Dimeric [Mo2 S12 ](2-) Cluster: A Molecular Analogue of MoS2 Edges for Superior Hydrogen-Evolution Electrocatalysis.
Proton reduction is one of the most fundamental and important reactions in nature. MoS2 edges have been identified as the active sites for hydrogen evolution reaction (HER) electrocatalysis. Designing molecular mimics of MoS2 edge sites is an attractive strategy to understand the underlying catalytic mechanism of different edge sites and improve their activities. Herein we report a dimeric molecular analogue [Mo2 S12 ](2-) , as the smallest unit possessing both the terminal and bridging disulfide ligands. Our electrochemical tests show that [Mo2 S12 ](2-) is a superior heterogeneous HER catalyst under acidic conditions. Computations suggest that the bridging disulfide ligand of [Mo2 S12 ](2-) exhibits a hydrogen adsorption free energy near zero (-0.05 eV). This work helps shed light on the rational design of HER catalysts and biomimetics of hydrogen-evolving enzymes.


7,8-Dihydroneopterin induces apoptosis of Jurkat T-lymphocytes via a Bcl-2-sensitive pathway.
Activated cell-mediated immunity is known to be accompanied by elevated concentrations of 7,8-dihydroneopterin which in high concentrations was found to interfere with the oxidant-antioxidant balance. In this study we investigated whether 7,8-dihydroneopterin mediates apoptosis of Jurkat T-lymphocytes via a CrmA- or Bcl-2-sensitive pathway. Transient transfection assays with CrmA and Bcl-2 expression constructs showed that apoptosis was not affected by CrmA whereas it was significantly decreased upon cotransfection with Bcl-2 constructs. Results suggest that 7,8-dihydroneopterin-induced apoptosis of T-lymphocytes is mediated by a Bcl-2-sensitive pathway.


Implementation of Machine Learning Mechanism for Recognising Prostate Cancer through Photoacoustic Signal.
Biological tissues may be studied using photoacoustic (PA) spectroscopy, which can yield a wealth of physical and chemical data. However, it is really challenging to directly analyse these tissues because of a lot of data. Data mining techniques can get around this issue. In order to diagnose prostate cancer via PA spectrum assessment, this work describes the machine learning (ML) technique implementation, such as supervised classification and unsupervised hierarchical clustering. The collected PA signals were preprocessed using Pwelch method, and the features are extracted using two methods such as hierarchical cluster and correlation assessment. The extracted features are classified using four ML-methods, namely, Support Vector Machine (SVM), Naïve Bayes (NB), decision tree C4.5, and Linear Discriminant Analysis (LDA). Furthermore, as these components alter throughout the progression of prostate cancer, this study focuses on the composition and distribution of collagen, lipids, and haemoglobin. In diseased tissues compared to normal tissues, there is a stronger correlation between the various chemical components ultrasonic power spectra, suggesting that the microstructural dispersion in tumour tissues has been more uniform. The accuracy of several classifiers used in cancer tissue diagnosis was greater than 94% for all four methods, which is effective than that of benchmark medical methods. Thus, the method shows significant promise for the noninvasive, early detection of severe prostate cancer.


Pre-treatment Pain Symptoms Influence Antidepressant Response to Ketamine in Depressive Patients.
Pain strongly coexists with depression. Ketamine has great analgesic and antidepressant effects, acting as a promising role in treating depression with pain. Few studies have evaluated impact of pain symptoms on antidepressant effect of ketamine infusions. Thus, present study investigated whether pain symptoms in individuals with depression moderate response to ketamine. One hundred and four individuals with major depressive disorder and bipolar depression received six intravenous infusions of ketamine. The Montgomery-Åsberg Depression Rating Scale (MADRS) was administered at baseline, the next morning after each infusion and 2 weeks (Day 26) after the last infusion. Pain symptoms were collected at baseline using the short-form McGill Pain Questionnaire (SF-MPQ). The prevalence of pain in patients with depression was 48.8%. Mix model analyses showed that pre-treatment pain symptoms assessed by each domain of SF-MPQ significantly moderated antidepressant response to six infusions of ketamine from baseline to day 26 (all p < 0.05). Then follow-up simple slopes analyses suggested that all patients across groups showed a significant symptomatic improvement after ketamine infusions (all p < 0.05), and patients with severe pain (across all domains of SF-MPQ) had greater improvement in depressive symptoms than those with mild pain or non-pain (all p < 0.05). A significant and rapid improvement in depressive symptoms was observed in patients with depression and pain after ketamine treatment. Ketamine may be a novel and promising antidepressant preferentially for the therapy of depression with severe pain.


Differential effect of troglitazone on the human bile acid transporters, MRP2 and BSEP, in the PXB hepatic chimeric mouse.
The aims of this study were to assess the utility of the PXB mouse model of a chimeric human/mouse liver in studying human-specific effects of an important human hepatotoxic drug, the PPARγ agonist, troglitazone. When given orally by gavage for 7 days, at dose levels of 300 and 600 ppm, troglitazone induced specific changes in the human hepatocytes of the chimeric liver without an effect on the murine hepatic portions. The human hepatocytes, in the vehicle-treated PXB mouse, showed an accumulation of electron-dense lipid droplets that appeared as clear vacuoles under the light microscope in H&E-stained sections. Following dosing with troglitazone, there was a loss of the large lipid droplets in the human hepatocytes, a decrease in the amount of lipid as observed in frozen sections of liver stained by Oil-red-O, and a decrease in the expression of two bile acid transporters, BSEP and MRP2. None of these changes were observed in the murine remnants of the chimeric liver. No changes were observed in the expression of three CYPs, CYP 3A2, CYP 1A1, and CYP 2B1, in either the human or murine hepatocytes, even though the baseline expression of the enzymes differed significantly between the two hepatocyte species with the mouse hepatocytes consistently showing increased expression of the protein of all three enzymes. This study has shown that the human hepatocytes, in the PXB chimeric mouse liver, retain an essentially normal phenotype in the mouse liver and, the albeit limited CYP enzymes studied show a more human, rather than a murine, expression pattern. In line with this conclusion, the study has shown a differential response of the human versus the mouse hepatocytes, and the effects observed are highly suggestive of a differential handling of the compound by the two hepatocyte species although the exact reasons are not as yet clear. The PXB chimeric mouse system therefore holds the clear potential to explore human hepatic-specific features, such as metabolism, prior to dosing human subjects, and as such should have considerable utility in drug discovery and development.


[The Club of Croatian War Veterans treated for PTSD as a form of psychosocial rehabilitation].
For the period after the war patients with complex disorders are specific. Their increased need for psychiatric protection stimulates people to organize additional, outpatient activities in the mental health area. The authors present their experiences of working in the Club of Croatian War veterans treated for PTSD (the PTSD Club) and the positive therapeutic effect of systematic work upon the principles of sociotherapeutic community, systematic family approach, and self-help. The PTSD club is one of possible problem solutions, and the right choice of how to organize and conduct preventive and rehabilitative programs for high-risk groups of patients.


Formant-frequency differences between isolated whispered and phonated vowel samples produced by adult female subjects.
This study was designed to investigate the formant frequencies of phonated and whispered productions of five test vowels (/i/, /u/, /ae/, /a/). Each test vowel was sustained twice in isolation--once phonated, one whispered--by 20 adult female subjects. The phoneme represented by each recorded production was identified independently by 11 listeners. Only those samples identified by 6 or more of the listeners as the vowel intended were retained for a further (acoustic) analysis. An acoustic spectrum of each retained sample was obtained to permit formant measurements. To provide the clearest formant delineation possible in our lab, the phonated samples were analyzed by broadband spectrography and the whispered samples by very narrow-band spectrography. This report presents the formant frequencies (F1-F3) of the test productions as measured from the acoustic vowel spectra and the formant-frequency differences between the phonated and whispered productions. In general, the results showed a trend for whispered vowel formants to be higher in frequency than phonated vowel formants, but that trend was only strongly evident for F1.


Auditory function in early syphilis. A follow up study.
Twenty-six patients with secondary or early latent syphilis were examined by auditory brainstem response (ABR) audiometry and by pure tone audiometry before and after treatment. Normalization was registered in four of seven patients with pathological ABR before treatment. while in three patients the ABR abnormalities remained after treatment. Thirteen patients exhibited a sensorineural hearing-loss before treatment. In two patients this hearing-loss improved after treatment and a syphilitic etiology seems plausible. The reversible lesions in the auditory system may be related to asymptomatic syphilitic meningitis. Permanent ABR abnormalities might reflect syphilitic vascular involvement in the brainstem.


Marginally Self-Averaging One-Dimensional Localization in Bilayer Graphene.
The combination of a field-tunable band gap, topological edge states, and valleys in the band structure makes insulating bilayer graphene a unique localized system, where the scaling laws of dimensionless conductance g remain largely unexplored. Here we show that the relative fluctuations in lng with the varying chemical potential, in strongly insulating bilayer graphene (BLG), decay nearly logarithmically for a channel length up to L/ξ≈20, where ξ is the localization length. This "marginal" self-averaging, and the corresponding dependence of ⟨lng⟩ on L, suggests that transport in strongly gapped BLG occurs along strictly one-dimensional channels, where ξ≈0.5±0.1 μm was found to be much longer than that expected from the bulk band gap. Our experiment reveals a nontrivial localization mechanism in gapped BLG, governed by transport along robust edge modes.


Phylogenetic evidence that both ancient vicariance and dispersal have contributed to the biogeographic patterns of anchialine cave shrimps.
Cave shrimps from the genera Typhlatya, Stygiocaris and Typhlopatsa (Atyidae) are restricted to specialised coastal subterranean habitats or nearby freshwaters and have a highly disconnected distribution (Eastern Pacific, Caribbean, Atlantic, Mediterranean, Madagascar, Australia). The combination of a wide distribution and a limited dispersal potential suggests a large-scale process has generated this geographic pattern. Tectonic plates that fragment ancestral ranges (vicariance) has often been assumed to cause this process, with the biota as passive passengers on continental blocks. The ancestors of these cave shrimps are believed to have inhabited the ancient Tethys Sea, with three particular geological events hypothesised to have led to their isolation and divergence; (1) the opening of the Atlantic Ocean, (2) the breakup of Gondwana, and (3) the closure of the Tethys Seaway. We test the relative contribution of vicariance and dispersal in the evolutionary history of this group using mitochondrial genomes to reconstruct phylogenetic and biogeographic scenarios with fossil-based calibrations. Given that the Australia/Madagascar shrimp divergence postdates the Gondwanan breakup, our results suggest both vicariance (the Atlantic opening) and dispersal. The Tethys closure appears not to have been influential, however we hypothesise that changing marine currents had an important early influence on their biogeography.


Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.
A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue. These data demonstrate a role for WSB1 in mutant LRRK2 pathogenesis, and suggest involvement in Lewy body pathology in sporadic PD. Our data indicate a role in PD for ubiquitin K27 and K29 linkages, and suggest that ubiquitination may be a signal for aggregation and neuronal protection in PD, which may be relevant for other neurodegenerative disorders. Finally, our study identifies a novel therapeutic target for PD.


Neural integrators for decision making: a favorable tradeoff between robustness and sensitivity.
A key step in many perceptual decision tasks is the integration of sensory inputs over time, but a fundamental questions remain about how this is accomplished in neural circuits. One possibility is to balance decay modes of membranes and synapses with recurrent excitation. To allow integration over long timescales, however, this balance must be exceedingly precise. The need for fine tuning can be overcome via a "robust integrator" mechanism in which momentary inputs must be above a preset limit to be registered by the circuit. The degree of this limiting embodies a tradeoff between sensitivity to the input stream and robustness against parameter mistuning. Here, we analyze the consequences of this tradeoff for decision-making performance. For concreteness, we focus on the well-studied random dot motion discrimination task and constrain stimulus parameters by experimental data. We show that mistuning feedback in an integrator circuit decreases decision performance but that the robust integrator mechanism can limit this loss. Intriguingly, even for perfectly tuned circuits with no immediate need for a robustness mechanism, including one often does not impose a substantial penalty for decision-making performance. The implication is that robust integrators may be well suited to subserve the basic function of evidence integration in many cognitive tasks. We develop these ideas using simulations of coupled neural units and the mathematics of sequential analysis.


Molecules in pain and sex: a developing story.
Microglia are dynamic immune cells with diverse roles in maintaining homeostasis of the central nervous system. Dysregulation of microglia has been critically implicated in the genesis of neuropathic pain. Peripheral nerve injury, a common cause of neuropathic pain, engages microglia-neuronal signalling which causes disinhibition and facilitated excitation of spinal nociceptive pathways. However, recent literature indicates that the role of microglia in neuropathic pain is sexually dimorphic, and that female pain processing appears to be independent of microglia, depending rather on T cells. Despite this sex difference, pain signalling in the spinal cord converges downstream of microglia, as NMDAR-mediated facilitated excitation in pain transmitting neurons is consistent between males and females. Determining whether pain signalling is sexually dimorphic in humans and, further, addressing the sex bias in pain research will increase the translational relevance of preclinical findings and advance our understanding of chronic pain in women.


Angiotensin converting enzyme and the arrhythmogenic action of angiotensin I: cardiac cell membrane as a site of angiotensin I conversion.
The influence of angiotensin I (Ang I) on heart excitability and refractoriness was investigated in isolated right ventricular muscle of adult rats as well as in isolated ventricular myocytes. The results indicated that Ang I (10(-8) M) added to the bath solution, decreased the action potential duration from 50.4 +/- 3.6 to 33.9 +/- 3.9 ms (P < 0.05) and reduced significantly the cardiac refractoriness. Consequently, a discharge of spontaneous action potentials was elicited when a second stimulus was applied during the relative refractory period. Moreover, the conduction velocity was reduced from 56.9 +/- 2.9 to 40 +/- 3.2 cm/s (P < 0.05). The question whether the effect of Ang I was related to its conversion to Ang II, was investigated on tissues exposed to enalapril maleate (10(-8) M). Under these conditions, the effect of Ang I was totally suppressed. Similar results were found with losartan (10(-7) M). To investigate if the conversion of Ang I to Ang II occurs at the level of surface cell membrane, measurements of inward calcium current (ICa) were performed in myocytes isolated from the rat ventricle. ICa was measured before and after the administration of Ang I (10(-8) M). The results indicated that Ang I (10(-8) M), added to the bath solution, reduced the peak ICa density by 26.3 +/- 2.6% (P < 0.05), an effect abolished by enalapril maleate (10(-8)M). Evidence is presented for the first time, that Ang I is converted to Ang II at the surface cell membrane in cardiac muscle with consequent generation of cardiac arrhythmias which are elicited by Ang II.


Free fibula long bone reconstruction in orthopedic oncology: a surgical algorithm for reconstructive options.
The fibula free flap became popular in orthopedic oncology for limb-sparing long bone tumor resection. It is particularly suitable for intercalary or resection arthrodesis options. In the present series, a surgical reconstruction algorithm was used, enabling each patient to receive a personalized technique. During the years 1998 to 2002, 30 patients underwent limb-sparing surgery for long bone sarcoma. There were 18 males and 12 females. Their mean age was 23 years (range, 9 to 70 years). The diagnoses were Ewing's sarcoma (11 patients), osteogenic sarcoma (eight patients), chondrosarcoma (five patients), giant cell tumor of bone (three patients), high-grade soft-tissue sarcoma (two patients), and leiomyosarcoma of bone (one patient). The majority of tumors where located in the lower extremity (23 patients), mostly in the femur (15 patients with four tumors in the proximal femoral shaft, five tumors in the distal femoral shaft, five tumors in the whole femoral shaft, and one tumor in the proximal femoral head). In seven patients, the upper extremity was involved; in six patients, the radius was involved; and in one patient, the humerus was involved. The free fibula flap was used in three types of approaches: vascularized fibula as an osseous flap only (18 patients), a combination of a vascularized fibula flap in conjunction with an allograft (Capanna's technique; 10 patients), and a free double-barreled fibula (two patients). All flaps survived. Postoperatively, all patients were monitored clinically, radiologically, and by radioisotope bone scan studies. Callus formation and union were shown 2.6 to 8 months postoperatively. Patients who underwent lower extremity reconstruction were nonweightbearing for 3 to 9 months, with a transition period in which they used a brace and gradually increased weightbearing until full weightbearing was achieved. Eight patients had 11 recipient-site complications. Two patients (6.7 percent) had hematomas, and three patients (10 percent) had infection and dehiscence of the surgical wound with bone exposure in one patient; all complications resolved with conservative treatment only. Failure of the hardware fixation system occurred in two patients, mandating surgical correction. No fibula donor-site complications were recorded. In intercalary resections, the use of the vascularized fibula flap as an isolated osseous flap might be insufficient. Different body sites have different stress loads to carry, depending on the age of the patient and on his individual physical status. To achieve initial strength in the early period, the authors combined the free fibula flap with an allograft (Capanna's method) or augmented it as a double-barreled fibula. They propose a surgical algorithm to assist the surgeon with the preferred method for reconstruction of various long bone defects in different body locations at childhood or adulthood. Long bone reconstruction using a vascularized fibula flap, alone or in combination with an allograft, autogenous bone graft, or double-barreled fibula for limb-sparing surgery, is a safe and reliable method with a predictable bony union, good functional outcome, and a low complication rate.


Leiomyoma of the nasal cavity.
A case of rare leiomyoma of the nasal cavity is reported. The pathological and clinical characteristics of this tumour are discussed.


The radial forearm osteocutaneous "sandwich" free flap for reconstruction of the bilateral subtotal maxillectomy defect.
Complex resections of the maxilla produce a three-dimensional defect that can be difficult to reconstruct using autogenous tissue without utilizing a free tissue transfer. The osteocutaneous flaps that have been described for reconstruction of this area have been the scapula, iliac crest, and fibula, which are often hampered by their bulkiness and less than ideal intraoral lining. The bilateral subtotal maxillectomy defect is particularly difficult to reconstruct because it requires restoration of the bony framework of the midface as well as the restoration of the palatal and nasal lining. We present a new technique for reconstruction of this type of defect using the osteocutaneous radial forearm free flap. Two patients with bilateral subtotal maxillectomy defects, in whom the entire hard palate and maxillary arch were resected, underwent primary reconstruction. The bone from the osteocutaneous flap was osteotomized and contoured to recreate the maxillary arch. The large skin island was folded around the bone, as in a sandwich, and used to replace the palatal and nasal lining. This sandwiched osteocutaneous flap allowed for secure fitting of a dental prosthesis and the future possibility of osteointegrated implants. Long-term stability of the bone without retrusion was achieved with an excellent functional and aesthetic outcome. The radial forearm osteocutaneous free flap is ideal for the reconstruction of the maxillary infrastructure in that (1) it provides bone and thin, pliable skin in the correct proportions; (2) the described "sandwich" technique restores an excellent functional and aesthetic state; and (3) dental rehabilitation can be further improved by using either a prosthesis or osteointegrated implants.


Improving miRNA Delivery by Optimizing miRNA Expression Cassettes in Diverse Virus Vectors.
The RNA interference pathway is an evolutionary conserved post-transcriptional gene regulation mechanism that is exclusively triggered by double-stranded RNA inducers. RNAi-based methods and technologies have facilitated the discovery of many basic science findings and spurred the development of novel RNA therapeutics. Transient induction of RNAi via transfection of synthetic small interfering RNAs can trigger the selective knockdown of a target mRNA. For durable silencing of gene expression, either artificial short hairpin RNA or microRNA encoding transgene constructs were developed. These miRNAs are based on the molecules that induce the natural RNAi pathway in mammals and humans: the endogenously expressed miRNAs. Significant efforts focused on the construction and delivery of miRNA cassettes in order to solve basic biology questions or to design new therapy strategies. Several viral vectors have been developed, which are particularly useful for the delivery of miRNA expression cassettes to specific target cells. Each vector system has its own unique set of distinct properties. Thus, depending on the specific application, a particular vector may be most suitable. This field was previously reviewed for different viral vector systems, and now the recent progress in the field of miRNA-based gene-silencing approaches using lentiviral vectors is reported. The focus is on the unique properties and respective limitations of the available vector systems for miRNA delivery.


