etoposide and cyclosporin. HLH may rarely present with symptoms and signs of surgical disease or complicate post-operative recovery. This diagnosis should be considered in children with unexplained prolonged fever, hepatosplenomegaly and pancytopenia, especially if associated with high ferritin levels. HLH can prove rapidly fatal without appropriate treatment.


[Intracellular perfusion of the giant neurons of snails].
The method is developed to perform intracellular perfusion of isolated Helix pomatia neurons. The cell is put under hydrostatic pressure into a pore in the plastic film separting the experimental chamber in two compartmentsmthe lower compartment is perfused with high-potassium solution that destroys the barrier properties of the lower part of the cell membrane. The upper compartment is oerfused with normal Ringer solution and the part of the membrane in contact with it demonstrates usual excitability; Replacement of the high-potassium solution in the lower compartment by a potassium-free one abolished the delayed outward current through the working part of the membrane indicating a free acess of ions to and from its inner surfacemthe investigated membrane maintains its excitability for several hours beeing perfused with the F- and PO4--salts of K+ and Tris


Environment-Assisted Holonomic Quantum Maps.
Holonomic quantum computation uses non-Abelian geometric phases to realize error resilient quantum gates. Nonadiabatic holonomic gates are particularly suitable to avoid unwanted decoherence effects, as they can be performed at high speed. By letting the computational system interact with a structured environment, we show that the scope of error resilience of nonadiabatic holonomic gates can be widened to include systematic parameter errors. Our scheme maintains the geometric properties of the evolution and results in an environment-assisted holonomic quantum map that can mimic the effect of a holonomic gate. We demonstrate that the sensitivity to systematic errors can be reduced in a proof-of-concept spin-bath model.


[Pathology diagnostics by human breath analyze].
Modern medicine experiences deficit of inexpensive rapid screening technologies despite progress in the development of diagnostic methods for various diseases. A promising approach is the analysis of exhaled air known to contain thousands of volatile organic substances whose composition differs considerably in health and disease. We isolated certain compounds that may be used as biomarkers of cardiovascular pathology (nitric oxide, carbon monoxide, pentane, isoprene, acetone). There is a variety of methods for the detection of substances in the exhaled air; such as gas spectrography, mass spectrometry, etc. However, ion mobility spectrometry appears the most suitable technique for the purpose of screening studies due to its high speed and sensitivity, small size of the apparatus, and possibility to measure trace amounts of the substances of interest. Possibilities to diagnose lung cancer based on exhaled air composition are considered.


Synthesized speech output and children: a scoping review.
Many computer-based augmentative and alternative communication systems in use by children have speech output. This article (a) provides a scoping review of the literature addressing the intelligibility and listener comprehension of synthesized speech output with children and (b) discusses future research directions. Studies investigating synthesized speech intelligibility and/or comprehension with children as listeners were systematically identified and coded according to their objectives and methodology. Ten studies were identified. They were organized according to the following variables: intelligibility variables related to the stimuli (context and rate), intelligibility variables related to aspects of the listener (age of the child, the language or languages spoken by the listener, experience, and practice effects), and comprehension. Each of these factors-and the research support with child participants-was discussed. Overall, there is a paucity of research investigating synthesized speech for use with children. Available evidence suggests that children produce similar trends but lower levels of intelligibility performance when compared with adults. Future areas of applied research are required to adequately define this relationship and the variables that may contribute to improving the intelligibility and comprehension of synthesized speech for children.


Localization and developmental changes in the neuron-specific cyclin-dependent kinase 5 activator (p35nck5a) in the rat brain.
Mammalian brains contain a cde2-like protein kinase which is a heterodimer of cyclin-dependent kinase 5 (Cdk5) and a brain-specific regulatory subunit with a molecular weight of 35,000. In this study, we examined the temporal and spatial expression patterns of p35nck5a in the developing rat brain. Northern blot analysis showed that p35nck5a messenger RNA expression was low in the brain of 12-day postcoitum rats, and increased to a much higher level from 18 days postcoitum to two weeks after birth, and then declined at three weeks after birth. These developmental changes in p35nck5a expression correlated with the changes in Cdk5-associated kinase activity during brain development. These data suggest that p35nck5a is the specific activator for Cdk5 in the brain. Immunohistochemical and in situ hybridization studies demonstrated the presence of p35nck5a protein in postmitotic neurons but not in glial cells at all stages of brain development, indicating that p35nck5a is a neuron-specific protein. In the adult brain, the protein was rich in cell bodies and dendrites, and only very low amounts were detected in axons. In fetal and neonatal brains, however, axonal pathways such as the corpus callosum and external capsule were also stained with anti-p35nck5a antibody. Our findings suggest that p35nck5a is neuron specific, and a specific activator for Cdk5, and the subcellular localization of the two is strictly regulated depending on brain development. Neuronal Cdc2-like kinase may play key roles in neuronal maturation, synaptic formation, and neuronal plasticity.


Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis.
Inactivation of tumour suppressor gene(s) (TSGs) on 3p appears to be a critical event in the pathogenesis of clear cell renal cell carcinoma (CC-RCC). Analysis of loss of heterozygosity (LOH) in sporadic RCC samples has implicated roles for TSGs in three specific regions of 3p in RCC development: (1) 3p12-p14, which includes the breakpoint of the familial t(3;8) constitutional translocation involved in hereditary RCC development and a recently cloned putative TSG, the FHIT gene: (2) 3p21.2-p21.3, a common region of deletion in many cancers including lung; and (3) 3p25-p26, which contains the von Hippel-Lindau (VHL) disease TSG. We and others have shown that most primary sporadic CC-RCCs contain somatic VHL gene mutations, clearly implicating inactivation of the VHL gene in the pathogenesis of CC-RCC. It is not known if CC-RCC without VHL gene mutations have alternative mechanisms of VHL gene inactivation or result from an alternative non-VHL pathway to RCC, e.g., inactivation of TSGs in 3p12-p21. We and others have reported hypermethylation and silencing of the VHL TSG in RCC from patients with VHL disease and in CC-RCC cell lines. However, the incidence and specificity of VHL methylation in primary sporadic RCC has not been defined. Therefore, we analysed methylation of the VHL, CDKN2, MYC, and H19 genes in primary RCC samples. Hypermethylation of the VHL promoter region was detected in 11% (11/99) of the primary RCCs analysed. In 10 of these tumours, there was no evidence of concomitant VHL gene mutation. VHL methylation was specific to CC-RCC (15%, 7/45) but was not detected in any non-CC tumours (n = 16). None of the 11 RCCs methylated at VHL had evidence of methylation at either CDKN2 or MYC (methylation at CDKN2 was, however, detected in 3%, or 1/33, of RCCs without VHL methylation). A normal methylation pattern at H19 was demonstrated in the three RCCs with methylated VHL analysed. Previous studies have suggested that, in addition to VHL, other 3p TSGs at 3p12-p14 and 3p21 may be involved in CC-RCC tumourigenesis. However, the interpretation of these studies has been difficult because information on VHL gene status has not been available for these data sets. Therefore, we investigated a subset of 55 sporadic RCCs (of known VHL gene methylation and mutation status) for LOH at polymorphic markers close to candidate TSG loci in the 3p14.2 and 3p21.2-p21.3 regions. Among tumours with LOH at one or more 3p markers, the incidence of 3p25 allele loss was higher in tumours with VHL alterations (mutation or methylation) than in those without. For tumours without detectable VHL alterations, the frequency of 3p14-p21 LOH was significantly higher than the frequency of 3p25-p26 LOH (93%, 13/14 vs. 43%, 6/14; P = 0.013), whereas, in RCC samples with VHL methylation or mutation, the frequency of 3p14-p21 LOH did not differ from that of sp25-p26 (72%, 18/25 vs. 59%, 13/22; P = 0.376). None of the 11 RCCs with 3p25 allele loss that were informative at 3p21 and 3p14 showed LOH at 3p25 only. These findings suggest that (1) VHL methylation is a specific and important event in the pathogenesis of CC-RCC; (2) in CC-RCC with 3p LOH but without VHL inactivation, mutations in TSGs at 3p14-p21 appear to have a primary role in tumourigenesis; and (3) inactivation of other 3p TSGs in addition to VHL may also be required for malignant transformation in tumours with VHL gene inactivation.


Neurons in primary culture are less efficiently infected by Toxoplasma gondii than glial cells.
Infection by Toxoplasma gondii is asymptomatic, leading to an immune response that controls the disease. In immune-compromised patients, however, quiescent cysts can reactivate, leading to toxoplasmic encephalitis. We studied the infection of cells of the central nervous system in an attempt to understand the process leading to this complication. Primary cultures of rat hippocampal glial cells and neurons were infected with the virulent strain RH and examined by immunofluorescent microscopy after fixation of cells and staining with antibodies specific to the different cell types. After 24 h of infection, glial cells were highly infected and showed active division of the parasite. Neurons, on the other hand, were much less efficiently infected than glial cells, but actual penetration of the parasites was demonstrated by confocal microscopy. Whereas glial cells contained vacuoles with several parasites, the vacuoles observed in neurons usually contained one parasite or, rarely, two, indicating that the parasites inside neurons did not undergo active division. This was corroborated by determination of the incorporation of [3H]-uracil. Little is known about the mechanism of neuronal infection by Toxoplasma. The experimental setup used in this study should help to improve our understanding of neuronal infection and bring insight into the physiopathology of toxoplasmic encephalitis.


