[Guideline for therapy of malignant thyroid tumours: pleading for an actualization].
Total (or near total) thyroidectomy (TE) followed by radioiodine ((131)I) ablation (RIA) of residual thyroid tissue is considered to be the ideal treatment for differentiated thyroid carcinoma. However, the actual guideline of the DGN (German Society of Nuclear Medicine) recommends for the so-called papillary micro-carcinoma of the thyroid (PMC) no further therapeutic strategy (no complete TE, no (131)I-ablation of the remaining lobe). PMC has been defined as papillary carcinoma measuring 1 cm (T1) in maximal diameter according to the World Health Organization classification system for thyroid tumours (1988). The new WHO-classification (starting in 2003) defines the T1-tumour measuring 2 cm in maximal diameter. The authors demand a new, modern guideline, following the new WHO classification. This includes, that despite the overall excellent prognosis for patients with PMC, the treatment of patients with T1-tumours of the new WHO-classification (including the "old" PMC) should be no different from the treatment of patients with conventional papillary thyroid carcinoma, i.e. complete surgery (TE and central lymph node dissection) followed by RIA of residual thyroid tissue. The authors argue that it is not appropriate to consider the tumour size as the single most important key factor for therapy and prognosis. Even small tumours may have poor prognostic factors, such as lymph node metastasis, multifocality or molecular characteristics (expression of oncogenes).


Cbl-b promotes chemotherapy-induced apoptosis in rat basophilic leukemia cells by suppressing PI3K/Akt activation and enhancing MEK/ERK activation.
The ubiquitin ligase Cbl-b is a negative regulator of the PI3K/Akt pathway, the survival pathway implicated in chemotherapy resistance. However, it remains unclear whether Cbl-b can regulate chemosensitivity through modulating Akt activation. In this study, VP-16-induced RBL-2H3 cells apoptosis was accompanied by the activation of Akt and ERK. The PI3K inhibitor LY294002, not the ERK inhibitor PD98059, enhanced the apoptosis. In addition, down-regulation of Cbl-b was also detected. Over expression of Cbl-b significantly enhanced VP-16-induced cell apoptosis with inhibition of Akt activity, while a dominant negative (DN) RING Finger domain mutation completely abolished this enhancement. On the other hand, ERK activity was enhanced by Cbl-b, and the ERK inhibitor PD98059 reversed Cbl-b-enhanced apoptosis. The consistent results were also showed in the process of Ara-c treatment. These observations indicate that Cbl-b promotes RBL-2H3 apoptosis induced by VP-16 or Ara-c, probably through inhibition of Akt and activation of ERK.


[Analysis of synaptic neurotransmitter release mechanisms using bacterial toxins].
Several bacterial toxins are powerful and highly specific tools for studying basic mechanisms involved in cell biology. Whereas the clostridial neurotoxins are widely used by neurobiologists, many other toxins (i.e. toxins acting on small G-proteins or actin) are still overlooked. Botulinum neurotoxins (BoNT, serotypes A-G) and tetanus neurotoxin (TeNT), known under the generic term of clostridial neurotoxins, are characterized by their unique ability to selectively block neurotransmitter release. These proteins are formed of a light (Mr approximately 50) and a heavy (Mr approximately 100) chain which are disulfide linked. The cellular action of BoNT and TeNT involves several steps: heavy chain-mediated binding to the nerve ending membrane, endocytosis, and translocation of the light chain (their catalytic moiety) into the cytosol. The light chains each cleaves one of three, highly conserved, proteins (VAMP/synaptobrevin, syntaxin, and SNAP-25 also termed SNAREs) implicated in fusion of synaptic vesicles with plasma membrane at the release site. Hence, when these neurotoxins are applied extracellularly, they can be used as specific tools to inhibit evoked and spontaneous transmitter release from certain neurones whereas, when the membrane limiting steps are bypassed by the mean of intracellular applications, BoNTs orTeNT can be used to affect regulated secretion in various cell types. Several members of the Rho GTPase family have been involved in intracellular trafficking of synaptic vesicles and secretory organelles. As they are natural targets for several bacterial exoenzymes or cytotoxins, their role in neurotransmitter release can be probed by examining the action of these toxins on neurotransmission. Such toxins include: i) the non permeant C3 exoenzymes from C. botulinum or C. limosum which ADP-ribosylate and thereby inactivate Rho, ii) exoenzyme S from Pseudomonas aeruginosa which ADP-ribosylates different members of the Ras, Rab, Ral and Rap families, iii) toxin B from C. difficile which glucosylates Rho, Rac and CDC42, iv) lethal toxin from C. sordellii which glucosylates Rac, Ras and to a lesser extent, Rap and Ral, but not on Rho or CDC42, and v) CNF deamidases secreted by pathogenic strains of E. coli which activate Rho and, to a lesser extent, CDC42. Since these toxins or exoenzymes have no or little ability to enter into the neurones, they must be applied intraneuronally to bypass the membrane limiting steps. Injection of several of these toxins into Aplysia neurones allowed us to reveal a new role for Rac in the control of exocytosis. ADP-ribosylating enzymes, which specifically act on monomeric actin (C2 binary toxin from C. botulinum and iota toxin from C. perfringens), are potential tools to probe the role of actin filaments during secretion.


The evolutionary potential of an insect invader under climate change.
Although the impacts of climate change and invasive species are typically studied in isolation, they likely interact to reduce the viability of plant and animal populations. Indeed, invasive species, by definition, have succeeded in areas outside of their native range and may therefore have higher adaptive capacity relative to native species. Nevertheless, the genetic architecture of the thermal niche, which sets a limit to the potential for populations to evolve rapidly under climate change, has never been measured in an invasive species in its introduced range. Here, we estimate the genetic architecture of thermal performance in the harlequin beetle (Harmonia axyridis), a Central Asian species that has invaded four continents. We measured thermal performance curves in more than 400 third-generation offspring from a paternal half-sib breeding experiment and analyzed the genetic variance-covariance matrix. We show that while the critical thermal limits in this species have an additive genetic basis, most components of the thermal performance curve have low heritability. Moreover, we found evidence that genetic correlations may constrain the evolution of beetles under climate change. Our results suggest that some invasive species may have limited evolutionary capacity under climate change, despite their initial success in colonizing novel environments.


Prognostic value of regional lymph node status in canine mammary carcinomas.
In this study, we have determined the prognostic value of the presence of the micrometastases and metastases greater than 2 mm in the regional lymph nodes for bitches with mammary carcinomas. The study involved 51 dogs diagnosed with a single malignant epithelial tumour in the 4th or 5th mammary gland. All animals underwent regional mastectomy; the 4th and 5th mammary glands were removed together with the inguinal lymph node. The lymph nodes were examined immunohistochemically using the anti-cytokeratin antibody, clone AE1/AE3. The bitches were followed up every 6 months for 2 years after surgery to determine the disease-free survival (DFS) and overall survival (OS). The Kaplan-Meier analysis showed a statistically significant difference in DFS and OS only between the group of bitches without metastases and the group with lymph node metastases greater than 2 mm. No significant differences between these two groups versus bitches with lymph node micrometastases were found.


Bacterial mechanosensitive channels as a paradigm for mechanosensory transduction.
Research on bacterial mechanosensitive (MS) channels has since their discovery been at the forefront of the MS channel field due to extensive studies of the structure and function of MscL and MscS, two of the several different types of MS channels found in bacteria. Just a few years after these two MS channels were cloned their 3D structure was solved by X-ray crystallography. Today, the repertoire of multidisciplinary approaches used in experimental and theoretical studies following the cloning and crystallographic determination of the MscL and MscS structure has expanded by including electronparamagnetic resonance (EPR) and Förster resonance energy transfer (FRET) spectroscopy aided by computational modelling employing molecular dynamics as well as Brownian dynamics simulations, which significantly advanced the understanding of structural determinants of the gating and conduction properties of these two MS channels. These extensive multidisciplinary studies of MscL and MscS have greatly contributed to elucidation of the basic physical principles of MS channel gating by mechanical force. This review summarizes briefly the major experimental and conceptual advancements, which helped in establishing MscL and MscS as a major paradigm of mechanosensory transduction in living cells.


The in vitro effects of dehydroepiandrosterone on human osteoarthritic chondrocytes.
To investigate the in vitro effects of dehydroepiandrosterone (DHEA) on human osteoarthritic chondrocytes. Chondrocytes isolated from human osteoarthritic knee cartilage were three-dimensionally cultured in alginate beads, except for cell proliferation experiment. Cells were treated with DHEA in the presence or absence of IL-1beta. The effects on chondrocytes were analyzed using a 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay (for chondrocyte proliferation), a dimethylmethylene blue (DMB) assay (for glycosaminoglycan (GAG) synthesis), and an indole assay (for DNA amount). Gene expressions of type I and II collagen, metalloproteinase-1 and -3 (MMP-1 and -3), and tissue inhibitor of metalloproteinase-1 (TIMP-1) as well as the IL-1beta-induced gene expressions of MMP-1 and -3 were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The protein synthesis of MMP-1 and -3 and TIMP-1 was determined by Western blotting. The treatment of chondrocytes with DHEA did not affect chondrocyte proliferation or GAG synthesis up to 100 micro M of concentration. The gene expression of type II collagen increased in a dose-dependent manner, while that of type I decreased. DHEA suppressed the expression of MMP-1 significantly at concentrations exceeding 50 micro M. The gene expression of MMP-3 was also suppressed, but this was without statistical significance. The expression of TIMP-1 was significantly increased by DHEA at concentrations exceeding 10 micro M. The effects of DHEA on the gene expressions of MMP-1 and -3 were more prominent in the presence of IL-1beta, in which DHEA suppressed not only MMP-1, but also MMP-3 at the lower concentrations, 10 and 50 micro M, respectively. Western blotting results were in agreement with RT-PCR, which indicates that DHEA acts at the gene transcription level. Our study demonstrates that DHEA has no toxic effect on chondrocytes up to 100 micro M of concentration and has an ability to modulate the imbalance between MMPs and TIMP-1 during OA at the transcription level, which suggest that it has a protective role against articular cartilage loss.