Rigour in phenomenological research: reflections of a novice nurse researcher.
This paper is intended to explore conflicts and doubts that novice researchers face when using phenomenological research methods, especially with regard to methodological rigour. There is an increasing interest in different qualitative approaches. The best way to evaluate the quality of qualitative studies has been debated intensively. The great theoretical and methodological diversity of qualitative approaches suggests that a single set of criteria may not be appropriate for all types of research. This is a methodological paper that discusses a personal experience of addressing rigour in a phenomenological study, supported by literature on the topic. Generic qualitative criteria may not be the most adequate to ensure rigour in phenomenological research. The different poles of discussion about the best way to ensure validity of phenomenological research puzzle novice nurse researchers. Focusing on integrative validity that addresses experiential and methodological concerns ensures that researchers will respect the philosophical assumptions underlying a method and allows them to recognise study soundness in the findings and the research process. Phenomenological research must demonstrate methodological congruence and provide meaningful results about lived experiences in a balanced way. Novice researchers need support to understand the articulation between philosophical and methodological foundations that guide the methods they use.


[Role of the EFSA in risk management system regarding food contact materials and articles].
The role of the European Food Safety Authority (EFSA) in the risk management system regarding food contact materials and articles is related with the risk assessment of the substances for the European Commission. General rules for the authorisation of substances used in materials and articles intended to contact with food is established in the Regulation (EC) no 1935/2004. For the evaluation of substances their toxicological properties and magnitude of migration into food simulants is taken into account. Toxicological studies include the mutagenicity tests, oral toxicity studies, carcinogenicity, reproduction and also studies on absorption, distribution, metabolism and excretion of the substance and other studies when needed. The set of the relevant toxicological data for substance depends on the magnitude of migration. In the case of positive opinion by EFSA the substance appears on the Community list of authorised substances. Sometimes, the earlier evaluated and authorized substances must undergo re-evaluation due to their new toxicological properties or as a result of a presence in the food of their earlier unknown decomposition products. Examples of the selected substances which underwent re-evaluation by EFSA in the light of the current toxicological knowledge and the relevant activities undertaken by the European Commission have been presented.


The first report of a single-port laparoscopic nephrectomy in a child.
There has been an exponential rise in the use of minimally invasive procedures in surgery, with obvious benefits to patients. Recently, transumbilical single-port laparoscopic surgery has been championed as the next major technical advance. In this article, we report the first case where single-port laparoscopic surgery has been used to manage a paediatric problem in the region.


Lupus humoral autoimmunity induced in a primate model by short peptide immunization.
Systemic lupus erythematosus (SLE) is characterized by humoral autoimmunity against the spliceosomal proteins, including Sm B/B'. In SLE patients with anti-Sm B/B' antibodies the proline rich sequence, PPPGMRPP, is the predominant Sm B/B' autoimmune epitope and appears to be an early target in the development of the anti-Sm B/B' response. Two female baboons were immunized with the PPPGMRPP peptide from the Sm B/B' spliceosomal protein constructed on a MAP backbone in Freund's adjuvant. One female control baboon was immunized with Freund's adjuvant alone. Baboon sera were collected and assessed for antibody binding to the spliceosomal proteins and compared to SLE patient and control sera. Peptide immunized baboons developed antibodies to multiple regions of the Sm B/B' protein, as well as reactivity against other spliceosomal proteins. Consistent with serologic manifestations found in SLE, experimental baboons also acquired anti-nuclear antibodies, anti-nuclear ribonucleoprotein (nRNP) antibodies and, in one animal, anti-double stranded DNA antibodies. The control animal had none of these immunologic findings. Immunization with PPPGMRPP is capable of initiating a humoral autoimmune response in primates against the Sm, nRNP complex from which the peptide was derived. The additional autoantibody specificities generated in experimental animals are similar to those found in human SLE sera. This study is the first evidence of peptide induction of SLE humoral autoimmunity in a primate model.


Developing an explanatory theoretical model for engagement with a web-based mental health platform: results of a mixed methods study.
With the growing need for accessible, high-quality mental health services, especially during the COVID-19 pandemic, there has been increasing development and uptake of web-based interventions in the form of self-directed mental health platforms. The Big White Wall (BWW) is a web-based platform for people experiencing mental illness and addiction that offers a range of evidence-based self-directed treatment strategies. Drawing on existing data from a large-scale evaluation of the implementation of BWW in Ontario, Canada (which involved a pragmatic randomized controlled trail with an embedded qualitative process evaluation), we sought to investigate the influences on the extent to which people engage with BWW. In this paper we drew on BWW trial participants' usage data (number of logins) and the qualitative data from the process evaluation that explored participants' experiences, engagement with and reactions to BWW. Our results showed that there were highly complex relationships between the influences that contributed to the level of engagement with BWW intervention. We found that a) how people expected to benefit from using a platform like BWW was an important indicator of their future usage, b) moderate perceived symptoms were linked with higher engagement; whereas fewer actual depressive symptoms predicted use and anxiety had a positive linear relationship with usage, and that c) usage depended on positive early experiences with the platform. Our findings suggest that the nature of engagement with platforms such as BWW is not easily predicted. We propose a theoretical framework for explaining the level of user engagement with BWW that might also be generalizable to other similar platforms.


[Pneumonitis induced by amiodarone].
Fifteen patients, eleven males and four females, with amiodarone induced pulmonary disease were studied. Their ages ranged between 52 and 79 (mean = 64.0) years. 66% of the patients were taking a daily dose of 200 mg of amiodarone. The time elapsed between the initial dose and the diagnosis of the pneumonitis varied from 2 to 84 (mean = 23.3) months. Premature ventricular beats and recurrent episodes of paroxistic supra ventricular tachycardia were the most common indications for the use of the drug. The most frequent clinical complaints were progressive dyspnea and cough. Weight loss was observed in five patients, fever in six and chest pain in two. The most habitual thoracic physical sign was diffuse crepitation. Chest roentgenograms disclosed bilateral interstitial infiltrates in all patients, associated to pleural effusions in two. An increased diffuse uptake of 67 gallium citrate was observed in the nine patients to whom it was done. Lung function tests showed a pattern of restrictive ventilatory respiratory insufficiency and hypoxemia. Lung tissue specimens were obtained in ten patients, bronchoalveolar lavage in one and pleural fluid in one. The material was examined by light and electron microscopy. Amiodarone was discontinued in all patients and corticosteroids were introduced in thirteen. Five patients (33.3%) died, eight improved and two remained with radiographic scars.


Metabolism-based identification of a potent thrombin receptor antagonist.
The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and three major metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.


Empirical force fields for biological macromolecules: overview and issues.
Empirical force field-based studies of biological macromolecules are becoming a common tool for investigating their structure-activity relationships at an atomic level of detail. Such studies facilitate interpretation of experimental data and allow for information not readily accessible to experimental methods to be obtained. A large part of the success of empirical force field-based methods is the quality of the force fields combined with the algorithmic advances that allow for more accurate reproduction of experimental observables. Presented is an overview of the issues associated with the development and application of empirical force fields to biomolecular systems. This is followed by a summary of the force fields commonly applied to the different classes of biomolecules; proteins, nucleic acids, lipids, and carbohydrates. In addition, issues associated with computational studies on "heterogeneous" biomolecular systems and the transferability of force fields to a wide range of organic molecules of pharmacological interest are discussed.


miR-101 sensitizes A549 NSCLC cell line to CDDP by activating caspase 3-dependent apoptosis.
MicroRNA-101 (miR-101) is evidently downregulated in several types of cancer, including non-small cell lung cancer (NSCLC), and is crucial in sensitizing cells to chemotherapy drugs. The aim of the present study was to investigate the correlation between miR-101 and chemosensitivity in the A549 NSCLC cell line. Here, we used the human A549 cell line for transfection with an miR-101 overexpressing vector and detected the cytotoxic acticity, proliferation and apoptosis of cis-diaminedichloroplatinum (CDDP) in A549-miR-101 and A549-mock cells. We demonstrated that overexpression of miR-101 sensitized A549 cells to CDDP, one of the most frequently used agents in curing or controlling NSCLC and enhanced CDDP-induced cell death and caspase 3-dependent apoptosis. In addition, miR-101 facilitated the inhibitory role of CDDP in A549 cell colony formation. Overall, the results of the present study demonstrated that miR-101 sensitizes the A549 NSCLC cell line to CDDP via the activation of caspase 3-dependent apoptosis.


Reversible 2D pseudopolyrotaxanes based on cyclodextrins and cucurbit[6]uril.
In this paper, a pseudorotaxane (2) was synthesized by reaction of cucurbit [6]uril with 6-[(6-aminohexyl)amino]-6-deoxy-beta-cyclodextrin chloride. Subsequently, pseudorotaxanes 2 were further assembled to form a 2D pseudopolyrotaxane (3) through an alpha,omega-PPG2000 diamino polymer threading the cavities of cyclodextrins in 2, and the resulting pseudopolyrotaxane was comprehensively characterized by FT-IR, NMR, TG-DTA, elemental analysis, and transmission electron microscopy. Significantly, the 2D pseudopolyrotaxane can turn into a main-chain pseudopolyrotaxane in the presence of base, and then the addition of alpha-cyclodextrins may result in a reversible switch between two different 2D pseudopolyrotaxanes.


The force attenuation provided by hip protectors depends on impact velocity, pelvic size, and soft tissue stiffness.
Wearable hip protectors represent a promising strategy for preventing hip fractures. However, there is lack of agreement on biomechanical testing standards and subsequent uncertainty about the ability of hip protectors to attenuate impact force during a fall. To address this issue, we designed a fall impact simulator that incorporated a "biofidelic" surrogate pelvis, which matched the surface geometry and soft tissue stiffness measured in elderly women (n=15). We then used this system to measure the attenuation in peak femoral neck force provided by two commercially available soft shell protectors (Safehip Soft and Hipsaver) and one rigid shell protector (Safehip Classic). Finally, we examined how the force attenuation provided by each protector was influenced by systematic changes in fall severity (impact velocity), body size (pelvis size), and soft tissue stiffness. With the biofidelic pelvis, the force attenuation averaged over all impact velocities was 27% for Safehip Soft, 17% for Safehip Classic, and 19% for Hipsaver. However, the rank order of hip protectors (and especially the performance of Safehip Classic) varied with the test conditions. Safehip Classic attenuated force by 33% during a low velocity (1 ms) fall, but only by 8% for a high velocity (4 ms) fall. In the latter condition, improved attenuation was provided by the soft shell hip protectors (19% by Safehip Soft and 21% by Hipsaver). As soft tissue stiffness increased from softest to most rigid, the attenuation provided by Safehip Classic increased 2.9-fold (from 26% to 76%), while Safehip Soft increased 1.7-fold (from 36% to 60%) and Hipsaver increased 1.1-fold (from 36% to 38%). As pelvis size decreased from largest to smallest, the attenuation provided by Safehip Classic increased 8-fold, but for a high velocity fall and moderate tissue stiffness, never exceeded that provided by Safehip Soft and Hipsaver. Our results indicate that, under biofidelic testing conditions, the soft shell hip protectors we examined generally provided greater force attenuation (averaging up to 27%) than the hard shell protector. Measured values of force attenuation were highly sensitive to variations in impact velocity, pelvic size, and pelvic soft tissue stiffness. This indicates the need to develop international testing standards to guide market approval, the selection of protectors for clinical trials, and the design of improved hip protectors.