Pillar[3]trianglamines: deeper cavity triangular macrocycles for selective hexene isomer separation.
The separation of α-olefins and their corresponding isomers continues to be a big challenge for the chemical industry due to their overlapping physical properties and low relative volatility. Herein, pillar[3]trianglamine (P-TA) macrocycles were synthesized for the molecular-sieving-like separation of 1-hexene (1-He) selectively over its positional isomer trans-3-hexene (trans-3-He) in the vapor and liquid state. This allyl-functionalized macrocycle features a deeper cavity compared to the previously reported trianglamine host molecules. Solid-vapor sorption experiments verified the successful separation of 1-He from an equimolar mixture of 1-He and trans-3-He. Single-crystal structures and powder X-ray diffraction patterns suggest that this selective adsorption arises from the formation of a thermodynamically stable host-guest complex between 1-He and P-TA. A reversible transformation between the nonporous guest-free structure and the guest-containing structure shows that 1-He separation can be carried out over multiple cycles without any loss of performance. Significantly, P-TA can separate 1-He directly from a liquid isomeric mixture and thus P-TA modified silica sieves (SBA-15) showed the ability to selectively separate 1-He when utilized as a stationary phase in column chromatography. This capitalizes on the prospects of employing macrocyclic hosts as molecular recognition units in real-life separations for sustainable and energy-efficient industrial practices.


Review article: pruritus in cholestatic and other liver diseases.
Pruritus is often the most troublesome symptom in patients with chronic liver disease, particularly when cholestasis is a prominent feature. The exact pathogenesis is unknown, but empirical treatment, such as cholestyramine, based on a liver-based origin of pruritus, has been used for many years. Recently, evidence for a central mechanism for pruritus has been obtained and opioid antagonists have been tried clinically with some benefit, but their use is not widespread. In addition, the pruritus associated with intrahepatic cholestasis of pregnancy can now be alleviated in many cases by ursodeoxycholic acid. As it also improves foetal outcome, this should become first-line therapy. We review the pathogenesis and therapy of pruritus, highlighting practical aspects to help with patients with seemingly intractable pruritus.


Floral colours in a world without birds and bees: the plants of Macquarie Island.
We studied biotically pollinated angiosperms on Macquarie Island, a remote site in the Southern Ocean with a predominately or exclusively dipteran pollinator fauna, in an effort to understand how flower colour affects community assembly. We compared a distinctive group of cream-green Macquarie Island flowers to the flora of likely source pools of immigrants and to a continental flora from a high latitude in the northern hemisphere. We used both dipteran and hymenopteran colour models and phylogenetically informed analyses to explore the chromatic component of community assembly. The species with cream-green flowers are very restricted in colour space models of both fly vision and bee vision and represent a distinct group that plays a very minor role in other communities. It is unlikely that such a community could form through random immigration from continental source pools. Our findings suggest that fly pollination has imposed a strong ecological filter on Macquarie Island, favouring floral colours that are rare in continental floras. This is one of the strongest demonstrations that plant-pollinator interactions play an important role in plant community assembly. Future work exploring colour choices by dipteran flower visitors would be valuable.


Validity of direct assessment of functional status as a tool for measuring Alzheimer's disease severity.
to assess the validity of the Direct Assessment of Functional Status (DAFS) performance-based functional scale for the staging of dementia severity by comparing it with established clinical, functional and cognitive scales. 93 consecutive Alzheimer's disease patients underwent DAFS. Socio-demographic variables, cognitive status (Mini-Mental State Examination; MMSE), global disease severity (Clinical Dementia Rating; CDR), disease duration, physical performance (Physical Performance Test, PPT) and functional status (as reported by the primary caregiver) were also recorded and basic (B) and instrumental (I) activities of daily living (ADL) assessed. a significant correlation was found between DAFS and MMSE (Pearson's r = 0.60; P < 0.01), PPT (r = 0.54; P < 0.01) and CDR (Spearman correlation coefficient: -0.48; P < 0.01). A mild, significant correlation was found between DAFS score and daily function as reported by the primary caregiver (r = -0.30 for BADL and r = - 0.27 for IADL). On multiple regression analysis, only MMSE and PPT were independently associated with the DAFS score, explaining 56% of DAFS total variance. ADL scales did not independently contribute to DAFS variance. A multivariate regression model of the association of DAFS with CDR showed that the association was significant even after adjustment for MMSE and PET, suggesting that DAFS scores provide additional information on dementia severity. DAFS is a valid tool for the assessment of dementia severity, capturing cognitive and physical aspects of disability.


Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists.
Use of angiotensin (Ang) II AT1 receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II-induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% (P<0.01 between drugs). The effect of each drug declined with time. At 24 hours, a residual effect was found with all 3 drugs, but at 30 hours, only irbesartan induced a marked, significant blockade versus placebo. Similar results were obtained when Ang II receptor blockade was assessed with an in vitro receptor assay and by the reactive rise in plasma Ang II levels. This study thus demonstrates that the first administration of the recommended starting dose of irbesartan induces a greater and longer lasting Ang II receptor blockade than that of valsartan and losartan in normotensive subjects.


Tuning dipolar and multipolar resonances of chiral silicon nanostructures for control of near field superchirality.
Chiral materials display a property called optical activity, which is the capability to interact differentially with left and right circularly polarised light. This leads to the ability to manipulate the polarisation state of light, which has a broad range of applications spanning from energy efficient displays to quantum technologies. Both synthesised and engineered chiral nanomaterials are exploited in such devices. The design strategy for optimising the optical activity of a chiral material is typically based on maximising a single parameter, the electric dipole-magnetic dipole response. Here we demonstrate an alternative approach of controlling optical activity by manipulating both the dipole and multipolar response of a nanomaterial. This provides an additional parameter for material design, affording greater flexibility. The exemplar systems used to illustrate the strategy are nanofabricated chiral silicon structures. The multipolar response of the structures, and hence their optical activity, can be controlled simply by varying their height. This phenomenon allows optical activity and the creation of so called superchiral fields, with enhanced asymmetries, to be controlled over a broader wavelength range, than is achievable with just the electric dipole-magnetic dipole response. This work adds to the material design toolbox providing a route to novel nanomaterials for optoelectronics and sensing applications.


An unusual OFF-ON fluorescence sensor for detecting mercury ions in aqueous media and living cells.
A novel azo derivative sensor (BDAA) based on alkynes was designed and utilized to direct detection of Hg(2+) in aqueous solution and living cells. The new strategy achieved off to on switchable fluorescence. permits the highly selective and sensitive detection of Hg(2+). This sensor can be used for imaging of Hg(2+) in living cells.


[Borderline mental disorders in parkinsonism patients and their drug correction].
70 patients with vascular parkinsonism (VP) were investigated. The total group of patients was divided into several groups depending upon: a) the forms of disease (with typical or atypical forms of disease), b) the different syndromes (with bradykinesia and rigidity or tremor). Borderline psychic disorders manifested as a light depression with cognitive disturbances and personality changes. Hamilton Depression Rating Scale and Hachinski Ischemic Score were administered to assess the severity of depression and cognitive disturbances, respectively. Patients were treated with cholinolytics and L-DOPA-containing preparations. After treatment the clinical improvements were observed in patients with typical (86.8%) and atypical (93.7%) forms of VP (difference between groups failed to reach statistical significance), with tremor (93.3%) and rigidity (83.7%) syndromes (difference between groups reached statistical significance, p < 0.05). Efficacy of antidepressant treatment reached 90.5% in patients with typical and in 100% atypical forms of VP, respectively. The efficacy was the same in patients with rigid forms of VP. Antidepressant treatment significantly elevated the level of social adaptation of patients with VP.


STATE TRANSITION7-Dependent Phosphorylation Is Modulated by Changing Environmental Conditions, and Its Absence Triggers Remodeling of Photosynthetic Protein Complexes.
In plants and algae, the serine/threonine kinase STN7/STT7, orthologous protein kinases in Chlamydomonas reinhardtii and Arabidopsis (Arabidopsis thaliana), respectively, is an important regulator in acclimation to changing light environments. In this work, we assessed STT7-dependent protein phosphorylation under high light in C. reinhardtii, known to fully induce the expression of light-harvesting complex stress-related protein3 (LHCSR3) and a nonphotochemical quenching mechanism, in relationship to anoxia where the activity of cyclic electron flow is stimulated. Our quantitative proteomics data revealed numerous unique STT7 protein substrates and STT7-dependent protein phosphorylation variations that were reliant on the environmental condition. These results indicate that STT7-dependent phosphorylation is modulated by the environment and point to an intricate chloroplast phosphorylation network responding in a highly sensitive and dynamic manner to environmental cues and alterations in kinase function. Functionally, the absence of the STT7 kinase triggered changes in protein expression and photoinhibition of photosystem I (PSI) and resulted in the remodeling of photosynthetic complexes. This remodeling initiated a pronounced association of LHCSR3 with PSI-light harvesting complex I (LHCI)-ferredoxin-NADPH oxidoreductase supercomplexes. Lack of STT7 kinase strongly diminished PSII-LHCII supercomplexes, while PSII core complex phosphorylation and accumulation were significantly enhanced. In conclusion, our study provides strong evidence that the regulation of protein phosphorylation is critical for driving successful acclimation to high light and anoxic growth environments and gives new insights into acclimation strategies to these environmental conditions.