Dynamics and plasticity of stimulus-selective persistent activity in cortical network models.
Persistent neuronal activity is widespread in many areas of the cerebral cortex of monkeys performing cognitive tasks with a working memory component. Modeling studies have helped understanding of the conditions under which persistent activity can be sustained in cortical circuits. Here, we first review several basic models of persistent activity, including bistable models with excitation only and multistable models for working memory of a discrete set of pictures or objects with structured excitation and global inhibition. In many experiments, persistent activity has been shown to be subject to changes due to associative learning. In cortical network models, Hebbian learning shapes the synaptic structure and, in turn, the properties of persistent activity when pictures are associated together in the course of a task. It is shown how the theoretical models can reproduce basic experimental findings of neurophysiological recordings from inferior temporal and perirhinal cortices obtained using the following experimental protocols: (i) the pair-associate task; (ii) the pair-associate task with color switch; and (iii) the delay match to sample task with a fixed sequence of samples.


Detection of Methylated Circulating DNA as Noninvasive Biomarkers for Breast Cancer Diagnosis.
Internationally, breast cancer is the most common female cancer, and is induced by a combination of environmental, genetic, and epigenetic risk factors. Despite the advancement of imaging techniques, invasive sampling of breast epithelial cells is the only definitive diagnostic procedure for patients with breast cancer. To date, molecular biomarkers with high sensitivity and specificity for the screening and early detection of breast cancer are lacking. Recent evidence suggests that the detection of methylated circulating cell-free DNA in the peripheral blood of patients with cancer may be a promising quantitative and noninvasive method for cancer diagnosis. Methylation detection based on a multi-gene panel, rather than on the methylation status of a single gene, may be used to increase the sensitivity and specificity of breast cancer screening. In this review, the results of 14 relevant studies, investigating the efficacy of cell-free DNA methylation screening for breast cancer diagnosis, have been summarized. The genetic risk factors for breast cancer, the methods used for breast cancer detection, and the techniques and limitations related to the detection of cell-free DNA methylation status, have also been reviewed and discussed. From this review, we conclude that the analysis of peripheral blood or other samples to detect differentially methylated cell-free DNA is a promising technique for use in clinical settings, and may improve the sensitivity of screening for both, early detection and disease relapse, and thus improve the future prognosis of patients with breast cancer.


Risser sign: the value of the lateral spinal radiograph to assess the excursion of the iliac apophysis.
The course of the ossification of the iliac apophysis is considered in adolescent patients with idiopathic scoliosis, under the name of the Risser sign, to determine the remaining spinal growth. Although the iliac crest develops in the three-dimensional space as a complex structure, the iliac apophysis ossification has been assessed only on a one plane frontal spinal radiograph. This study points out the usefulness of the lateral radiograph for the visualization of the whole iliac crest, especially the posterior region which otherwise cannot be observed. Two young female pelvis specimen were examined with anatomical measurements and radiography. Lateral spinal radiographs of 201 girls were analyzed for the iliac apophysis excursion. The measures of the width of the iliac bone beneath the iliac crest revealed one anterior and one posterior thick regions, coupled with an intermediate thin region. The regions of the maximal thickness corresponded to the earliest appearance of the apophysis ossification (Risser 1), while the thin part of the iliac bone corresponded to late appearance of the apophysis ossification (Risser 3-4). The ossification of the posterior part of the crest was best visualized with the lateral radiograph, which was exclusive in showing the posterior superior iliac spine region. On the frontal spinal radiograph the end of the course of the apophysis (Risser 3-4) is usually searched at the level of the sacroiliac joint, while in reality this point was found to be situated more caudal, and accessible for observation on the lateral radiograph.


The emergence of spin electronics in data storage.
Electrons have a charge and a spin, but until recently these were considered separately. In classical electronics, charges are moved by electric fields to transmit information and are stored in a capacitor to save it. In magnetic recording, magnetic fields have been used to read or write the information stored on the magnetization, which 'measures' the local orientation of spins in ferromagnets. The picture started to change in 1988, when the discovery of giant magnetoresistance opened the way to efficient control of charge transport through magnetization. The recent expansion of hard-disk recording owes much to this development. We are starting to see a new paradigm where magnetization dynamics and charge currents act on each other in nanostructured artificial materials. Ultimately, 'spin currents' could even replace charge currents for the transfer and treatment of information, allowing faster, low-energy operations: spin electronics is on its way.


Acidic fibroblast growth factor prevents death of spinal cord motoneurons in newborn rats after nerve section.
The death of spinal axotomised motoneurons provides a useful tool for studying neurotrophic factors which could prevent motoneuron loss in vivo. Median and ulnar nerves of newborn rats were unilaterally sectioned and topically treated with either a vehicle solution or acidic fibroblast growth factor (aFGF). aFGF treatment increased the survival of the median and ulnar spinal motoneurons, after 7 days of axotomy, from 37% to 63%. These results show that aFGF is a neurotrophic factor for newborn spinal motoneurons, and suggest that this protein is a potential therapeutic agent for preventing the death of damaged motoneurons.


[Peroxidase activity of catalase modified by progesterone].
Catalase conjugates with 3, 7, 9 and 42 progesterone molecules were obtained by the reaction between the enzyme and N-oxy-succinimide ether of 3-0-carboxymethyloxime of progesterone. The enzyme modified by 42 progesterone molecules is effective in o-dianisidine oxidation by hydrogen peroxide and has a kcat/KM value of 512 M-1 s-1. The catalase conjugates with 3, 7 and 9 progesterone molecules exhibit a high activity during o-dianisidine oxidation by cumene hydroperoxide. The activity of conjugates is higher than that of the native non-modified enzyme in the same reaction. The maximum effectiveness was observed for catalase modified by 7 progesterone molecules. This conjugate is characterized by kcat/KM of 99,000 M-1 s-1 at 30 degrees C. The effect of the degree of enzyme modification on the kinetic parameters of o-dianisidine oxidation by H2O2 and cumene hydroperoxide is discussed.


Simultaneous Cardiac Surgery and Renal Transplantation Compared With Renal Transplantation After Cardiac Surgery.
Patients with end-stage renal disease (ESRD) have a high prevalence of coronary artery disease and cardiovascular death. The mortality and the morbidity rates of cardiac surgery are particularly high in these patients with end-stage renal disease. Performing cardiac surgery and kidney transplantation in the same session can reduce these complications in the early postoperative period by normalizing renal function. We compared the mortality and morbidity rates between patients who had undergone cardiac surgery and kidney transplantation separately and patients who had combined surgeries. This retrospective study consisted of 75 patients. One group of 60 patients underwent cardiac surgery and kidney transplantation in separate sessions, and the other group of 15 patients had combined surgeries in the same session, between March 2008 and September 2012. Patients who had combined surgeries achieved fluid electrolytic balance more easily, had shorter extubation times, used less blood and blood products, and had fewer major complications. The patients recovered faster and thus had shorter stays in the intensive care unit and hospital. This combined surgical approach allows normalized kidney function in patients with end-stage renal disease, so mortality and morbidity in the early postoperative period could be significantly reduced.


The magnitude and correlates of unintended childbearing in Kenya: Implications for the family planning programme.
This paper investigates the magnitude and correlates of unintended childbearing among Kenyan women. The data are drawn from the 1993 Kenya Demographic and Health survey. The results obtained indicate that unintended childbearing is quite high in the country with mistimed childbearing being higher than unwanted childbearing. Unintended child bearing and its components vary significantly according to the socio-economic and characteristics of the population. The high prevalence of unintended childbearing in the country indicates that the existing reproductive and family planning programmes have not been very effective in enabling the majority of Kenyan couples and individuals in realising their fertility preferences. Since one of the goals of family planning and reproductive health programmes is to ensure that women, and indeed couples, have the right to decide whether to have children, how many and when to have them, it is imperative that the high level of unintended child bearing is substantially eliminated by providing couples and individuals with effective means and strategies. Eliminating unintended childbearing requires substantial increase in people's access to and correct use of effective contraception methods. Therefore, reproductive health and family planning programmes should aim not only at increasing their coverage, but also at making effective contraceptives available to all individuals needing them and providing education and information that promotes correct us of contraceptive methods. This entails persuading nonusers to become users of effective methods and emphasising eliminating unintended child bearing among women who are already contracepting.


Porcine Parvovirus Infection Causes Pig Placenta Tissue Damage Involving Nonstructural Protein 1 (NS1)-Induced Intrinsic ROS/Mitochondria-Mediated Apoptosis.
Porcine parvovirus (PPV) is an important pathogen causing reproductive failure in pigs. PPV-induced cell apoptosis has been recently identified as being involved in PPV-induced placental tissue damages resulting in reproductive failure. However, the molecular mechanism was not fully elucidated. Here we demonstrate that PPV nonstructural protein 1 (NS1) can induce host cell apoptosis and death, thereby indicating the NS1 may play a crucial role in PPV-induced placental tissue damages and reproductive failure. We have found that NS1-induced apoptosis was significantly inhibited by caspase 9 inhibitor, but not caspase 8 inhibitor, and transfection of NS1 gene into PK-15 cells significantly inhibited mitochondria-associated antiapoptotic molecules Bcl-2 and Mcl-1 expressions and enhanced proapoptotic molecules Bax, P21, and P53 expressions, suggesting that NS1-induced apoptosis is mainly through the mitochondria-mediated intrinsic apoptosis pathway. We also found that both PPV infection and NS1 vector transfection could cause host DNA damage resulting in cell cycle arrest at the G1 and G2 phases, trigger mitochondrial ROS accumulation resulting in mitochondria damage, and therefore, induce the host cell apoptosis. This study provides a molecular basis for elucidating PPV-induced cell apoptosis and reproductive failure.


Amphipolar, Amphiphilic 2,4-diarylpyrano[2,3-b]indoles as Turn-ON Luminophores in Acidic and Basic Media.
A versatile amphiphilic pyrano[2,3-b]indole for halochromic turn-ON luminescence in acidic or basic media is accessed by an insertion-coupling-cycloisomerization and adjusting solubilizing and phenolic functionalities. While almost non-emissive in neutral solutions, treatment with acids or bases like trifluoroacetic acid (TFA) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) reveals distinct luminescence at wavelengths of 540 nm or 630 nm in propan-2-ol, respectively. Turn-ON emission can be detected at pH values as mild as pH = 5.31 or 8.70. Quantum yields in propan-2-ol are substantial for protonated (Φf = 0.058) and deprotonated (Φf = 0.059) species. Photometrically, pKa1 of 3.5 and pKa2 of 10.5 were determined in propan-2-ol. With lipophilic polyether sidechains and hydrophilic protonation and deprotonation sites the molecule can be regarded as amphipolar, which results in good solubility properties for different organic solvents. In aqueous media, an organic co-solvent like propan-2-ol (35%) or tetrahydrofuran (25%) is needed, and the solution can be diluted with pure water without precipitation of the compound. At higher concentrations of water, a turbid solution is formed, which indicates the formation of micellar structures or clusters. With dynamic light scattering we could show that these clusters increase in size with increasing water content.