Stepping strategies of young adults undergoing sudden external perturbation from different directions.
Stepping strategies following external perturbations from different directions is investigated in this work. We analysed the effect of the perturbation angle as well as the level of awareness of individuals and characterised steps out of the sagittal plane between Loaded Side Steps (LSS), Unloaded Medial Steps (UMS) and Unloaded Crossover Steps (UCS). A novel experimental paradigm involving perturbations in different directions was performed on a group of 21 young adults (10 females, 11 males, 20-38 years). Participants underwent 30 randomised perturbations along 5 different angles with different levels of awareness of the upcoming perturbations (with and without wearing a sensory impairment device) for a total of 1260 recorded trials. Results showed that logistic models based on the minimal values of the Margin of Stability (MoS) or on the minimal values of the Time to boundary (Ttb) performed the best in the sagittal plane. However, their accuracy stayed above 79% regardless of the perturbation angle or level of awareness. Regarding the effect of the experimental condition, evidences of different balance recovery behaviours due to the variation of perturbation angles were exposed, but no significant effect of the level of awareness was observed. Finally, we proposed the Distance to Foot boundary (DtFb) as a relevant quantity to characterise the stepping strategies in response to perturbations out of the sagittal plane.


The occurrence and spatial distribution of organophosphorous pesticides in Chinese surface water.
The organophosphorous pesticides (OPPs) contaminations have been reported to occur in some Chinese waters. To describe the contamination status and the spatial distribution of OPPs in the surface water throughout China, samples were collected from over 600 sites located in the surface water of seven major river basins and three main internal rivers drainage areas during 2003 and 2004. The surface water samples were analyzed for the representative OPPs including dichlorvos, demeton, dimethoate, methyl parathion, malathion and parathion. In general, the most frequently detected compound was dichlorvos and demeton, being detected in 89.1% of samples (mean = 17.8 ng/L; range <1.4-1,552.0 ng/L) for dichlorvos, and 78.2% of samples (mean = 35.4 ng/L; range <1.5-2,560.0 ng/L) for demeton. While the detection frequencies of the dimethoate, methyl parathion, malathion, and parathion were all less than 50% in all the surface water samples. Measured concentrations for the six compounds were low and rarely exceed the environment quality standard for surface water of China. The six OPPs compounds were more frequently detected at much higher concentrations in the rivers of north China compared with those of south China. The results of this investigation indicate that OPPs contamination in the Yellow River, Huaihe River, Liaohe River, and Haihe River basins of north China should be of particular concern. When compared with other regions of the world, it appears that the Chinese surface water is some moderately polluted by dimethoate, methyl parathion, malathion, parathion and contaminated by dichlorvos and demeton in certain degree.


Spasticity in kids. An intrathecal option.
The painful muscle rigidity and severe spasms suffered by patients with brain and spinal injury can be managed even more successfully than in the past with intrathecal baclofen. For many, it's provided effective relief and improved levels of function.


Transcranial magnetic stimulation and gait disturbances in Parkinson's disease: A systematic review.
Transcranial magnetic stimulation (TMS) may offer a reliable means of characterizing important pathophysiologic aspects of motor impairments in Parkinson's disease (PD). Moreover, high-frequency repetitive TMS (rTMS), especially if delivered bilaterally over motor cortical regions, can have beneficial effects on parkinsonian motor symptoms. However, only a few studies have investigated the effects of rTMS on freezing of gait (FOG) and other gait disturbances in PD. We aimed at investigating in this narrative review the usefulness of TMS for exploring the pathophysiology of gait impairment and at evaluating the therapeutic effects of rTMS in this context. The combination of rTMS and treadmill training was found to enhance the effect of physical therapy. Use of an H-coil enables stimulation of deep regions of the brain (for example medial prefrontal cortex) and may be used as a target for add-on therapy in the future. In contrast, theta burst stimulation has proven to be ineffective in treating gait disturbances in PD patients. Dual-mode NIBS, in particular preconditioning motor cortex rTMS by transcranial direct current stimulation, might also represent a novel therapeutic approach for patients with gait disturbances. Recent studies suggest that the supplementary motor area could be an appropriate target for brain stimulation when treating PD patients with FOG. Further large sample and well-designed clinical studies are required to evaluate how the possible positive effects of rTMS can be sustained over time and to determine the optimal stimulation protocols including target, stimulation intensity/duration and number of sessions.


New local electrical diagnostic tool for dielectric barrier discharge (DBD).
A new diagnostic tool to study dielectric barrier discharges (DBDs) at atmospheric pressure by local electrical measurements is introduced. The square ground electrode is divided into 64 square segments (3.44 mm side length) so as to measure the discharge currents and gas voltages with spatial resolutions, which allows a 2D mapping. The electrical measurement results are validated by a comparison with short exposure time photographs taken from the top view of the discharge cell. For this purpose, we changed the local discharge behavior by varying locally the gas gap and the barrier capacitance and also by using a gas flow. Then, in both situations, the breakdown voltage depends on the position, and the discharge current and gas voltage are different as well. The measurements performed for a planar DBD in nitrogen with admixed nitrous oxide gas show that even if the discharge operates in a diffuse regime, the discharge does not behave exactly homogeneously on the whole surface area. The resulting electrical parameters allow us to refine the understanding of planar DBDs. The discharge activity changes the gas composition and thus, the level of preionization in the direction of the gas flow. This influences the local breakdown voltage and thus, the discharge morphology and local power density on the surface. The use of this new electrical diagnostic tool will allow us to refine the analysis of the spatial development of the discharge. This work gives some clues to improve the spatial resolution of this tool in the future.


Different measurements of waist circumference and sagittal abdominal diameter and their relationship with cardiometabolic risk factors in elderly men.
Measures of central adiposity such as waist circumference (PC) and sagittal abdominal diameter (SAD) are better predictors of metabolic complications than measures of total body fat. Thus, this study aimed to assess the relationship of different measures of WC and SAD with cardiometabolic risk factors in elderly men. This is a cross-sectional study that included 69 men (aged 60-92 years old) enrolled in the Family Health Program of Viçosa, Minas Gerais, Brazil. The evaluations comprised anthropometric, biochemical and haemodynamic measurements. The WC (i.e., umbilical level; the narrowest waist; immediately above the iliac crests; and the midpoint between the last rib and iliac crest) and SAD (i.e., the narrowest point between the last rib and the iliac crest; higher abdominal diameter; umbilical level; and the midpoint between the iliac crests) were measured at different anatomical sites. Statistical analysis consisted of correlation coefficients between measures of abdominal adiposity and cardiometabolic risk factors. The strongest correlations were between the WC measured at the narrowest waist and triglycerides (TG), fasting blood glucose (FBG) and high-density lipoprotein cholesterol (HDL-C) levels, and between the SAD measured at the midpoint between the iliac crests and TG, FBG and HDL-C. SAD measured at the midpoint between the iliac crests and WC measured at the narrowest waist showed the best relationships with cardiometabolic risk factors in elderly men.


Glass fragility and the stability of pharmaceutical preparations--excipient selection.
The objectives of this study were, first, to calculate the zero mobility temperatures, T0, of trehalose and sucrose by the Pikal method from the width of the glass transition and compare these to the literature, obtained by enthalpy relaxation measurement, and second, to compare the T0 values and physicochemical properties of trehalose to those of sucrose in terms of potential to stabilize labile actives in the glassy state. Differential scanning calorimetry and coulometric Karl-Fischer analysis were used. The glass transition temperatures, Tg, for the two carbohydrates at circa 0.7% moisture were 101 degrees C and 64 degrees C for trehalose and sucrose, respectively. Anhydrous amorphous trehalose had a Tg of 116 degrees C. The T0 values were found to be 44 and 3.5 degrees C for trehalose and sucrose, respectively. The Tg-T0 value for sucrose was compared, and found to be in good agreement with that found by enthalpy relaxation measurements. Trehalose was found to be resistant to crystallization above the glass temperature. The study supports the validity of the calculation method proposed by Pikal for T0. It has been proposed in the literature that T0 is a better measure of stability than Tg. Trehalose has a significantly higher T0 than sucrose and thus would work more effectively in stabilizing a labile active.


Redox state of tumor suppressor p53 regulates its sequence-specific DNA binding in DNA-damaged cells by cysteine 277.
Using a bio-oligo pull-down DNA-binding assay we investigated the binding capacity of endogenous, DNA damage-induced p53 in human diploid fibroblasts to several p53-responsive elements (REs) present in p53-regulated genes. During the course of p53 accumulation, we observed a decrease in p53 binding to the GADD45 but not to the p21(WAF1/CIP1) RE. Using mutated GADD45 sequences we show that this change is dependent on the presence of cytosines at position 3 in RE pentamers and on the p53 redox state. Site-directed mutagenesis experiments demonstrated that Cys277 (a residue directly contacting base 3 in a RE pentamer) is critical for differential regulation of GADD45 in DNA-damaged cells. These data represent a novel mechanism for differential affinity of p53 to distinct REs.