[Anti-Sp100 and anti-Gp210 in the diagnosis of primary biliary cirrhosis in patients with autoimmune cholangitis].
We describe 2 women with features of autoimmune cholangitis. Serum biochemical studies showed cholestasis and increased immunoglobulin M with negative antimitochondrial antibodies. Markers of hepatitis B and C viruses were absent. Both had positive antinuclear antibodies. One had a speckled pattern (multiple nuclear dots) and the other a perinuclear pattern (pore nuclear). In the first case anti-Sp100 was positive by EIA and in the second anti-Gp210 was detected by immunoblot. Diagnosis of primary biliary cirrhosis was made and the patients were treated with UDCA. Current knowledge indicates that determination of anti-Sp100 and anti-Gp210 substantially improves diagnosis of primary biliary cirrhosis as these ANA are highly specific for this disease. These autoantibodies may lead to the classification of different groups of patient included in autoimmune cholangitis. All patients with autoimmune cholangitis should be tested for anti-Sp100 and anti-Gp210.


Associations between objectively assessed physical activity levels and fitness and self-reported health-related quality of life in community-dwelling older adults.
Previous studies investigated the associations between health-related quality of life (HRQoL) and self-reported physical activity (PA) and/or self-reported physical fitness which are not the most reliable methods to assess PA and fitness. Therefore, this study aimed to examine the associations between HRQoL and each of objectively assessed habitual PA and physical fitness. Eighty-five community-dwelling older adults (60-83 years) completed assessments for PA (counts/min and steps/day using accelerometers), physical fitness (six-minute walk test [6MWT] and hand-grip strength), and self-reported HRQoL (using the eight subscales of the SF-36). In adjusted logistic regression models, the upper quartile was compared against the lower three quartiles of scores on each HRQoL subscale. Results report the odds ratios that were significant in the adjusted models at P < 0.05. Individuals with higher PA levels assessed by counts/min were more likely to score higher on physical functioning (PF) subscale (OR = 1.90). Individuals with superior 6MWT performance were more likely to score higher on PF (OR = 1.87), role limitations due to physical problems (RP) (OR = 1.95), and vitality (VT) (OR = 1.79). Individuals with superior hand-grip strength were more likely to score higher on RP (OR = 2.37) and VT (OR = 1.83). Objectively assessed PA and physical fitness measures were positively associated with physical health HRQoL subscales as reported by community-dwelling older adults.


High-Phosphate Diet Improved the Skeletal Development of Fam20c-Deficient Mice.
FAM20C (family with sequence similarity 20 - member C) is a protein kinase that phosphorylates secretory proteins, including the proteins that are essential to the formation and mineralization of calcified tissues. Previously, we reported that inactivation of Fam20c in mice led to hypophosphatemic rickets/osteomalacia along with increased circulating fibroblast growth factor 23 (FGF23) levels and dental defects. In this study, we examined whether a high-phosphate (hPi) diet could rescue the skeletal defects in Fam20c-deficient mice. Fam20c conditional knockout (cKO) mice were generated by crossing female Fam20c-floxed mice (Fam20cfl/fl) with male Sox2-Cre;Fam20cfl/+ mice. The pregnant female Fam20cfi/fl mice were fed either a normal or hPi diet until the litters were weaned. The cKO and control offspring were continuously given a normal or hPi diet for 4 weeks after weaning. Plain X-ray radiography, micro-CT, histology, immunohistochemistry (FGF23, DMP1, OPN, and SOX9), and in situ hybridization (type II and type X collagen) analyses were performed to evaluate the effects of an hPi diet on the mouse skeleton. Plain X-ray radiography and micro-CT radiography analyses showed that the hPi diet improved the shape and mineral density of the Fam20c-deficient femurs/tibiae, and rescued the growth plate defects in the long bone. Histology analyses further demonstrated that an hPi diet nearly completely rescued the growth plate-widening defects in the long bone and restored the expanded hypertrophic zone to nearly normal width. These results suggested that the hPi diet significantly improved the skeletal development of the Fam20c-deficient mice, implying that hypophosphatemia partially contributed to the skeletal defects in Fam20c-deficient subjects.


Recent Immigration to Canada and the United States: A Mixed Tale of Relative Selection.
Using large-scale census data and adjusting for sending-country fixed effect to account for changing composition of immigrants, we study relative immigrant selection to Canada and the U.S. during 1990-2006, a period characterized by diverging immigration policies in the two countries. Results show a gradual change in selection patterns in educational attainment and host country language proficiency in favor of Canada as its post-1990 immigration policy allocated more points to the human capital of new entrants. Specifically, in 1990, new immigrants in Canada were less likely to have a B.A. degree than those in the U.S.; they were also less likely to have a high-school or lower education. By 2006, Canada surpassed the U.S. in drawing highly-educated immigrants, while continuing to attract fewer low-educated immigrants. Canada also improved its edge over the U.S. in terms of host-country language proficiency of new immigrants. Entry-level earnings, however, do not reflect the same trend: recent immigrants to Canada have experienced a wage disadvantage compared to recent immigrants to the U.S., as well as Canadian natives. One plausible explanation is that, while the Canadian points system has successfully attracted more educated immigrants, it may not be effective in capturing productivity-related traits that are not easily measurable.


CAR T cells: continuation in a revolution of immunotherapy.
The recent clinical successes of immunotherapy, as a result of a broader and more profound understanding of cancer immunobiology, and the leverage of this knowledge to effectively eradicate malignant cells, has revolutionised the field of cancer therapeutics. Immunotherapy is now considered the fifth pillar of cancer care, alongside surgery, chemotherapy, radiotherapy, and targeted therapy. Recently, the success of genetically modified T cells that express chimeric antigen receptors (CAR T cells) has generated considerable excitement. CAR T-cell therapy research and development has built on experience generated by laboratory research and clinical investigation of lymphokine-activated killer cells, tumour-infiltrating lymphocytes, and allogeneic haemopoietic stem-cell transplantation for cancer treatment. This Review aims to provide a background on the field of adoptive T-cell therapy and the development of genetically modified T cells, most notably CAR T-cell therapy. Many challenges exist to optimise efficacy, minimise toxicity, and broaden the application of immunotherapies based on T cells.


Feasibility of Postoperative Radiotherapy Using Conventional Fractionation for Lymph Node Metastasis from Cutaneous Melanoma.
In the present study we assessed if postoperative radiotherapy (PORT) using conventional fractionation confers a benefit in cutaneous melanoma patients with lymph node (LN) metastasis. Sixty-two patients with axillary or inguinal LN metastasis were retrospectively reviewed. Twenty-eight patients received PORT. The median RT dose was 50 Gy in 25 fractions. The high-risk group was defined by the presence of any of the following: ≥3 LNs, size ≥3 cm, extranodal extension. The median follow-up time was 34 months. PORT showed a significant benefit on 5-year axilla-inguinal recurrence-free survival (RFS) in high-risk patients (RT 100% vs. No-RT 37%, p=0.001). There was also a benefit of RT on 5-year out-field RFS in the high-risk population (RT 93% vs. No-RT 29%, p=0.002). There were no ≥grade 2 lymphedemas after RT. PORT using conventional fractionation for high-risk LN metastasis from cutaneous melanoma is feasible with comparable regional control and minimal toxicity.


On the mechanism of protein fold-switching by a molecular sensor.
Alternate frame folding (AFF) is a mechanism by which conformational change can be engineered into a protein. The protein structure switches from the wild-type fold (N) to a circularly-permuted fold (N'), or vice versa, in response to a signaling event such as ligand binding. Despite the fact that the two native states have similar structures, their interconversion involves folding and unfolding of large parts of the molecule. This rearrangement is reported by fluorescent groups whose relative proximities change as a result of the order-disorder transition. The nature of the conformational change is expected to be similar from protein to protein; thus, it may be possible to employ AFF as a general method to create optical biosensors. Toward that goal, we test basic aspects of the AFF mechanism using the AFF variant of calbindin D(9k). A simple three-state model for fold switching holds that N and N' interconvert through the unfolded state. This model predicts that the fundamental properties of the switch--calcium binding affinity, signal response (i.e., fluorescence change upon binding), and switching rate--can be controlled by altering the relative stabilities of N and N'. We find that selectively destabilizing N or N' changes the equilibrium properties of the switch (binding affinity and signal response) in accordance with the model. However, kinetic data indicate that the switching pathway does not require whole-molecule unfolding. The rate is instead limited by unfolding of a portion of the protein, possibly in concert with folding of a corresponding region.


The use of mid-infrared spectra to map genes affecting milk composition.
The aim of this study was to investigate the feasibility of using mid-infrared (MIR) spectroscopy analysis of milk samples to increase the power and precision of genome-wide association studies (GWAS) for milk composition and to better distinguish linked quantitative trait loci (QTL). To achieve this goal, we analyzed phenotypic data of milk composition traits, related MIR spectra, and genotypic data comprising 626,777 SNP on 5,202 Holstein, Jersey, and crossbred cows. We performed a conventional GWAS on protein, lactose, fat, and fatty acid concentrations in milk, a GWAS on individual MIR wavenumbers, and a partial least squares regression (PLS), which is equivalent to a multi-trait GWAS, exploiting MIR data simultaneously to predict SNP genotypes. The PLS detected most of the QTL identified using single-trait GWAS, usually with a higher significance value, as well as previously undetected QTL for milk composition. Each QTL tends to have a different pattern of effects across the MIR spectrum and this explains the increased power. Because SNP tracking different QTL tend to have different patterns of effect, it was possible to distinguish closely linked QTL. Overall, the results of this study suggest that using MIR data through either GWAS or PLS analysis applied to genomic data can provide a powerful tool to distinguish milk composition QTL.