Iso-lactam and reduced amide analogues of the peptidomimetic dopamine receptor modulator 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide.
An analogue of the highly potent gamma-lactam Pro-Leu-Gly-NH(2) peptidomimetic, 3(R)-[(2(S)-pyrrolidinylcarbonyl) amino]-2-oxo-1-pyrrolidineacetamide (2), 4(R)-[[2(S)-pyrrolidinylcarbonyl]amino]-2-oxo-1-pyrrolidineacetamide (3), in which the lactam carbonyl moiety has been placed in a different position with respect to the 3-amino group was synthesized. Also, a series of analogues of 2, compounds 4-6, were synthesized in which each of the amide bonds of 2 were systematically replaced with a reduced amide bond surrogate. The analogues were tested for their ability to enhance the binding of [3H]N-propylnorapomorphine to dopamine receptors in a functional in vitro assay utilizing bovine striatal membranes. Peptidomimetic 3 was shown to be more potent than 2, while 4 and 5 were significantly less effective than 2. Peptidomimetic 6 had a pharmacological profile similar to that of 2.


Sepsis-induced myocardial dysfunction.
Sepsis leads to a complex intramyocardial inflammatory response that results in sepsis-induced myocardial dysfunction. Here, recent findings are reviewed in a physiologic context. Decreased systolic contractility during sepsis limits ventricular ejection and stroke volume. Initially, this effect is compensated for by increased diastolic filling during volume resuscitation. Reduced afterload due to arterial vasodilation also compensates so that cardiac output can be maintained or increased. Recent results recognize the importance of diastolic dysfunction, reduced ventricular diastolic compliance that impedes ventricular filling. Diastolic dysfunction becomes increasingly important as severity of septic shock increases. When impaired ventricular ejection is coupled with limited diastolic filling, stroke volume must decrease. Accordingly, diastolic dysfunction is more closely related to mortality than systolic dysfunction. Recent trials of beta-adrenergic agonists and levosimendan have been disappointing, while approaches to modulating the intramyocardial inflammatory response show promise. Sepsis-induced myocardial dysfunction is increasingly recognized as a major contributor to outcome of septic shock. Significant strides have been made in understanding the intramyocardial inflammatory response that causes myocardial dysfunction. A number of novel approaches show promise by modulating the intramyocardial inflammatory response.


A Src/Abl kinase inhibitor, SKI-606, blocks breast cancer invasion, growth, and metastasis in vitro and in vivo.
The central role of Src in the development of several malignancies, including breast cancer, and the accumulating evidence of its interaction with receptor tyrosine kinases, integrins, and steroid receptors have identified it as an attractive therapeutic target. In the current study, we have evaluated the effect of a Src/Abl kinase inhibitor, SKI-606, on breast cancer growth, migration, invasion, and metastasis. Treatment of human breast cancer cells MDA-MB-231 with SKI-606 caused a marked inhibition of cell proliferation, invasion, and migration by inhibiting mitogen-activated protein kinase and Akt phosphorylation. For in vivo studies, MDA-MB-231 cells transfected with the plasmid encoding green fluorescent protein (GFP; MDA-MB-231-GFP) were inoculated into the mammary fat pads of female BALB/c nu/nu mice. Once tumor volume reached 30 to 50 mm(3), animals were randomized and treated with vehicle alone or 150 mg/kg SKI-606 by daily oral gavage. Experimental animals receiving SKI-606 developed tumors of significantly smaller volume (45-54%) compared with control animals receiving vehicle alone. Analysis of lungs, liver, and spleen of these animals showed a significant decrease in GFP-positive tumor metastasis in animals receiving SKI-606 at a dose that was well tolerated. Western blot analysis and immunohistochemical analysis of primary tumors showed that these effects were due to the ability of SKI-606 to block tumor cell proliferation, angiogenesis, growth factor expression, and inhibition of Src-mediated signaling pathways in vivo. Together, the results from these studies provide compelling evidence for the role of Src inhibitors as therapeutic agents for blocking breast cancer growth and metastasis.


SphereCon-a method for precise estimation of residue relative solvent accessible area from limited structural information.
In proteins, solvent accessibility of individual residues is a factor contributing to their importance for protein function and stability. Hence one might wish to calculate solvent accessibility in order to predict the impact of mutations, their pathogenicity and for other biomedical applications. A direct computation of solvent accessibility is only possible if all atoms of a protein three-dimensional structure are reliably resolved. We present SphereCon, a new precise measure that can estimate residue relative solvent accessibility (RSA) from limited data. The measure is based on calculating the volume of intersection of a sphere with a cone cut out in the direction opposite of the residue with surrounding atoms. We propose a method for estimating the position and volume of residue atoms in cases when they are not known from the structure, or when the structural data are unreliable or missing. We show that in cases of reliable input structures, SphereCon correlates almost perfectly with the directly computed RSA, and outperforms other previously suggested indirect methods. Moreover, SphereCon is the only measure that yields accurate results when the identities of amino acids are unknown. A significant novel feature of SphereCon is that it can estimate RSA from inter-residue distance and contact matrices, without any information about the actual atom coordinates. https://github.com/kalininalab/spherecon. email@example.com. Supplementary data are available at Bioinformatics online.


MicroRNAs in colorectal cancer as markers and targets: Recent advances.
MicroRNAs are evolutionarily conserved small non-coding RNA molecules encoded by eukaryotic genomic DNA, and function in post-transcriptional regulation of gene expression via base-pairing with complementary sequences in target mRNAs, resulting in translational repression or degradation of target mRNAs. They represent one of the major types of epigenetic modification and play important roles in all aspects of cellular activities. Altered expression of microRNAs has been found in various human diseases including cancer. Many efforts have been made to discover the characteristic microRNA expression profiles, to understand the roles of aberrantly expressed microRNAs and underlying mechanisms in different cancers. With the application of DNA microarray, real-time quantitative polymerase chain reaction and other molecular biology techniques, increasing evidence has been accumulated which reveal that aberrant microRNAs can be detected not only intracellularly within the cancer cells, but also extracellularly in plasma of patients, postulating the potential of aberrant microRNAs as promising diagnostic/prognostic markers and attracting therapeutic targets. This review is intended to provide the most recent advances in microRNA studies in one of the most common cancers, colorectal cancer, especially the identification of those specifically altered microRNAs in colorectal cancer, validation for their relevance to clinical pathological parameters of patients, functional analyses and potential applications of these microRNAs.


Challenges in tin perovskite solar cells.
Perovskite solar cells are the rising star of third-generation photovoltaic technology. With a power conversion efficiency of 25.5%, the record efficiency is close to the theoretical maximum efficiency of a single-junction solar cell. However, lead toxicity threatens commercialization efforts and market accessibility. In this context, Sn-based perovskites are a safe alternative. Nevertheless, the efficiency of Sn-based devices falls far behind the efficiency of Pb-based counterparts. This concise review sheds light on the challenges that the field faces toward making Sn-based perovskites the perovskite photovoltaic benchmark. We identified four key challenges: materials and solvents, film formation, Sn(II) oxidation, and energy band alignment. We illustrate every single challenge and highlight the most successful attempts to overcome them. Finally, we provide our opinion on the most promising trends of this field in the future.


Dental health education programme for 6-year-olds: a cluster randomised controlled trial.
Oral health is a reflection of general health and significantly influences the quality of life. Dental caries is one of the most common chronic diseases of childhood which may adversely affect physical, mental and social growth of children. Oral hygiene methods can effectively prevent oral and dental diseases, and oral hygiene education plays an important role in this regard. The aim of the present study was then to assess the effect of oral hygiene education on the oral and dental health of 6-year-olds. A hundred and sixty 6-year-old children from 4 pre-school centers were divided into two groups, case and control, in this cluster randomised controlled trail. The children in the case group received oral and dental education in one session. The parents of the case group were also instructed in one session. The children and parents of the control group did not receive any instructions. Plaque index (PI): Turesky-Gilmore-Glickman; gingival index (GI): Loe & Silness; at a) baseline, b) 1.5 and c) 6 months after the first examination. Data were analysed by repeated measure ANOVA. PI: A significant difference was found between the baseline examination and the first follow-up (p < 0.01), and between the baseline examination and the second follow-up (p < 0.001). GI: Although values in the case group were lower, no statistically significant difference was found between the two groups and within each group (p > 0.05). Regarding the number of brushing times, a statistically significant difference was found between the first and the second follow-ups of the study groups (p > 0.05). The brushing type and the application of other hygienic measures did not show any difference (p > 0.05). Within the limitations of the present study it may be concluded that oral hygiene instruction to 6-year-old children and their parents improves their dental health.


Maximal Ca2+-activated force and myofilament Ca2+ sensitivity in intact mammalian hearts. Differential effects of inorganic phosphate and hydrogen ions.
Myofilament Ca2+ sensitivity and maximal Ca2+-activated force are fundamental properties of the contractile proteins in the heart. Although these properties can be evaluated directly in skinned preparations, they have remained elusive in intact tissue. A novel approach is described that allows maximal Ca2+-activated force to be measured and myofilament Ca2+ sensitivity to be deduced from isovolumic pressure in intact perfused ferret hearts. Phosphorus nuclear magnetic resonance spectra are obtained sequentially to measure the intracellular inorganic phosphate (Pi) and hydrogen ion (H+) concentrations. After a period of perfusion with oxygenated, HEPES-buffered Tyrode solution, hypoxia is induced as a means of elevating [Pi]. The decline in twitch pressure can then be related to the measured increase in [Pi]. After recovery, hearts are perfused with ryanodine to enable tetanization and the measurement of maximal Ca2+-activated pressure. Hypoxia is induced once again, and maximal pressure is correlated with [Pi]. We then compare the relations between [Pi] and maximal pressure on the one hand, and [Pi] and twitch pressure on the other. If the two relations differ only by a constant scaling factor, then the decline in twitch pressure can be attributed solely to a decline in maximal pressure, with no change in myofilament sensitivity. We obtained such a result during hypoxia, which indicated that Pi accumulation decreases maximal force but does not change myofilament sensitivity. We compared these results with acidosis (induced by bubbling with 5% CO2). In contrast with Pi, the accumulation of H+ decreases twitch force primarily by shifting myofilament Ca2+ sensitivity. This approach in intact tissue has strengths and limitations complementary to those of skinned muscle experiments.