A randomized controlled trial of late conversion from CNI-based to sirolimus-based immunosuppression following renal transplantation.
Maintenance immunosuppression with calcineurin inhibitors (CNIs) following renal transplantation is associated with nephrotoxicity and accelerated graft loss. We aimed to assess whether conversion to sirolimus-based immunosuppression would affect the progression of renal impairment. In this single center, randomized controlled trial, 40 renal transplant recipients between 6 months and 8 years post-transplant were randomly assigned to remain on their CNI (cyclosporin or tacrolimus) or to switch to sirolimus. The primary outcome measure was change in glomerular filtration rate (GFR) measurement at 12 months. Analysis was by intention-to-treat. Of the 40 patients randomized, 2 patients never took the study drugs and were excluded, leaving 19 patients per group. There was a significant change in GFR at 12 months following conversion to sirolimus (12.9 mL/min, 95% CI 6.1-19.7; p < 0.001). Following conversion, the principal adverse events were the development of rashes (68%), particularly acne, and mouth ulcers (32%). No patient in either group experienced an acute rejection episode. In renal transplant recipients, a change in maintenance therapy from CNIs to sirolimus is associated with significant improvement in GFR at 12 months.


Direct Determination of Hydroxymethyl Conformations of Plant Cell Wall Cellulose Using 1H Polarization Transfer Solid-State NMR.
In contrast to the well-studied crystalline cellulose of microbial and animal origins, cellulose in plant cell walls is disordered due to its interactions with matrix polysaccharides. Plant cell wall (PCW) is an undisputed source of sustainable global energy; therefore, it is important to determine the molecular structure of PCW cellulose. The most reactive component of cellulose is the exocyclic hydroxymethyl group: when it adopts the tg conformation, it stabilizes intrachain and interchain hydrogen bonding, while gt and gg conformations destabilize the hydrogen-bonding network. So far, information about the hydroxymethyl conformation in cellulose has been exclusively obtained from 13C chemical shifts of monosaccharides and oligosaccharides, which do not reflect the environment of cellulose in plant cell walls. Here, we use solid-state Nuclear Magnetic Resonance (ssNMR) spectroscopy to measure the hydroxymethyl torsion angle of cellulose in two model plants, by detecting distance-dependent polarization transfer between H4 and H6 protons in 2D 13C-13C correlation spectra. We show that the interior crystalline portion of cellulose microfibrils in Brachypodium and Arabidopsis cell walls exhibits H4-H6 polarization transfer curves that are indicative of a tg conformation, whereas surface cellulose chains exhibit slower H4-H6 polarization transfer that is best fit to the gt conformation. Joint constraints by the H4-H6 polarization transfer curves and 13C chemical shifts indicate that it is unlikely for interior cellulose to have a significant population of the gt and gg conformation mixed with the tg conformation, while surface cellulose may adopt a small percentage of the gg conformation. These results provide new constraints to the structure and matrix interactions of cellulose in plant cell walls, and represent the first direct determination of a torsion angle in an important noncrystalline carbohydrate polymer.


Stroke prediction in patients presenting with isolated dizziness in the emergency department.
Diagnosing stroke in patients experiencing dizziness without neurological deficits is challenging for physicians. The aim of this study was to evaluate the prevalence of acute stroke in patients who presented with isolated dizziness without neurological deficits at the emergency department (ED), and determine the relevant stroke predictors in this population. This was an observational, retrospective record review of consecutive 2215 adult patients presenting with dizziness at the ED between August 2019 and February 2020. Multivariate analysis was performed to identify risk factors for acute stroke. 1239 patients were enrolled and analyzed. Acute stroke was identified in 55 of 1239 patients (4.5%); most cases (96.3%) presented as ischemic stroke with frequent involvement (29.1%) of the cerebellum. In the multivariate analysis, the history of cerebrovascular injury (odds ratio [OR] 3.08 [95% confidence interval {CI} 1.24 to 7.67]) and an age of > 65 years (OR 3.01 [95% CI 1.33 to 6.83]) were the independent risk factors for predicting acute stroke. The combination of these two risks showed a higher specificity (94.26%) than that of each factor alone. High-risk patients, such as those aged over 65 years or with a history of cerebrovascular injury, may require further neuroimaging workup in the ED to rule out stroke.


Fermented dairy products, dietary calcium and colon cancer: a case-control study in The Netherlands.
To examine whether the consumption of fermented dairy products or the dietary intake of calcium decreases colon cancer risk, a case-control study was conducted in the The Netherlands. Dietary patterns were assessed in detail (for cases before diagnosis or symptoms occurred) using a structured dietary history questionnaire. After adjustment for potential confounding variables, consumption of fermented dairy products, hard cheese and unfermented dairy products was not significantly associated with risk of colon cancer: an odds ratio (OR) of 1.1 was found for individuals consuming more than one serving of fermented dairy products per day as compared to those consuming less than 10% of one serving a day. Adjustment for dietary calcium attenuated the associations. Total dietary calcium was positively but non-significantly associated with colon cancer risk after adjustment for age, gender, urbanization level and total energy intake. Additional adjustment for a positive family history of colorectal cancer, cholecystectomy and energy-adjusted intake of total fat, dietary fibre, vitamin C and alcohol increased the association. No differences were observed between calcium from fermented and from unfermented dairy sources. The observed associations for fermented dairy products and dietary calcium differed between men and women: positive significant associations were observed in men, while in women non-significant inverse associations were found. Our results do not support the hypothesis that an increased intake of commercially available, commonly used fermented dairy products or dietary calcium decreases the risk of colon cancer.


A comprehensive study of Candida-specific antibodies in the saliva of human immunodeficiency virus-positive individuals with oropharyngeal candidiasis.
Oropharyngeal candidiasis (OPC) is a common oral opportunistic infection among human immunodeficiency virus (HIV)-positive individuals. Although most cases of OPC correlate with reduced systemic levels of CD4(+) T cells, the role of humoral immunity in protection against mucosal candidiasis, including OPC, remains questionable. In the present study, a comprehensive analysis of saliva from 33 HIV-negative and 68 HIV-positive individuals, stratified by OPC status and peripheral CD4(+) cell count, was conducted to measure levels of total and Candida-specific immunoglobulin A(IgA) and IgG antibodies, including subclasses and secretory IgA. Despite changes in total immunoglobulin levels, when levels of Candida-specific antibodies were normalized to total protein or total immunoglobulin of the corresponding isotype, no distinct differences in IgG (including subclasses), IgA (including subclasses), or secretory IgA levels were seen, regardless of HIV status, OPC status, or CD4(+) cell count. These data suggest that when a complete repertoire of antibodies is evaluated, with appropriate normalization of data, there is no evidence of appreciable changes in levels of Candida-specific antibodies in saliva that would account for the prevalence of OPC among HIV-positive individuals.


Blastocoel cavity formation by preimplantation rat embryos in the presence of cyanide and other inhibitors of oxidative phosphorylation.
The role of oxidative phosphorylation in blastocoel development in rats was determined by culturing morula stage embryos for 24 h in the presence of three inhibitors of ATP generation: cyanide, antimycin-A and 2,4-dinitrophenol (DNP). Rat morulae could form blastocysts in concentrations of cyanide that are toxic to the embryos of other mammals. Similar results were obtained with antimycin-A and DNP, although DNP reduced the number of blastocysts that formed. A non-invasive ultramicrofluorometric assay was used on single blastocysts and the glycolytic pathway was shown to be stimulated in the presence of these inhibitors. These results suggest that, uniquely among preimplantation embryos studied, the developing rat blastocyst does not have an absolute requirement for oxidative phosphorylation but may be able to compensate by increasing the amount of glucose consumed and metabolized by glycolysis. This pattern of metabolism may be related to the changing maternal environment during development, with blastocoel cavity formation and implantation taking place in increasingly anoxic conditions.


Rx for low cash yields.
Certain strategies can offer not-for-profit hospitals potentially greater investment yields while maintaining stability and principal safety. Treasury inflation-indexed securities can offer good returns, low volatility, and inflation protection. "Enhanced cash" strategies offer liquidity and help to preserve capital. Stable value "wrappers" allow hospitals to pursue higher-yielding fixed-income securities without an increase in volatility.


The visual field after trabeculectomy. A follow-up study using computerized perimetry.
Series of visual fields in 20 eyes in which trabeculectomy had been performed were studied retrospectively. Computerized perimetry was used and the condition of the visual field was summarized into single numbers. Regression analysis was applied to series of such performance numbers. No correlation was found between the regression coefficient and the mean post-operative pressure or the mean pressure reduction. A dependence of the regression coefficient on the size of the visual field defect was observed.


Comparison of fluvoxamine, imipramine, and placebo in the treatment of outpatients with panic disorder.
Fluvoxamine and imipramine were compared to placebo in an 8-week doubleblind randomized multicentre trial comprising of 148 outpatients between 19 and 57 years of age (mean: 35) with a DSM-III-R diagnosis of Panic Disorder. mean daily dose at endpoint was: fluvoxamine, 171.4 mg; imipramine 164.7 mg. The mean number of panic attacks per week at baseline were 10.9, 14.4 and 6.5 for fluvoxamine, imipramine and placebo, respectively. The intent-to-treat analysis of the change from baseline (difference score) of the number of panic attacks at endpoint revealed: a difference of 3.3 attacks (95% CI: -0.3, 6.8) between fluvoxamine and placebo and a difference of 6.0 attacks (95% CI: 1.5, 10.5) between imipramine and placebo. Treatment was stopped prematurely in 31 (62%) on fluvoxamine, 16 (33%) on imipramine and 29 (58%) on placebo. The number of patients withdrawing due to intolerance was 13 (26%) for fluvoxamine, 10 (21%) for imipramine and 4 (8%) for placebo. The number of patients withdrawing due to lack of efficacy was 10 (20%) for fluvoxamine, 4 (8%) for imipramine and 12 (24%) for placebo. Overall, this study demonstrated that fluvoxamine was not effective in the treatment of panic disorder but did show a strong effect for imipramine. A chance occurrence of significantly fewer number of panic attacks in the placebo group at baseline may limit the conclusions of this study.


Evidence of disease control: a realistic concept beyond NEDA in the treatment of multiple sclerosis.
Although no evidence of disease activity (NEDA) permits evaluation of response to treatment in the systematic follow-up of patients with multiple sclerosis (MS), its ability to accomplish detection of surreptitious activity of disease is limited, thus being unable to prevent patients from falling into a non-reversible progressive phase of disease. A protocol of evaluation based on the use of validated biomarkers that is conducted at an early stage of disease would permit the capture of abnormal neuroimmunological phenomena and lead towards intervention with modifying therapy before tissue damage has been reached.