Casposon integration shows strong target site preference and recapitulates protospacer integration by CRISPR-Cas systems.
Casposons are a recently discovered group of large DNA transposons present in diverse bacterial and archaeal genomes. For integration into the host chromosome, casposons employ an endonuclease that is homologous to the Cas1 protein involved in protospacer integration by the CRISPR-Cas adaptive immune system. Here we describe the site-preference of integration by the Cas1 integrase (casposase) encoded by the casposon of the archaeon Aciduliprofundum boonei Oligonucleotide duplexes derived from the terminal inverted repeats (TIR) of the A. boonei casposon as well as mini-casposons flanked by the TIR inserted preferentially at a site reconstituting the original A. boonei target site. As in the A. boonei genome, the insertion was accompanied by a 15-bp direct target site duplication (TSD). The minimal functional target consisted of the 15-bp TSD segment and the adjacent 18-bp sequence which comprises the 3' end of the tRNA-Pro gene corresponding to the TΨC loop. The functional casposase target site bears clear resemblance to the leader sequence-repeat junction which is the target for protospacer integration catalyzed by the Cas1-Cas2 adaptation module of CRISPR-Cas. These findings reinforce the mechanistic similarities and evolutionary connection between the casposons and the adaptation module of the prokaryotic adaptive immunity systems.


Self-efficacy for deprescribing: A survey for health care professionals using evidence-based deprescribing guidelines.
Although polypharmacy is associated with significant morbidity, deprescribing can be challenging. In particular, clinicians express difficulty with their ability to deprescribe (i.e. reduce or stop medications that are potentially inappropriate). Evidence-based deprescribing guidelines are designed to help clinicians take action on reducing or stopping medications that may be causing more harm than benefit. Determine if implementation of evidence-based guidelines increases self-efficacy for deprescribing proton pump inhibitor (PPI), benzodiazepine receptor agonist (BZRA) and antipsychotic (AP) drug classes. A deprescribing self-efficacy survey was developed and administered to physicians, nurse practitioners and pharmacists at 3 long-term care (LTC) and 3 Family Health Teams in Ottawa, Canada at baseline and approximately 6 months after sequential implementation of each guideline. For each drug class, overall and domain-specific self-efficacy mean scores were calculated. The effects of implementation of each guideline on self-efficacy were tested by estimating the difference in scores using paired t-test. A linear mixed-effects model was used to investigate change over time and over practice sites. Of eligible clinicians, 25, 21, 18 and 13 completed the first, second, third and fourth survey respectively. Paired t-tests compared 14 participants for PPI and BZRA, and 9 for AP. Overall self-efficacy score increased for AP only (95% confidence intervals (CI) 0.32 to 19.79). Scores for domain 2 (develop a plan to deprescribe) increased for PPI (95% CI 0.52 to 24.12) and AP guidelines (95% CI 2.46 to 18.11); scores for domain 3 (implement the plan for deprescribing) increased for the PPI guideline (95% CI 0.55 to 14.24). Longitudinal analysis showed an increase in non-class specific scores, with a more profound effect for clinicians in LTC where guidelines were routinely used. Implementation of evidence-based deprescribing guidelines appears to increase clinicians' self-efficacy in developing and implementing a deprescribing plan for specific drug classes.


Linguistic determinants of formal thought disorder in first episode psychosis.
Thought disorder is a core feature of schizophrenia but assessment of disordered thinking is challenging, which may contribute to the paucity of mechanistic understanding of disorganization in early psychosis. We studied the use of linguistic connectives in relation to clinically quantified dimensions of thought disorder using automated speech analysis in untreated, first episode psychosis (FEPs) and healthy controls (HCs). 39 treatment-naïve, actively psychotic FEPs and 23 group matched HCs were recruited. Three one-minute speech samples were induced in response to photographs from the Thematic Apperception Test and speech was analysed using COH-METRIX software. Five connectives variables from the Coh-Metrix software were reduced using principle component analysis, resulting in two linguistic connectives factors. Thought disorder was assessed using the Thought Language Index (TLI) and the PANSS-8. Connective factors predicted disorganization, but not impoverishment suggesting aberrant use of connectives is specific to positive thought disorder. An independent t test comparing low and high disorganization FEPs showed higher load of acausal temporal connectives in high disorganization FEPs compared to low disorganization FEPs (mean [SD] in high vs low disorganization FEPs = 0.64 (1.1) vs -0.37 (1.02); t = 2.91, P = .006). Acausal-temporal connectives were not correlated with severity of symptoms or cognition suggesting connective use is a specific index of disorganized thinking rather than overall illness status. Clinical assessment of disorganization in psychosis is likely linked to the aberrant use of connectives resulting in an intuitive sense of incoherence. In early psychosis, thought disorder may be reliably quantifiable using automated syntax analysis.


Adherence and acceptability of telehealth appointments for high-risk obstetrical patients during the coronavirus disease 2019 pandemic.
Telehealth has been successfully implemented for the delivery of obstetrical care. However, little is known regarding the attitudes and acceptability of patients and providers in high-risk obstetrics and whether the implementation of a telehealth model improves access to care in nonrural settings. This study aimed to describe patient and provider attitudes toward telehealth for the delivery of high-risk obstetrical care in a large healthcare system with both urban and suburban settings and to determine whether the implementation of a telehealth model improves patient adherence to scheduled appointments in this patient population. Two self-administered surveys were designed. The first survey was sent to all high-risk obstetrical patients who received a telehealth visit between March 1, 2020, and May 30, 2020. The second survey was designed for providers who participated in these visits. We also compared the attended, cancelled, and no-show visit rates before (March 1 to May 30, 2019) and after (March 1 to May 30, 2020) the telehealth implementation and telehealth vs in-person visits in 2020. We reviewed scheduled high-risk prenatal care appointments, diabetes mellitus education sessions, and genetic counseling and Maternal-Fetal Medicine consultations. A total of 91 patient surveys and 33 provider surveys were analyzed. Overall, 86.9% of patients were satisfied with the care they received and 78.3% would recommend telehealth visits to others. Notably, 87.8% of providers reported having a positive experience using telehealth, and 90.9% believed that telehealth improved patients' access to care. When comparing patient and provider preference regarding future obstetrical care after experiencing telehealth, 73.8% of patients desired a combination of in-person and telehealth visits during their pregnancy. However, a significantly higher rate of providers preferred in-person than telehealth visits (56% vs 23%, P=.024, respectively). When comparing visits between 2019 and 2020, there was a significantly lower rate of no-show appointments (8.49% vs 4.61%, P<.001), patient-cancelled appointments (7.06% vs 4.96%, P<.001), and patient same-day cancellations (2.30% vs 1.35%, P<.001) with the implementation of telehealth. There was also a significantly lower rate of patient-cancelled appointments (3.82% vs 5.44%, P=.021) and patient same-day cancellations (0.60% vs 1.65%, P=.002) with those receiving telehealth visits than in-person visits in 2020. The implementation of a telehealth model in high-risk obstetrics has the potential to improve access to high-risk obstetrical care, by reducing the rate of missed appointments. Both patients and providers surveyed expressed a high rate of satisfaction with telehealth visits and a desire to integrate telehealth into the traditional model of high-risk obstetrical care.


Tumor necrosis factor receptor -1 and -2 double deficiency reduces graft arterial disease in murine cardiac allografts.
Graft arterial disease (GAD) remains the leading cause of long-term solid organ allograft failure. Tumor necrosis factor (TNF) promotes multiple aspects of allograft rejection via binding to type 1 (p55) and type 2 (p75) receptors. We used TNF type 1 receptor deficient (TNFR1KO), type 2 receptor deficient (TNFR2KO) and receptor double-deficient (TNFRDKO) mice to assess the relative roles of TNFR in acute rejection and GAD. Heterotopic cardiac transplantation was performed between C57BL/6 (B/6) and Balb/c (B/c) mice (total allomismatches) to assess the effects on graft survival; B/6 and Bm12 mice (class II mismatches) were used to assess the effects on GAD 8 weeks after transplantation. We found that graft survival in the total allomismatch combinations was the same regardless of TNFR status. In class II mismatches, wild-type (WT) combinations showed severe GAD, and GAD was not diminished when WT hearts were transplanted into TNFRDKO hosts. TNFR1KO donors or TNFR2KO donors had GAD comparable to WT donors, however, GAD was significantly diminished in B/6 TNFRDKO donor hearts. We conclude that both p55 and p75 signals on donor vascular wall cells are involved in the development of GAD, and either TNFR is capable of mediating a response that will culminate in GAD.


