Effects of a novel gel containing 5-aminolevulinic acid and red LED against bacteria involved in peri-implantitis and other oral infections.
Antibiotic resistance is a major public health problem worldwide and the finding of alternative methods for eliminating bacteria is one of the prerogatives of medical research. The indiscriminate use of antibiotics in dentistry, especially for the treatment of peri-implantitis, could lead to superinfections. Alternative methods, like photodynamic therapy mediated by the use of aminolevulinic acid and a red light has been largely described, especially in dentistry, but results were encouraging against Gram-positive bacteria, but limited against Gram-negative. The effectiveness of photodynamic therapy mediated by a novel product containing aminolevulinic acid, Aladent (ALAD) has been tested in this in vitro study, against different types of bacteria particularly involved in the infections of the oral cavity and peri-implantitis. The novelty of ALAD is the marked hydrophilicity that should increase the passage of the molecule through the membrane pores of Gram-negative bacteria. Considering the novelty of the product a preliminary experiment permitted to test the effectiveness against Enterococcus faecalis after 1 h of ALAD incubation at different concentrations, with or without different timings of LED irradiation. The count of CFUs and the live/dead observation with fluorescent microscopy showed a significant reduction and killing of bacterium. Then, in the second stage, that could meet the necessity of effectiveness and the clinician's requests to reduce the timing of treatment, ALAD, with and without irradiation, was tested on Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Veillonella parvula and Porphyromonas gingivalis. In particular, the efficiency of different concentrations of the product after a 25 min incubation was tested with and without the adjunctive LED irradiation for 5 min. A slight ALAD bactericidal effect was reported for all bacteria, also without LED irradiation, however, the most effective treatment was 25 min of 50% ALAD incubation followed by 5 min of a red LED. The in vitro tests demonstrated that ALAD gel with LED irradiation exerts a potent antibacterial activity on different bacteria, both Gram-positive and Gram-negative.


Lack of an association between antibodies to Plasmodium falciparum glycosylphosphatidylinositols and malaria-associated placental changes in Cameroonian women with preterm and full-term deliveries.
Sequestration of Plasmodium falciparum parasites within the placenta often leads to an accumulation of macrophages within the intervillous space and increased production of tumor necrosis factor alpha (TNF-alpha), a cytokine associated with placental pathology and poor pregnancy outcomes. P. falciparum glycosylphosphatidylinositol (GPI) anchors have been shown to be the major parasite component that induces TNF-alpha production by monocytes and macrophages. Antibodies against P. falciparum GPI (anti-PfGPI), however, can inhibit the induction of TNF-alpha and inflammation. Thus, the study was undertaken to determine whether anti-PfGPI antibodies down-regulate inflammatory-type changes in the placentas of women with malaria. Anti-PfGPI immunoglobulin M (IgM) and IgG levels were measured in 380 pregnant women with or without placental malaria, including those who delivered prematurely and at term. Results showed that anti-PfGPI antibody levels increased with gravidity and age and that malaria infection boosted anti-PfGPI antibodies in pregnant women. However, no association was found between anti-PfGPI antibodies and placental TNF-alpha levels or the presence of acute or chronic placental malaria. Furthermore, anti-PfGPI antibody levels were similar in women with preterm and full-term deliveries and were not associated with an increase in infant birth weight. Thus, these results fail to support a strong role for anti-PfGPI antibodies in the prevention of chronic placental malaria infections and malaria-associated poor birth outcomes.


Effects of phytoestrogen supplementation in postmenopausal women with dry eye syndrome: a randomized clinical trial.
To evaluate the correlation between tear osmolarity and blood levels of 17-β estradiol, estrone, and testosterone in postmenopausal women with dry eye syndrome, and to assess the efficacy and safety of oral supplementation with phytoestrogens, lipoic acid, and eicosapentaenoic acid in this population. Cross-sectional study including 66 postmenopausal women with dry eye syndrome. Sixty-six postmenopausal women with dry eye syndrome were enrolled in a randomized, double-blind, placebo-controlled, crossover study. Patients were divided into 2 groups (groups A and B) and treated, respectively, with phytoestrogen (Bioos, Montegiorgio, Italy) tablets or placebo tablets for 30 days. The 2 treatment periods were separated by a 30-day washout. Patients were examined on days 0 and 30 of each period. Assessments included blood levels of sex hormones, the Schirmer test for tear production, and measurement of tear osmolarity and tear film break-up time. At baseline, all patients had low sex hormone levels, which were correlated with high tear film osmolarity values (r = -0.59,-0.61,-0.58, respectively). After 30 days of therapy, the group treated with Lacrisek® (Bioos) had significantly decreased tear osmolarity (P<0.005) and significantly increased tear production evaluated with the Schirmer test and tear film break-up time values (P<0.001) compared with the placebo-treated group. Our study confirms that steroid hormones play an important role in ocular surface equilibrium and functions. Consequently, reduced blood levels of these hormones can produce changes at the ocular surface. Phytoestrogen supplementation can significantly improve the signs and symptoms of dry eye syndrome in postmenopausal women.


