Sex after sixty.
Although sexuality is an intrinsic part of one's humanity throughout the lifespan, health professionals frequently ignore the sexual needs and concerns of the elderly. Deterrents to sexual activity may include society's disapproval of sexual expression by the elderly, lack of a partner, the elderly person's own lack of sexual knowledge or belief that nonreproductive sexuality is wrong, and lack of privacy. Physicians must accept elderly people's sexuality and develop attitudes and skills which facilitate communication. It is particularly important to make elderly patients aware that they do not have to have intercourse in order to express their sexuality, and to educate them about the physiological and pathological changes with aging, so they realize these changes need not mean the end of sexual expression.


Contribution of transgender sex workers to the complexity of the HIV-1 epidemic in the metropolitan area of Milan.
Transgender people are disproportionately affected by the HIV-1 epidemic. We evaluated the origin of HIV-1 variants carried by South American transgenders living in Milan by combining accurate phylogenetic methods and epidemiological data. We collected 156 HIV-1 pol sequences obtained from transgender patients engaged in sex work (TSWs) followed between 1999 and 2015 at L. Sacco Hospital, Milan, Italy. Phylogenetic analyses were conducted by HIV-TRACE, MrBayes, MacClade and Beast programs. Reference sequences were retrieved from Los Alamos and local databases. Last negative testing or proxy data from clinical records of infected individuals were used to investigate the country of infection. Among South American TSWs, the most represented HIV-1 subtypes were B (70.5%), F1 (12.8%) and C (4.4%). Gene flow migrations of B subtype indicated significant fluxes from TSWs to Italians (21.3%) belonging to all risk groups (26.4% to heterosexuals (HEs), 18.9% to men who have sex with men (MSM), 15.1% to injecting drug users). The largest proportion of bidirectional fluxes were observed between Italians and TSWs (24.6%). For F1 subtype, bidirectional viral fluxes involved TSWs and Italians (7.1% and 14.3%), and a similar proportion of fluxes linked TSWs and Italian HEs or MSM (both 15.8%). Significant fluxes were detected from Italians to TSWs for subtype C involving both MSM (30%) and HEs (40%). Country of HIV-1 acquisition was identified for 72 subjects; overall, the largest proportion of patients with B subtype (73.5%) acquired HIV-1 infection in South America. Our results indicated that South American transgenders largely contribute to the heterogeneity of HIV-1 variants in our country. The high number of clusters based on all subtypes indicated numerous transmission chains in which TSWs were constantly intermixed with HEs and MSM. Our results strongly advocate interventions to facilitate prevention, diagnosis and HIV-1 care continuum among transgender people.


Modulation of multidrug resistance gene (mdr-1) with antisense oligodeoxynucleotides.
1. Multidrug resistance is the major obstacle to successful cancer chemotherapy. Circumventing multidrug resistance therefore represents a high priority for clinical anti-cancer treatment. Among many reversal strategies, antisense oligodeoxynucleotides may offer a molecular targeting tool for overcoming cellular multidrug resistance. 2. Two 17-mer phosphorothioate antisense oligomers, complementary to the 5' end of the ATG initiator codon-containing region and loop-forming site (located at nucleotides 991-1007 from the first ATG codon) in mdr-1 cDNA sequence, were synthesized. The purpose was to study their effects on the function and expression of P-glycoprotein and mdr-1 gene. 3. The results showed that 10 mumol/l antisense oligomers could significantly inhibit the growth of multidrug resistant K562/Adm cells cultured in adriamycin-containing medium. No such effect was observed for parental (sensitive) K562/S cells. Intracellular daunorubicin accumulation increased greatly in the K562/Adm cells after they were treated with oligomers for 48 h and P-glycoprotein synthesis was strikingly reduced. 4. Further investigation with [alpha-32P]dCTP incorporation by the reverse transcriptase-polymerase chain reaction method revealed that antisense oligomers could result in a reduction in the level of mdr-1 mRNA, probably through hindering mdr-1 gene transcription. 5. The high reversal efficiency and specificity of antisense oligomers in regulating mdr-1 gene expression suggest a potential clinical application in gene therapy for drug resistant malignancies.


Incommensurate van der Waals epitaxy of nanowire arrays: a case study with ZnO on muscovite mica substrates.
The requirement of lattice matching between a material and its substrate for the growth of defect-free heteroepitaxial crystals can be circumvented with van der Waals epitaxy (vdWE). However, the utilization and characteristics of vdWE in nonlamellar/nonplanar nanoarchitectures are still not very well-documented. Here we establish the characteristics of vdWE in nanoarchitectures using a case study of ZnO nanowire (NW) array on muscovite mica substrate without any buffer/seed layer. With extensive characterizations involving electron microscopy, diffractometry, and the related analyses, we conclude that the NWs grown via vdWE exhibit an incommensurate epitaxy. The incommensurate vdWE allows a nearly complete lattice relaxation at the NW-substrate heterointerface without any defects, thus explaining the unnecessity of lattice matching for well-crystallized epitaxial NWs on muscovite mica. We then determine the polarity of the NW via a direct visualization of Zn-O dumbbells using the annular bright field scanning transmission electron miscroscopy (ABF-STEM) in order to identify which atoms are at the base of the NWs and responsible for the van der Waals interactions. The information from the ABF-STEM is then used to construct the proper atomic arrangement at the heterointerface with a 3D atomic modeling to corroborate the characteristics of the incommensurate vdWE. Our findings suggest that the vdWE might be extended for a wider varieties of compounds and epitaxial nanoarchitectures to serve as a universal epitaxy strategy.


Lectin-mediated resistance impairs plant virus infection at the cellular level.
Plants possess a multilayered defense response, known as plant innate immunity, to infection by a wide variety of pathogens. Lectins, sugar binding proteins, play essential roles in the innate immunity of animal cells, but the role of lectins in plant defense is not clear. This study analyzed the resistance of certain Arabidopsis thaliana ecotypes to a potexvirus, plantago asiatica mosaic virus (PlAMV). Map-based positional cloning revealed that the lectin gene JACALIN-TYPE LECTIN REQUIRED FOR POTEXVIRUS RESISTANCE1 (JAX1) is responsible for the resistance. JAX1-mediated resistance did not show the properties of conventional resistance (R) protein-mediated resistance and was independent of plant defense hormone signaling. Heterologous expression of JAX1 in Nicotiana benthamiana showed that JAX1 interferes with infection by other tested potexviruses but not with plant viruses from different genera, indicating the broad but specific resistance to potexviruses conferred by JAX1. In contrast with the lectin gene RESTRICTED TEV MOVEMENT1, which inhibits the systemic movement of potyviruses, which are distantly related to potexviruses, JAX1 impairs the accumulation of PlAMV RNA at the cellular level. The existence of lectin genes that show a variety of levels of virus resistance, their targets, and their properties, which are distinct from those of known R genes, suggests the generality of lectin-mediated resistance in plant innate immunity.


Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole.
Synthetic triterpenoid analogues of oleanolic acid are potent inducers of the phase 2 response as well as inhibitors of inflammation. We show that the triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), is a highly potent chemopreventive agent that inhibits aflatoxin-induced tumorigenesis in rat liver. The chemopreventive potency of CDDO-Im was evaluated by measuring inhibition of formation of putative preneoplastic lesions (glutathione S-transferase P positive foci) in the liver of rats exposed to aflatoxin B1. CDDO-Im produces an 85% reduction in the hepatic focal burden of preneoplastic lesions at 1 micromol/kg body weight and a >99% reduction at 100 micromol/kg body weight. CDDO-Im treatment reduces levels of aflatoxin-DNA adducts by approximately 40% to 90% over the range of 1 to 100 micromol/kg body weight. Additionally, changes in mRNA levels of genes involved in aflatoxin metabolism were measured in rat liver following a single dose of CDDO-Im. GSTA2, GSTA5, AFAR, and EPHX1 transcripts are elevated 6 hours following a 1 micromol/kg body weight dose of CDDO-Im. Microarray analysis using wild-type and Nrf2 knockout mice confirms that many phase 2 and antioxidant genes are induced in an Nrf2-dependent manner in mouse liver following treatment with CDDO-Im. Thus, low-micromole doses of CDDO-Im induce cytoprotective genes, inhibit DNA adduct formation, and dramatically block hepatic tumorigenesis. As a point of reference, oltipraz, an established modulator of aflatoxin metabolism in humans, is 100-fold weaker than CDDO-Im in this rat antitumorigenesis model. The unparalleled potency of CDDO-Im in vivo highlights the chemopreventive promise of targeting Nrf2 pathways with triterpenoids.


The Economic Burden of Hepatitis A, B, and C in South Korea.
The prevalence of hepatitis in South Korea is relatively high compared to that in other high-income countries. For this reason, viral hepatitis infection not only affects the population's health, but also impacts national healthcare costs. This study was performed in order to estimate the individual economic costs of the hepatitis A, B, and C viruses as well as to determine, using nationally representative data, the trends in South Korea with respect to these viruses during the 2008-2011 period. The study found that the prevalence of hepatitis A had decreased, but those of hepatitis B and C had increased overall. The mortality rate of hepatitis C was higher than that of the other two types. The mortality rate of hepatitis B had changed little, whereas that of hepatitis C had risen. The total cost of hepatitis A had decreased, from US $62.2 million to US $45.7 million, although a notable exception occurred in 2009, when the cost was US $126.6 million. Conversely, the total cost of hepatitis B had increased rapidly during the same period, from US $501.4 million to US $607.8 million. Finally, the total cost of hepatitis C had also increased from US $63.9 million to US $90.7 million. The direct costs of hepatitis A, B, and C were estimated to account for approximately 35.5%, 46.6%, and 58.0% of the total, respectively. These findings demonstrate the economic burden associated with hepatitis A, B, and C, and demonstrate the need to establish an effective prevention and management policy for future planning in South Korea.