Volatile compound profiling of Turkish Divle Cave cheese during production and ripening.
The formation of volatile compounds in Turkish Divle Cave cheese produced in 3 different dairy farms was determined during production and ripening, revealing 110 compounds including acids, alcohols, ketones, esters, and terpenes. The presence and concentration of these volatile compounds varied between specific phases of the production and the 120-d ripening process. Smaller differences were also detected between cheeses produced at different farms. Carboxylic acids were established as a major class at the end of ripening. The relative amounts of acids and ketones increased until d 90 of ripening, whereas alcohols increased for the first 30d and tailed off during the remaining part of the ripening process. The level of esters increased gradually until the end of ripening. Butanoic, acetic, and valeric acids, 2-butanol, 2-butanone, 2-heptanone, ethyl butanoate, α-pinene, and toluene were the most abundant compounds, likely contributing to the characteristic aroma of this traditional cheese.


Brain injury and altered brain growth in preterm infants: predictors and prognosis.
To define the nature and frequency of brain injury and brain growth impairment in very preterm (VPT) infants by using MRI at term-equivalent age and to relate these findings to perinatal risk factors and 2-year neurodevelopmental outcomes. MRI scans at term-equivalent age from 3 VPT cohorts (n = 325) were reviewed. The severity of brain injury, including periventricular leukomalacia and intraventricular and cerebellar hemorrhage, was graded. Brain growth was assessed by using measures of biparietal width (BPW) and interhemispheric distance. Neurodevelopmental outcome at age 2 years was assessed across all cohorts (n = 297) by using the Bayley Scales of Infant Development, Second Edition (BSID-II) or Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and evaluation for cerebral palsy. Of 325 infants, 107 (33%) had some grade of brain injury and 33 (10%) had severe injury. Severe brain injury was more common in infants with lower Apgar scores, necrotizing enterocolitis, inotropic support, and patent ductus arteriosus. Severe brain injury was associated with delayed cognitive and motor development and cerebral palsy. Decreased BPW was related to lower gestational age, inotropic support, patent ductus arteriosus, necrotizing enterocolitis, prolonged parenteral nutrition, and oxygen at 36 weeks and was associated with delayed cognitive development. In contrast, increased interhemispheric distance was related to male gender, dexamethasone use, and severe brain injury. It was also associated with reduced cognitive development, independent of BPW. At term-equivalent age, VPT infants showed both brain injury and impaired brain growth on MRI. Severe brain injury and impaired brain growth patterns were independently associated with perinatal risk factors and delayed cognitive development.


From Cardiovascular Prevention and Differential Diagnosis to the Treatment of Myocardial Damage-Experimental and Human Perspectives.
Cardiovascular diseases are characterized by many clinical, morphological, functional, and biochemical markers, including age, sex, genetic factors, plasma lipids, glycemia, and many other laboratory parameters [...].


Photosynthetic responses to water deficit in six Mediterranean sclerophyll species: possible factors explaining the declining distribution of Rhamnus ludovici-salvatoris, an endemic Balearic species.
We sought to explain the declining distribution in the Balearic Islands of the endemic shrub Rhamnus ludovici-salvatoris R. Chodat, by comparing its photosynthetic response to drought with that of several widely distributed, competing Mediterranean species (R. alaternus L., Quercus ilex L., Pistacia lentiscus L., Q. humilis Mill. and P. terebinthus L.). All of the study species, except for the two Rhamnus species, avoided desiccation by rapidly adjusting their stomatal conductance at the onset of drought, and maintaining constant leaf relative water content. The two Rhamnus species showed desiccation-tolerant behavior; i.e., as drought progressed, their predawn leaf relative water content decreased simultaneously with stomatal closure. All four desiccation-avoiding species showed a significant positive correlation between leaf thermal dissipation (estimated by the fluorescence parameter NPQ (non-photochemical quenching)) and the de-epoxidation state of the xanthophyll cycle (DPS). The two Rhamnus species exhibited maximum DPS regardless of treatment, but only R. alaternus increased NPQ in response to drought. Rhamnus ludovici-salvatoris had a high ratio of photorespiration to photosynthesis and a low intrinsic water-use efficiency; traits that are likely to be unfavorable for plant productivity under arid conditions. It also had the lowest DPS and thermal dissipation among the six species. We conclude that the photosynthetic traits of R. ludovici-salvatoris account for its limited ability to compete with other species in the Mediterranean region.


Coliform MPN counts of municipal raw sewage and sewage treatment plant in relation to the water of Buckingham Canal at Kalpakkam (Tamil Nadu, India).
Most Probable Number (MPN) of Total Coliforms (TC) and Faecal Coliforms (FC), and the physicochemical variables - temperature, Dissolved Oxygen (D.O.), Biochemical Oxygen Demand (B.O.D.), Chemical Oxygen Demand (C.O.D.), nitrates, phosphates and chlorides of municipal raw sewage and that of aeration tank and secondary clarifier of the Sewage Treatment Plant (STP), in relation to water at the treated sewage out-fall point, down-stream and up-stream of the Buckingham Canal at Kalpakkam were analyzed. Total Coliform and Faecal Coliform MPN counts were higher, 170 and 70/100 mL respectively in the raw sewage. However, the counts of the former in the aeration tank though remained similar, that of FC decreased to 50/100 mL; both of the counts further decreased to 30 and 44/100 mL respectively, in the secondary clarifier and were 110 and 23/100 mL, respectively at the treated sewage out-fall point in the canal. Total coliforms MPN was more than 18 times less in the water at the up-stream than that of the treated sewage out-fall point in the canal. Interestingly MPN of the FC in the up-stream water was nil while it was 8/100 mL in the canal's down-stream point. It is concluded that the FC, B.O.D., C.O.D., nitrates, phosphates and chlorides decreased and the D.O. increased in the treated-sewage due to the treatment of raw sewage through the STP.


Older women's experience with breast cancer treatment: A systematic review of qualitative literature.
The experience of older women during breast cancer treatment is insufficiently described by quantitative studies. This study aimed to systematically review qualitative data describing factors that influence older women's (≥65 years old) experience with breast cancer treatment. A systematic review was performed in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA) principles. MEDLINE, CINAHL, PsycINFO, and EMBASE were searched (inception - 2020). Quality assessment of essential item reporting was performed using the Standards for Reporting Qualitative Research (SRQR) criteria. Common ideas were coded, thematically organized, and synthesized within a theoretical framework. Of 7,773 studies identified, twelve were included. The median SRQR score was 13.4 (range 11.3-15.9) (maximum score: 21). Data synthesis revealed that older women experienced breast cancer as a journey with challenges during each phase. During diagnosis, they delayed seeking medical help despite symptoms. Age and experience gave them perspective on the impact of their diagnosis. During decision-making, preconceptions and personal values determined choices. In the treatment phase, women experienced medical and social barriers to care. During the post-treatment phase, many experienced treatment adverse effects, but could move on or compartmentalize as coping mechanisms. Older women with breast cancer have unique challenges specific to each phase of their treatment journey. Older women may benefit from proactive treatment discussions with health care providers to address their specific needs, individualize care, and assist with cancer care navigation.


Oceanographic upwelling conditions influence signaling pathways involved in muscle growth of intertidal fish.
Few studies have addressed the impact of the upwelling oceanographical conditions on biological processes, such as growth, using a molecular and physiological approach. Upwelling conditions are characterized by low temperature seawater and high nutrient availability, which represents an ideal opportunity to understand how habitat modulates animal performance at different levels of biological complexity. We aimed to assess intraspecific variations in weight, oxygen consumption, protein content, and key signaling pathways involved in muscle-growth (protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)) under experimental trials considering high/low seawater temperatures with full/restricted food rations. For this purpose, we studied Girella laevifrons, one of the most abundant fish species inhabiting rocky intertidal zones along the Eastern South Pacific coasts. Using fish obtained from upwelling (U) and non-upwelling (NU) zones, we reported that U animals displayed higher growth performance during both contrasting trials, with a weight gain (~3 g), lower oxygen consumption (~12%), and higher protein contents (~20%). Only ERK showed significant differences during the trials (~2-fold downregulation between NU and U fish). We also found that U fish increased protein ubiquitination in high water temperature and restricted food ration in contrast to NU fish. Our results help to elucidate how upwelling conditions may influence fish growth at physiological and molecular levels. Still, future analyses are necessary to improve the information regarding the impact of U and NU condition on animals, as well as the possible applications of this data in the aquaculture industry.


Brachytherapy for the prevention of stenosis in a canine hemodialysis graft model: preliminary observations.
To determine whether gamma brachytherapy can prevent in-stent stenosis in hemodialysis grafts. Six-millimeter polytetrafluoroethylene arteriovenous grafts were created bilaterally in six dogs. After 1 month, Wallstents spanning the venous anastomosis were placed to accelerate restenosis. Gamma irradiation (12 Gy) was delivered endoluminally to one of the two grafts by using an iridium 192 source; thus, each animal served as its own control. Fistulography was performed monthly for 10 months or until graft thrombosis, with measurement of stenosis at each time point. At the conclusion of the study period, the treated area was examined histologically, and a computer model was used to calculate the volume of intimal hyperplasia. Delayed stent migration resulted in exclusion of one dog. In the remaining five dogs; maximum stenosis across all time intervals was less for the treated side (P < .04), and the volume of intimal hyperplasia was less for the treated side (P < .045). In one animal studied at 1 year, this trend reversed in terms of percentage stenosis but not total neointimal volume. Brachytherapy with 192Ir (gamma) delivered at the time of stent placement reduces restenosis in this hemodialysis graft model, but, depending on the parameter evaluated (stenosis vs total volume of neointima), the benefit may wane or even reverse with time.