Epitope analysis and utility of monoclonal antibodies to native and recombinant human thymidylate synthase.
The expression of thymidylate synthase (TS) in human cancer tissues has been suggested to be a prognostic factor for patients receiving 5-fluorouracil-based chemotherapy. We generated monoclonal antibodies to both recombinant and native TS and analyzed the epitopes on the TS molecule. Two monoclonal antibodies were obtained from recombinant human TS proteins (RTSMA1 and RTSMA2) and two monoclonal antibodies raised to native TS in human cancers (NTSMA1 and NTSMA2) were obtained, and were found to have a high affinity and specificity for TS proteins. To identify the human TS epitope that these monoclonal antibodies recognized, we constructed plasmids to produce full-length and two partially deleted TS proteins fused to glutathion-S-transferase (GST). Western blot analysis showed that RTSMA1 and 2 only reacted with full-length TS and NTSMA1 and 2 reacted with all three recombinant TS proteins, suggesting that the epitopes of the former were located at C-terminal sites (D186-V313), and those of the latter were at N-terminal sites (M1-M61). The RTSMA 1 and 2 epitopes were more accurately mapped using 8 oligopeptides to the region of I267 to L282 which was situated at the surface of the TS protein. Highly sensitive detection of human TS was also possible by sandwich ELISA using a combination of different types of antibody rather than a single type. In conclusion, different type monoclonal antibodies to human TS protein may contribute to the detection of TS in cancer patients.


Neurosurgical tactile discrimination training with haptic-based virtual reality simulation.
To determine if a computer-based simulation with haptic technology can help surgical trainees improve tactile discrimination using surgical instruments. Twenty junior medical students participated in the study and were randomized into two groups. Subjects in Group A participated in virtual simulation training using the ImmersiveTouch simulator (ImmersiveTouch, Inc., Chicago, IL, USA) that required differentiating the firmness of virtual spheres using tactile and kinesthetic sensation via haptic technology. Subjects in Group B did not undergo any training. With their visual fields obscured, subjects in both groups were then evaluated on their ability to use the suction and bipolar instruments to find six elastothane objects with areas ranging from 1.5 to 3.5 cm2 embedded in a urethane foam brain cavity model while relying on tactile and kinesthetic sensation only. A total of 73.3% of the subjects in Group A (simulation training) were able to find the brain cavity objects in comparison to 53.3% of the subjects in Group B (no training) (P = 0.0183). There was a statistically significant difference in the total number of Group A subjects able to find smaller brain cavity objects (size ≤ 2.5 cm2) compared to that in Group B (72.5 vs. 40%, P = 0.0032). On the other hand, no significant difference in the number of subjects able to detect larger objects (size ≧ 3 cm2) was found between Groups A and B (75 vs. 80%, P = 0.7747). Virtual computer-based simulators with integrated haptic technology may improve tactile discrimination required for microsurgical technique.


A p53-dependent mouse spindle checkpoint.
Cell cycle checkpoints enhance genetic fidelity by causing arrest at specific stages of the cell cycle when previous events have not been completed. The tumor suppressor p53 has been implicated in a G1 checkpoint. To investigate whether p53 also participates in a mitotic checkpoint, cultured fibroblasts from p53-deficient mouse embryos were exposed to spindle inhibitors. The fibroblasts underwent multiple rounds of DNA synthesis without completing chromosome segregation, thus forming tetraploid and octaploid cells. Deficiency of p53 was also associated with the development of tetraploidy in vivo. These results suggest that murine p53 is a component of a spindle checkpoint that ensures the maintenance of diploidy.


Interstellar carbon in meteorites.
The Murchison and Allende chondrites contain up to 5 parts per million carbon that is enriched in carbon-13 by up to + 1100 per mil (the ratio of carbon-12 to carbon-13 is approximately 42, compared to 88 to 93 for terrestrial carbon). This "heavy" carbon is associated with neon-22 and with anomalous krypton and xenon showing the signature of the s-process (neutron capture on a slow time scale). It apparently represents interstellar grains ejected from late-type stars. A second anomalous xenon component ("CCFXe") is associated with a distinctive, light carbon (depleted in carbon-13 by 38 per mil), which, however, falls within the terrestrial range and hence may be of either local or exotic origin.