Origin of informational polymers and the search for non-terran life: protection of the polymeric state of DNA by phosphate minerals.
An in-depth analysis of the effects exerted on the DNA backbone by 25 crystal phosphate minerals is reported. Degradation of DNA oligomers was performed with two different reactions: Hydrolysis following Nucleophilic Degradation (HND), initiated by the nucleophilic addition of formamide on both purine and pyrimidine nucleobases, and Hydrolysis following Nucleophilic Substitution (HNS) carried on by water and starting with the removal of a nondegraded base. A complete panel of effects on the phosphoester bonds, from protection to enhanced instability to absence of interference, is described. These effects differ in the different degradation pathways and in different physical-chemical conditions. The relationship between the hardness of the mineral and its protective ability is discussed. In addition to its interest per se, this study was prompted by the observed catalytic abilities of soluble and mineral phosphates (Saladino et al., 2006c) on the synthetic reactions by formamide. The relevance of these observations in the search for nonterran life is discussed.


Postural orientation and equilibrium: what do we need to know about neural control of balance to prevent falls?
Postural control is no longer considered simply a summation of static reflexes but, rather, a complex skill based on the interaction of dynamic sensorimotor processes. The two main functional goals of postural behaviour are postural orientation and postural equilibrium. Postural orientation involves the active alignment of the trunk and head with respect to gravity, support surfaces, the visual surround and internal references. Sensory information from somatosensory, vestibular and visual systems is integrated, and the relative weights placed on each of these inputs are dependent on the goals of the movement task and the environmental context. Postural equilibrium involves the coordination of movement strategies to stabilise the centre of body mass during both self-initiated and externally triggered disturbances of stability. The specific response strategy selected depends not only on the characteristics of the external postural displacement but also on the individual's expectations, goals and prior experience. Anticipatory postural adjustments, prior to voluntary limb movement, serve to maintain postural stability by compensating for destabilising forces associated with moving a limb. The amount of cognitive processing required for postural control depends both on the complexity of the postural task and on the capability of the subject's postural control system. The control of posture involves many different underlying physiological systems that can be affected by pathology or sub-clinical constraints. Damage to any of the underlying systems will result in different, context-specific instabilities. The effective rehabilitation of balance to improve mobility and to prevent falls requires a better understanding of the multiple mechanisms underlying postural control.


Interferon-gamma release assays for tuberculosis: current and future applications.
Interferon-gamma release assays (IGRAs) represent the first new tool to diagnose latent tuberculosis infection for more than 100 years. They have advantages over the traditional tuberculin skin test which has a poor specificity due to false-positive responses in people who are BCG vaccinated as there is a cross-reactivity of proteins present in both BCG and the tuberculin skin test. IGRAs rely on the concept of detecting the ex vivo release of the cytokine IFN-γ, a key anti-Mycobacterium tuberculosis cytokine, from T cells which react specifically to antigens from M. tuberculosis. T cells are sensitized to the antigens in vivo, and then react when they encounter the same proteins ex vivo. The readouts are used to determine presence of sensitized cells, acting as a surrogate for latent tuberculosis infection. IGRAs are now being incorporated into national guidance for diagnosis and research is ongoing into next-generation versions of the test.


A Multi Factorial Analysis of the epidemiology of Injuries from Falls from Heights.
Fall from height is a common cause of morbidity and mortality in suburban population in India. These cases are either domestic or workplace injuries with different causative factors. We analyzed different aspects of these falls to identify their risk factors. We conducted prospective and retrospective epidemiological study to identify various causative, contributory factors, and resultant injuries in cases of fall from height. The study group comprised of semiurban population and involved both domestic and workplace injuries presenting to a tertiary care hospital. There were 208 cases of workplace (112) and domestic (96) fall from height. In domestic cases absence of parapet on roof was the commonest cause, most of falls occurred during summer and rainy season. Alcohol consumption prior to fall was commonest associated factor in adult males. Children mostly fell while playing on roof and climbing trees. Among workplace cases, civil construction site injuries were commonest and absence of any protective gear and long working and evening hours were commonest associated factors. Mean injury severity score was 10.86 in domestic cases and 14.87 in workplace cases. There were 17 mortalities with head injury being commonest associated cause. Only difference in incidence of alcohol consumption and permanent disability was statistically significant between workplace and domestic falls. Different factors are responsible for domestic and workplace cases of fall from height. Most of these cases are potentially preventable.


Casein kinase II and protein kinase C modulate hepatitis delta virus RNA replication but not empty viral particle assembly.
Hepatitis delta virus (HDV) contains two virus-specific delta antigens (HDAgs), large and small forms, which are identical in sequence except that the large one contains 19 extra amino acids at the C terminus. HDAgs are nuclear phosphoproteins with distinct biological functions; the small form activates HDV RNA replication, whereas the large form suppresses this process but is required for viral particle assembly. In this study, we have characterized the phosphorylative property of HDAg in a human hepatoma cell line (HuH-7) and examined the role of phosphorylation in HDAg function. As demonstrated by in vivo labeling and kinase inhibitor experiments, the phosphorylation levels of both HDAgs were diminished by the inhibitor of casein kinase II (CKII). Nevertheless, phosphorylation of only the small form could be markedly reduced by the protein kinase C (PKC) inhibitor, suggesting different phosphorylation properties between the two HDAgs. When these two kinase inhibitors were added separately to the transient-expression system, HDV RNA replication was profoundly suppressed. In contrast, the inhibitors did not affect the assembly of empty HDAg particle from HDAgs and hepatitis B virus surface antigen. To further examine the role of phosphorylation in HDAg function, two conservative CKII recognition sites at Ser-2 and Ser-123 of both HDAgs and one potential PKC recognition site at Ser-210 of the large HDAg were altered to alanine by site-directed mutagenesis. Transfection experiments indicated that mutation at Ser-2, but not Ser-123, significantly impaired the activity of the small HDAg in assisting HDV RNA replication. This property is in accordance with our observation that Ser-2, not Ser-123, was the predominant CKII phosphorylation site in the small HDAg. Our studies also excluded the possibility that the phosphorylation of Ser-2, Ser-123, or Ser-210, had roles in the trans-suppression activity of the large HDAg, in the assembly of empty virus-like HDAg particle, and in the nuclear transport of HDAgs. In conclusion, our results indicate that both CKII and PKC positively modulate HDV RNA replication but not the assembly of empty HDAg particle. The role of CKII in HDV replication may at least in part be accounted for by the phosphorylation of Ser-2 in the small HDAg. The effect of PKC on HDV RNA replication is, however, not to mediate the phosphorylation of the conservative Ser-210 in the large HDAg but rather to act on as-yet-unidentified Ser or Thr residues in the small HDAg or cellular factors. These findings provide the first insight into the roles of phosphorylation of the two HDAgs in the HDV replication cycle.


The health and health preparation of long-term Australian travellers.
A growing number of Australians are travelling domestically for extended periods. This creates challenges in both continuity of health care and burdens on health services. This paper reports a cross-sectional survey aimed to explore the health needs and health planning of long-term travellers. In total, 316 respondents who had travelled for more than 3 months consecutively in the last year participated. Most respondents were retired (n=197; 62.3%); however, ages ranged from 26 to 89 years. Nearly half of the respondents or their travel companion had a long-term illness that affected their daily life (n=135; 42.7%). Nearly half of respondents visited a GP (n=133; 42.1%), nearly one-quarter visited an Emergency Department (n=72; 22.8%) and 19.9% (n=63) visited another health provider while travelling. The level of preparation around health while travelling varied between participants. This study highlights that long-term travellers have significant health needs and are likely to require health services during their extended travel. Additionally, it identifies that currently few strategies are used to plan for health care during travel. This raises issues for rural and remote health services in terms of both capacity and continuity of care.


NFkappaB-mediated metabolic inflammation in peripheral tissues versus central nervous system.
Obesity, type 2 diabetes, and the associated metabolic syndrome are known as the aggregate products from nutritional excess, and have become huge epidemics and represent public health problems in the developed world. Yet, there exist few successful approaches for the treatment and prevention of these complex diseases, in part because they are not well understood at the molecular levels. Recent research has revealed that many nutrient- and pathogen-sensing systems can be highly integrated, positing the regulatory system of immune response at the mechanistic interface between metabolic regulation and the development of overnutrition-related diseases. The underlying molecular processes have been associated with the basis of how nutritional changes trigger atypical inflammation and how metabolic inflammation affects the signaling and functions of metabolic tissues and cells. In this endeavor, the pro-inflammatory axis consisting of the nuclear transcription factor NFkappaB and its upstream kinase IKKbeta has been identified as one critical mediator that is responsible for nutritionally-induced inflammation, and a large body of research has been documented to support the concept that IKKbeta/NFkappaB represents a general cause of various metabolic dysfunctions under overnutrition. Here, we comparatively review the tissue-specific programs and actions of IKKbeta/NFkappaB in causing and promoting overnutrition-related diseases.


Serum metabolomics indicate altered cellular energy metabolism in children with cystic fibrosis.
Cystic fibrosis (CF) is a multi-system disease affecting multiple organs and cells besides the respiratory system. Metabolomic profiling allows simultaneous detection of biochemicals originating from cells, organs, or exogenous origin that may be valuable for monitoring of disease severity or in diagnosis. We hypothesized that metabolomics using serum from children would differentiate CF from non-CF lung disease subjects and would provide insight into metabolism in CF. Serum collected from children with CF (n = 31) and 31 age and gender matched children with other lung diseases was used for metabolomic profiling by gas- and liquid-chromatography. Relative concentration of metabolites was compared between the groups using partial least square discriminant analyses (PLS-DA) and linear modeling. A clear separation of the two groups was seen in PLS-DA. Linear model found that among the 459 detected metabolites 92 differed between CF and non-CF. These included known biochemicals in lipid metabolism, oxidants, and markers consistent with abnormalities in bile acid processing. Bacterial metabolites were identified and differed between the groups indicating intestinal dysbiosis in CF. As a novel finding several pathways were markedly different in CF, which jointly point towards decreased activity in the β-oxidation of fatty acids. These pathways include low ketone bodies, low medium chain carnitines, elevated di-carboxylic acids and decreased 2-hydroxybutyrate from amino acid metabolism in CF compared to non-CF. Serum metabolomics discriminated CF from non-CF and show altered cellular energy metabolism in CF potentially reflecting mitochondrial dysfunction. Future studies are indicated to examine their relation to the underlying CF defect and their use as biomarkers for disease severity or for cystic fibrosis transmembrane regulator (CFTR) function in an era of CFTR modifying drugs.