Bisphosphonates: a review of their novel anti-inflammatory properties and potential for the treatment of rheumatoid arthritis.
Bisphosphonates (BP) are synthetic pyrophosphates with a stable P-C-P bond replacing the more labile P-O-P bond. This structural class has been used extensively for the treatment of bone diseases, such as osteoporosis and hypercalcemia due to the propensity of BP to bind mineralized tissues and prevent bone resorption. Rheumatoid arthritis (RA) is characterized by chronic inflammatory synovitis, pannus tissue formation and erosion of bone and cartilage, which is a major, disabling, pathogenic feature poorly managed with existing disease modifying anti-rheumatic drugs (DMARDs). A few investigators have used BP in combination with anti-arthritic therapy to treat the bone erosion component of RA, reports of which are mainly anecdotal. We review data suggesting that BP possess novel anti-inflammatory properties which may also be of benefit for the treatment of the chronic inflammatory component of RA, thus modifying the subsequent destructive disease process by mechanisms unrelated to direct inhibition of bone resorption. The rationale for pursuing this therapeutic approach to demonstrate BP anti-inflammatory activity will be reviewed. The subsequent design and synthesis of new BP chemical entities and their altered pharmacokinetic properties will also be discussed.


A multicentre study of how goal-setting is practised during inpatient stroke rehabilitation.
To describe goal-setting during inpatient stroke rehabilitation. There were two stages: an electronic questionnaire for multidisciplinary teams and an analysis of goal-setting documentation for rehabilitation patients. Five inpatient stroke units. Staff involved in goal-setting and patients undergoing stroke rehabilitation. A total of 13 therapists and 49 patients were recruited, and 351 documented goals were examined. All units used therapist-led goal-setting (60% of goals were set by therapists). In total, 72% of goals were patient-focused but patients and families were rarely directly involved. Goals focussed on basic mobility and activities of daily living (~50% and ~25% of goals, respectively). Only 41% of documented goals met the SMART criteria. Review of progress was limited: 48% of goals were never reviewed and 24% of the remainder were merely marked as 'ongoing' without a date or plan for completion. New goals and actions were often documented without any connection to previous goals. Integration between goals and treatment/action plans was mixed. In two units, goals were unconnected to a treatment or action plan, but for the remainder it was 90%-100%. However, that connection was generally vague and amounted to suggestions of the type of treatment modality that staff might employ. Goal-setting during inpatient stroke rehabilitation is therapist-led but discussed with the multidisciplinary team. Therapists mainly identified patient-focussed mobility and activities of daily living goals. Monitoring progress and revising goals were often uncompleted. Links between goals and treatment, action plans and progress were patchy.


In vitro evaluation of antibiotic synergy for polymyxin B-resistant carbapenemase-producing Klebsiella pneumoniae.
Since carbapenemase-producing Klebsiella pneumoniae strains were first reported in North Carolina, these highly resistant organisms have been isolated with increasing frequency, especially in the New York City area. Polymyxin B is one of the few antimicrobials that retain reliable activity against these organisms. However, polymyxin B MICs are elevated against K. pneumoniae isolates with increasing frequency, leaving clinicians with few therapeutic options. We investigated several antimicrobial agents for potential synergy with polymyxin B against 12 clinical strains of carbapenemase-producing K. pneumoniae. A broth microdilution assay using a 96-well plate was developed in which graded dilutions of polymyxin B and the study drug were incubated with resistant isolates in a checkerboard pattern. Polymyxin B was studied in combination with cefazolin, ceftriaxone, cefepime, imipenem, gentamicin, tigecycline, doxycycline, and rifampin. All K. pneumoniae strains tested positive for K. pneumoniae carbapenemase (KPC) genes by real-time PCR and had elevated polymyxin B MIC values ranging from 16 to 128 μg/ml. Synergy was observed with the combination of polymyxin B and rifampin as well as with polymyxin B and doxycycline, resulting in at least a 4-fold decrease in the polymyxin B MIC. For both combinations, this effect occurred at physiologically achievable concentrations. Less pronounced synergy was noted with tigecycline and polymyxin B. No synergy was observed at physiologic concentrations with the other antimicrobials studied. These results suggest that rifampin, doxycycline, and tigecycline may be useful additions to polymyxin B in the treatment of infections caused by highly resistant carbapenemase-producing K. pneumoniae. Further studies are warranted to determine if these in vitro findings translate into clinical efficacy.


Supramolecular Self-Assembly To Control Structural and Biological Properties of Multicomponent Hydrogels.
Self-assembled nanofibers are ubiquitous in nature and serve as inspiration for the design of supramolecular hydrogels. A multicomponent approach offers the possibility of enhancing the tunability and functionality of this class of materials. We report on the synergistic multicomponent self-assembly involving a peptide amphiphile (PA) and a 1,3:2,4-dibenzylidene-d-sorbitol (DBS) gelator to generate hydrogels with tunable nanoscale morphology, improved stiffness, enhanced self-healing, and stability to enzymatic degradation. Using induced circular dichroism of Thioflavin T (ThT), electron microscopy, small-angle neutron scattering, and molecular dynamics approaches, we confirm that the PA undergoes self-sorting, while the DBS gelator acts as an additive modifier for the PA nanofibers. The supramolecular interactions between the PA and DBS gelators result in improved bulk properties and cytocompatibility of the two-component hydrogels as compared to those of the single-component systems. The tunable mechanical properties, self-healing ability, resistance to proteolysis, and biocompatibility of the hydrogels suggest future opportunities for the hydrogels as scaffolds for tissue engineering and drug delivery vehicles.


Prevalence and Associated Factors of Diabetes Mellitus Among Adult Population in Hawassa Zuria Woreda, Sidama Region, Ethiopia.
Diabetes mellitus (DM) is one of the main health problems in unindustrialized countries. According to the International Diabetes Federation report, adults living with diabetes were growing from time to time globally. Worldwide, diabetes mellitus accounts for 8.8% (424.9 million) morbidity and 4 million deaths. Ethiopia is one of the countries frequently affected by the disease with about 2.567 million (5.2%) of its population affected with diabetes mellitus. This study was aimed at determining the prevalence and associated factors of diabetes mellitus among adult population in Hawassa Zuria Woreda, Sidama Region, Ethiopia. Community-based cross-sectional study was conducted from January 1 to February 15, 2019 among 519 adult population. A study participant was selected using a multistage sampling technique. We had employed the World Health Organization (WHO) stepwise method for non-communicable disease surveillance to collect the data. Fasting glucose meter was used from venous blood to test for blood glucose level. EPI info was used to enter and clean the data and the data were transported to SPSS for analysis. To assess associated factors with diabetes mellitus adjusted odds ratio (aORs) with 95% confidence intervals (CIs) was employed and p.value <0.05 was considered significant. A total of 516 participants were included in the study. The diabetes mellitus prevalence was found to be 12.4% (95% CI: 9.5-15.2). Factors associated with diabetes mellitus were being obese [AOR=9.2, 95% CI:4.3, 19.8], hypertensive (AOR=3.8, 95% CI:1.75, 8.4), cigarette smoking (AOR=7.8, 95% CI: 3.45, 18.1) and high waist circumference (AOR=25, 95% CI:8.5, 79). This study revealed that the prevalence of diabetes mellitus was found to be high, which was greater than the estimated national prevalence of diabetes mellitus. Obesity, hypertension, cigarette smoking and high waist circumference were determinant factors for diabetes mellitus. Appropriate actions such as creating community awareness on regular blood sugar testing and preventive measures are recommended.


PD-L1 blockade TAM-dependently potentiates mild photothermal therapy against triple-negative breast cancer.
The present work was an endeavor to shed light on how mild photothermia possibly synergizes with immune checkpoint inhibition for tumor therapy. We established mild photothermal heating protocols to generate temperatures of 43 °C and 45 °C in both in vitro and in vivo mouse 4T1 triple-negative breast cancer (TNBC) models using polyglycerol-coated carbon nanohorns (CNH-PG) and 808 nm laser irradiation. Next, we found that 1) CNH-PG-mediated mild photothermia (CNH-PG-mPT) significantly increased expression of the immune checkpoint PD-L1 and type-1 macrophage (M1) markers in the TNBC tumors; 2) CNH-PG-mPT had a lower level of anti-tumor efficacy which was markedly potentiated by BMS-1, a PD-L1 blocker. These observations prompted us to explore the synergetic mechanisms of CNH-PG-mPT and BMS-1 in the context of tumor cell-macrophage interactions mediated by PD-L1 since tumor-associated macrophages (TAMs) are a major source of PD-L1 expression in tumors. In vitro, the study then identified two dimensions where BMS-1 potentiated CNH-PG-mPT. First, CNH-PG-mPT induced PD-L1 upregulation in the tumor cells and showed a low level of cytotoxicity which was potentiated by BMS-1. Second, CNH-PG-mPT skewed TAMs towards an M1-like anti-tumor phenotype with upregulated PD-L1, and BMS-1 bolstered the M1-like phenotype. The synergistic effects of BMS-1 and CNH-PG-mPT both on the tumor cells and TAMs were more pronounced when the two cell populations were in co-culture. Further in vivo study confirmed PD-L1 upregulation both in tumor cells and TAMs in the TNBC tumors following treatment of CNH-PG-mPT. Significantly, TAMs depletion largely abolished the anti-TNBC efficacy of CNH-PG-mPT alone and in synergy with BMS-1. Collectively, our findings reveal PD-L1 upregulation to be a key response of TNBC to mild photothermal stress, which plays a pro-survival role in the tumor cells while also acting as a brake on the M1-like activation of the TAMs. Blockade of mPT‑induced PD‑L1 achieves synergistic anti-TNBC efficacy by taking the intrinsic survival edge off the tumor cells on one hand and taking the brakes off the M1-like TAMs on the other. Our findings reveal a novel way (i.e. mild thermia plus PD-L1 blockade) to modulate the TAMs-tumor cell interaction to instigate a mutiny of the TAMs against their host tumor cells.