Geography and ethnicity related variation in the Chinese human milk serum proteome.
Human milk provides a range of nutrients and bioactive components, which can support the growth and development of infants. However, human milk composition may change due to geographic and ethnic variation. This study investigated the variation of the Chinese human milk serum proteome based on mothers with different ethnicities living in different parts of China, using TMT labeling combined with Nano-LC Q Exactive HF MS/MS proteomics. In total, 693 proteins were identified and quantified in human milk serum from Yunnan (Han and Bai ethnicity), Gansu (Han and Tibetan ethnicity), Xinjiang (Uygur ethnicity), and Inner Mongolia (Mongolian ethnicity). The biological function distribution of identified proteins and the summed intensity of proteins belonging to each biological function were similar among groups. The five relatively highly abundant milk serum proteins, lactoferrin, serum albumin, polymeric immunoglobulin receptor, macrophage mannose receptor 1, and bile salt-activated lipase were not significantly different among different geographies and ethnicities. On the other hand, we found 34 proteins that did significantly differ with geography and ethnicity. Those significantly different proteins have known strong interaction in inflammation response and regulation of multi-organism processes. Taken together, biological function distribution was similar on both the qualitative and quantitative levels, and proteins with similar abundance are important in providing basic nutrition and protection for infants, whereas the significantly different proteins may be important for the healthy development of infants from different locations and ethnicities.


The wrong and wounding road: Paediatric polytrauma admitted to a level 1 trauma intensive care unit over a 5-year period.
Injury in childhood is a major cause of potentially preventable morbidity and mortality. In order to implement effective preventive strategies, epidemiological data on mechanisms of injury and outcome are essential. To assess the causation, severity of injury, morbidity and mortality of paediatric trauma admitted to a level 1 trauma intensive care unit (TICU). Children were defined as being <16 years of age. The study covered the 5-year period January 2008-December 2012. Eligible patients were identified from a prospective database maintained in the level 1 TICU at Inkosi Albert Luthuli Central Hospital, Durban, South Africa. Data extracted were referral source, mechanism of injury, age and gender distribution, injury severity score (ISS), anatomical distribution of injury and mortality. A total of 181 patients admitted during the study period accounted for 15.9% of all admissions. There were 84 females (46.4%) and 97 males (53.6%), with a median age of 7 years (interquartile range (IQR) 4-10). Sources of admission were directly from the scene in 38 cases (21.0%), from a primary healthcare facility in 47 (26.0%), from a regional hospital in 56 (31.0%) and from a tertiary facility in 40 (22.0%). Mortality rates according to location of transfer were regional hospital 8 deaths (30.8%), tertiary facility 7 (26.9%), primary health clinic 7 (26.9%), and from the scene 4 (15.4%). Mechanisms of injury were pedestrian-motor vehicle collision (PMVC) in 105 cases (58.0%), motor vehicle passenger in 38 (21.0%), non-vehicular blunt trauma in 18 (10.0%), gunshot wounds (GSWs) in 12 (6.6%), stab wounds in 6 (3.3%), bull goring in 1 (0.5%) and bicycle accident 1 (0.5%). The median ISS for all admissions was 25 (IQR 16-38). ISSs were >25 in 98 patients (54.1%), 16-25 in 51 (28.2%), 9-15 in 9 (4.9%) and <9 in 13 (7.2%); 61.9% of patients had head injuries, 48.1% injuries to the extremities, 41.4% abdominal trauma, 40.3% thoracic trauma, 20.4% external soft-tissue trauma, 9.9% cervical injury and 9.4% facial trauma. There were 26 deaths (14.4%), of which PMVCs accounted for 16 (61.5%), motor vehicle passengers for 7 (26.9%), blunt trauma for 2 (7.7%) and GSWs for 1 (3.8%). The majority of deaths (92%) were of patients with an ISS>25. Of the 26 patients who died, 88.4% had a head injury, 46.2% an extremity injury, 38.5% an external injury, 34.6% abdominal or chest injuries, 19.2% neck injury and 11.5% facial injury. Motor vehicle-related injuries, especially PMVCs, dominate severe paediatric trauma and there is an urgent need for more road traffic education and stringent measures to decrease the incidence and associated morbidity and mortality.