Pax genes during neural development and their potential role in neuroregeneration.
Pax genes encode a family of transcription factors that have long been recognised as obligate contributors to embryonic development of the CNS, with evidence obtained from various animal models illustrating phylogenetically conserved functions. Within the CNS, Pax genes play substantial roles in cellular and regional specification, proliferation, progenitor cell maintenance, anti-apoptosis and neural differentiation. This comprehensive review details the critical functions of those Pax genes involved in pre- and post-natal CNS development, provides possible molecular mechanisms by which Pax genes contribute to proliferation and differentiation of neuronal cells, and explains observed changes in Pax gene expression in response to neurotrauma in the mature animal. Knowledge of the ability of individual Pax genes to specify precise lineages within the CNS is beneficial for cell replacement strategies, particularly in the production of "designer" cells for the treatment of neurodegenerative disorders. The manipulation of stem or committed cells so that they express definitive Pax genes may indeed assist in the pursuit of the holy grail of regenerative medicine - that of CNS cell replacement therapies leading to functional repair. We explain here, however, that only the sophisticated and precise use of Pax genes will lead to a successful outcome.


Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo.
Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumor-induced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let-Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVX-Let mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically.


Is post-marketing drug surveillance possible in the family practice setting? A collaborative study.
Post-marketing surveillance is a mechanism to identify and quantify harmful, as well as beneficial, effects of drugs used under conditions different from those in which they were tested. The College of Family Physicians of Canada collaborated with the authors in a pilot, office-based, post-marketing, surveillance study. Target medications were selected from all prescriptions, written or authorized by participating physicians. The participants collected the prescriptions by using duplicate prescription pads. Follow-up data was collected from the patients by means of a self-administered questionnaire and from the physicians by means of a medical-chart review. This method of research allows the identification of a cohort of drug users in a systematic, non-biased fashion.


Nonalcoholic beer reduces inflammation and incidence of respiratory tract illness.
Strenuous exercise significantly increases the incidence of upper respiratory tract illness (URTI) caused by transient immune dysfunction. Naturally occurring polyphenolic compounds present in food such as nonalcoholic beer (NAB) have strong antioxidant, antipathogenic, and anti-inflammatory properties.The objective of this study was to determine whether ingestion of NAB polyphenols for 3 wk before and 2 wk after a marathon would attenuate postrace inflammation and decrease URTI incidence. Healthy male runners (N = 277, age = 42 ± 9 yr) were randomly assigned to 1-1.5 L · d(-1) of NAB or placebo (PL) beverage (double-blind design) for 3 wk before and 2 wk after the Munich Marathon. Blood samples were collected 4 and 1 wk before the race and immediately and 24 and 72 h after the race and analyzed for inflammation measures (interleukin-6 and total blood leukocyte counts). URTI rates, assessed by the Wisconsin Upper Respiratory Symptom Survey, were compared between groups during the 2-wk period after the race. Change in interleukin-6 was significantly reduced in NAB compared with PL immediately after the race (median (interquartile range) = 23.9 (15.9-38.7) vs 31.6 (18.5-53.3) ng · L(-1), P = 0.03). Total blood leukocyte counts were also reduced in NAB versus PL by approximately 20% immediately and 24 h after the race (P = 0.02). Incidence of URTI was 3.25-fold lower (95% confidence interval = 1.38-7.66) (P = 0.007) in NAB compared with PL during the 2-wk postmarathon period. Consumption of 1-1.5 L · d(-1) of NAB for 3 wk before and 2 wk after marathon competition reduces postrace inflammation and URTI incidence.


Malignant fibrous histiocytoma of the lung: prognosis and therapy of a rare disease. Report of two cases and review of the literature.
On the basis of 2 own patients and 18 cases reported in the literature, clinicopathological features of primary malignant fibrous histiocytoma of the lung are reviewed. Of the 20 patients (age-range: 14-75 yrs; 13 male, 7 female), 14 underwent resection. Recurrences were noted in 7 of them. 8 patients were free of disease at least 8 months postoperatively, one having undergone successful pulmonary metastasectomy. Postresection disease-free survival ranged from 8 months to 10 years. Adjuvant chemotherapy or irradiation (3/14) did not influence postoperative outcome. After chemotherapy, irradiation or conservative measures alone (6/20) survival did not exceed 12 months; remissions were not reported. The course was fatal within 12 months in 9/20 cases due to distant metastasis or local growth. 1 patient died of tumour-associated hypoglycemia. Age, sex, localization of the tumor and histologic subtype did not influence prognosis. Small tumors, asymtomatic at time of detection probably carry a better prognosis than larger ones.


Lantern-like bismuth oxyiodide embedded typha-based carbon via in situ self-template and ion exchange-recrystallization for high-performance photocatalysis.
Efficient photocatalysts induced by visible light (e.g. BiOI) have attracted wide attention for energy storage and environmental pollutant rehabilitation. In this work, N-doped bamboo tube-like carbon (NTC) was derived directly from the carbonization of bio-waste (withered typha grass) under an ammonia atmosphere. During fabrication, the BiOI/NTC material was used as a self-sacrificing template and I- ions were gradually replaced by OH- ions from NH3·H2O solution. Then Bi7O9I3/NTC was formed with micro-/nanohierarchical structures, which could exactly be explained by the in situ ion exchange-recrystallization mechanism. Thereinto, the well-defined hierarchical lantern-like Bi7O9I3 composed of interconnecting ultrathin nanosheets firmly embedded the "bamboo tubes" of NTC, which endow sufficient interface and high specific surface area (40 m2 g-1). The multiple synergistic effects of the lantern-like structure with ultrathin nanosheets, low iodine content and well-contacted interface endow the synthesized Bi7O9I3/NTC with outstanding visible-light catalytic activity. The results show that the obtained Bi7O9I3/NTC degraded 93.5% of methyl orange and 97.6% of rhodamine B within 2 hours, showing superior performance as compared to the pure BiOI. Therefore, our work demonstrates a controllable approach that can provide guidelines for designing optimized bismuth oxyiodide-based photocatalyst materials and has the potential for application in environmental remediation.


Thirty years of transcranial magnetic stimulation: where do we stand?
Transcranial magnetic stimulation (TMS) has been first described 30 years ago, and since then has gained enormous attention by neurologists, psychiatrists, neurosurgeons, clinical neurophysiologists, psychologists, and neuroscientist alike. In the early days, it was primarily used to test integrity of the corticospinal tract. Beyond further developments of TMS in diagnostics, mapping and monitoring of the motor system, major other applications expanded into using TMS as research tool in the cognitive neurosciences, and as therapeutic tool in neurological and psychiatric disease by virtue of inducing long-term change in excitability and connectivity of the stimulated brain networks. This mini-review will highlight these developments by reviewing the 10 most frequently cited TMS publications. Despite the tremendous popularity and success of TMS as a non-invasive technique to stimulate the human brain, several aims remain unresolved. This review will end with highlighting those 10 most frequently cited papers that have been published in 2014-2016 to indicate the currently hottest topics in TMS research and major avenues of development.


Low-stress and high-stress singing have contrasting effects on glucocorticoid response.
Performing music in public is widely recognized as a potentially stress-inducing activity. However, despite the interest in music performance as an acute psychosocial stressor, there has been relatively little research on the effects of public performance on the endocrine system. This study examined the impact of singing in a low-stress performance situation and a high-stress live concert on levels of glucocorticoids (cortisol and cortisone) in 15 professional singers. The results showed a significant decrease in both cortisol and cortisone across the low-stress condition, suggesting that singing in itself is a stress-reducing (and possibly health-promoting) activity, but significant increases across the high-stress condition. This is the first study to demonstrate that singing affects cortisol as well as cortisone responses and that these responses are modulated by the conditions of performance.


Integrated nonlinear Mach Zehnder for 40 Gbit/s all-optical switching.
We report on the experimental demonstration of a novel silicon based fully integrated nonlinear Mach Zehnder device. A standard silicon waveguide is used as a nonlinear arm, conversely a large mode SU-8 waveguide acts as a purely linear arm. Given this asymmetry, an intensity dependent phase shift can be introduced between the two interferometric arms. Thanks to a fine tuning of the silicon arm optical properties, a low power, ultrafast, picosecond operation is demonstrated, allowing the use of this device for ultrafast all-optical signal processing in high density communication networks.


Thyrotropin-releasing hormone immunoreactive boutons form close appositions with medullary expiratory neurons in the rat.
The aim of the present study was to assess the size of the input from TRH immunoreactive varicosities to medullary respiratory neurons in the Bötzinger complex and caudal ventral respiratory group. Neurobiotin was intracellularly injected into seven neurons in the Bötzinger complex, between 0.4 and 0.9 mm caudal to the facial nucleus. Five of the seven Bötzinger neurons had extensive local axonal projections, with bouton-like varicosities clustered predominantly between their somata and the nucleus ambiguus. Seven neurons in the caudal ventral respiratory group, located between 1.6 and 2.4 mm caudal to the facial nucleus, were also labelled. All but one caudal respiratory neurons had no, or very few, medullary collaterals. TRH immunoreactive fibres were seen in many medullary nuclei, including the ventral reticular formation. Bötzinger neurons were closely apposed by an average of 29 +/- 8 TRH immunoreactive boutons/neuron (mean +/- S.D., n = 7). In contrast, caudal ventral respiratory group neurons were apposed by only 5 +/- 3 TRH immunoreactive boutons/neuron (n = 7). Bötzinger neurons form many intramedullary and bulbospinal inhibitory connections with premotoneurons and motoneurons that are important in the timing, amplitude and shape, of respiratory activity. Our findings suggest a role for endogenous TRH-containing neurons in modulating the activity of inhibitory Bötzinger neurons and neurons in the caudal ventral respiratory group. The significance of the apparent difference in size of this input remains to be determined.