Monitoring Wind-Borne Particle Matter Entering Poultry Farms via the Air-Inlet: Highly Pathogenic Avian Influenza Virus and Other Pathogens Risk.
Wind-supported transport of particle matter (PM) contaminated with excreta from highly pathogenic avian influenza virus (HPAIv)-infected wild birds may be a HPAIv-introduction pathway, which may explain infections in indoor-housed poultry. The primary objective of our study was therefore to measure the nature and quantity of PM entering poultry houses via air-inlets. The air-inlets of two recently HPAIv-infected poultry farms (a broiler farm and a layer farm) were equipped with mosquito-net collection bags. PM was harvested every 5 days for 25 days. Video-camera monitoring registered wild bird visits. PM was tested for avian influenza viruses (AIV), Campylobacter and Salmonella with PCR. Insects, predominantly mosquitoes, were tested for AIV, West Nile, Usutu and Schmallenberg virus. A considerable number of mosquitoes and small PM amounts entered the air-inlets, mostly cobweb and plant material, but no wild bird feathers. Substantial variation in PM entering between air-inlets existed. In stormy periods, significantly larger PM amounts may enter wind-directed air-inlets. PM samples were AIV and Salmonella negative and insect samples were negative for all viruses and bacteria, but several broiler and layer farm PM samples tested Campylobacter positive. Regular wild (water) bird visits were observed near to the poultry houses. Air-borne PM and insects-potentially contaminated with HPAIv or other pathogens-can enter poultry air-inlets. Implementation of measures limiting this potential introduction route are recommended.


Phylogenetic signal in module composition and species connectivity in compartmentalized host-parasite networks.
Abstract Across different taxa, networks of mutualistic or antagonistic interactions show consistent architecture. Most networks are modular, with modules being distinct species subsets connected mainly with each other and having few connections to other modules. We investigate the phylogenetic relatedness of species within modules and whether a phylogenetic signal is detectable in the within- and among-module connectivity of species using 27 mammal-flea networks from the Palaearctic. In the 24 networks that were modular, closely related hosts co-occurred in the same module more often than expected by chance; in contrast, this was rarely the case for parasites. The within- and among-module connectivity of the same host or parasite species varied geographically. However, among-module but not within-module connectivity of host and parasites was somewhat phylogenetically constrained. These findings suggest that the establishment of host-parasite networks results from the interplay between phylogenetic influences acting mostly on hosts and local factors acting on parasites, to create an asymmetrically constrained pattern of geographic variation in modular structure. Modularity in host-parasite networks seems to result from the shared evolutionary history of hosts and by trait convergence among unrelated parasites. This suggests profound differences between hosts and parasites in the establishment and functioning of bipartite antagonistic networks.


Seroprevalence of Coxiella burnetii in Australian dogs.
The role of dogs in the transmission of Coxiella burnetii to humans is uncertain, and extensive seroprevalence studies of dogs have not been previously conducted in Australia. This study determined C. burnetii exposure in four diverse canine subpopulations by adapting, verifying and comparing an indirect immunofluoresence assay (IFA) and an enzyme-linked immunosorbent assay (ELISA) used to detect anti-C. burnetii antibodies in humans. Canine serum samples (n = 1223) were tested with IFA from four subpopulations [breeding establishments; household pets; free-roaming dogs in Aboriginal communities; shelter dogs]. The proportions of seropositive dogs were as follows: breeding (7/309, 2.3%), household pets (10/328, 3%), Aboriginal communities (21/321, 6.5%) and shelters (5/265, 1.9%). Dogs from Aboriginal communities were 2.8 times (CI 1.5-5.1; P < 0.001) more likely to be seropositive than dogs from other populations. The ELISA was used on 86 of 1223 sera tested with IFA, and a Cohen's Kappa coefficient of 0.60 (CI 0.43-0.78) indicated good agreement between the two assays. This study has established that Australian dogs within all four subpopulations have been exposed to C. burnetii and that a higher seroprevalence was observed amongst free-roaming dogs associated with Aboriginal communities. As C. burnetii recrudesces during pregnancy and birth products contain the highest concentration of organism, individuals assisting at the time of parturition, those handling pups shortly after birth as well as those residing in the vicinity of whelping dogs are potentially at risk of developing Q fever. However, the identification of active antigen shed in excreta from seropositive dogs is required in order to accurately define and quantify the public health risk.


Sea-level rise exponentially increases coastal flood frequency.
Sea-level rise will radically redefine the coastline of the 21st century. For many coastal regions, projections of global sea-level rise by the year 2100 (e.g., 0.5-2 meters) are comparable in magnitude to today's extreme but short-lived increases in water level due to storms. Thus, the 21st century will see significant changes to coastal flooding regimes (where present-day, extreme-but-rare events become common), which poses a major risk to the safety and sustainability of coastal communities worldwide. So far, estimates of future coastal flooding frequency focus on endpoint scenarios, such as the increase in flooding by 2050 or 2100. Here, we investigate the continuous shift in coastal flooding regimes by quantifying continuous rates of increase in the occurrence of extreme water-level events due to sea-level rise. We find that the odds of exceeding critical water-level thresholds increases exponentially with sea-level rise, meaning that fixed amounts of sea-level rise of only ~1-10 cm in areas with a narrow range of present-day extreme water levels can double the odds of flooding. Combining these growth rates with established sea-level rise projections, we find that the odds of extreme flooding double approximately every 5 years into the future. Further, we find that the present-day 50-year extreme water level (i.e., 2% annual chance of exceedance, based on historical records) will be exceeded annually before 2050 for most (i.e., 70%) of the coastal regions in the United States. Looking even farther into the future, the present-day 50-year extreme water level will be exceeded almost every day during peak tide (i.e., daily mean higher high water) before the end of the 21st century for 90% of the U.S. coast. Our findings underscore the need for immediate planning and adaptation to mitigate the societal impacts of future flooding.


Integrated care for older adults during the COVID-19 pandemic in Belgium: Lessons learned the hard way.
The corona pandemic challenges countries worldwide in many different ways. Due to its magnitude and impact on global health, this health crisis exposes several shortcomings in their health systems and emphasizes their shortcomings and deficiencies. These deficiencies have quickly affected the most frail citizens, such as older people. The first wave of the COVID19 pandemic in Belgium has quickly shown that nursing homes were not prepared for these kinds of crises. The nature, speed and extent gave rise to an accelerated and more extensive collaboration between various nursing homes and Ghent University Hospital. Before this crisis, the level of integrated care between nursing homes and hospitals was mostly limited. But setting up a strong collaboration model and integrated care between nursing homes and hospitals enables the nursing homes to manage this specific and complex care in their own environment. IMPLICATIONS FOR PRACTICE: This case study shows that integrated care is possible and that both the hospital and the nursing homes benefit from such a system. Investments in people, resources, training and guidance concerning transitional care and knowledge exchange between hospitals and nursing homes, are necessary to guarantee a more efficient and robust approach to (pandemic) crises in nursing homes.


Employment status of people with mental illness: national survey data from 2009 and 2010.
The aim of this study was to describe employment according to mental illness severity in the United States during 2009 and 2010. The sample included all working-age participants (ages 18-64) from the 2009 and 2010 National Survey on Drug Use and Health (N=77,326). Two well-established scales of mental health distinguished participants with none, mild, moderate, and serious mental illness. Analyses compared employment rate and income by mental illness severity. Employment status was estimated with logistic regression models that controlled for demographic characteristics and substance use disorders. In secondary analyses the relationship between mental illness and employment was assessed for variation by age and education status. Employment rates decreased with increasing mental illness severity (no mental illness, 75.9% employment; mild, 68.8%; moderate, 62.7%; and serious, 54.5%, p<.001). Over a third of people with serious mental illness, 38.5%, had incomes <$10,000 (compared with 23.1% of people with no mental illness, p<.001). The gap in adjusted employment rates comparing persons with serious versus no mental illness was 1% among people 18-25 years old versus 21% among people 50-64 (p<.001). More severe mental illness was associated with lower employment rates in 2009 and 2010. People with serious mental illness are less likely than people with no, mild, or moderate mental illness to be employed after age 49.


Convolutional Neural Network for Estimating Spatiotemporal and Kinematic Gait Parameters using a Single Inertial Sensor.
Lower limb disability severely impacts gait, thus requiring clinical interventions. Inertial sensor systems offer the potential for objective monitoring and assessment of gait in and out of the clinic. However, it is imperative such systems are capable of measuring important gait parameters while being minimally obtrusive (requiring few sensors). This work used convolutional neural networks to estimate a set of six spatiotemporal and kinematic gait parameters based on raw inertial sensor data. This differs from previous work which either was limited to spatiotemporal parameters or required conventional strap-down integration techniques to estimate kinematic parameters. Additionally, we investigated a data segmentation method which does not rely on gait event detection, further supporting its applicability in real-world settings.Preliminary results demonstrate our model achieved high accuracy on a mix of spatiotemporal and kinematic gait parameters, either meeting or exceeding benchmarks based on literature. We achieved 0.04 ± 0.03 mean absolute error for stance-time symmetry ratio and an absolute error of 4.78 ± 4.78, 4.50 ± 4.33, and 6.47 ± 7.37cm for right and left step length and stride length, respectively. Lastly, errors for knee and hip ranges of motion were 2.31 ± 4.20 and 1.73 ± 1.93°, respectively. The results suggest that machine learning can be a useful tool for long-term monitoring of gait using a single inertial sensor to estimate measures of gait quality.


The physical state of potassium ion in the living cell.
This review summarizes more than 30 years of experimental testing (and confirmation) of a key postulate of the association-induction (AI) hypothesis: most K+ ions in resting cells are adsorbed on beta- and gamma-carboxyl group of cell proteins in a close-contact one ion-one site manner. Failure of healthy, cytoplasm-free, squid axon-membrane sacs to selectively accumulate K+ over Na+ and success of muscle cells without a functional cell membrane (and postulated pumps) to achieve the same, point to the cytoplasm as the seat of selective K+ accumulation. Four independent techniques unanimously confirmed the predicted localization in striated muscle cells, of the bulk of cell K+ in the A-bands where 65% of the beta- and gamma-carboxyl groups are located. Strict adherence to the Langmuir adsorption isotherm in the equilibrium distribution of K+ in muscle cells in the absence and presence of competing ions, proved one ion-one site, close contact adsorption of cell K+ on anionic groups. The "effectively membrane-pumpless open-ended cell" (EMOC) technique, further helped to establish close contact adsorption of K+ to take place in the cytoplasm rather than the cell membrane. A pK, of 3.9 obtained by titration of the cytoplasmic anions groups and a sensitivity to specific carboxyl group-reagent, 1-ethyl-3-(3-dimethylamino-propyl) carbodimide HCl combine to establish that the cytoplasmic anionic sites adsorbing K+ are indeed beta- and gamma-carboxyl groups.