Molecular dynamics simulations on the first two helices of Vpu from HIV-1.
Vpu is an 81 amino acid protein of HIV-1 with two phosphorylation sites. It consists of a short N-terminal end traversing the bilayer and a longer cytoplasmic part. The dual functional role of Vpu is attributed to these topological distinct regions of the protein. The first 52 amino acids of Vpu (HV1H2) have been simulated, which are thought to be embedded in a fully hydrated lipid bilayer and to consist of a transmembrane helix (helix-1) connected via a flexible linker region, including a Glu-Tyr-Arg (EYR) motif, with a second helix (helix-2) residing with its helix long axis on the bilayer surface. Repeated molecular dynamics simulations show that Glu-28 is involved in salt bridge formation with Lys-31 and Arg-34 establishing a kink between the two helices. Helix-2 remains in a helical conformation indicating its stability and function as a "peptide float," separating helix-1 from the rest of the protein. This leads to the conclusion that Vpu consists of three functional modules: helix-1, helix-2, and the remaining residues toward the C-terminal end.


Immunologic abnormalities in alcoholic hepatitis.
There are many unanswered questions in the possible autoimmune pathogenesis of alcoholic liver disease. Why do only 15-20% of chronic alcoholic patients develop alcoholic hepatitis and cirrhosis? What factors make a patient susceptible to immune events in alcoholism? What initiates immune reactivity in susceptible patients? What permits accumulation of alcoholic hyalin in patients with alcoholic hepatitis? Is alcoholic hyalin central to the pathogenesis of alcoholic hepatitis? If adducts play a role, why don't more alcoholics develop liver disease, as adducts probably form in all patients? Unfortunately, the lack of an appropriate animal model will probably allow these questions to remain unanswered for some time. However, further research into the role of adducts in alcoholic liver disease may be helpful. Isolation of adducts from hepatocytes of patients with alcoholic hepatitis may permit study of their intracellular location, formation and perhaps of their timing in the sequence of liver disease. These studies should provide additional clues to the pathogenesis of alcoholic liver disease.


[Therapeutic effects of oxytocin in autism: Current status of the research].
The neuropeptide oxytocin (OT) is an evolutionary highly conserved molecule that plays a part in the regulation of complex social cognition and behaviours. From a pathophysiological point of view, several studies have evidenced dysfunctions of the oxytocinergic system in autism spectrum disorders (ASD): a lowering of plasma OT and genetic or epigenetic anomalies of the OT receptor. Therefore, some authors have hypothesized that an abnormality in the OT neurotransmission may account for several features of autism and that a treatment restoring a normal OT pathway functioning could improve social abilities. OT administration has thus been used in clinical trials, especially in groups of subjects suffering from autism. Some studies found that OT decreased repetitive behaviours, enhanced emotional understanding of speech intonation, improved performance of the Reading the Mind in the Eyes Test and reinforced cooperation. Nevertheless, the findings of the OT administration studies on clinical samples show great diversity. The context, the personality and childhood experiences of the subject could be moderators influencing the effect of exogenous OT. Besides, three mechanisms could play a part in the action of OT on ASD social symptoms: anxiety reduction (with a lowering in the hypothalamic-pituitary-adrenal axis responsiveness and in the amygdale reactivity to social stimuli), increased affiliative motivation (involving the dopaminergic pathway and several regions of the social brain) and enhanced perceptual selectivity and social stimuli salience. To conclude, OT could be a promising molecule used as a treatment to promote social behaviours, helping individuals with ASD to develop new relationships. OT could be administered during a cognitive-behavioural therapy to reinforce the efficacy of such procedures. More studies are needed, on larger samples, to investigate the safety and efficacy of OT administration and to specify optimal dosages and characteristics of patients who may benefit from this treatment.