Prognostic relevance of sidedness in older patients with colon cancer: A review and pooled analysis of 227,218 patients.
Age is a major risk factor for sporadic colon cancer (CC). In the general population, the side of the tumor (right versus left) shows a possible significant prognostic effect, with right tumors displaying the worst outcome due to biological differences. However, little is known about the role of sidedness in the older population. We conducted a pooled analysis of observational and prospective studies to confirm or reject the hypothesis that side is a prognostic variable, even in older patients with CC. Using the terms ("colorectal" or "colon") and ("cancer" or "carcinoma") and ("elderly" or "older" or "65 years" or "70 years" or "75 years") and ("side" or "site" or "right" or "left"), we searched PubMed, Embase, and the Cochrane Library through January 2023. We selected studies in the English language to compare the prognosis of left versus right CC in older patients (with a lower age limit of 65 years). The primary endpoint was overall survival (OS). Hazard ratios (HRs) for OS with relative 95% confidence intervals (CIs) were extracted from each study. Summary HRs were calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies. The review process led to the inclusion of 13 articles. The studies reported the OS data for a total of 227,218 patients with CC. The CC side was not independently associated with mortality risk in older CC patients (HR 0.97; 95% CI 0.9-1.04; p = 0.34). High heterogeneity was observed in the main analysis (P < 0.01; I2 = 85%). In conclusion, our analysis shows that the tumor being on the left or right side in older patients with CC has no significant role in the risk of overall death. These data support the use of other parameters, such as stage, biology, comorbidities, and life expectancy, to decide on treatment and the prolongation of screenings until a patient's latest years.


Pleionea sediminis sp. nov., isolated from coastal sediment and emendation of the description of the genus Pleionea.
A Gram-stain-negative, rod-shaped and non-motile bacterium, designated strain S1-5-21T, was isolated from coastal sediment in Quanzhou Bay, PR China, and subjected to taxonomic characterization. Growth of strain S1-5-21T was observed at 15-40 °C (optimum, 30-35 °C), NaCl tolerance of 0.5-10 % NaCl (w/v; optimum, 1 %), and pH range of 5-8 (optimum, pH 7). Catalase activity and oxidase activity were found to be positive. The nearly complete 16S rRNA gene sequence of strain S1-5-21T shows maximum sequence similarity to Pleionea mediterranea MOLA115T (95.7 %), followed by Kangiella chungangensis CAU 1040T (90.4 %) and Aliikangiella marina GYP-15T (90.1 %). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain S1-5-21T forms a distinct monophyletic branch affiliated to the genus Pleionea. The ANI value between strain S1-5-21T and close relative P. mediterranea MOLA115T was estimated to be 70.8 %. The respiratory quinone was found to be Q-8. The predominant fatty acids (>10 %) were identified as iso-C15 : 0, summed feature 9 (iso-C17 : 1 ω9c and/or C16 : 0 10-methyl) and iso-C16 : 0. The polar lipids were identified as phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, two aminolipids, three phospholipids and five unidentified polar lipids. The draft genome size of strain S1-5-21T is 5.2 Mb with genomic G+C content of 40.1 mol%. Based on these results, strain S1-5-21T is concluded to represent a novel species within the genus Pleionea, for which the name Pleioneasediminis sp. nov. is proposed with the type strain S1-5-21T (=MCCC 1K03814T=KCTC 72149T).


Dietary carotenoids and certain cancers, heart disease, and age-related macular degeneration: a review of recent research.
Key epidemiologic studies show associations between high dietary intakes of certain carotenoid-containing fruits and vegetables and reduced risk of prostate cancer, breast cancer, head and neck cancers, cardiovascular disease, and age-related macular degeneration, although overall the evidence is inconsistent. Little is known about the potential biochemical mechanisms whereby carotenoids might protect against disease, and human intervention trials are limited to high dose beta-carotene, which is not protective against lung cancer or cardiovascular disease. Authoritative scientific organizations continue to emphasize increased consumption of fruits and vegetables but do not make specific recommendations for carotenoids because of a lack of data that directly link them to disease reduction.


Initial treatment of Parkinson's disease.
Initial treatment of early idiopathic Parkinson's disease (PD) begins with diagnosis based on clinical evaluation supplemented by laboratory studies and brain imaging to exclude causes of secondary parkinsonism. In most cases, testing is normal and the diagnosis of PD rests on clinical criteria. In patients with mild symptoms and signs, the diagnosis of PD may not initially be apparent, and follow-up evaluation is needed to arrive at a diagnosis. Once the diagnosis is made, pharmacologic treatment may not be the first step. First, patient education is essential, especially because PD is a high-profile disease for which information and misinformation are readily available to patients and families. Counseling concerning prognosis, future symptoms, future disability, and treatment must be provided. Questions from patients concerning diet, lifestyle, and exercise are especially common at this point. The decision of when to initiate treatment is the next major consideration. Much controversy but relatively little light has been brought to bear on this issue. L-dopa was the first major antiparkinson medication to be introduced and remains the "gold standard" of treatment. Next in efficacy are the dopamine agonists (DAs). A debate has raged concerning whether initial dopaminergic treatment should be with L-dopa or DAs. Physicians have been concerned about forestalling the appearance of dyskinesias and motor fluctuations, whereas patients have incorrectly understood that L-dopa and possibly other antiparkinson drugs have a finite duration of usefulness, making it important to defer treatment for as long as possible. This has created "L-dopa phobia," which may stand in the way of useful treatment. In spite of this controversy, there is uniform agreement that the appropriate time to treat is when the patient is beginning to be disabled. This varies from patient to patient and depends on age, employment status, nature of job, level of physical activity, concern about appearance, and other factors. The choice of a specific drug is sometimes dictated by the patient's symptoms. For example, L-dopa is preferable for severe akinesia, an anticholinergic may be useful when tremor is the most prominent symptom (especially in those aged younger than 70 years), and DAs may be indicated for younger patients, more prone to dyskinesias and fluctuations, with relatively mild symptoms. It is also important to manage non-motor symptoms in patients with early PD. Anxiety and depression are particularly common at this stage and may be presenting symptoms of PD. Where appropriate, counseling and/or treatment with anxiolytics and antidepressants should be considered.


Incidence of lymphohaematopoietic malignancies in a petrochemical industry cohort: 1983-94 follow up.
In response to a previous finding of increased mortality from lymphohaematopoietic (LH) malignancies, this study examines incidence of LH malignancy in a petrochemical industry cohort. Emphasis is on chronic lymphocytic leukaemia (CLL) and on comparisons by period of first employment. The study cohort consists of 8942 employees who were active in the period 1970-92 and alive on 31 December 1982. Record linkage with the Louisiana tumour registry (LTR) provided information on cancer for cases occurring between 1983 and 1994. Standardised incidence ratios (SIR), with the south Louisiana population as a comparison, were computed for all cancers, all LH malignancies and specific LH subtypes. Analyses were conducted for sex and race categories, and by period of first employment, job type, duration of employment, and latency. 672 Cases of cancer were identified, including 59 LH malignancies. Women (n=1169) had an overall cancer SIR below unity and four LH malignancies versus 2.28 expected. Among the 7773 men, those first employed before 1950 had no overall cancer excess, a significant 1.4-fold increase in overall LH malignancies (43 observed versus 30.78 expected), and four CLL cases versus 3.27 expected. Findings for men first employed after 1950 are based on fewer cases, but there was no indication of excesses of overall cancer or LH malignancy. Numbers were too small in the group first employed after 1950 for meaningful analysis of LH malignancy subtypes such as CLL (one case). These findings do not suggest a continuing excess of CLL but do suggest a small increase in incidence of overall LH malignancy for workers first employed before 1950. This may reflect associations with earlier workplace conditions, although work related patterns are mixed. Interpretation is limited by the diverse group of diseases within LH malignancies, and the lack of control for non-work factors other than sex, age, race, and period of diagnosis. This study has a major advantage of more complete and reliable cancer ascertainment compared with the mortality investigation, and shows the feasibility and benefits of using cancer registry incidence data in an occupational cohort study.


Vitamin D receptor: key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands.
The vitamin D hormone, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], binds with high affinity to the nuclear vitamin D receptor (VDR), which recruits its retinoid X receptor (RXR) heterodimeric partner to recognize vitamin D responsive elements (VDREs) in target genes. 1,25(OH)(2)D(3) is known primarily as a regulator of calcium, but it also controls phosphate (re)absorption at the intestine and kidney. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced in osteoblasts that, like PTH, lowers serum phosphate by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR and reporter gene transfection assays were used to probe VDR-mediated transcriptional control by 1,25(OH)(2)D(3). Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR ligands. 1,25(OH)(2)D(3) induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses 1,25(OH)(2)D(3) synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH)(2)D(3)-mediated intestinal absorption and counterbalancing renal reabsorption of phosphate, thereby reversing hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH)(2)D(3)-FGF23 axis regulating phosphate is comparable in importance to the 1,25(OH)(2)D(3)-PTH axis that regulates calcium. 1,25(OH)(2)D(3) also elicits regulation of LRP5, Runx2, PHEX, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic. Regulation of mouse RANKL by 1,25(OH)(2)D(3) supports a cloverleaf model, whereby VDR-RXR heterodimers bound to multiple VDREs are juxtapositioned through chromatin looping to form a supercomplex, potentially allowing simultaneous interactions with multiple co-modulators and chromatin remodeling enzymes. VDR also selectively binds certain omega3/omega6 polyunsaturated fatty acids (PUFAs) with low affinity, leading to transcriptionally active VDR-RXR complexes. Moreover, the turmeric-derived polyphenol, curcumin, activates transcription of a VDRE reporter construct in human colon cancer cells. Activation of VDR by PUFAs and curcumin may elicit unique, 1,25(OH)(2)D(3)-independent signaling pathways to orchestrate the bioeffects of these lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues.