What is the effect of mandatory pasteurisation on the biogas transformation of solid slaughterhouse wastes?
The effect of mandatory pasteurisation on Category 3 offals, according to the Animal By-Products Regulation (ABPR 1069/2009/EC), was determined using Biochemical Methane Potential (BMP) assays as well as kinetic and statistical analysis. Pasteurised and unpasteurised offals sampled from cattle, pig and chicken slaughterhouses were characterised and their specific methane yields (SMYs) and their bioavailability was assessed. The resultant SMYs were high (465-650mLCH4gVS(-1)) with no statistically significant increase in methane production identified due to pasteurisation. However, the kinetics of the biogas transformation processes highlighted increased bioavailability of the organics due to pasteurisation. This was brought to light by the change in maximum daily SMY from day 22 to day 1 for the cattle offal (p=0.001), day 17 to day 1 for chicken offal (p=0.025) and an increase of 18.8% in the maximum daily SMY of the pig offal on day 1 (p=0.003). The increased bioavailability of the offals manifested itself in two ways with the determining factor being identified as the physical characteristics of the fats i.e. particle size. Firstly reducing the hydrolytic lag phase for the cattle offal, λ=7.46-1.52days (p=0.013). Secondly, causing increased accumulation of Long Chain Fatty Acids to acute inhibitory levels in the chicken and pig offal indicated by increased lag phases λ=5.05-21.91days (p=0.012), λ=15.54-23.04days (p=0.007) respectively.


Protective effects of Sosihotang extract against ultraviolet B-induced skin photoageing in hairless mice.
Sosihotang (SSH) is an herbal medicine traditionally used against the common cold, and hepatic and gastric diseases, in Northeast Asia. In this study, we investigated whether SSH extract can protect against UVB-induced skin damage and photoageing. HaCaT cells were treated with SSH extract and exposed UVB irradiation at 20 mJ/cm2 . Hairless mice were orally administered SSH extract (100 mg/kg per mouse) as UVB irradiation was increased from 60 to 120 mJ/cm2 over the course of 12 weeks. Treatment with SSH extract inhibited the upregulation of MMP-1 and MMP-9 expression in UVB-irradiated HaCaT cells. In UVB-irradiated hairless mice, treatment with SSH extract restored the levels of factors instrumental in skin hydration (TEWL, capacitance, HA and TGF-β) and those regulating collagen content (procollagen, MMP-1 and MMP-9). This activity inhibited epidermal thickening and disorganization of collagen fibres. Administration of SSH extract also ameliorated the expression of UVB-induced pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and phosphorylation of MAPK family members (MEK, JNK, ERK and p38) by upregulating the activity of antioxidant enzymes (SOD, CAT, Nrf-2, HO-1 and NQO-1). These results indicate that SSH extract can be used therapeutically for the treatment of UVB-induced skin damage and photoageing.


Separate gating mechanisms mediate the regulation of K2P potassium channel TASK-2 by intra- and extracellular pH.
TASK-2 (KCNK5 or K(2P)5.1) is a background K(+) channel that is opened by extracellular alkalinization and plays a role in renal bicarbonate reabsorption and central chemoreception. Here, we demonstrate that in addition to its regulation by extracellular protons (pH(o)) TASK-2 is gated open by intracellular alkalinization. The following pieces of evidence suggest that the gating process controlled by intracellular pH (pH(i)) is independent from that under the command of pH(o). It was not possible to overcome closure by extracellular acidification by means of intracellular alkalinization. The mutant TASK-2-R224A that lacks sensitivity to pH(o) had normal pH(i)-dependent gating. Increasing extracellular K(+) concentration acid shifts pH(o) activity curve of TASK-2 yet did not affect pH(i) gating of TASK-2. pH(o) modulation of TASK-2 is voltage-dependent, whereas pH(i) gating was not altered by membrane potential. These results suggest that pH(o), which controls a selectivity filter external gate, and pH(i) act at different gating processes to open and close TASK-2 channels. We speculate that pH(i) regulates an inner gate. We demonstrate that neutralization of a lysine residue (Lys(245)) located at the C-terminal end of transmembrane domain 4 by mutation to alanine abolishes gating by pH(i). We postulate that this lysine acts as an intracellular pH sensor as its mutation to histidine acid-shifts the pH(i)-dependence curve of TASK-2 as expected from its lower pK(a). We conclude that intracellular pH, together with pH(o), is a critical determinant of TASK-2 activity and therefore of its physiological function.


Effectiveness and Quality of Life with Montelukast in Asthma - A double-blind randomized control trial.
To determine the role of montelukast - a leukotriene receptor antagonist (LTRA) - in improving the quality of life (QOL) and asthma control of adult patients with mild to moderate persistent asthma. Randomized, double-blind, placebo-controlled, non-crossover trial was conducted from March 2017 till November 2018 in three hospitals of Karachi and Hyderabad. Adults of age 15 years or more with mild to moderate persistent asthma. Treatment group was administered tablet montelukast 10mg once daily; the other group was given a similar looking placebo; as an adjuvant to the current medication. QOL was assessed with Asthma Quality of Life Questionnaire - Standard (AQLQ-S) before and after the treatment. Asthma control was monitored via Asthma Control Test (ACT). After 4 weeks, the mean ± SD of overall QOL on AQLQ-S improved from 3.74±0.88 to 5.06±0.89 for montelukast group and from 3.58±0.92 to 4.71±0.97 for placebo group (p=0.02). The improvement in sub-domains of symptoms, activity, and emotional functions was not significant; however, the sub-domain "environmental stimuli" significantly improved with 5.06±0.89 for montelukast group and 4.71±0.97 for placebo group (p=0.02). The mean ± SD of ACT, after four weeks, for montelukast group was 18.19±2.91 and for placebo group 17.28±3.36. Only on ACT, Montelukast did not show any statistically insignificant results. The role of montelukast in improving QOL of adult patients with mild to moderate persistent asthma is quite beneficial. It improves patient quality of life. It has the ease of once daily oral administration and also eradicates side effects associated with long-term adherence to steroids.


Estimation of the available free energy in a LOV2-J alpha photoswitch.
Protein photosensors are versatile tools for studying ligand-regulated allostery and signaling. Fundamental to these processes is the amount of energy that can be provided by a photosensor to control downstream signaling events. Such regulation is exemplified by the phototropins--plant serine/threonine kinases that are activated by blue light via conserved LOV (light, oxygen and voltage) domains. The core photosensor of oat phototropin 1 is a LOV domain that interacts in a light-dependent fashion with an adjacent alpha-helix (J alpha) to control kinase activity. We used solution NMR measurements to quantify the free energy of the LOV domain-J alpha-helix binding equilibrium in the dark and lit states. These data indicate that light shifts this equilibrium by approximately 3.8 kcal mol(-1), thus quantifying the energy available through LOV-J alpha for light-driven allosteric regulation. This study provides insight into the energetics of light sensing by phototropins and benchmark values for engineering photoswitchable systems based on the LOV-J alpha interaction.


Benign epithelioid peripheral nerve sheath tumour resembling schwannoma.
Peripheral nerve sheath tumours (PNST) with epithelial appearing cells compromise a heterogeneous group of neoplasms that are rare and diagnostically challenging. Of these, malignant PNSTs with epithelioid features (epithelioid MPNST) are commonly described in literature. However benign epithelioid PNSTs are rare and till date about 38 cases have been described in the literature. We report a benign epithelioid PNST with light microscopical and immunohistochemical features suggestive of schwannoma, presenting as a thigh mass in a 23-year-old female. The tumour was encapsulated, showed epithelioid cells in aggregates, and expressed vimentin and S-100 positivity. There was no expression of CD34, CK, EMA, CD99, p63 and HMB 45. Typical Antoni A and Antoni B areas were absent. At 18 months follow-up, the patient was well.


Two epidemics of pseudobacteremia due to Staphylococcus aureus and Aerococcus viridans.
Two epidemics of pseudobacteremia are reported. The first, due to Staphyloccus aureus, was caused by a physician who had active staphylococcal skin infection and nasal colonization. Because the blood culture system in use at the time was open, and used screw cap bottles, we assume that the physician contaminated the bottles at the time of inoculation. The second outbreak, caused by Aerococcus viridans, was traced to contamination of the blood culture bottle tops as they were received from the manufacturer. We assume that there was inadequate disinfection of the bottle tops by the physicians prior to their use.


New type of helix and 2(7) ribbon structure formation in poly DeltaLeu peptides: construction of a single-handed template.
alpha,beta-Dehydroamino acid residues due to the presence of Calpha = Cbeta double bond influences the main chain and the side chain conformations. These residues have interesting chemical features including the increased resistance to enzymatic degradation. The chain length dependent conformational behavior of poly alpha,beta-dehydroleucine (DeltaLeu) peptides in both the pure forms Z and E and their various combinations like alternate ZE/EZ etc. have been investigated by using quantum mechanical method PCILO (perturbative configuration interaction of localized orbitals). The conformational states in alternate Z and E forms, with Phi, Psi values of -10 degrees , 105 degrees /1 degrees , -88 degrees for Z form and 35 degrees , 22 degrees /-34 degrees , -27 degrees for the E form are found to be the most stable and degenerate than the states in pure Z and E forms and the EZ form etc. The repeated Phi, Psi values give rise to altogether new types of left and right handed helices, and their stability increases with increasing chain length. These structures are stabilized by intramolecular hydrogen bonding, carbonyl-carbonyl interactions and hydrophobic interactions between the side chains of DeltaZLeu and DeltaELeu residues. The 2(7) ribbon structure (seven-membered hydrogen-bonded ring involving two consecutive amino acid residues) is found to be most stable and degenerate in the pentapeptide Ac-DeltaELeu5-NHMe, due to the formation of maximum hydrogen bonds. A right-handed template from achiral DeltaLeu peptides has been achieved by incorporating L-Leu at the C-terminal or D-Leu at the N-terminal.


[Protoplast mutagenesis for improving beta-glucosidase production of Aspergillus niger].
The aims of this research were to isolate a Aspergillus niger strain with higher beta-glucosidase activity. We utilized the beta-glucosidase producing strain Aspergillus niger CGMCC 3.316 as the original strain to first obtain a mutant 3-3M through ultraviolet irradiation. Then we studied the conditions of protoplast release and regeneration for strain 3-3M. We treated the protoplasts of strain 3-3M via ultraviolet irradiation and obtained another isolated mutant 60B-3D. The strain 60B-3D showed much higher beta-glucosidase production than the original strain and 3-3M strain. The beta-glucosidase activity of strain 60B-3D was 23.4 IU/mL, with an improvement of 39% compared with the original strain, and 23% compared with strain 3-3M. We also studied the fermentation process of strain 60B-3D, and compared it with the original strain and strain 3-3M. We found the strain 60B-3D exhibited an improvement in xylanase production. The comparison results also showed that the strain 60B-3D secreted more protein. These results were beneficial for producing beta-glucosidase through this productive mutant.