Neuromechanical Model of Rat Hindlimb Walking with Two-Layer CPGs.
This work demonstrates a neuromechanical model of rat hindlimb locomotion undergoing nominal walking with perturbations. In the animal, two types of responses to perturbations are observed: resetting and non-resetting deletions. This suggests that the animal locomotor system contains a memory-like organization. To model this phenomenon, we built a synthetic nervous system that uses separate rhythm generator and pattern formation layers to activate antagonistic muscle pairs about each joint in the sagittal plane. Our model replicates the resetting and non-resetting deletions observed in the animal. In addition, in the intact (i.e., fully afferented) rat walking simulation, we observe slower recovery after perturbation, which is different from the deafferented animal experiment. These results demonstrate that our model is a biologically feasible description of some of the neural circuits in the mammalian spinal cord that control locomotion, and the difference between our simulation and fictive motion shows the importance of sensory feedback on motor output. This model also demonstrates how the pattern formation network can activate muscle synergies in a coordinated way to produce stable walking, which motivates the use of more complex synergies activating more muscles in the legs for three-dimensional limb motion.


Republished: going glass to digital: virtual microscopy as a simulation-based revolution in pathology and laboratory science.
The recent technological advance of digital high resolution imaging has allowed the field of pathology and medical laboratory science to undergo a dramatic transformation with the incorporation of virtual microscopy as a simulation-based educational and diagnostic tool. This transformation has correlated with an overall increase in the use of simulation in medicine in an effort to address dwindling clinical resource availability and patient safety issues currently facing the modern healthcare system. Virtual microscopy represents one such simulation-based technology that has the potential to enhance student learning and readiness to practice while revolutionising the ability to clinically diagnose pathology collaboratively across the world. While understanding that a substantial amount of literature already exists on virtual microscopy, much more research is still required to elucidate the full capabilities of this technology. This review explores the use of virtual microscopy in medical education and disease diagnosis with a unique focus on key requirements needed to take this technology to the next level in its use in medical education and clinical practice.


Disruption of fungal cell wall by antifungal Echinacea extracts.
In addition to widespread use in reducing the symptoms of colds and flu, Echinacea is traditionally employed to treat fungal and bacterial infections. However, to date the mechanism of antimicrobial activity of Echinacea extracts remains unclear. We utilized a set of ∼4,600 viable gene deletion mutants of Saccharomyces cerevisiae to identify mutations that increase sensitivity to Echinacea. Thus, a set of chemical-genetic profiles for 16 different Echinacea treatments was generated, from which a consensus set of 23 Echinacea-sensitive mutants was identified. Of the 23 mutants, only 16 have a reported function. Ten of these 16 are involved in cell wall integrity/structure suggesting that a target for Echinacea is the fungal cell wall. Follow-up analyses revealed an increase in sonication-associated cell death in the yeasts S. cerevisiae and Cryptococcus neoformans after Echinacea extract treatments. Furthermore, fluorescence microscopy showed that Echinacea-treated S. cerevisiae was significantly more prone to cell wall damage than non-treated cells. This study further demonstrates the potential of gene deletion arrays to understand natural product antifungal mode of action and provides compelling evidence that the fungal cell wall is a target of Echinacea extracts and may thus explain the utility of this phytomedicine in treating mycoses.


LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.
Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75% of families. To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections. Exome sequencing was used to identify the mutation responsible for a large family with thoracic aortic aneurysms and dissections. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was used to investigate mutations in LOX in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections. These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.


Evidence-Based Spiritual Care Practice in the Canadian Context: Twenty Years Later.
Reviews developments, strengths and challenges in evidence-based spiritual care practice (EBSCP) using a hermeneutical method which compares and interprets a variety of written texts. EBSCP originated from evidence-based medicine (EBM) developed at McMaster University and was adopted as evidence-based practice (EBP) by multiple professional disciplines. EBSCP was first addressed in Canada and American spiritual care researchers in the US have since advanced EBSCP. Questions are raised about processes of integrating EBSCP in a Canadian context as well as areas for future research.


Philadelphia chromosome-negative acute myeloid leukemia with 11q23/MLL translocation in a patient with chronic myelogenous leukemia.
Although defined by the presence of t(9;22), chronic myelogenous leukemia (CML) can have other concurrent additional cytogenetic changes, especially during disease progression. Additional chromosomal changes (ACAs) in CML often occur in Philadelphia chromosome (Ph)-positive cells and are associated with disease acceleration and treatment resistance. Occasionally chromosomal changes occur in Ph-negative cells and this phenomenon is often transient and does not correlate with disease progression. Very rarely myelodysplastic syndrome or acute leukemia can develop in Ph-negative cells. In this study, we report an unusual case of acute myeloid leukemia (AML) with 11q23/MLL translocation emerging from Ph-negative cells in a patient with CML.


The effectiveness of nurse-led, home-based pulmonary rehabilitation in patients with COPD in Turkey.
The goal of this study was to determine the effectiveness of nurse-led, home-based pulmonary rehabilitation in patients with stage 3 or 4 chronic obstructive pulmonary disease (COPD), according to the Global Initiative for COPD (GOLD) staging system. The study consisted of 32 patients--a nurse-led, home-based pulmonary rehabilitation group (16) and a control group (16). In the rehabilitation program, patients received education about their diseases and performed breathing exercises and lower- and upper-extremity aerobic exercises at their homes during the 3-month period of the study. There was meaningful improvement in the rehabilitation group in terms of pulmonary function tests (FEV1 % predicted value), artery blood gases (PaCO2), quality of life, dyspnea, and functional capacity. On the other hand, no meaningful change was observed in the control group. The study showed that the nurse-led, home-based pulmonary rehabilitation program had positive effects on the patients with COPD.


Effectiveness and Safety of Acupuncture for Poststroke Dysphagia: Study Protocol for a Pragmatic Multicenter Nonrandomized Controlled Trial.
Background. Dysphagia is one of the most common complications of stroke. Acupuncture is widely employed to treat poststroke dysphagia in East Asia. No evidence is established to support such treatment approach. This proposed study aims to evaluate the effectiveness and safety of acupuncture for the treatment of poststroke dysphagia. Methods and Design. This is a multicenter, pragmatic, single-blinded, nonrandomized controlled clinical trial. A total of 140 eligible patients will be enrolled in the study. Subjects who are eligible in study but refuse to have acupuncture treatment will be put on the no-acupuncture control arm. Both groups of patients will receive standard routine care, while the patients of intervention group will receive add-on standardized acupuncture treatment. Each participant in intervention group will receive a total of 24 sessions of acupuncture treatment (three times per week). The primary outcome measure is the Royal Brisbane Hospital Outcome Measure for Swallowing (RBHOMS). Secondary outcome measures include functional oral intake scale, swallow quality-of-life questionnaire in Chinese version, BMI of the participant, and adverse events. All outcome measures will be assessed at baseline, at the end of acupuncture treatment (month 2), and at two months after treatment (month 4). Ethics and Dissemination. The ethics approval of clinical research study was granted by the Research Ethics Committee of both New Territories East and West Cluster of Hong Kong. Written informed consent will be obtained from all participants and the study will be undertaken according to the ICH-GCP Guidelines. Trial Registration. This trial is registered with chictr.org (registration number: ChiCTR-TRC-12002621 and registration date: 2012-10-26).


Cellular heterogeneity during embryonic stem cell differentiation to epiblast stem cells is revealed by the ShcD/RaLP adaptor protein.
The Shc family of adaptor proteins are crucial mediators of a plethora of receptors such as the tyrosine kinase receptors, cytokine receptors, and integrins that drive signaling pathways governing proliferation, differentiation, and migration. Here, we report the role of the newly identified family member, ShcD/RaLP, whose expression in vitro and in vivo suggests a function in embryonic stem cell (ESC) to epiblast stem cells (EpiSCs) transition. The transition from the naïve (ESC) to the primed (EpiSC) pluripotent state is the initial important step for ESCs to commit to differentiation and the mechanisms underlying this process are still largely unknown. Using a novel approach to simultaneously assess pluripotency, apoptosis, and proliferation by multiparameter flow cytometry, we show that ESC to EpiSC transition is a process involving a tight coordination between the modulation of the Oct4 expression, cell cycle progression, and cell death. We also describe, by high-content immunofluorescence analysis and time-lapse microscopy, the emergence of cells expressing caudal-related homeobox 2 (Cdx2) transcription factor during ESC to EpiSC transition. The use of the ShcD knockout ESCs allowed the unmasking of this process as they presented deregulated Oct4 modulation and an enrichment in Oct4-negative Cdx2-positive cells with increased MAPK/extracellular-regulated kinases 1/2 activation, within the differentiating population. Collectively, our data reveal ShcD as an important modulator in the switch of key pathway(s) involved in determining EpiSC identity.


The correlation of intramuscular fat content between muscles of the lamb carcass and the use of computed tomography to predict intramuscular fat percentage in lambs.
Intramuscular fat (IMF) % contributes positively to the juiciness and flavour of lamb and is therefore a useful indicator of eating quality. A rapid, non-destructive method of IMF determination like computed tomography (CT) would enable pre-sorting of carcasses based on IMF% and potential eating quality. Given the loin muscle (longissimus lumborum) is easy to sample, a single measurement at this site would be useful, providing is correlates well to other muscles. To determine the ability of CT to predict IMF%, this study used 400 animals and examined 5 muscles from three sections of the carcass: from the fore-section the m. supraspinatus and m. infraspinatus, from the saddle-section the m. longissimus lumborum and from the hind-section the m. semimembranosus and m. semitendinosus. The average CT pixel density of muscle was negatively associated with IMF% and can be used to predict IMF% although precision in this study was poor. The ability of CT to predict IMF% was greatest in the m. longissimus lumborum (slope -0.07) and smallest in the m. infraspinatus (slope -0.02). The correlation coefficients of IMF% between the five muscles were variable, with the highest correlation coefficients evident between muscles of the fore section (0.67 between the m. supraspinatus and the m. infraspinatus) and the weakest correlations were between the muscle of the fore and hind section. The correlation between the m. longissimus lumborum to the other muscles was fairly consistent with values ranging between 0.34 and 0.40 (partial correlation coefficient). The correlation between the proportion of carcass fat and the IMF% of the five muscles varied and was greatest in the m. longissimus lumborum (0.41).