HPA axis dampening by limited sucrose intake: reward frequency vs. caloric consumption.
Individuals often cope with stress by consuming calorically-dense, highly-palatable 'comfort' foods. The present work explores the stress-relieving properties of palatable foods in a rat model of limited sucrose intake. In this model, adult male rats with free access to chow and water are given additional access to a small amount of sucrose drink (or water as a control). A history of such limited sucrose intake reduces the collective (HPA axis, sympathetic, and behavioral-anxiety) stress response. Moreover, the stress-dampening by sucrose appears to be mediated primarily by its rewarding properties, since beneficial effects are reproduced by the noncaloric sweetener saccharin but not oral intragastric gavage of sucrose. The present work uses an alternate strategy to address the hypothesis that the rewarding properties of sucrose mediate its stress-dampening. This work varies the duration, frequency, and/or volume of sucrose and assesses the ability to attenuate HPA axis stress responses. The data indicate that HPA-dampening is optimal with a greater duration and/or frequency of sucrose, whereas increasing the volume of sucrose consumed is without effect. This finding suggests that the primary factor mediating stress-dampening is the number/rate of reward (i.e., sucrose) exposures, rather than the total sucrose calories consumed. Collectively, these data support the hypothesis that stress relief by limited palatable food intake is mediated primarily by its hedonic/rewarding properties. Moreover, the results support the contention that naturally rewarding behaviors are a physiological means to produce stress relief.


Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.
Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R(met) strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.


All-Cause Mortality and Cardiovascular Outcomes With Non-Vitamin K Oral Anticoagulants Versus Warfarin in Patients With Heart Failure in the Food and Drug Administration Adverse Event Reporting System.
Many patients with heart failure (HF) are treated with warfarin or non-vitamin K oral anticoagulants (NOACs). Randomized outcome-driven comparisons of different anticoagulant strategies in HF are lacking. Data from international, government-mandated registries may be useful in understanding the real-life use of various anticoagulants and how they are linked to outcomes. To assess 2015 annual all-cause mortality, myocardial infarction, and stroke rates co-reported for warfarin and NOACs in subjects with and without HF in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. We extracted and examined outcome cases in subjects with HF and on warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban and stratified these according to anticoagulants. Annual all-cause mortality, myocardial infarction, and stroke in FAERS. Odds ratio (OR) and χ(Equation is included in full-text article.)for oral anticoagulants from FAERS with and without HF among complete primary reports issued in 2015. FAERS reported 137,026 HF cases, with death co-reported in 42,942 (31.3%). In total, 11,278 (8.2%) HF patients were treated with anticoagulants, with more prescribed warfarin (n = 8260) than all NOACs combined (n = 3018). Very few reports for edoxaban were available. Warfarin consistently displayed a signal for excess adverse events compared to NOACs: OR (95% confidence interval) for the composite of mortality, myocardial infarction, and stroke were 1.91 (1.76-2.07) versus apixaban, 1.92 (1.81-2.03) versus dabigatran, 4.09 (3.38-4.37) versus rivaroxaban, and 2.64 (2.53-2.76) versus all NOACs combined (all P < 0.001). Warfarin, compared to all NOACs combined, demonstrated higher rates of all-cause mortality [OR = 2.69 (95% confidence interval, 2.49-2.90)], myocardial infarction [5.30 (4.17-6.74)], stroke [OR = 8.85 (6.61-11.84)], and ischemic stroke [OR = 12.73 (8.87-18.27); all P < 0.001]. Annual 2015 FAERS profiles in HF patients reveal that warfarin was numerically dominant. Warfarin was associated with higher risk of death, myocardial infarction, and stroke compared to NOACs. These observational data provide real-world insight into a potential safety benefit of NOACs over warfarin in the setting of HF.


The impact of infant formula production on the concentrations of 3-MCPD and glycidyl esters.
Fatty acid esters of 3-monochloropropanediol (3-MCPD), 2-monochlorpropanediol (2-MCPD), and glycidol are process-induced chemical contaminants found in refined vegetable oils. Due to their toxicological properties, there is potential concern regarding exposure to these compounds, particularly for formula-fed infants where refined edible oils are the primary fat source in commercial infant formulas. In order to assess exposure, 55 commercial oil samples, specifically intended for use in infant formula, were collected in 2015 from various infant formula manufacturers in the United States and analysed using a LC-MS/MS direct detection method. At the time of collection, there were no validated methods for the analysis of MCPD and glycidyl esters in infant formula. Therefore, analysis of these commercial oil samples served as an alternative for confirming the presence of these ester contaminants in infant formula. Bound 3-MCPD and glycidol concentrations in these oils ranged from below the limit of quantitation (<LOQ) to 5.13 µg g-1 and <LOQ to 6.14 µg g-1, respectively. Highest ester concentrations were observed in palm olein samples. Concentrations of bound 3-MCPD and glycidol in the commercial oils were consistent with previously published occurrence studies at the time, suggesting that oils used in the manufacture of infant formula were similar (or processed in a similar manner) as refined oils marketed directly to consumers in 2015. In order to determine if conditions during infant formula production impact the presence of 3-MCPD and glycidyl esters in the finished products, concentrations in oils were compared to concentrations in finished infant formula collected at approximately the same time. The comparison revealed that conditions used in the manufacture of infant formula likely initiate the destruction or conversion of glycidyl esters to other compounds, resulting in lower amounts of bound glycidol in the final product relative to the concentrations originally present in the refined oils.


Use of representational difference analysis to identify Escherichia coli O157-specific DNA sequences.
Whereas several important virulence factors in Escherichia coli O157 have been identified, studies suggest they are not always essential and are probably insufficient to account for the severe clinical manifestation of E. coli O157 infection. Identification of putative virulence determinants is crucial to the understanding of bacterial pathogenesis and genomic comparison analysis may aid the characterisation of unidentified virulence attributes. In this study, representational difference analysis (RDA) was used for genomic comparison of E. coli O157 with the proposed ancestral strain, E. coli O55. Unique E. coli O157 gene sequences were isolated and one, termed RDA-1, taken forward for further analysis. Southern blotting with labelled RDA-1 as a probe showed it to be present in 77% of E. coli O157 isolates and absent in all non-E. coli O157 screened. Sequence flanking RDA-1 was obtained from a genomic clone identified by hybridisation, and contained an open reading frame predicted to encode a novel iron-regulated outer membrane protein.


Response of haemocyte lysosomes to bacterial inoculation in the oysters Ostrea edulis L. and Crassostrea gigas (Thunberg) and the scallop Pecten maximus (L).
Data are presented that demonstrate the application of the neutral red retention assay (NRR) to monitor the effects of a bacterial inoculation on the haemocyte lysosomes of the European flat oyster Ostrea edulis, Pacific oyster Crassostrea gigas and scallop Pecten maximus. Bivalves were acclimated to three temperature regimes (5, 15 and 25 degrees C), at constant salinity for 7 days in the laboratory. Once baseline responses to acclimation temperature had been established, the effects of an in vivo inoculation on haemocyte lysosomal stability were assessed using the NRR assay. Lysosomal membrane stability was reduced in the presence of bacteria for all three species of bivalve, but destabilisation of C. gigas haemocyte lysosomes appeared to be most sensitive to the presence of the bacterium Listonella anguillarum. For all three bivalve species, the reduction in lysosomal stability appeared to be proportional to the growth of the bacterial inoculate. Using appropriate controls, the NRR assay was demonstrated to have great potential as a tool with which to make rapid initial assessments of the immune status of bivalve molluscs.


Staphylococcus aureus in chronic rhinosinusitis: the effect on the epithelial chloride channel (cystic fibrosis transmembrane conductance regulator, CFTR) and the epithelial sodium channel (ENaC) physiology.
Background: Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and the paranasal sinuses, often associated with an infection by Staphylococcus aureus (S. aureus). Disturbance in the function of ion channels is regarded as an etiological factor for pathogenesis of CRS. Aims: The study aims to measure the mRNA expression of the ENaC and CFTR ion channels in nasal epithelial cells (NECs) and to investigate the effect of both the budesonide and S. aureus on these ion channels. Materials and method: NECs biopsies obtained from healthy volunteers and patients with CRS. NECs were infected with S. aureus strains and/or budesonide to study the mRNA expression levels of the ENaC and CFTR ion channels. Results: The mRNA expression level of CFTR was increased while that of ENaC was decreased. S. aureus infection and budesonide treatment induced a significant modulation of ENaC and CFTR ion channels expression. Conclusion: The CFTR and ENaC ion channel physiology are of importance in the pathogenesis of CRS. Exposure to S. aureus infection and treatment with budesonide modulated the mRNA expression of CFTR and ENaC ion channels. Significance: Better understanding of the pathophysiology of CRS.