Stability of ranitidine syrup re-packaged in unit-dose containers.
The stability of ranitidine syrup re-packaged in unit-dose containers was studied. Oral ranitidine hydrochloride syrup containing 16.8 mg/mL of ranitidine hydrochloride (equivalent to 15 mg of ranitidine) in original bulk containers and re-packaged in unit-dose amber-colored glass bottles sealed with aluminum caps were obtained from commercial sources. For extended-stability determinations, samples were stored for 52 weeks at 25 degrees C and 40% relative humidity and analyzed at 0, 4, 13, 26, 39, and 52 weeks. For accelerated stability determinations, samples were stored for 13 weeks at 40 degrees C and 25% relative humidity and analyzed at 0, 4, 9, and 13 weeks. Stability was assessed using high-performance liquid chromatography and by measuring changes in pH and sample weight. The principal impurity and total impurities were also measured. No significant changes in pH were demonstrated, and all values remained well within acceptable limits. The weight change in samples was greater for re-packaged samples stored in accelerated conditions compared with that of samples in the original packaging; however, the differences were not significant. Ranitidine hydrochloride samples in both types of packaging remained stable when stored at 25 degrees C and 40% relative humidity for 52 weeks and at 40 degrees C and 25% relative humidity for 13 weeks. The impurity profiles remained within acceptable limits for all samples. Re-packaged ranitidine syrup was stable for up to 52 weeks when stored at 25 degrees C and 40% relative humidity and for up to 13 weeks when stored at 40 degrees C and 25% relative humidity.


Nanostructure of an ionic liquid-glycerol mixture.
The nanostructure of a 50 : 50 vol% mixture of glycerol and ethylammonium formate (EAF), a protic ionic liquid (IL), has been investigated using neutron diffraction and empirical potential structure refinement (EPSR) fits. EPSR fits reveal that the mixture is nanostructured. Electrostatic interactions between IL charge groups leads to the formation of ionic regions. These solvophobically repel cation alkyl groups which cluster together to form apolar domains. The polar glycerol molecules are preferentially incorporated into the charged domains, and form hydrogen bonds with EAF groups rather than with other glycerol molecules. However, radial distribution functions reveal that glycerol molecules pack around each other in a fashion similar to that found in pure glycerol. This suggests that a glycerol channel runs through the ionic domain of EAF. The absence of significant glycerol-glycerol hydrogen bonding indicates that glycerol molecules are able to span the polar domain, bridging EAF charge groups. Glycerol can adopt six distinct conformations. The distribution of conformers in the EAF mixture is very different to that found in the pure liquid because hydrogen bonds form with EAF rather than with other glycerol molecules, which imparts different packing constraints.


The effects of discourse genre on English language complexity in school-age deaf students.
This study explored the effects of discourse genre on the complexity of English language produced by school-age deaf students. Subjects were 13 profoundly deaf students, ages 7;1 to 14;8, who had been educated using only an English-based sign system in public schools. Language samples were elicited in three conditions: a traditional spontaneous interaction, a narrative elicitation using pictures, and an interview in which the examiner asked cognitively and linguistically challenging questions. The results show that students produced the most complex English language during the interview, as measured by the use of embedded clauses, conjunctions, and modals. In contrast to previous studies, utterance length in this one did not vary as a function of sample type, likely because segmentation of the samples was based on the T-unit, not sentences. The results have implications for language sampling with school-age students, both in terms of efficacy and ecological validity.


pp60c-src expression in the developing rat brain.
We have studied pp60c-src expression in the striatum, hippocampus, and cerebellum of the developing rat brain. In the striatum, pp60c-src protein kinase activity peaks during embryonic development and then declines in the adult. The peak activity occurs in the striatum on embryonic day 20 (E20) when it is 18- to 20-fold higher than the activity in fibroblasts and 4- to 5-fold higher than the activity in the striatum at E15 or in the adult striatum. In the hippocampal region, pp60c-src activity reaches a maximum shortly after birth but remains high throughout life. On postnatal day 2 (P2) the activity in the hippocampus is 9- to 13-fold higher than the activity in fibroblasts and twice as high as the activity in the hippocampus at E18. In the cerebellum, the kinase activity remains constant from E20 onward and is 6- to 10-fold higher than that observed in fibroblasts. The increase in pp60c-src kinase activity observed during the development of the striatum and hippocampus is due to an increase in the amount of pp60c-src protein and to an increase in the specific activity of the kinase. The increase in specific activity in these regions coincides with the peak periods of neurogenesis and neuronal growth. In the striatum, we have found that the increase in pp60c-src activity also parallels the increase observed in culture as embryonic striatal neurons differentiate. Taken together, our results are consonant with the idea that pp60c-src is the product of a developmentally regulated gene that is important for the differentiation and/or the continuing function of neurons.


Percutaneous sciatic nerve block with tramadol induces analgesia and motor blockade in two animal pain models.
Local anesthetic efficacy of tramadol has been reported following intradermal application. Our aim was to investigate the effect of perineural tramadol as the sole analgesic in two pain models. Male Wistar rats (280-380 g; N = 5/group) were used in these experiments. A neurostimulation-guided sciatic nerve block was performed and 2% lidocaine or tramadol (1.25 and 5 mg) was perineurally injected in two different animal pain models. In the flinching behavior test, the number of flinches was evaluated and in the plantar incision model, mechanical and heat thresholds were measured. Motor effects of lidocaine and tramadol were quantified and a motor block score elaborated. Tramadol, 1.25 mg, completely blocked the first and reduced the second phase of the flinching behavior test. In the plantar incision model, tramadol (1.25 mg) increased both paw withdrawal latency in response to radiant heat (8.3 ± 1.1, 12.7 ± 1.8, 8.4 ± 0.8, and 11.1 ± 3.3 s) and mechanical threshold in response to von Frey filaments (459 ± 82.8, 447.5 ± 91.7, 320.1 ± 120, 126.43 ± 92.8 mN) at 5, 15, 30, and 60 min, respectively. Sham block or contralateral sciatic nerve block did not differ from perineural saline injection throughout the study in either model. The effect of tramadol was not antagonized by intraperitoneal naloxone. High dose tramadol (5 mg) blocked motor function as well as 2% lidocaine. In conclusion, tramadol blocks nociception and motor function in vivo similar to local anesthetics.


Clinical features and carotid duplex sonography in patients with carotid transient ischemic attacks.
Transient ischemic attack (TIA) is recognized as a precursor of cerebral infarction. It is prompted by an embolism from extracranial carotid artery disease. However, extracranial carotid disease is less prevalent in Chinese patients. Non-invasive duplex sonography has been used for initial screening for extracranial carotid artery disease. One hundred and twenty-seven consecutive patients with carotid TIA were divided into two groups according to sonographic results, Group I: < or = 50%, and Group II: > 50% stenosis of the carotid artery. The two groups were compared for the clinical manifestations, risk factors, brain computed tomography (CT) findings and subsequent stroke. An age and sex-matched group of patients with lacunar stroke was also collected from the same neurosonological data bank for further comparative analysis. The mean age at onset was 59 +/- 12 (mean SD) years. Hypertension was the most common risk factor. The most common symptom was transient focal motor deficit (73%) with or without other complaints. Eighty-two percent of the TIA episodes were less than one hour in duration. In Group I, there were 114 patients (90%) with stenosis < or = 50% ipsilateral to the symptomatic side. Group II included only 13 patients (10%) with the ipsilateral carotid artery stenosis > 50%. Mean age was older and cigarette smoking was more common in Group II (p < 0.05). Otherwise, no significant difference was noted between the two groups in initial characteristics of TIAs, risk factors, brain CT findings or subsequent stroke. Further, there was no statistical significant difference between the TIA and lacunar stroke groups in the degree of carotid stenosis. Hypertension was the most common risk factor for carotid TIAs. The prevalence of extracranial carotid artery disease was low in Chinese patients with carotid TIAs. The severity of the carotid artery was not predictive of recurrence of TIA or of subsequent stroke. There was no significant difference between patients with TIA and with lacunar stroke in sonographic findings of extracranial carotid arteries.


Epigenetic RELN Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders.
REELIN (RELN) is a large (420 kDa) glycoprotein that in adulthood is mostly synthesized in GABAergic neurons of corticolimbic structures. Upon secretion in the extracellular matrix (ECM), RELN binds to VLDL, APOE2, and α3β2 Integrin receptors located on dendritic shafts and spines of postsynaptic pyramidal neurons. Reduced levels of RELN expression in the adult brain induce cognitive impairment and dendritic spine density deficits. RELN supplementation recovers these deficits suggesting a trophic action for RELN in synaptic plasticity. We and others have shown that altered RELN expression in schizophrenia (SZ) and bipolar (BP) disorder patients is difficult to reconcile with classical Mendelian genetic disorders and it is instead plausible to associate these disorders with altered epigenetic homeostasis. Support for the contribution of altered epigenetic mechanisms in the down-regulation of RELN expression in corticolimbic structures of psychotic patients includes the concomitant increase of DNA-methyltransferases and the increased levels of the methyl donor S-adenosylmethionine (SAM). It is hypothesized that these conditions lead to RELN promoter hypermethylation and a reduction in RELN protein amounts in psychotic patients. The decreased synthesis and release of RELN from GABAergic corticolimbic neurons could serve as a model to elucidate the epigenetic pathophysiological mechanisms acting at pyramidal neuron dendrites that regulate synaptic plasticity and cognition in psychotic and non-psychotic subjects.


HIV type 1 phenotype correlates with the stage of infection in vertically infected children.
A cohort of 39 vertically infected children (class N, A, B, and C of the CDC HIV classification for pediatric infection) was studied by virus isolation and non-syncytium inducing (NSI)/syncytium inducing (SI) HIV-1 phenotype evaluation. The HIV-1 isolates were recovered from PBMCs and the MT-2 cell line was used to perform the syncytium assay. HIV-1 could be isolated in 34 of 39 (87%) infected children, regardless of the clinical and immunological stage of the disease. Class N and A subjects harbored exclusively NSI strains, whereas the SI phenotype was detected in two of eight class B and five of nine class C patients. All of the SI variants were observed in severely CD4-depleted children (class 3 patients). The capability of pediatric HIV-1 isolates to induce a cytopathic effect is associated with the clinical status and the degree of CD4 depletion. These data suggest that the biological properties of HIV-1 isolates in children do not differ from those observed in adults, and that viral phenotype strictly correlates with disease progression in vertically infected children.