Dynamic modularity in protein interaction networks predicts breast cancer outcome.
Changes in the biochemical wiring of oncogenic cells drives phenotypic transformations that directly affect disease outcome. Here we examine the dynamic structure of the human protein interaction network (interactome) to determine whether changes in the organization of the interactome can be used to predict patient outcome. An analysis of hub proteins identified intermodular hub proteins that are co-expressed with their interacting partners in a tissue-restricted manner and intramodular hub proteins that are co-expressed with their interacting partners in all or most tissues. Substantial differences in biochemical structure were observed between the two types of hubs. Signaling domains were found more often in intermodular hub proteins, which were also more frequently associated with oncogenesis. Analysis of two breast cancer patient cohorts revealed that altered modularity of the human interactome may be useful as an indicator of breast cancer prognosis.


Perceptual match effects in direct tests of memory: the role of contextual fan.
The aim of the present study was to determine whether physical attributes of a memory representation would affect explicit memory performance and, if so, what type of factors would affect the size of a perceptual match effect. Subjects studied words in different, uncommon fonts and were later asked whether the word had been studied earlier. Words could be re-presented in the original font, a font studied with another word, or a font not seen earlier. In two additional experiments, we varied the numbers of words studied in the same unusual font (1 vs. 12 words per font). Recognition memory for the words was better if the test and study fonts matched, and this effect was larger for fonts not shared with other words. Moreover, old judgments were most likely to be classified as remember responses when words were re-presented in the same font when it had not been studied with other words. Although we found a significant effect of levels of processing, this factor did not interact with whether the font matched between study and test. These results are consistent with the predictions of the source of activation confusion model of memory and suggest that perceptual information operates according to the same memory principles as conceptual information.


Anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor.
Secretory leukoprotease inhibitor (SLPI), a 12-kD nonglycosylated serine antiprotease with a high capacity for inhibiting neutrophil elastase (NE), is produced by cells of mucosal surfaces including the human lung. The molar concentrations of SLPI in total respiratory tract epithelial lining fluid (ELF) were 56 +/- 10% that of alpha 1-antitrypsin, suggesting SLPI may be more important for the anti-NE protection of the pulmonary epithelial surface than previously thought. However, evaluation demonstrated that SLPI in respiratory ELF was only one-third functional. Studies aerosolizing recombinant SLPI (rSLPI) to sheep demonstrated that in the short term, neither aerosolization and alveolar deposition nor the lavage procedure inactivated the SLPI molecule. In vitro studies with rSLPI demonstrated that exposure to oxidants did not modify the form of the molecule, while exposure to oxidants and NE caused the molecule to be cleaved from 12 to 8 kD. Consistent with this, evaluation of SLPI in lavage fluid of individuals with cystic fibrosis (a condition with oxidants and NE on the respiratory epithelium) showed that the SLPI was degraded. However, evaluation of SLPI in normal ELF by molecular sieve analysis and Western analysis demonstrated an intact 12-kD molecule, suggesting that the partial inactivation of SLPI in normals in vivo is not because it is complexed to NE or exposed to oxidants + NE. Together, these observations demonstrate that SLPI is present in large amounts in respiratory ELF, but since the majority of the SLPI is inactive, it likely does not play a significant role in protecting the normal respiratory epithelium, except perhaps in the upper airways where the levels of SLPI are the highest.


The MetaCyc Database of metabolic pathways and enzymes and the BioCyc collection of Pathway/Genome Databases.
MetaCyc (MetaCyc.org) is a universal database of metabolic pathways and enzymes from all domains of life. The pathways in MetaCyc are curated from the primary scientific literature, and are experimentally determined small-molecule metabolic pathways. Each reaction in a MetaCyc pathway is annotated with one or more well-characterized enzymes. Because MetaCyc contains only experimentally elucidated knowledge, it provides a uniquely high-quality resource for metabolic pathways and enzymes. BioCyc (BioCyc.org) is a collection of more than 350 organism-specific Pathway/Genome Databases (PGDBs). Each BioCyc PGDB contains the predicted metabolic network of one organism, including metabolic pathways, enzymes, metabolites and reactions predicted by the Pathway Tools software using MetaCyc as a reference database. BioCyc PGDBs also contain predicted operons and predicted pathway hole fillers-predictions of which enzymes may catalyze pathway reactions that have not been assigned to an enzyme. The BioCyc website offers many tools for computational analysis of PGDBs, including comparative analysis and analysis of omics data in a pathway context. The BioCyc PGDBs generated by SRI are offered for adoption by any interested party for the ongoing integration of metabolic and genome-related information about an organism.


Epidermal growth factor receptor activation protects gastric epithelial cells from Helicobacter pylori-induced apoptosis.
Helicobacter pylori infection disrupts the balance between gastric epithelial cell proliferation and apoptosis, which is likely to lower the threshold for the development of gastric adenocarcinoma. H pylori infection is associated with epidermal growth factor (EGF) receptor (EGFR) activation through metalloproteinase-dependent release of EGFR ligands in gastric epithelial cells. Because EGFR signaling regulates cell survival, we investigated whether activation of EGFR following H pylori infection promotes gastric epithelial survival. Mouse conditionally immortalized stomach epithelial cells (ImSt) and a human gastric epithelial cell line, AGS cells, as well as wild-type and kinase-defective EGFR (EGFRwa2) mice, were infected with the H pylori cag+ strain 7.13. Apoptosis, caspase activity, EGFR activation (phosphorylation), and EGFR downstream targets were analyzed. Inhibiting EGFR kinase activity or decreasing EGFR expression significantly increased H pylori-induced apoptosis in ImSt. Blocking H pylori-induced EGFR activation with a heparin-binding (HB)-EGF neutralizing antibody or abrogating a disintegrin and matrix metalloproteinase-17 (ADAM-17) expression increased apoptosis of H pylori-infected AGS and ImSt, respectively. Conversely, pretreatment of ImSt with HB-EGF completely blocked H pylori-induced apoptosis. H pylori infection stimulated gastric epithelial cell apoptosis in EGFRwa2 but not in wild-type mice. Furthermore, H pylori-induced EGFR phosphorylation stimulated phosphotidylinositol-3'-kinase-dependent activation of the antiapoptotic factor Akt, increased expression of the antiapoptotic factor Bcl-2, and decreased expression of the proapoptotic factor Bax. EGFR activation by H pylori infection has an antiapoptotic effect in gastric epithelial cells that appears to involve Akt signaling and Bcl family members. These findings provide important insights into the mechanisms of H pylori-associated tumorigenesis.


Alzheimer's disease treated with combined therapy based on nourishing marrow and reinforcing Qi.
To study the efficacy and safety of combined Traditional Chinese Medicine (TCM) therapy based on nourishing marrow to improve intellect and reinforcing Qi to activate bloodon mild to moderate Alzheimer's disease (AD). Sixty-six patients with AD, whose Mini-Mental State Examination (MMSE) score were from 10-24, were randomized equally into an intervention group and a control group. The control group was given Aricept (5 mg, once daily). The intervention group was further divided into Yang-Qi deficiency (n = 18) and of Yin-Qi deficiency (n = 15) subgroups. Patients in the Yang-Qi deficiency group were intravenously administered shenfu injection, 60 mL, and deproteinized calf blood injection (DCBI), 1.2 g, once daily. The Yin-Qi deficiency group was given shenmai injection, 60 mL, and DCBI, 1.2 g, once daily. Each course lasted 21 days. Compared with the control group and with pre-treatment in the same group, MMSE, clinical dementia rating, and activities of daily living scale scores in the intervention group were significantly improved (all P < 0.05). These metrics mildly improved in the control group compared with before treatment (P > 0.05). No adverse effects were observed in any group during treatment. We found that combined TCM therapy is effective and safe for managing mild to moderate AD.


Application of a tetrazolium salt with a water-soluble formazan as an indicator of viability in respiring bacteria.
The tetrazolium salt sodium 3'-{1-[(phenylamino)-carbonyl]-3,4-tetrazolium}-bis (4-methoxy-6-nitro)benzene-sulfonic acid hydrate (XTT) was examined for use as a colorimetric indicator of viability in respiring bacteria. XTT was reduced to an orange, water-soluble formazan product by Methylosinus trichosporium OB3b, Pseudomonas putida, Escherichia coli, and Bacillus subtilis. Formazan production was proportional to live cell biomass, and XTT was reduced by all cultures in the absence of added electron-coupling agents. XTT reduction by M. trichosporium OB3b was linear over several hours and was stimulated by the presence of an exogenous substrate (methanol). Addition of cyanide to cultures incubated under oxic conditions gave an initial 10-fold increase in XTT reduction. Viability of bacteria incubated in the absence of exogenous carbon substrates was measured as XTT reduction and compared with viability estimates from plate counts. Results obtained with the two methods were generally comparable, but the XTT assay was superior when cell recovery on plates was low. Incubation of E. coli for 7 days in the absence of exogenous carbon substrates decreased viability by 90%, whereas the corresponding decreases for cultures of M. trichosporium OB3b, P. putida, and B. subtilis were less than 40%.