Glucagon-like peptide-1 excites pancreas-projecting preganglionic vagal motoneurons.
Glucagon-like peptide-1 (GLP-1) increases pancreatic insulin secretion via a direct action on pancreatic beta-cells. A high density of GLP-1-containing neurons and receptors is also present in brain stem vagal circuits; therefore, the aims of the present study were to investigate 1) whether identified pancreas-projecting neurons of the dorsal motor nucleus of the vagus (DMV) respond to exogenously applied GLP-1, 2) the mechanism(s) of action of GLP-1, and 3) whether the GLP-1-responsive neurons (putative modulators of endocrine secretion) could be distinguished from DMV neurons responsive to peptides that modulate pancreatic exocrine secretion, specifically pancreatic polypeptide (PP). Whole cell recordings were made from identified pancreas-projecting DMV neurons. Perfusion with GLP-1 induced a concentration-dependent depolarization in approximately 50% of pancreas-projecting DMV neurons. The GLP-1 effects were mimicked by exendin-4 and antagonized by exendin-(9-39). In approximately 60% of the responsive neurons, the GLP-1-induced depolarization was reduced by tetrodotoxin (1 microM), suggesting both pre- and postsynaptic sites of action. Indeed, the GLP-1 effects were mediated by actions on potassium currents, GABA-induced currents, or both. Importantly, neurons excited by GLP-1 were unresponsive to PP and vice versa. These data indicate that 1) GLP-1 may act on DMV neurons to control pancreatic endocrine secretion, 2) the effects of GLP-1 on pancreas-projecting DMV neurons are mediated both via a direct excitation of their membrane as well as via an effect on local circuits, and 3) the GLP-1-responsive neurons (i.e., putative endocrine secretion-controlling neurons) could be distinguished from neurons responsive to PP (i.e., putative exocrine secretion-controlling neurons).


Functional coupling of acoustic and chemical signals in the courtship behaviour of the male Drosophila melanogaster.
During courtship, the male Drosophila melanogaster sends signals to the female through two major sensory channels: chemical and acoustic. These signals are involved in the stimulation of the female to accept copulation. In order to determine the respective importance in the courtship of these signals, their production was controlled using genetical and surgical techniques. Males deprived of the ability to emit both signals are unable to mate, demonstrating that other (e.g. visual or tactile) signals are not sufficient to stimulate the female. If either acoustic or chemical signals are lacking, the courtship success is strongly reduced, the lack of the former having significantly more drastic effects. However, the accelerated matings of males observed with males bearing wild-type hydrocarbons compared with defective ones, whichever the modality of acoustic performance (wing vibration or playback), strongly support the role of cuticular compounds to stimulate females. We can conclude that among the possible factors involved in communication during courtship, acoustic and chemical signals may act in a synergistic way and not separately in D. melanogaster.


Late virus replication events in microglia are required for neurovirulent retrovirus-induced spongiform neurodegeneration: evidence from neural progenitor-derived chimeric mouse brains.
CasBrE is a neurovirulent murine retrovirus which induces a spongiform myeloencephalopathy in susceptible mice. Genetic mapping studies have indicated that sequences responsible for neurovirulence reside within the env gene. To address the question of direct envelope protein neuroxicity in the central nervous system (CNS), we have generated chimeric mice expressing the CasBrE envelope protein in cells of neuroectodermal origin. Specifically, the multipotent neural progenitor cell line C17.2 was engineered to express the CasBrE env gene as either gp70/p15E (CasE) or gp70 alone (CasES). CasE expression in these cells resulted in complete (>10(5)) interference of superinfection with Friend murine leukemia virus clone FB29, whereas CasES expression resulted in a 1.8-log-unit decrease in FB29 titer. Introduction of these envelope-expressing C17.2 cells into the brains of highly susceptible IRW mice resulted in significant engraftment as integral cytoarchitecturally correct components of the CNS. Despite high-level envelope protein expression from the engrafted cells, no evidence of spongiform neurodegeneration was observed. To examine whether early virus replication events were necessary for pathogenesis, C17.2 cells expressing whole virus were transplanted into mice in which virus replication in the host was specifically restricted by Fv-1 to preintegration events. Again, significant C17.2 cell engraftment and infectious virus expression failed to precipitate spongiform lesions. In contrast, transplantation of virus-expressing C17.2 progenitor cells in the absence of the Fv-1 restriction resulted in extensive spongiform neurodegeneration by 2 weeks postengraftment. Cytological examination indicated that infection had spread beyond the engrafted cells, and in particular to host microglia. Spongiform neuropathology in these animals was directly correlated with CasBrE env expression in microglia rather than expression from neural progenitor cells. These results suggest that the envelope protein of CasBrE is not itself neurotoxic but that virus infectious events beyond binding and fusion in microglia are necessary for the induction of CNS disease.


Chewing ability and associated factors in older adults in Germany. Results from GEDA 2019/2020-EHIS.
Oral well-being is an important component of general well-being and quality of life, as it is greatly influenced by the ability to chew and speak, and thus by central factors of social interaction. Because quality of life and participation are important factors for health in older age, the aim of this article was to examine the chewing ability, including associated factors, for the older population in Germany on the basis of a nationally representative sample. Database is the German Health Update (GEDA 2019/2020-EHIS), a population based cross-sectional survey of the Robert Koch Institute. In the telephone interview, participants aged 55 years and older were asked: "Do you have difficulty biting and chewing on hard foods such as a firm apple? Would you say 'no difficulty', 'some difficulty', 'a lot of difficulty' or 'cannot do at all/ unable to do'?" Prevalences and multivariate prevalence ratios (PR) were calculated with 95% confidence intervals (95% CI) from log-Poisson regressions. Sociodemographic, health-, behavioral- and care-related characteristics were investigated as associated factors. The analyses were based on data from 12,944 participants (7,079 women, 5,865 men). The proportion of people with reduced chewing ability was 20.0%; 14.5% had minor difficulty, 5.5% had major difficulty. There were no differences between women and men. The most important associated factors for reduced chewing ability were old age (PR 1.8, 95% CI 1.5-2.1), low socioeconomic status (PR 2.0, 95% CI 1.7-2.5), limitations to usual activities due to health problems (PR 1.9, 1.6-2.2), depressive symptoms (PR 1.7, 1.5-2.1), daily smoking (PR 1.6, 95% CI 1.3-1.8), low dental utilization (PR 1.6, 95% CI 1.4-1.9), and perceived unmet needs for dental care (PR 1.7, 95% CI 1.5-2.1). One fifth of adults from 55 years of age reported reduced chewing ability. Thus, this is a very common functional limitation in older age. Reduced chewing ability was associated with almost all investigated characteristics. Therefore, its prevention requires a holistic view in the living environment and health care context of older people. Given that chewing ability influences quality of life and social participation, maintaining or improving chewing ability is important for healthy aging.


Prevalence of Recurrent Stroke among a Rehabilitation Cohort in Nigeria.
A recurrent stroke increases the rates of mortality and morbidity after an initial stroke. There is, however, a dearth of data on the prevalence of recurrent stroke in Nigeria. A secondary analysis of the data obtained from 100 stroke survivors undergoing physiotherapy at 2 health facilities in Nigeria was carried out to document the prevalence of recurrent stroke. The association between recurrent stroke and selected socio-demographic and clinical factors of the participants was explored using logistic regression analysis. Thirty-two (32%) participants had had a recurrent stroke. Employment status and educational level were significantly associated with recurrent stroke. The outcome of the logistic regression analysis further showed that participants who were employed (OR = 0.08; P<0.001; 95% CI = 0.02-0.32) and who had no formal education (OR = 0.22; P = 0.03; 95% CI = 0.05-0.87) were significantly less likely to present with recurrent stroke compared to the unemployed participants and those who had tertiary educational qualification, respectively. Approximately 1 in 3 stroke survivors undergoing rehabilitation had experienced stroke recurrence. The finding of this study buttresses the urgent need to emphasize and aggressively pursue secondary stroke prevention. Further studies are, however, required to explore those potentially modifiable factors that are associated with recurrent stroke, and having more representative samples.


Pemetrexed Versus Erlotinib in the Second-line Treatment of Patients with Advanced-stage Non-squamous NSCLC Harboring Wild-type EGFR Gene.
Pemetrexed and erlotinib represent different agents commonly used for the second-line treatment of patients with advanced-stage non-small cell lung cancer (NSCLC). We analyzed data of 137 patients with advanced-stage non-squamous NSCLC treated with pemetrexed or erlotinib in the second line. All patients harbored a wild-type epidermal growth factor receptor gene. Genetic testing was performed using a combination of denaturing capillary electrophoresis and direct Sanger sequencing. overall response rate and disease control rate in patients treated with pemetrexed was 20.8% and 62.5% vs. 6.3% and 53.2% in patients treated with erlotinib (p=0.022; p=0.358). Median progression-free and overall survival in patients treated with pemetrexed was 1.6 and 11.3 months vs. 1.9 and 11.4 months in patients treated with erlotinib (p=0.470 and p=0.942, respectively). Erlotinib was associated with skin rash and diarrhea; pemetrexed was associated with hematological toxicity and fatigue. A similar efficacy and different, although well-tolerated, toxicity profile of both pemetrexed and erlotinib was shown.