High-Speed Imaging of Microsphere Transport by Cavitation Activity in a Tissue-Mimicking Phantom.
Ultrasound-mediated cavitation has been harnessed to improve the delivery of various therapeutics, including the extravasation of small molecule drugs and nanoparticles (<1 µm) into soft tissue. This study investigated whether cavitation could also enhance the extravasation of larger (>10 µm) therapeutic particles, representative of radio- or chemo-embolic particles, in a tissue-mimicking phantom. High-speed (103-106 frames/s) optical imaging was used to observe the motion of glass microspheres with diameters of 15-32 or 105-107 µm in an agar phantom under exposure to high-intensity focused ultrasound (0.5 MHz) at a range of peak negative pressures (1.9-2.8 MPa) in the presence of SonoVue microbubbles. In contrast to the microstreaming reported to be responsible for nanoparticle transport, the formation and translation of bubble clouds were found to be primarily responsible for the motion of glass microspheres. The bubble clouds were seen both to create channels in the phantom and to travel along them under the action of primary acoustic radiation force, either propelling or entraining microspheres with them. Collisions between microspheres were also seen to promote cloud formation and cavitation activity. Ultrasound-mediated cavitation can promote the transport of solid microparticles in tissue-mimicking material. Further work is needed to understand the influence of tissue mechanical properties and ultrasound exposure parameters on the extent and uniformity of particle distribution that can be achieved.


Identification, quantification and antioxidant activity of acylated flavonol glycosides from sea buckthorn (Hippophae rhamnoides ssp. sinensis).
A novel acylated flavonol glycoside: isorhamnetin (3-O-[(6-O-E-sinapoyl)-β-D-glucopyranosyl-(1→2)]-β-D-glucopyranosyl-7-O-α-L-rhamnopyranoside) (1), together with two known acylated flavonol glycosides: quercetin (3-O-[(6-O-E-sinapoyl)-β-D-glucopyranosyl-(1→2)]-β-D-glucopyranosyl-7-O-α-L-rhamnopyranoside) (2) and kaempferol (3-O-[(6-O-E-sinapoyl)-β-D-glucopyranosyl-(1→2)]-β-D-glucopyranosyl-7-O-α-L-rhamnopyranoside) (3) were isolated from the n-butanol fraction of sea buckthorn (Hippophae rhamnoides ssp. sinensis) berries for the first time by chromatographic methods, and their structures were elucidated using UV, MS, (1)H and (13)C NMR, and 2D NMR. Compounds 1-3 showed good scavenging activities, with respective IC50 values of 8.91, 4.26 and 30.90 μM toward the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical; respective Trolox equivalent antioxidant capacities of 2.89, 4.04 and 2.44 μM μM(-1) toward 2,2'-azino-bis-3-ethyl-benzothiazoline-6-sulphonate (ABTS) radical. The quantitative analysis of the isolated acylated flavonol glycosides was performed by HPLC-DAD method. The contents of compounds 1-3 were in the range of 12.2-31.4, 4.0-25.3, 7.5-59.7 mg/100 g dried berries and 9.1-34.5, 75.1-182.1, 29.2-113.4 mg/100 g dried leaves, respectively.


A multi-district audit of the management of HIV infection in pregnant women and the prevention of mother-to-child transmission: Yorkshire HIV pregnancy audit.
A regional audit was performed to compare clinical practice against the British HIV Association guidelines for the management of HIV infection in pregnancy. Data were collected from 2000 to 2002 from eight clinics across Yorkshire using a questionnaire. There were 22 live births to 22 HIV + pregnant women. There were no cases of transmission of HIV from mother to child. The majority (20/22) of mothers received therapy as recommended in the guidelines, with only two initially receiving inappropriate dual therapy. In all, 16/22 (73%) had elective caesarean sections, 5/22 (23%) emergency sections after the onset of labour and one had a vaginal delivery. Also, 12/22 (55%) definitely received intravenous zidovudine during delivery. Added to these, 19/22 infants received appropriate antiretroviral medication for four to six weeks after birth. No mothers were known to have breast-fed.


WormFarm: a quantitative control and measurement device toward automated Caenorhabditis elegans aging analysis.
Caenorhabditis elegans is a leading model organism for studying the basic mechanisms of aging. Progress has been limited, however, by the lack of an automated system for quantitative analysis of longevity and mean lifespan. To address this barrier, we developed 'WormFarm', an integrated microfluidic device for culturing nematodes. Cohorts of 30-50 animals are maintained throughout their lifespan in each of eight separate chambers on a single WormFarm polydimethylsiloxane chip. Design features allow for automated removal of progeny and efficient control of environmental conditions. In addition, we have developed computational algorithms for automated analysis of video footage to quantitate survival and other phenotypes, such as body size and motility. As proof-of-principle, we show here that WormFarm successfully recapitulates survival data obtained from a standard plate-based assay for both RNAi-mediated and dietary-induced changes in lifespan. Further, using a fluorescent reporter in conjunction with WormFarm, we report an age-associated decrease in fluorescent intensity of GFP in transgenic worms expressing GFP tagged with a mitochondrial import signal under the control of the myo-3 promoter. This marker may therefore serve as a useful biomarker of biological age and aging rate.


Human papillomavirus (HPV) genotype distribution in invasive cervical cancers in France: EDITH study.
Invasive cervical cancer (ICC) remains a significant cause of morbidity and mortality in France. Since human papillomavirus (HPV) is the necessary cause of ICC, the aim of this study was to assess the type-specific prevalence of HPV in ICC in France in order to locally evaluate the potential benefit of an HPV 16/18 L1 virus-like particles (VLP) vaccination. A total of 516 histological specimens collected in 15 centers were analyzed. Among them, 86% had a diagnosis of squamous cell carcinoma (SCC) whereas 14% were adenocarcinomas (ADC). HPV genotyping was performed using the INNO-LiPA assay allowing the specific detection of 24 HPV genotypes both high risk (HR) and low risk (LR). The overall HPV prevalence in ICC was 97%. The most prevalent genotypes were HPV 16 (73%) and HPV 18 (19%) followed by HPV 31 (7%), 33, 68, 45, 52 and 58 (4.1-2.3%). HPV 16 and/or 18 were associated with 82% of ICC, 10% being HPV 16 and 18 coinfections. While HPV 16 was the most prevalent type in both SCC (74%) and ADC (64%), HPV 18 was by far more prevalent in ADC (37%) compared to SCC (16%; p < 0.001). Multiple infections with at least two different HR HPV genotypes were observed in 22% of ICC. Given the high HPV 16/18 prevalence and taking into account possible production of crossneutralizing antibodies against other HPV types, HPV 16/18 L1 VLP vaccination would be expected to significantly reduce the burden of ICC in France.


High-Performance All-Solid-State Na-S Battery Enabled by Casting-Annealing Technology.
Room-temperature all-solid-state Na-S batteries (ASNSBs) using sulfide solid electrolytes are a promising next-generation battery technology due to the high energy, enhanced safety, and earth abundant resources of both sodium and sulfur. Currently, the sulfide electrolyte ASNSBs are fabricated by a simple cold-pressing process leaving with high residential stress. Even worse, the large volume change of S/Na2S during charge/discharge cycles induces additional stress, seriously weakening the less-contacted interfaces among the solid electrolyte, active materials, and the electron conductive agent that are formed in the cold-pressing process. The high and continuous increase of the interface resistance hindered its practical application. Herein, we significantly reduce the interface resistance and eliminate the residential stress in Na2S cathodes by fabricating Na2S-Na3PS4-CMK-3 nanocomposites using melting-casting followed by stress-release annealing-precipitation process. The casting-annealing process guarantees the close contact between the Na3PS4 solid electrolyte and the CMK-3 mesoporous carbon in mixed ionic/electronic conductive matrix, while the in situ precipitated Na2S active species from the solid electrolyte during the annealing process guarantees the interfacial contact among these three subcomponents without residential stress, which greatly reduces the interfacial resistance and enhances the electrochemical performance. The in situ synthesized Na2S-Na3PS4-CMK-3 composite cathode delivers a stable and highly reversible capacity of 810 mAh/g at 50 mA/g for 50 cycles at 60 °C. The present casting-annealing strategy should provide opportunities for the advancement of mechanically robust and high-performance next-generation ASNSBs.


Inferring polydomy: a review of functional, spatial and genetic methods for identifying colony boundaries.
Identifying the boundaries of a social insect colony is vital for properly understanding its ecological function and evolution. Many species of ants are polydomous: colonies inhabit multiple, spatially separated, nests. Ascertaining which nests are parts of the same colony is an important consideration when studying polydomous populations. In this paper, we review the methods that are used to identify which nests are parts of the same polydomous colony and to determine the boundaries of colonies. Specifically, we define and discuss three broad categories of approach: identifying nests sharing resources, identifying nests sharing space, and identifying nests sharing genes. For each of these approaches, we review the theoretical basis, the limitations of the approach and the methods that can be used to implement it. We argue that all three broad approaches have merits and weaknesses, and provide a methodological comparison to help researchers select the tool appropriate for the biological question they are investigating.


[Overweight and obesity: review and update].
Obesity is an epidemic with important health repercussions in addition to high treatment-related costs. Between 2006 and 2007 the WHO developed new assessment tools, which aren't being globally used. In fact, there is no unified problem management across the hemisphere. To update obesity epidemiology, to promote application of WHO's standards, to review new findings on physiopathology (i.e., fatty tissue as endocrine organ, intestinal microbiota), to update epidemiological information, and to provide management guidelines that can be integrated in clinical care. LAPSGHAN called up its members to collaborate in preparing this review article under the direction of an editor/coordinator, who selected the contents and literature with the best evidencetogether with the members. Each member prepared a separate document for each content. The chosen contents were later collated, unified, and edited. Results. This documents highlights the following: 1) Although extreme obesity is increasing in the US, overweight and obesity prevalence has stabilized, while in other countries it is alarmingly increasing; 2) New information regarding role of fatty tissue as endocrine organ and self-regulator of obesity; 3) The promising role of microbiota; and 4) Guidelines for children handling during consultation and follow-up. There is no widespread implementation of standards and guidelines from the World Health Organization (WHO). There is no agreement as to whether z-scores or percentiles should be used, especially regarding children under 2 due to their changing body complexion. The most accepted tool to assess overweight, obesity and severe obesity is the Body Mass Index (BMI). This document provides recommendations on how to approach clinical care with affected children.