Reduced order methods for parametric optimal flow control in coronary bypass grafts, toward patient-specific data assimilation.
Coronary artery bypass grafts (CABG) surgery is an invasive procedure performed to circumvent partial or complete blood flow blockage in coronary artery disease. In this work, we apply a numerical optimal flow control model to patient-specific geometries of CABG, reconstructed from clinical images of real-life surgical cases, in parameterized settings. The aim of these applications is to match known physiological data with numerical hemodynamics corresponding to different scenarios, arisen by tuning some parameters. Such applications are an initial step toward matching patient-specific physiological data in patient-specific vascular geometries as best as possible. Two critical challenges that reportedly arise in such problems are: (a) lack of robust quantification of meaningful boundary conditions required to match known data as best as possible and (b) high computational cost. In this work, we utilize unknown control variables in the optimal flow control problems to take care of the first challenge. Moreover, to address the second challenge, we propose a time-efficient and reliable computational environment for such parameterized problems by projecting them onto a low-dimensional solution manifold through proper orthogonal decomposition-Galerkin.


Analyzing the temporal regulation of translation efficiency in mouse liver.
Mammalian physiology and behavior follow daily rhythms that are orchestrated by endogenous timekeepers known as circadian clocks. Rhythms in transcription are considered the main mechanism to engender rhythmic gene expression, but important roles for posttranscriptional mechanisms have recently emerged as well (reviewed in Lim and Allada (2013) [1]). We have recently reported on the use of ribosome profiling (RPF-seq), a method based on the high-throughput sequencing of ribosome protected mRNA fragments, to explore the temporal regulation of translation efficiency (Janich et al., 2015 [2]). Through the comparison of around-the-clock RPF-seq and matching RNA-seq data we were able to identify 150 genes, involved in ribosome biogenesis, iron metabolism and other pathways, whose rhythmicity is generated entirely at the level of protein synthesis. The temporal transcriptome and translatome data sets from this study have been deposited in NCBI's Gene Expression Omnibus under the accession number GSE67305. Here we provide additional information on the experimental setup and on important optimization steps pertaining to the ribosome profiling technique in mouse liver and to data analysis.


Comparisons of the strength of associations with future type 2 diabetes risk among anthropometric obesity indicators, including waist-to-height ratio: a meta-analysis.
The aim of this meta-analysis was to compare the association of waist-to-height ratio (WHtR) with risk of incident diabetes with the associations of 3 other conventional obesity indicators (body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR)) with risk of incident diabetes. Literature searches in MEDLINE (January 1950 to April 27, 2011) and EMBASE (January 1974 to April 27, 2011) were conducted for prospective studies that made it possible to estimate the relative risk of diabetes per 1-standard deviation increase in WHtR, in addition to the RR of BMI, WC, or WHR. Strength of the estimated pooled relative risk for a 1-standard deviation increase of each indicator (expressed as RR(WHtR), RR(BMI), RR(WC), and RR(WHR)) was compared with a bivariate random-effects model. Pooled relative risks of the 15 eligible studies with 6,472 diabetes cases were 1.62 (95% CI: 1.48, 1.78) for RR(WHtR), 1.55 (95% CI: 1.43, 1.69) for RR(BMI), 1.63 (95% CI: 1.49, 1.79) for RR(WC), and 1.52 (95% CI: 1.40, 1.66) for RR(WHR). WHtR had an association stronger than that of BMI (P<0.001) or WHR (P<0.001). The present meta-analysis showed that WHtR has a modestly but statistically greater importance than BMI and WHR in prediction of diabetes. Nevertheless, measuring height in addition to WC appeared to have no additional benefit.


The Accuracy of Prevalent Vertebral Fracture Detection in Children Using Targeted Case-Finding Approaches.
Due to concerns about cumulative radiation exposure in the pediatric population, it is not standard practice to perform spine radiographs in most conditions that predispose to vertebral fracture (VF). In this study we examined the accuracy of two clinical predictors, back pain and lumbar spine bone mineral density (LS BMD), to derive four case-finding paradigms for detection of prevalent VF (PVF). Subjects were 400 children at risk for PVF (leukemia 186, rheumatic disorders 135, nephrotic syndrome 79). Back pain was assessed by patient report, LS BMD was measured by dual-energy X-ray absorptiometry, and PVF were quantified on spine radiographs using the modified Genant semiquantitative method. Forty-four patients (11.0%) had PVF. Logistic regression analysis between LS BMD and PVF produced an odds ratio (OR) of 1.9 (95% confidence interval [CI], 1.5 to 2.5) per reduction in Z-score unit, an area under the receiver operating characteristic curve of 0.70 (95% CI, 0.60 to 0.79), and an optimal BMD Z-score cutoff of -1.6. Case identification using either low BMD alone (Z-score < -1.6) or back pain alone gave similar results for sensitivity (55%, 52%, respectively), specificity (78%, 81%, respectively), positive predictive value (PPV; 24%, 25%, respectively), and negative predictive value (NPV; 93%, 93%, respectively). The paradigm using low BMD plus back pain produced lower sensitivity (32%), higher specificity (96%), higher PPV (47%), and similar NPV (92%). The approach using low BMD or back pain had the highest sensitivity (75%), lowest specificity (64%), lowest PPV (20%), and highest NPV (95%). All paradigms had increased sensitivities for higher fracture grades. Our results show that BMD and back pain history can be used to identify children with the highest risk of PVF so that radiography can be used judiciously. The specific paradigm to be applied will depend on the expected PVF rate and the clinical approach to the use of radiography. © 2019 American Society for Bone and Mineral Research.


Clonal variation in high- and low-level phenotypic and genotypic mupirocin resistance of MRSA isolates in south-east London.
Both low-level mupirocin resistance (LMR) and high-level mupirocin resistance (HMR) have been identified. The aim of this study was to determine the epidemiology of LMR and HMR in MRSA isolates at five hospitals that have used mupirocin for targeted decolonization as part of successful institutional control programmes. All MRSA identified in three microbiology laboratories serving five central and south-east London hospitals and surrounding communities between November 2011 and February 2012 were included. HMR and LMR were determined by disc diffusion testing. WGS was used to derive multilocus sequence types (MLSTs) and the presence of HMR and LMR resistance determinants. Prevalence of either HMR or LMR amongst first healthcare episode isolates from 795 identified patients was 9.69% (95% CI 7.72-11.96); LMR was 6.29% (95% CI 4.70-8.21) and HMR was 3.40% (95% CI 2.25-4.90). Mupirocin resistance was not significantly different in isolates identified from inpatients at each microbiology laboratory, but was more common in genotypically defined 'hospital' rather than 'community' isolates (OR 3.17, 95% CI 1.36-9.30, P = 0.002). LMR was associated with inpatient stay, previous history of MRSA and age ≥65 years; HMR was associated with age ≥65 years and residential postcode outside London. LMR and HMR varied by clone, with both being low in the dominant UK MRSA clone ST22 compared with ST8, ST36 and ST239/241 for LMR and with ST8 and ST36 for HMR. V588F mutation and mupA carriage had high specificity (>97%) and area under the curve (>83%) to discriminate phenotypic mupirocin resistance, but uncertainty around the sensitivity point estimate was large (95% CI 52.50%-94.44%). Mutations in or near the mupA gene were found in eight isolates that carried mupA but were not HMR. Mupirocin resistance was identified in <10% of patients and varied significantly by clone, implying that changes in clonal epidemiology may have an important role in determining the prevalence of resistance in conjunction with selection due to mupirocin use.


Resistance training and vibration improve muscle strength and functional capacity in female patients with multiple sclerosis.
The purpose of this study was to evaluate the effect of an eight-week progressive resistance training and vibration program on strength and ambulatory function in multiple sclerosis (MS) patients. Twenty-Four female MS patients with the following demographics: age 27-45 years, and expanded disability status scale (EDSS) 2-4, participated in this study. The subjects were randomly allocated to one of two groups. The exercise group (n = 12) trained according to a progressive program, mainly consisting of resistance training and vibration, three times a week for eight weeks and compared with subjects in the control group (n = 12) that received no intervention. Subjects completed one set of 5-12 reps at%50-70 maximal voluntary contraction (MVC). After 5-10 minutes rest, six postures on plate vibration were done. Isotonic MVC of knee extensors, abduction of the scapula and downward rotation of the scapular girdle muscle groups were predicted by using the Brzycki formula. Right leg balance (RLB), left leg balance (LLB), and walking speed (10-Meter Walk Test) were assessed before and after the training program. Descriptive statistics and Co-variance were used for analyzing data. After eight weeks of training the exercise group showed significant increase in MVC of Knee extensors (32.3%), Abduction of the scapula (24.7%) and Downward Rotation Scapular (39.1%) muscle groups, RLB (33.5%), LLB (9.5%), and decrease in 10-Meter Walk Test (10MWT) (9.3%), (P<0.05). The results of this study indicated this type of training can cause improvements in muscle strength and functional capacity in patients with multiple sclerosis.


Significance and interpretation of elevated troponin in septic patients.
Because no bedside method is currently available to evaluate myocardial contractility independent of loading conditions, a biological marker that could detect myocardial dysfunction in the early stage of severe sepsis would be a helpful tool in the management of septic patients. Clinical and experimental studies have reported that plasma cardiac troponin levels are increased in sepsis and could indicate myocardial dysfunction and poor outcome. The high prevalence of elevated levels of cardiac troponins in sepsis raises the question of what mechanism results in their release into the circulation. Apart from focal ischemia, several factors may contribute to the microinjury and minimal myocardial cell damage in the setting of septic shock. A possible direct cardiac myocytotoxic effect of endotoxins, cytokines or reactive oxygen radicals induced by the infectious process and produced by activated neutrophils, macrophages and endothelial cells has been postulated. The presence of microvascular failure and regional wall motion abnormalities, which are frequently observed in positive-troponin patients, also suggest ventricular wall strain and cardiac cell necrosis. Altogether, the available studies support the contention that cardiac troponin release is a valuable marker of myocardial injury in patients with septic shock.