[Dietary habits of Japanese renal stone formers and clinical effects of prophylactic dietary treatment].
The daily consumption of various nutrients and the daily habits of 241 male stone formers were investigated. The patients (especially uric acid stone formers and hypercalciuric (greater than or equal to 300 mg/day) calcium stone formers) ingested much more total protein and animal protein than healthy Japanese. However, the amount of ingested calcium by the patients (470 mg) was less than that of healthy subjects (553 mg) and did not reach the level of the daily nutritive requirement (600 mg). The amount of ingested nutrients during the evening meal by the patients was about 50% of the daily amount with over 60% of the daily animal protein being ingested at dinner. This tendency was high in subjects who were in their 20's to 40's. The interval from dinner until retiring in the patients was not different from that of healthy males, but it was under 4 hours in over 50% of those in their 30's and 40's in both groups. From these results, we thought that a rapid change in nutritional status and dietary style in the short period after World War II had strongly affected the incidence of renal stone disease in Japan. Therefore, we have established the following general guidelines: 1) increased fluid intake, especially after dinner, 2) correct and avoid unbalanced diet (the diet should include all kinds of food, with vegetables being eaten at every meal and avoidance of an excessive intake of meat), 3) eat three meals a day and avoid an excessive intake at dinner, and 4) extend the interval from dinner until retiring. By following these individual dietary guidelines, the 5-year stone recurrence rate and the stone episode rate decreased remarkably in the period of not only outpatient visits but also in the period when the outpatient visits were discontinued. From these results, we conclude that individual dietary management should be the primary measure for the prophylaxis of renal stone disease in Japan.


Combined Effects of Temperature, Irradiance, and pH on Teleaulax amphioxeia (Cryptophyceae) Physiology and Feeding Ratio For Its Predator Mesodinium rubrum (Ciliophora)1.
The cryptophyte Teleaulax amphioxeia is a source of plastids for the ciliate Mesodinium rubrum and both organisms are members of the trophic chain of several species of Dinophysis. It is important to better understand the ecology of organisms at the first trophic levels before assessing the impact of principal factors of global change on Dinophysis spp. Therefore, combined effects of temperature, irradiance, and pH on growth rate, photosynthetic activity, and pigment content of a temperate strain of T. amphioxeia were studied using a full factorial design (central composite design 23 *) in 17 individually controlled bioreactors. The derived model predicted an optimal growth rate of T. amphioxeia at a light intensity of 400 μmol photons · m-2 · s-1 , more acidic pH (7.6) than the current average and a temperature of 17.6°C. An interaction between temperature and irradiance on growth was also found, while pH did not have any significant effect. Subsequently, to investigate potential impacts of prey quality and quantity on the physiology of the predator, M. rubrum was fed two separate prey: predator ratios with cultures of T. amphioxeia previously acclimated at two different light intensities (100 and 400 μmol photons · m-2 s-1 ). M. rubrum growth appeared to be significantly dependent on prey quantity while effect of prey quality was not observed. This multi-parametric study indicated a high potential for a significant increase of T. amphioxeia in future climate conditions but to what extent this would lead to increased occurrences of Mesodinium spp. and Dinophysis spp. should be further investigated.


Total lymphoid irradiation for treatment of intractable cardiac allograft rejection.
The ability of postoperative total lymphoid irradiation to reverse otherwise intractable cardiac allograft rejection was examined in a group of 10 patients in whom conventional rejection therapy (including pulsed steroids and monoclonal or polyclonal anti-T-cell antibody therapy) had failed to provide sustained freedom from rejection. Follow-up periods range from 73 to 1119 days since the start of total lymphoid irradiation. No patient died or sustained serious morbidity because of the irradiation. Three patients have had no further rejection (follow-up periods, 105 to 365 days). Two patients died--one in cardiogenic shock during the course of total lymphoid irradiation, the other with recurrent rejection caused by noncompliance with his medical regimen. Total lymphoid irradiation appears to be a safe and a moderately effective immunosuppressive modality for "salvage" therapy of cardiac allograft rejection unresponsive to conventional therapy.


Ghost imaging with shaped incoherent sources.
We show that the image quality of ghost imaging (GI) can be controlled by the use of shaped incoherent sources. The formula for the point-spread function in the GI system has been derived and is determined by the Fourier transform of the source intensity distribution. Compared with the widely used Gaussian Schell-model source, we find that using a cosine-Gaussian Schell-model source can lead to the degradation of GI quality, while the quality of GI can be increased with a cosh-Gaussian Schell-model source. Even under atmospheric turbulence, the image resolution of GI still can be improved by means of the cosh-Gaussian Schell-model source.