A function for the RING finger domain in the allosteric control of MDM2 conformation and activity.
The MDM2 oncoprotein plays multiple regulatory roles in the control of p53-dependent gene expression. A picture of MDM2 is emerging where structurally discrete but interdependent functional domains are linked through changes in conformation. The domain structure includes: (i) a hydrophobic pocket at the N terminus of MDM2 that is involved in both its transrepressor and E3-ubiqutin ligase functions, (ii) a central acid domain that recognizes a ubiquitination signal in the core DNA binding domain of p53, and (iii) a C-terminal C2H2C4 RING finger domain that is required for E2 enzyme-binding and ATP-dependent molecular chaperone activity. Here we show that the binding affinity of MDM2s hydrophobic pocket can be regulated through the RING finger domain and that increases in pocket affinity are reflected by a gain in MDM2 transrepressor activity. Thus, mutations within the RING domain that affect zinc coordination, but not one that inhibits ATP binding, produce MDM2 proteins that have a higher affinity for the BOX-I transactivation domain of p53 and a reduced I(0.5) for p53 transrepression. An allosteric model for regulation of the hydrophobic pocket is supported by differences in protein conformation and pocket accessibility between wild-type and the RING domain mutant MDM2 proteins. Additionally the data demonstrate that the complex relationship between different domains of MDM2 can impact on the efficacy of anticancer drugs directed toward its hydrophobic pocket.


Impact of timing of atrial fibrillation, CHA2DS2-VASc score and cancer therapeutics on mortality in oncology patients.
To investigate timing and age distribution of atrial fibrillation (AF) in selected oncology patients, and the impact of AF timing, CHA2DS2-VASc score and cancer therapeutics on mortality. This is a retrospective cohort study of oncology patients referred to the cardio-oncology service from 2011 to 2018 for echocardiographic cardiosurveillance and/or pre-existing cardiovascular risk factor/disease management. Rates of first AF diagnosis was assessed using a parametric multiphase hazard model (predictive modelling) and non-parametrically by Kaplan-Meier with transformations tested using a bootstrap methodology. Among 6754 patients identified, 174 patients had their first AF diagnosis before cancer while 609 patients had their first diagnosis of AF after cancer. Most first AF diagnosis occurred at/early after cancer diagnosis. Increasing AF prevalence at time of cancer diagnosis was seen across older age groups ranges. Diagnosis of cancer at an older age and exposure to cardiotoxic treatment (anthracyclines, HER2-neu inhibitors, tyrosine kinase inhibitors including ibrutinib and radiation) were associated with an increased risk of AF.Modelling of the hazard function of AF identified a high left-skewed peak within 3 years after cancer diagnosis ('early phase'), followed by a gradual late slight rise 3 years after cancer diagnosis ('late phase'). AF diagnosis was only associated with death in the early phase (p<0.001), while CHA2DS2-VASc score was only associated with death in the late phase (p<0.001). This study reports a nuanced/complex relationship between AF and cancer. First diagnosis of AF in patients with cancer was more common at/early after cancer diagnosis, especially in older patients and those exposed to cardiotoxic treatment. Pre-existing AF or a diagnosis of AF within 3 years after cancer diagnosis carried a negative prognosis. CHA2DS2-VASc score did not relate to mortality in those that developed AF within 3 years of cancer diagnosis.


17p13 (p53 locus), 5q21 (APC locus) and 9p21 (p16 locus) allelic deletions are frequently found in oral exfoliative cytology cells from smoker patients with non-small-cell lung cancer.
Molecular cytogenetic and LOH analyses of non-small cell lung cancer (NSCLC) have shown frequent allelic deletions in a variety of chromosomes where tumour suppressor genes are located. Allelic loss at 9p21 (p16 locus), 17p13 (p53) and 5q21(APC) has been frequently described in NSCLC and has also been described in premalignant epithelial lesions of the bronchus and normal bronchial cells. These findings suggest that a tissue field of somatic genetic alterations precedes the histopathological phenotypic changes of carcinoma. Similar changes have been described in oral and laryngeal epithelial tumours associated with smoke exposure. We previously reported frequent LOH at 5q21, 9p21 and TP53 in tumor cells and peritumoral normal bronchial cells from surgically resected NSCLC. We now analyze 96 cases of normal oral exfoliative cytology in which normal epithelial cells were obtained: 43 cases from smoker patients with NSCLC diagnosis, 33 smoker patients with no evidence of malignancy and 20 non-smoker patients with no evidence of tumour. All groups had a similar age and sex distribution. PCR amplification was performed utilising the specific markers D5S346, D9S157 and TP53. In normal oral mucosae cells from patients with NSCLC, we found that 21% of the informative cases showed LOH at any of the three analyzed loci distributed as follows: 14.3% of the informative cases showed LOH at 5q21, 7.7% at 9p21 and 22.2% at TP53. Within the smoker risk group only one case (4% of the informative cases) showed LOH at TP53, while no LOH was found at 5q21 or 9p21. No LOH was found in non-smokers. In conclusion, our results show that a significant number of patients with NSCLC have LOH at TP53, 5q21 and 9p21 in normal oral mucosae, while LOH at these loci is unusual in similar cells obtained from patients with no evidence of malignancy. Our study demonstrates that LOH studies can detect smoker patients with a mutated genotype in normal epithelial cells. Further prospective studies may confirm whether LOH studies can detect patients with a higher risk of NSCLC.


Mediterranean Diet and Incidence of Advanced Age-Related Macular Degeneration: The EYE-RISK Consortium.
To investigate associations of adherence to the Mediterranean diet (MeDi) with incidence of advanced age-related macular degeneration (AMD; the symptomatic form of AMD) in 2 European population-based prospective cohorts. Prospective cohort study of the Rotterdam Study I (RS-I) and the Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires (Alienor) Study populations. Four thousand four hundred forty-six participants 55 years of age or older from the RS-I (The Netherlands) and 550 French adults 73 years of age or older from the Alienor Study with complete ophthalmologic and dietary data were included in the present study. Examinations were performed approximately every 5 years over a 21-year period (1990-2011) in RS-I and every 2 years over a 4-year period (2006-2012) in the Alienor Study. Adherence to the MeDi was evaluated using a 9-component score based on intake of vegetables, fruits, legumes, cereals, fish, meat, dairy products, alcohol, and the monounsaturated-to-saturated fatty acids ratio. Associations of incidence of AMD with MeDi were estimated using multivariate Cox proportional hazard models. Incidence of advanced AMD based on retinal fundus photographs. Among the 4996 included participants, 155 demonstrated advanced incident AMD (117 from the RS-I and 38 from the Alienor Study). The mean follow-up time was 9.9 years (range, 0.6-21.7 years) in the RS-I and 4.1 years (range, 2.5-5.0 years) in the Alienor Study. Pooling data for both the RS-I and Alienor Study, participants with a high (range, 6-9) MeDi score showed a significantly reduced risk for incident advanced AMD compared with participants with a low (range, 0-3) MeDi score in the fully adjusted Cox model (hazard ratio, 0.59; 95% confidence interval, 0.37-0.95; P = 0.04 for trend). Pooling data from the RS-I and Alienor Study, higher adherence to the MeDi was associated with a 41% reduced risk of incident advanced AMD. These findings support the role of a diet rich in healthful nutrient-rich foods such as fruits, vegetables, legumes, and fish in the prevention of AMD.


[School and vocational training, vocational status and myocardial infarct--a study with data of the mandatory health insurance].
We analysed whether indicators of social status (education and training, occupational grade) are associated with a first acute myocardial infarction (ICD-410) between 1987 and 1996. Analyses were based on data from a statutory health insurance (Allgemeine Ortskrankenkasse) in Northrhine-Westfalia, Germany. 132,255 men and women aged 30-69 years who were employed or were employed before retirement have been included in the investigation. The cumulated incidence of first myocardial infarction was 2.1% (n = 1938) among men and 0.8% (n = 327) among women. After adjustment for age and length of the observation period an increasing infarction risk with decreasing social status was observed in men. Respective odds ratios (OR) were 3.96 in the lowest educational and training group and 3.41 in the medium group as compared to men with the highest educational and training level. With regard to occupational grade respective odds ratios were 1.92 for the lowest (semi- and unskilled workers) and 1.73 for the medium group (skilled workers) compared to those with the highest grade level (skilled non-manuals, intermediate, professionals). Among women the risk was 1.47 in the lowest educational and training group and 1.03 in the medium group. In semi- and unskilled women the OR was 1.58 and 1.67 in skilled women as compared to the highest occupational group. Although associations were observed between indicators of social status and risk of first myocardial infarction it is concluded that further research is needed due to the selection of the population under study with regard to education and occupational grade. Future research activities should concentrate on health insurances for skilled non-manual employees.


[Free transplantation of anterior rectus sheath-cutaneous flap for the repair of defects of Achilles tendon and its neighboring soft tissues].
The author used free anterior rectus sheath-cutaneous flap for one-step reconstruction of defects of the Achilles tendon and its neighboring skin and soft tissue complicated by infection in 2 patients. In both of them the operation was successful. Two-year follow up showed that both of them have obtained good function and could attend manual labour. The details of surgical procedure were described in this article.


Student nurses' knowledge acquisition on oral medication administration: comparison of lecture demonstration vs. video demonstration.
Oral Medication administration is one of the paramount nursing procedures, where nurses must pay their utmost commitment. The vital aims are to reduce medication errors and ensure patient safety. The objectives of this study were to evaluate whether the nursing students could learn and retain the basic guidelines for oral medication administration when they are taught using a video-assisted teaching method compared with the lecture-demonstration method and to assess the students' attitudes towards the two types of teaching methods. This study was conducted as a quasi-experimental study with a pre and post-test design. Forty-five students in the first year of the bachelor's degree in nursing programme participated. All the participants completed a self- administered questionnaire, including socio demographic data and questions of oral medication administration. Subsequently, participants were randomly assigned to two groups. Oral medication administration procedure was taught using two different teaching methods. Finally, the post-test knowledge scores of both groups were assessed and analysed using the paired-sample t-test. The results revealed that there was no significant difference in terms of age, gender and type of residence of students in the two groups. When comparing the pre-test mean score and post-test mean score using paired sample t-test, there was a statistically significant difference in both video demonstration group (t = - 4.533, p < 0.001) and lecture-demonstration group (t = - 4.208, p < 0.001). Almost all the students obtained good knowledge scores regardless of the method used in teaching oral medication administration. However, when comparing post-test scores of both groups using an independent sample t-test, it was identified that there was no significant difference between the two groups. Therefore, it was difficult to identify which method was effective than the other. According to the student feedback obtained at the end of the study, 67% of them preferred to have more video demonstrations in their skills classes. The results of this study suggested that oral medication administration can be effectively taught using lecture-demonstration and video-demonstration teaching methods.