GGA1 is expressed in the human brain and affects the generation of amyloid beta-peptide.
The beta-amyloid peptide (Abeta) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the beta-amyloid precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase. BACE1 cleaves APP at the N terminus of the Abeta domain, generating a membrane-bound C-terminal fragment (CTF-beta) that can be subsequently cleaved by gamma-secretase within the transmembrane domain to release Abeta. Because BACE1 initiates Abeta generation, it represents a potential target molecule to interfere with Abeta production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, gamma-ear-containing, ADP ribosylation factor-binding (GGA) proteins that are involved in the subcellular trafficking of BACE1. Here, we show that GGA1 is preferentially expressed in neurons of the human brain. GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains. Functional analyses with cultured cells demonstrate that GGA1 is implicated in the proteolytic processing of APP. Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF-beta generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of Abeta. The modulation of APP processing by GGA1 is independent of a direct interaction of both proteins. Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular trafficking of BACE1 or other GGA1-dependent proteins contribute to changes in APP processing and Abeta generation. Thus, GGA proteins might be involved in the pathogenesis of AD.


Dynamics of antibody nuclease activity in blood of women during pregnancy and lactation.
In human milk we previously found catalytic antibodies (abzymes) catalyzing hydrolysis of DNA, RNA, NMP, NDP, and NTP and also phosphorylation of proteins and lipids. In the present study we have analyzed nuclease activities of antibodies in blood of women during pregnancy and lactation. Blood of healthy male and female volunteers lacked catalytically active antibodies, whereas antibodies from blood of pregnant women hydrolyzed DNA and RNA and their relative activity varied over a wide range. Relative blood abzyme activities significantly increased after delivery and at the beginning of lactation. The highest abzyme activity was observed in blood of parturient women. Although the dynamics of changes in antibody DNase activity during pregnancy was rather individual for each woman, there was a common trend in the increase in antibody activity in the first and/or third trimester of the pregnancy. The DNase activity of IgG and IgM from blood of healthy pregnant women was 4-5 times less than that from pregnant women with pronounced autoimmune thyroiditis.


Data sharing in the undiagnosed diseases network.
The Undiagnosed Diseases Network (UDN) builds on the successes of the Undiagnosed Diseases Program at the National Institutes of Health (NIH UDP). Through support from the NIH Common Fund, a coordinating center, six additional clinical sites, and two sequencing cores comprise the UDN. The objectives of the UDN are to: (1) improve the level of diagnosis and care for patients with undiagnosed diseases through the development of common protocols designed by an enlarged community of investigators across the network; (2) facilitate research into the etiology of undiagnosed diseases, by collecting and sharing standardized, high-quality clinical and laboratory data including genotyping, phenotyping, and environmental exposure data; and (3) create an integrated and collaborative research community across multiple clinical sites, and among laboratory and clinical investigators, to investigate the pathophysiology of these rare diseases and to identify options for patient management. Broad-based data sharing is at the core of achieving these objectives, and the UDN is establishing the policies and governance structure to support broad data sharing.


Modulation of the heteromeric Kir4.1-Kir5.1 channels by P(CO(2)) at physiological levels.
Several inward rectifier K(+) (Kir) channels are pH-sensitive, making them potential candidates for CO(2) chemoreception in cells. However, there is no evidence showing that Kir channels change their activity at near physiological level of P(CO(2)), as most previous studies were done using high concentrations of CO(2). It is known that the heteromeric Kir4.1-Kir5.1 channels are highly sensitive to intracellular protons with pKa value right at the physiological pH level. Such a pKa value may allow these channels to regulate membrane potentials with modest changes in P(CO(2)). To test this hypothesis, we studied the Kir4.1-Kir5.1 currents expressed in Xenopus oocytes and membrane potentials in the presence and absence of bicarbonate. Evident inhibition of these currents (by approximately 5%) was seen with P(CO(2)) as low as 8 torr. Higher P(CO(2)) levels (23-60 torr) produced stronger inhibitions (by 30-40%). The inhibitions led to graded depolarizations (5-45 mV with P(CO(2)) 8-60 torr). Similar effects were observed in the presence of 24 mM bicarbonate and 5% CO(2). Indeed, the Kir4.1-Kir5.1 currents were enhanced with 3% CO(2) and suppressed with 8% CO(2) in voltage clamp, resulting in hyper- (-9 mV) and depolarization (16 mV) in current clamp, respectively. With physiological concentration of extracellular K(+), the Kir4.1-Kir5.1 channels conduct substantial outward currents that were similarly inhibited by CO(2) as their inward rectifying currents. These results therefore indicate that the heteromeric Kir4.1-Kir5.1 channels are modulated by a modest change in P(CO(2)) levels. Such a modulation alters cellular excitability, and enables the cell to detect hypercapnia and hypocapnia in the presence of bicarbonate.


Intelligent micro-/nanorobots as drug and cell carrier devices for biomedical therapeutic advancement: Promising development opportunities and translational challenges.
Nanotechnology and microfabrication approaches are playing instrumental roles in the development of innovative technologies to fight human diseases. Because of promising in vitro and preclinical outcomes, micro-/nanorobots (MNRs), are increasingly being considered for personalized and precision therapeutic diagnoses, sensing, drug delivery, and surgery. Today, designing MNR-based devices to improve the safety and efficacy of drugs for targeted cells and tissues represents a novel and promising area of therapeutic development. Progress has primarily been due to many scientific breakthroughs made in design, fabrication, and operational technologies, which greatly enhanced the capabilities of MNRs to meet the requirements of biomedical applications. This review focuses on the development and emerging biomedical applications of micro-/nanostructures encompassing nanoswimmers, nanoengines, 3D-motion nanomachines, and biologically inspired microbots, nanofish, nanorockets, etc. Promising applications of these novel devices in various therapeutic areas are discussed. We examine the impacts of the rapid progress made in developing these novel devices for drug delivery applications. We also summarize the current fabrication, scale-up development and clinical translational challenges and the main roadblocks that need to be overcome, particularly those related to patient safety and personalized medicine approaches, areas that require the design of safe innovative materials. As MNRs are new, scientists should systematically investigate their behavior, functionality, biocompatibility, toxicity, biodistribution, and efficacy before considering any potential clinical evaluations, while also ensuing that they comply with ethical principles. Although still an emerging area, MNRs are steadily becoming a realistic prospect as vital future therapeutic tools for a vast array of biomedical applications.


High-Frame-Rate Contrast-Enhanced Ultrasound for Velocimetry in the Human Abdominal Aorta.
Treatment of abdominal aortic (AA) aneurysms and stenotic lesions may be improved by analyzing their associated blood-flow patterns. Angle-independent blood-flow patterns in the AA can be obtained by combining echo-particle image velocimetry (ePIV) with high-frame-rate (HFR) contrast-enhanced ultrasonography. However, ePIV performance is affected by ultrasound contrast agent (UCA) concentration, microbubble stability, and tissue clutter. In this study, we assessed the influence of acoustic pressure and UCA concentration on image quality for ePIV analysis. We also compared amplitude modulation (AM) and singular value decomposition (SVD) as tissue suppression strategies for ePIV. Fourteen healthy volunteers were imaged in the region of the distal AA. We tested four different UCA bolus volumes (0.25, 0.5, 0.75, and 1.5 mL) and four different acoustic output pressures (mechanical indices: 0.01, 0.03, 0.06, and 0.09). As image quality metrics, we measured contrast-to-background ratio, bubble disruption ratio, and maximum normalized cross-correlation value during ePIV. At mechanical indices ≥ 0.06, we detected severe bubble destruction, suggesting that very low acoustic pressures should be used for ePIV. SVD was able to suppress tissue clutter better than AM. The maximum tracking correlation was affected by both UCA concentration and flow rate, where at high flow rates, lower UCA concentrations resulted in slightly higher correlation values but more signal drop-outs during late diastole. HFR ePIV was successfully performed in the AA of healthy volunteers and shows promise for future studies in patients.


TECNOB: study design of a randomized controlled trial of a multidisciplinary telecare intervention for obese patients with type-2 diabetes.
Obesity is one of the most important medical and public health problems of our time: it increases the risk of many health complications such as hypertension, coronary heart disease and type 2 diabetes, needs long-lasting treatment for effective results and involves high public and private costs. Therefore, it is imperative that enduring and low-cost clinical programs for obesity and related co-morbidities are developed and evaluated. TECNOB (TEChnology for OBesity) is a comprehensive two-phase stepped down program enhanced by telemedicine for the long-term treatment of obese people with type 2 diabetes seeking intervention for weight loss. Its core features are the hospital-based intensive treatment (1-month), that consists of diet therapy, physical training and psychological counseling, and the continuity of care at home using new information and communication technologies (ICT) such as internet and mobile phones. The effectiveness of the TECNOB program compared with usual care (hospital-based treatment only) will be evaluated in a randomized controlled trial (RCT) with a 12-month follow-up. The primary outcome is weight in kilograms. Secondary outcome measures are energy expenditure measured using an electronic armband, glycated hemoglobin, binge eating, self-efficacy in eating and weight control, body satisfaction, healthy habit formation, disordered eating-related behaviors and cognitions, psychopathological symptoms and weight-related quality of life. Furthermore, the study will explore what behavioral and psychological variables are predictive of treatment success among those we have considered. The TECNOB study aims to inform the evidence-based knowledge of how telemedicine may enhance the effectiveness of clinical interventions for weight loss and related type-2 diabetes, and which type of obese patients may benefit the most from such interventions. Broadly, the study aims also to have a effect on the theoretical model behind the traditional health care service, in favor of a change towards a new "health care everywhere" approach.


Genetic heterogeneity within electrophoretic "alleles" of xanthine dehydrogenase in Drosophila pseudoobscura.
An experimental plan for an exhaustive determination of genic variation at structural gene loci is presented. In the initial steps of this program, 146 isochromosomal lines from 12 geographic populations of D. pseudoobscura were examined for allelic variation of xanthine dehydrogenase by the serial use of 4 different electrophoretic conditions and a head stability test. The 5 criteria revealed a total of 37 allelic classes out of the 146 genomes examined where only 6 had been previously revealed by the usual method of gel electrophoresis. This immense increase in genic variation also showed previously unsuspected population differences between the main part of the species distribution and the isolated population of Bogotá population. The average heterozygosity at the Xdh locus is at least 72% in natural populations. This result, together with the very large number of alleles segregating and the pattern of allelic frequencies, has implications for theories of genetic polymorphism which are discussed.