Cell dynamics in cervical loop epithelium during transition from crown to root: implications for Hertwig's epithelial root sheath formation.
Some clinical cases of hypoplastic tooth root are congenital. Because the formation of Hertwig's epithelial root sheath (HERS) is an important event for root development and growth, we have considered that understanding the HERS developmental mechanism contributes to elucidate the causal factors of the disease. To find integrant factors and phenomenon for HERS development and growth, we studied the proliferation and mobility of the cervical loop (CL). We observed the cell movement of CL by the DiI labeling and organ culture system. To examine cell proliferation, we carried out immunostaining of CL and HERS using anti-Ki67 antibody. Cell motility in CL was observed by tooth germ slice organ culture using green fluorescent protein mouse. We also examined the expression of paxillin associated with cell movement. Imaging using DiI labeling showed that, at the apex of CL, the epithelium elongated in tandem with the growth of outer enamel epithelium (OEE). Cell proliferation assay using Ki67 immunostaining showed that OEE divided more actively than inner enamel epithelium (IEE) at the onset of HERS formation. Live imaging suggested that mobility of the OEE and cells in the apex of CL were more active than in IEE. The expression of paxillin was observed strongly in OEE and the apex of CL. The more active growth and movement of OEE cells contributed to HERS formation after reduction of the growth of IEE. The expression pattern of paxillin was involved in the active movement of OEE and HERS. The results will contribute to understand the HERS formation mechanism and elucidate the cause of anomaly root.


Toward a Broader Role for Occupational Therapy in Supportive Oncology Care.
Supportive care in oncology helps people cope with cancer and its psychological, physical, and emotional side effects. However, cancer survivors report dissatisfaction with supportive care and a need for more psychosocial and self-management services. Occupational therapy practitioners represent an integral part of the supportive care team because their scope of practice emphasizes function. Through a focus on function, practitioners address the full spectrum of physical and psychosocial care. Currently, conceptualizations of occupational therapy for cancer survivors often focus solely on physical interventions and, therefore, do not represent the unique involvement of the profession in supportive oncology care. We advocate for a focused framework for occupational therapy practitioners in oncology as experts in function and providers of both physical and psychosocial treatments. Barriers to a focus on function are identified, and strategies are suggested for expanding involvement for the profession in supportive oncology care.


Human leukocyte antigenic specificity HL-A3: frequency of occurrence.
Reactivity of antiserum against HL-A3, a human leukocyte and tissue antigenic specificity, depends upon a property of the lymphocyte as well as on the potency of the serum. Many reactions of HL-A3 antiserums can only be recognized through absorption or by a two-stage test not in general use. Interpretations of donor-recipient compatibility and of the constitution of HL-A alleles affected by these findings.


Activation of AMPK enhances neutrophil chemotaxis and bacterial killing.
An inability of neutrophils to eliminate invading microorganisms is frequently associated with severe infection and may contribute to the high mortality rates associated with sepsis. In the present studies, we examined whether metformin and other 5' adenosine monophosphate-activated protein kinase (AMPK) activators affect neutrophil motility, phagocytosis and bacterial killing. We found that activation of AMPK enhanced neutrophil chemotaxis in vitro and in vivo, and also counteracted the inhibition of chemotaxis induced by exposure of neutrophils to lipopolysaccharide (LPS). In contrast, small interfering RNA (siRNA)-mediated knockdown of AMPKα1 or blockade of AMPK activation through treatment of neutrophils with the AMPK inhibitor compound C diminished neutrophil chemotaxis. In addition to their effects on chemotaxis, treatment of neutrophils with metformin or aminoimidazole carboxamide ribonucleotide (AICAR) improved phagocytosis and bacterial killing, including more efficient eradication of bacteria in a mouse model of peritonitis-induced sepsis. Immunocytochemistry showed that, in contrast to LPS, metformin or AICAR induced robust actin polymerization and distinct formation of neutrophil leading edges. Although LPS diminished AMPK phosphorylation, metformin or AICAR was able to partially decrease the effects of LPS/toll-like receptor 4 (TLR4) engagement on downstream signaling events, particularly LPS-induced IκBα degradation. The IκB kinase (IKK) inhibitor PS-1145 diminished IκBα degradation and also prevented LPS-induced inhibition of chemotaxis. These results suggest that AMPK activation with clinically approved agents, such as metformin, may facilitate bacterial eradication in sepsis and other inflammatory conditions associated with inhibition of neutrophil activation and chemotaxis.