Mitochondrial damage in the soybean seed axis during imbibition at chilling temperatures.
The development of mitochondria during seed germination is essential for plant growth. However, the developmental process is still poorly understood. Temperature plays a key role in soybean germination, and in this study we characterized the mitochondrial ultrastructure and proteome after imbibition at 22, 10 and 4 degrees C for 24 h. The mitochondria from the soybean seed axis can be divided into light and heavy mitochondria by Percoll density gradient centrifugation. The axes imbibed at 4 degrees C mainly contained light mitochondria, which had lower levels of specific mitochondrial enzymes and oxidative phosphorylation activity. In contrast, the axes imbibed at 22 degrees C mainly contained heavy mitochondria, which exhibited higher metabolism. Electron microscopy revealed that mitochondria in the axes imbibed at 4 degrees C had a poorly developed internal membrane system with few cristae, while the mitochondria in the axes imbibed at 22 degrees C developed more normally. Furthermore, we compared the axis mitochondrial proteomes during imbibition at different temperatures. The differentially expressed proteins were identified using ESI-Q-TOF-MS/MS (electrospray ionization quadrupole time-of-flight tandem mass spectrometry). Proteins involved in mitochondrial metabolites including malate dehydrogenase (tricarboxylic acid cycle enzyme), putative ATP synthase subunit (oxidative phosphorylation complex subunits), mitochondrial chaperonin-60 (heat shock protein), arginase (urea cycle enzyme) and mitochondrial elongation factor Tu (mitochondrial genome transcript enzyme) were identified. The reduced expression of these proteins might not support normal mitochondrial metabolism. We conclude that chilling during imbibition causes mitochondrial damage at both ultrastructural and metabolic levels.


What Are "Social Prescriptions" and How Should They Be Integrated Into Care Plans?
Health consequences of social isolation and loneliness include worsened morbidity and mortality. Despite wide recognition of this fact, little is understood about how to intervene successfully. "Social prescribing" is one approach by which clinicians can intervene on social determinants of health, which include social isolation and loneliness. This commentary on a case defines social prescribing and suggests how to integrate it into practice.


A pollen tube growth-promoting arabinogalactan protein from nicotiana alata is similar to the tobacco TTS protein.
Upon germination on the stigma, pollen tubes elongate in the stylar transmitting tract, aided by female factors, with speed and directionality not mimicked in in vitro pollen tube growth cultures. We have shown that a stylar transmitting tissue arabinogalactan protein (AGP) from Nicotiana tabacum (tobacco), TTS protein, stimulates pollen tube growth in vivo and in vitro and attracts pollen tubes grown in a semi-in vivo culture system. It has been reported that the self-incompatible Nicotiana alata produced a stylar glycoprotein, GaRSGP, which had a backbone polypeptide that shared 97% identity with those of TTS proteins but some of its properties were different from those described for TTS proteins. We report here the characterization of a family of stylar transmitting tissue glycoproteins from N. alata that is virtually identical to tobacco TTS proteins and which we refer to as NaTTS proteins. Like their tobacco counterparts, NaTTS proteins are recognized by the traditional AGP-diagnostic reagent beta-glucosyl Yariv reagent, and they are also recognized by JIM13, a monoclonal antibody against AGP. NaTTS proteins also stimulate pollen tube elongation in vitro and attract pollen tubes in a semi-in vivo pollen tube culture system. Biochemical and immunological characterization of NaTTS proteins revealed that they have extraordinary variability in the extent of sugar modifications of their polypeptide backbones. The extent of sugar modifications on NaTTS proteins significantly affects their biochemical properties, influences how they interact with the transmitting tissue extracellular matrix, and affects their solubility from this matrix. Our results suggest that the strategy used to purify GaRSGP only recovered a less glycosylated, more tightly extracellular matrix-bound sub-population of the entire spectrum of N. alata TTS proteins.


Severe tail defects in the spermatozoa ejaculated by an English bulldog.
This paper describes the case of a 2-year-old English Bulldog with severe teratozoospermia that consisted mainly of "Dag-like" defects, which is strong coiling of the tail. Although libido, semen volume and sperm concentration were normal, sperm motility was 5.0%, and 93.3% of spermatozoa exhibited morphological abnormalities affecting the tail. Transmission electron microscopic examination of the spermatozoa revealed strong folding, coiling and fracture of sperm midpieces and tails, axonemal defects and the presence of swollen and unevenly distributed mitochondria. Taking into account the dog's history and examinations and the constantly high percentage of abnormal spermatozoa over time, the defect was considered to be genetic in origin.


A new fungal isolate from Paspalum scrobiculatum, Linn. with new biologically active metabolites.
A new fungal isolate from the host plant Paspalum scrobiculatum Linn., is reported. It is characterized and designated as a separate species Phomopsis paspali (n. sp.), not only for the different morphological characters as compared with the commonly occurring Phomopsis species in India, but also in view of its distinctive feature of producing biologically active new metabolites, cytochalasans. In addition, the genus Phomopsis has not been reported on this plant anywhere in the world.


Biodegradation of alpha- and beta-hexachlorocyclohexane in a soil slurry under different redox conditions.
Aerobic conditions proved to be best for the microbiol conversion of alpha-hexachlorocyclohexane (alpha-HCH) in a soil slurry. The dry soil contained 400 mg of alpha-HCH per kg. This xenobiotic compound was mineralized within about 18 days at an initial rate of 23 mg/kg of soil per day by the mixed native microbial population of the soil. The only intermediate that was detected during breakdown was pentachlorocyclohexene, which was detected at very small concentrations. Alpha-HCH was also bioconverted under methanogenic conditions. However, a rather long acclimation period (about 30 days) was necessary before degradation started, at a rate of 13 mg/kg of soil per day. Mass balance calculations showed that about 85% of the initial alpha-HCH that was present was converted to monochlorobenzene, 3,5-dichlorophenol, and a trichlorophenol isomer, possibly 2,4,5-trichlorophenol. Under both denitrifying and sulfate-reducing conditions, no significant bioconversion of alpha-HCH was observed. The beta isomer of HCH was recalcitrant at all of the four redox conditions studied. We propose that the specific spatial chloride arrangement of the beta isomer is responsible for its stability. The results reported here with complex soil slurry systems showed that alpha-HCH is, in contrast to the existing data in the literature, best degraded biologically in the presence of oxygen.


Cardiorespiratory interactions in humans and animals: rhythms for life.
The cardiorespiratory system exhibits oscillations from a range of sources. One of the most studied oscillations is heart rate variability, which is thought to be beneficial and can serve as an index of a healthy cardiovascular system. Heart rate variability is dampened in many diseases including depression, autoimmune diseases, hypertension, and heart failure. Thus, understanding the interactions that lead to heart rate variability, and its physiological role, could help with prevention, diagnosis, and treatment of cardiovascular diseases. In this review, we consider three types of cardiorespiratory interactions: respiratory sinus arrhythmia (variability in heart rate at the frequency of breathing), cardioventilatory coupling (synchronization between the heart beat and the onset of inspiration), and respiratory stroke volume synchronization (the constant phase difference between the right and the left stroke volumes over one respiratory cycle). While the exact physiological role of these oscillations continues to be debated, the redundancies in the mechanisms responsible for its generation and its strong evolutionary conservation point to the importance of cardiorespiratory interactions. The putative mechanisms driving cardiorespiratory oscillations as well as the physiological significance of these oscillations will be reviewed. We suggest that cardiorespiratory interactions have the capacity to both dampen the variability in systemic blood flow as well as improve the efficiency of work done by the heart while maintaining physiological levels of arterial CO2. Given that reduction in variability is a prognostic indicator of disease, we argue that restoration of this variability via pharmaceutical or device-based approaches may be beneficial in prolonging life.


Temporal Trends, Predictors, and Outcomes of In-Hospital Gastrointestinal Bleeding Associated With Percutaneous Coronary Intervention.
Since the introduction of new antiplatelet and anticoagulant agents in the last decade, large-scale data studying gastrointestinal bleeding (GIB) in patients undergoing percutaneous coronary intervention (PCI) are lacking. Using the Nationwide Inpatient Sample, we identified all hospitalizations from 2006 to 2012 that required PCI. Temporal trends in the incidence and multivariate predictors of GIB associated with PCI were analyzed. A total of 4,376,950 patients underwent PCI in the United States during the study period. The incidence of GIB was 1.1%. Mortality rate in the GIB group was significantly higher (9.71% vs 1.1%, p <0.0001). Although the incidence of GIB remained stable during the study period (0.97% in 2006 to 1.19% in 2012), in-hospital mortality rate increased significantly from 7.9% in 2006 to 10.78% in 2012, with a peak of 12% in 2010. The GIB group had a longer median length of stay (5.80 vs 1.57 days) and an increased median cost of hospitalization ($26,564 vs $16,879). The predictors of GIB included cardiovascular co-morbidities such as acute myocardial infarction, cardiogenic shock, atrial fibrillation, congestive heart failure, valvular heart diseases, and a history of transient ischemic attack/stroke. Gastrointestinal co-morbidities including diverticulosis, esophageal cancer, stomach cancer, small intestine cancer, large intestine cancer, rectosigmoid cancer, gastrointestinal ulcer, and liver disease were predictors of GIB. Interestingly, a lower risk of GIB was associated with obese patients and patients with private insurance. A higher risk of GIB was noted in urgent versus elective admissions and weekend versus weekday admissions. In conclusion, the incidence of GIB in patients who underwent PCI remained stable from 2006 to 2012; however, the in-hospital mortality increased significantly. Identifying patients at higher risk for GIB is critically important to develop preventive strategies to reduce morbidity and mortality.