Regeneration of the hepatic nerves following surgical denervation of the liver in dogs.
This study was conducted to examine the regeneration process of hepatic nerves following surgical hepatic denervation in dogs. A denervation model was surgically created by removing all visible nerves around the hepatoduodenal ligament along with the peri-hepatic tissues. The hepatic nerves were examined on the hepatic specimens taken at 1 week, 1 month and 3 months post-denervation by means of immunohistochemical staining, and also electron microscopy. At 1 week post-denervation, the extrinsic hepatic nerves were observed not to have regenerated. However, at 1 month post-denervation, GAP-43-positive nerves were identified and regenerating axons were shown to be present on electron microscopic observation. The immunoreactivity for anti-GAP-43 antibody was not shown any longer at 3 months post-denervation, and the regenerated nerve axons were shown to be similar to those at pre-denervation on ultrastructural study. Results of the present study suggested that regeneration of the extrinsic hepatic nerves began to appear about 1 month after the hepatic denervation, and was completed by 3 months post-denervation.


Spasticity and contracture. Physiologic aspects of formation.
Disruption of the upper motor neuron inhibitory pathways by stroke, brain trauma, or spinal cord injury leads to muscle spasticity. Spasticity is characterized by increased muscle tone, hyperactive reflexes, and possible clonus or rigidity. The increased muscle tone may result in loss of joint motion, leading to contractures. Treatment of established contractures is difficult. Prevention of contractures by joint mobilization is emphasized as a goal in the management of patients with spasticity.


Intensity and Types of Physical Exercise in Relation to Dementia Risk Reduction in Community-Living Older Adults.
To systematically examine the amount and type of physical exercise that might reduce the future risk of dementia in community-living older people. Six-year observational study. All the Elderly Health Centers (EHCs) of the Department of Health in Hong Kong. A total of 15,589 community-living Chinese aged 65 years and older with no history of stroke, clinical dementia, or Parkinson disease when they completed health assessment at the EHCs in the first 6 months of 2005. Self-reported habitual physical exercise patterns, including the frequency, duration, and type of exercise, at baseline and Year 3 were analyzed. The study outcome was incident dementia in 6 years. Dementia was defined by presence of clinical dementia in accordance with the 10th revision of the International Statistical Classification of Diseases and Related Health Problems or Clinical Dementia Rating of 1 to 3. Both the cognitively stable and incident groups reported exercising a median of 7 days per week and 45 minutes per day at baseline and Year 3. The former practiced aerobic and mind-body exercises more at baseline and Year 3, whereas the latter practiced stretching and toning exercises more. The odds ratio for dementia remained significant for aerobic (0.81; 95% confidence interval 0.68-0.95; P = .01) and mind-body exercises (0.76; 0.63-0.92; P = .004) after excluding participants who developed dementia within 3 years after baseline and adjusting for important potential confounders, such as age, gender, educational level, and physical and psychiatric comorbidities. Although physical exercise is widely promoted as a nonpharmacological intervention for dementia prevention, not all types of exercise appear to be useful in reducing risk of dementia in older people. Our findings suggest that daily participation in aerobic and mind-body but not stretching and toning exercises might protect community-living older adults from developing dementia.


Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer cell lines.
Nerve growth factor (NGF) has antiproliferative and differentiating effects on adenomas of neuroendocrine origin. Cell lines derived from small-cell lung carcinoma (SCLC), a very aggressive neuroendocrine tumor, express NGF receptors. The role of NGF in the control of proliferation and progression of this carcinoma, however, has never been investigated. Chronic exposure of NCI-N-592 and GLC8 SCLC cell lines to NGF remarkably inhibited their proliferation rate both in vitro and in vivo, prevented their anchorage-independent clonal growth in soft agar, impaired their invasive capacity in vitro, and abolished their tumorigenic potential in nude mice. The proliferative response of SCLC cell lines to nicotine was also remarkably impaired by in vitro NGF treatment. Furthermore, NGF treatment activates in SCLC cell lines the expression and secretion of NGF. NGF thus reverts SCLC cell lines to a noninvasive, nontumorigenic phenotype that does not respond to nicotine and produces NGF.


Effects of antihypertensive agents on circadian blood pressure and heart rate patterns. Review.
Blood pressure and heart rate exhibit a circadian rhythm, with both rising rapidly during the morning hours and then decreasing throughout the day to a nadir around 3 AM. Current evidence suggests a possible link between cardiovascular events, such as myocardial infarction and sudden cardiac death, which have been shown to occur most frequently during the morning hours, and the rapid rise in blood pressure and heart rate during this same time period. We review data from ambulatory blood pressure studies to ascertain which antihypertensive agents provide the most satisfactory control of blood pressure and heart rate during the hours of 6 AM to 12 noon. Of the forms of drug therapy studied, labetalol, a combined alpha- and beta-blocker, and two calcium channel blockers, nifedipine and verapamil, appear to be the most effective in blunting the rise in arterial blood pressure during these critical morning hours.


Endobronchial resection with the Nd-YAG laser--two years experience in an Australian unit.
In a two year period 44 endobronchial resections using the Neodymium-YAG laser have been performed in 28 patients. The majority of cases had either bronchogenic carcinoma (57%) or metastatic carcinoma (18%) involving the bronchial tree. Adenoid cystic carcinoma, benign tumours, lymphoma, tracheal papillomatosis, Wegener's granulomatosis and benign stricture comprised the other cases. Rigid bronchoscopy and general anaesthesia were used in the majority. Symptomatic improvement of dyspnoea when relief of bronchial obstruction occurred was marked in ten of 17 cases, moderate in four and absent in three. Haemoptysis was markedly improved in two of three cases and obstructive pneumonitis resolved in one of two cases. Significant respiratory function improvement was observed in Raw (most sensitive), FEV11, FVC and TLC. Laser treatment restored the lumen to normal calibre in 52% (including all patients with tracheal lesions), to greater than half normal in 28% and to less than half normal in 20% of cases. Re-expansion of a collapsed lung or lobe occurred in seven of eight patients. In six of these patients laser treatment was the initial therapy resulting in immediate re-expansion and symptomatic relief prior to further therapy. In patients with bronchogenic carcinoma the mean time to retreatment or death was 72 days. For metastatic carcinoma this was 60 days. Two early deaths (3 hours, 36 hours) due to respiratory failure occurred in patients with very severe bilateral bronchial obstruction too advanced for effective clearance. Other complications included laryngeal oedema requiring prolonged intubation (1), bronchospasm (1), atrial fibrillation (1), and acute pulmonary oedema (1). Laser treatment provides effective palliation for bronchial obstruction and haemoptysis in selected proximal endobronchial cancers.


Druggable transcriptomic pathways revealed in Parkinson's patient-derived midbrain neurons.
Complex genetic predispositions accelerate the chronic degeneration of midbrain substantia nigra neurons in Parkinson's disease (PD). Deciphering the human molecular makeup of PD pathophysiology can guide the discovery of therapeutics to slow the disease progression. However, insights from human postmortem brain studies only portray the latter stages of PD, and there is a lack of data surrounding molecular events preceding the neuronal loss in patients. We address this gap by identifying the gene dysregulation of live midbrain neurons reprogrammed in vitro from the skin cells of 42 individuals, including sporadic and familial PD patients and matched healthy controls. To minimize bias resulting from neuronal reprogramming and RNA-seq methods, we developed an analysis pipeline integrating PD transcriptomes from different RNA-seq datasets (unsorted and sorted bulk vs. single-cell and Patch-seq) and reprogramming strategies (induced pluripotency vs. direct conversion). This PD cohort's transcriptome is enriched for human genes associated with known clinical phenotypes of PD, regulation of locomotion, bradykinesia and rigidity. Dysregulated gene expression emerges strongest in pathways underlying synaptic transmission, metabolism, intracellular trafficking, neural morphogenesis and cellular stress/immune responses. We confirmed a synaptic impairment with patch-clamping and identified pesticides and endoplasmic reticulum stressors as the most significant gene-chemical interactions in PD. Subsequently, we associated the PD transcriptomic profile with candidate pharmaceuticals in a large database and a registry of current clinical trials. This study highlights human transcriptomic pathways that can be targeted therapeutically before the irreversible neuronal loss. Furthermore, it demonstrates the preclinical relevance of unbiased large transcriptomic assays of reprogrammed patient neurons.


Absorption of oleic and palmitic acids from emulsions and micellar solutions.
A lipid mixture (monoolein, oleic acid-1-(14)C, and palmitic acid-9,10-(3)H) was infused intraduodenally at a steady rate for 8 hr in fasted, unanesthetized rats. The same dose of lipid was given together with pure conjugated bile salts either as an emulsion, 2.5 mM bile salts, or as a micellar solution, 10 mM bile salts. The emulsion contained very little or no micellar lipid. Thoracic duct lymph was collected and in some experiments bile and pancreatic juice were drained to the exterior. After 4-5 hr infusion the same steady lymphatic output of radioactive fatty acids was obtained with emulsion as with micellar solution. It was concluded that absorption of fatty acid could proceed efficiently in the virtual absence of micellar solubilization. In rats with biliary plus pancreatic fistulae, labeled triglyceride was absorbed poorly relative to free fatty acids in the same emulsified particles. This suggested that fatty acids were transferred to the absorptive cells in monomolecular solution and not as emulsion particles. Substitution of a synthetic nonionic detergent for bile salts in lipid mixtures given to rats with biliary and pancreatic fistulae did not affect the lymphatic output of radioactive fatty acids. This indicated that mucosal esterification of labeled free fatty acids was normal in the absence of bile salts. The physical state of the lipid did not affect the pathway of absorption. Finally, comparison of the increased output of esterified fat in the lymph with the output of labeled fat suggested that fat absorption did not greatly affect the turnover of endogenous, unlabeled fat. Results were consistent with the view that most of the endogenous lymph fat comes from reabsorbed biliary lipid.