Service readiness, health facility management practices, and delivery care utilization in five states of Nigeria: a cross-sectional analysis.
Existing studies of delivery care in Nigeria have identified socioeconomic and cultural factors as the primary determinants of health facility delivery. However, no study has investigated the association between supply-side factors and health facility delivery. Our study analyzed the role of supply-side factors, particularly health facility readiness and management practices for provision of quality maternal health services. Using linked data from the 2005 and 2009 health facility and household surveys in the five states in which the Community Participation for Action in the Social Sector (COMPASS) project was implemented, indices of health service readiness and management were developed based on World Health Organization guidelines. Multilevel logistic regression models were run to determine the association between these indices and health facility delivery among 2710 women aged 15-49 years whose last child was born within the five years preceding the surveys and who lived in 51 COMPASS LGAs. The health facility delivery rate increased from 25.4 % in 2005 to 44.1 % in 2009. Basic amenities for antenatal care provision, readiness to deliver basic emergency obstetric and newborn care, and management practices supportive of quality maternal health services were suboptimal in health facilities surveyed and did not change significantly between 2005 and 2009. The LGA mean index of basic amenities for antenatal care provision was more positively associated with the odds of health facility delivery in 2009 than in 2005, and in rural than in urban areas. The LGA mean index of management practices was associated with significantly lower odds of health facility delivery in rural than in urban areas. The LGA mean index of facility readiness to deliver basic emergency obstetric and neonatal care declined slightly from 5.16 in 2005 to 3.98 in 2009 and was unrelated to the odds of health facility delivery. Supply-side factors appeared to play a role in health facility delivery after controlling for socio-demographic factors. Improving uptake of delivery care would require greater attention to rural-urban inequities and health facility management practices, and to increasing the number of health facilities with fundamental elements for delivery of basic emergency obstetric and neonatal care.


Cardiovascular evaluation and management of severely obese patients undergoing surgery: a science advisory from the American Heart Association.
Obesity is associated with comorbidities that may lead to disability and death. During the past 20 years, the number of individuals with a body mass index >30, 40, and 50 kg/m(2), respectively, has doubled, quadrupled, and quintupled in the United States. The risk of developing comorbid conditions rises with increasing body mass index. Possible cardiac symptoms such as exertional dyspnea and lower-extremity edema occur commonly and are nonspecific in obesity. The physical examination and electrocardiogram often underestimate cardiac dysfunction in obese patients. The risk of an adverse perioperative cardiac event in obese patients is related to the nature and severity of their underlying heart disease, associated comorbidities, and the type of surgery. Severe obesity has not been associated with increased mortality in patients undergoing cardiac surgery but has been associated with an increased length of hospital stay and with a greater likelihood of renal failure and prolonged assisted ventilation. Comorbidities that influence the preoperative cardiac risk assessment of severely obese patients include the presence of atherosclerotic cardiovascular disease, heart failure, systemic hypertension, pulmonary hypertension related to sleep apnea and hypoventilation, cardiac arrhythmias (primarily atrial fibrillation), and deep vein thrombosis. When preoperatively evaluating risk for surgery, the clinician should consider age, gender, cardiorespiratory fitness, electrolyte disorders, and heart failure as independent predictors for surgical morbidity and mortality. An obesity surgery mortality score for gastric bypass has also been proposed. Given the high prevalence of severely obese patients, this scientific advisory was developed to provide cardiologists, surgeons, anesthesiologists, and other healthcare professionals with recommendations for the preoperative cardiovascular evaluation, intraoperative and perioperative management, and postoperative cardiovascular care of this increasingly prevalent patient population.


Refractory response to platelet transfusion therapy.
Platelet transfusions are commonly used for prophylaxis and treatment of bleeding. After a transfusion, an increment or "boost" is expected to occur. While a number of factors can contribute to a poor posttransfusion increment, refractoriness is typically defined as failure to achieve an appropriate increment after receiving 2 consecutive transfusions with fresh ABO-compatible platelets. The most common cause of refractoriness is contamination of the platelet product with leukocytes, resulting in human leukocyte antigens antibody formation. ABO incompatibility and human platelet antigens are also implicated in the development of refractoriness. Nurses who infuse platelets must understand these causes to assist in prevention and management.


A program of symptom management for improving self-care for patients with HIV/AIDS.
The purpose of this study was to investigate the effect of a symptom management program on self-care of medication side effects among AIDS/HIV-positive patients. Sixty-seven patients from a sexually transmitted disease control center, a medical center, and a Catholic AIDS support group in Taipei were randomly assigned to three groups: one-on-one teaching, group teaching, and a control group. All subjects in each teaching group attended a 60- or 90-minute program on highly active antiretroviral therapy (HAART) side effect self-care education and skill training once per week for 3 weeks; subjects also underwent counseling by telephone. A medication side effect self-care knowledge questionnaire, Rosenberg's Self-Esteem Scale (RSES), and unscheduled hospital visits were used to evaluate the effectiveness of the symptom management program. The results revealed there were significant differences in mean difference of knowledge and unscheduled hospital visits between baseline and post-testing at 3 months for symptom management in the two groups. The mean difference of the self-esteem scale was not significant between the two groups. In summary, the symptom management program effectively increased the ability of AIDS/HIV-positive patients to self-care for medication side effects. We recommend that this program be applied in the clinical nursing practice.