Phantom limbs: pain, embodiment, and scientific advances in integrative therapies.
Research over the past two decades has begun to identify some of the key mechanisms underlying phantom limb pain and sensations; however, this continues to be a clinically challenging condition to manage. Treatment of phantom pain, like all chronic pain conditions, demands a holistic approach that takes into consideration peripheral, spinal, and central neuroplastic mechanisms. In this review, we focus on nonpharmacological treatments tailored to reverse the maladaptive neuroplasticity associated with phantom pain. Recent scientific advances emerging from interdisciplinary research between neuroscience, virtual reality, robotics, and prosthetics show the greatest promise for alternative embodiment and maintaining the integrity of the multifaceted representation of the body in the brain. Importantly, these advances have been found to prevent and reduce phantom limb pain. In particular, therapies that involve sensory and/or motor retraining, most naturally through the use of integrative prosthetic devices, as well as peripheral (e.g., transcutaneous electrical nerve stimulation) or central (e.g., transcranial magnetic stimulation or deep brain stimulation) stimulation techniques, have been found to both restore the neural representation of the missing limb and to reduce the intensity of phantom pain. While the evidence for the efficacy of these therapies is mounting, but well-controlled and large-scale studies are still needed. WIREs Cogn Sci 2014, 5:221-231. doi: 10.1002/wcs.1277 CONFLICT OF INTEREST: The authors have no financial or other relationship that might lead to a conflict of interest. For further resources related to this article, please visit the WIREs website.


Post-traumatic stimulus suppressible myoclonus of peripheral origin.
A patient is described who presented with myoclonus of the first dorsal interosseus muscle of the right foot. This myoclonus occurred 18 months after trauma of the cutaneous branch of the deep peroneal nerve on the dorsal aspect of the foot. Tactile stimulation in the dermatome of this nerve, or an anaesthetic block of the deep peroneal nerve stopped the myoclonus. The different innervation between the efferent motor activity responsible for the movements and the sensory afference suppressing it points firmly towards involvement of central connections. However, abolition of the movement by anaesthesia suggests the presence of a peripheral ectopic generator. This finding confirms that focal myoclonus can have its origin in the peripheral nervous system and may be modulated by sensory inputs.


Differential induction of Hsp70-encoding genes in human hematopoietic cells.
The rapid transcriptional activation of heat shock genes in response to stress is crucial for the cellular survival and the development of thermotolerance. Although heat shock response is a widespread phenomenon, certain cells exhibit a diminished induction of heat shock gene expression upon stress stimuli. Here we have analyzed the development of thermotolerance and induction of distinct Hsp70 encoding genes in three cell lines representing different hematopoietic cell types. We show that in response to heat shock, cell survival and induction of thermotolerance are impaired in Raji and HL60 cells, as compared with K562 cells. Accordingly, transcriptional induction of the hsp70 gene is diminished in Raji and HL60 cells. This appears to be due to inability of transcription factors, including HSF1 to bind to the hsp70.1 promoter in vivo. Consistent with the genomic footprint, analysis of hsp70.1 mRNA expression using a specific 3'-untranslated region probe reveals that induction of the hsp70.1 gene upon heat shock is completely abolished in Raji and HL60 cells. The suppression of the hsp70.1 promoter is not caused by impaired function of HSF1, since HSF1 is equally activated in all cell types and occupies another heat-inducible promoter, hsp90 alpha. Furthermore, among distinct inducible hsp70 genes, suppression seems to be specific for the hsp70.1 gene, since heat shock results in induction of hsp70.2 and hsp70B' mRNA expression in all cell lines. Taken together, our results demonstrate that distinct Hsp70-encoding genes contribute to the heat shock response in a cell type-dependent manner.


Reduced burden of disease and improved outcome of patients with rheumatoid factor positive rheumatoid arthritis compared with dropouts. A 10 year observational study.
Our objective was to determine outcome and burden of disease in a 10 year study of patients with rheumatoid factor positive rheumatoid arthritis (RF+ RA) compared with study dropouts. Three hundred and one consecutive subjects with disease duration of 3-255 months at presentation were enrolled. The acute (as measured by C-reactive protein, CRP) and chronic (by erythrocyte sedimentation rate, ESR) phases of RF+ RA were suppressed by pulse intravenous (IV) combination of low dose methylprednisolone (MPS) + cyclophosphamide (CYC) for 3 consecutive days and weekly intravenous methotrexate (MTX) with simultaneous oral cyclosporine (CSA) + mycophenolate mofetil (MPM). After achieving negative CRP and ESR < 40 mm/h, IV therapy was tapered and switched to oral low dose MTX+CSA+MPM until negative CRP titer and ESR < 25 mm/h (men < 15 mm) Westergren were achieved. American Rheumatism Association (ARA) functional classification measured disability. Dropouts did not complete the study for various reasons. At baseline, cases and dropouts were comparable in age and sex distribution, including mean age, disease duration, disease features, and associated conditions. Mortality in 274 cases was 2.9% versus 25.9% in dropouts. ARA functional class in cases decreased from 3.2 + 0.7 to 1.4 + 0.3 and in dropouts was 3.2 + 0.6 at baseline versus 3.5 + 0.5 at outcome. Disability of dropouts was significantly worse compared with cases. In dropouts, more associated conditions occurred than in cases. The burden of disease and outcomes were significantly worse in dropouts compared with cases.


Routine follow-up visits after first-trimester induced abortion.
Routine follow-up visits after abortion are intended to confirm that the abortion is complete and to diagnose and treat complications. Many clinicians also take advantage of the follow-up visit to provide general reproductive health care: discussing contraceptive plans and providing family planning services; diagnosing sexually transmitted infections; performing a Pap test or discussing abnormal Pap results. We reviewed the evidence related to the routine postabortion follow-up visit. Other than mifepristone medical abortion performed at 50 days of gestation or later and methotrexate medical abortion, we found little evidence that mandatory follow-up visits typically detect conditions that women themselves could not be taught to recognize. In addition, the natural history of the most severe complications after abortion-infection and unrecognized ectopic pregnancy-have time courses inconsistent with the usual timing of the follow-up visit. Costs associated with this visit can be great. These include travel expenses, lost wages, child-care expenses, privacy and emotional burdens for women, and scheduling disruptions and the related opportunity costs caused by "no-shows" for the provider. Follow-up appointments should be scheduled for those women likely to benefit from a physical examination. For the remainder of women, simple instructions and advice about detecting complications, possibly coupled with telephone follow-up, might suffice. Although arguably valuable in their own right, counseling, family planning services, or sexually transmitted infection diagnosis and treatment should not be so inflexibly bundled with postabortion care. Protocols that require in-person follow-up after abortion may not make the best use of a women's time or abilities, or of the medical system.


Frailty Levels In Geriatric Hospital paTients (FLIGHT)-the prevalence of frailty among geriatric populations within hospital ward settings: a systematic review protocol.
Frailty is a common and clinically significant condition in geriatric populations, associated with adverse health outcomes such as hospitalisation, disability and mortality. Although there are systematic reviews/meta-analyses assessing the prevalence of frailty in community-dwelling older adults, nursing home residents, and cancer and general surgery patients, there are none assessing the overall prevalence of frailty in geriatric hospital inpatients. This review will systematically search and analyse the prevalence of frailty within geriatric hospital inpatients within the literature. A search will be employed on the platforms of Ovid, Web of Science and databases of Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, SCOPUS and the Cochrane Library. Any observational or experimental study design which utilises a validated operational definition of frailty, reports the prevalence of frailty, has a minimum age ≥65 years, attempts to assess the whole ward/clinical population and occurs in hospital inpatients, will be included. Title and abstract and full-text screenings will be conducted by three reviewers. Methodological quality of eligible studies will be assessed using the Joanna Briggs Institute critical appraisal tool. Data extraction will be performed by two reviewers. If sufficient data are available, a meta-analysis synthesising pooled estimates of the prevalence of frailty and pre-frailty, as well as the prevalence of frailty stratified by age, sex, operational frailty definition, prevalent morbidities, ward type and location, among older hospitalised inpatients will be conducted. Clinical heterogeneity will be assessed by two reviewers. Statistical heterogeneity will be assessed through a Cochran Q test, and an I 2 test performed to assess its magnitude. Ethical approval was not required as primary data will not be collected. Findings will be disseminated through publication in peer reviewed open access scientific journals, public engagement events, conference presentations and social media. 79202.


Evaluation of the impact of the Family Health Program on infant mortality in Brazil, 1990-2002.
To use publicly available secondary data to assess the impact of Brazil's Family Health Program on state level infant mortality rates (IMR) during the 1990s. Longitudinal ecological analysis using panel data from secondary sources. Analyses controlled for state level measures of access to clean water and sanitation, average income, women's literacy and fertility, physicians and nurses per 10,000 population, and hospital beds per 1,000 population. Additional analyses controlled for immunisation coverage and tested interactions between Family Health Program and proportionate mortality from diarrhoea and acute respiratory infections. 13 years (1990-2002) of data from 27 Brazilian states. From 1990 to 2002 IMR declined from 49.7 to 28.9 per 1,000 live births. During the same period average Family Health Program coverage increased from 0% to 36%. A 10% increase in Family Health Program coverage was associated with a 4.5% decrease in IMR, controlling for all other health determinants (p<0.01). Access to clean water and hospital beds per 1,000 were negatively associated with IMR, while female illiteracy, fertility rates, and mean income were positively associated with IMR. Examination of interactions between Family Health Program coverage and diarrhoea deaths suggests the programme may reduce IMR at least partly through reductions in diarrhoea deaths. Interactions with deaths from acute respiratory infections were ambiguous. The Family Health Program is associated with reduced IMR, suggesting it is an important, although not unique, contributor to declining infant mortality in Brazil. Existing secondary datasets provide an important tool for evaluation of the effectiveness of health services in Brazil.