Combining surface and fiber geometry: an integrated approach to brain morphology.
Despite the fact that several theories link cortical development and function to the development of white matter and its geometrical structure, the relationship between gray and white matter morphology has not been widely researched. In this paper, we propose a novel framework for investigating this relationship. Given a set of fiber tracts which connect to a particular cortical region, the key idea is to compute two scalar fields that represent geometrical characteristics of the white matter and of the surface of the cortical region. The distributions of these scalar values are then linked via Mutual Information, which results in a quantitative marker that can be used in the study of normal and pathological brain structure and development. We apply this framework to a population study on autism spectrum disorder in children.


Femtosecond mid-infrared study of the dynamics of water molecules in water-acetone and water-dimethyl sulfoxide mixtures.
We study the vibrational relaxation dynamics and the reorientation dynamics of HDO molecules in binary water-dimethyl sulfoxide (DMSO) and water-acetone mixtures with polarization-resolved femtosecond mid-infrared spectroscopy. For low solute concentrations we observe a slowing down of the reorientation of part of the water molecules that hydrate the hydrophobic methyl groups of DMSO and acetone. For water-DMSO mixtures the fraction of slowed-down water molecules rises much steeper with solute concentration than for water-acetone mixtures, showing that acetone molecules show significant aggregation already at low concentrations. At high solute concentrations, the vibrational and reorientation dynamics of both water-DMSO and water-acetone mixtures show a clear distinction between the dynamics of water molecules donating hydrogen bonds to other water molecules and the dynamics of water donating a hydrogen bond to the S═O/C═O group of the solute. For water-DMSO mixtures both types of water molecules show a very slow reorientation. The water molecules forming hydrogen bonds to the S═O group reorient with a time constant that decreases from 46 ± 14 ps at XDMSO = 0.33 to 13 ± 2 ps at XDMSO = 0.95. The water molecules forming hydrogen bonds to the C═O group of acetone show a much faster reorientation with a time constant that decreases from 6.1 ± 0.2 ps at Xacet = 0.3 to 2.96 ± 0.05 ps at Xacet = 0.9. The large difference in reorientation time constant of the solute-bound water for DMSO and acetone can be explained from the fact that the hydrogen bond between water and the S═O group of DMSO is much stronger than the hydrogen bond between water and the C═O group of acetone. We attribute the strongly different behavior of water in DMSO-rich and acetone-rich mixtures to their difference in molecular shape.


Photorefractive holographic recording in strontium barium niobate fibers.
We describe what are to our knowledge the first photorefractive holographic recordings in a fiber. A plane-wave reference and an image-carrying object beam are incident upon the fiber in a reflection geometry. We report results on the angular sensitivity of the recordings, the image quality, and readout efficiency as a function of the reference-wave input angle when the object wave propagates along the bore of the fiber. These experiments are carried out for two relatively short, 4- and 8-mm, multimode 1-mm-diameter fibers. The results suggest that an array of fibers might favorably replace bulk materials for certain computer and signal-processing applications.


Annual surveillance mammography after early-stage breast cancer and breast cancer mortality.
After treatment for early-stage breast cancer (bca), annual surveillance mammography (asm) is recommended based on the assumption that early detection of an invasive ipsilateral breast tumour recurrence or subsequent invasive contralateral primary bca reduces bca mortality. We studied women with unilateral early-stage bca treated by breast-conserving surgery from 1994 to 1997 who subsequently developed an ipsilateral recurrence or contralateral primary more than 24 months after initial diagnosis, without prior regional or distant metastases. Annual surveillance mammography was defined as 2 episodes of bilateral mammography 11-18 months apart during the 2 years preceding the ipsilateral recurrence or contralateral primary. The association between asm and bca death was evaluated using a Cox proportional hazards model. We identified 669 women who experienced invasive ipsilateral recurrence (n = 455) or a contralateral primary (n = 214) at a median interval of 53 months [interquartile range (iqr): 37-72 months] after initial diagnosis, 64.7% of whom had received asm during the preceding 2 years. The median interval between the 2 bilateral mammograms was 12.3 months (iqr: 11.9-13.0 months), and the median interval between the 2nd mammogram and histopathologic confirmation of ipsilateral recurrence or contralateral primary was 1.5 months (iqr: 0.8-3.9 months). Median followup after ipsilateral recurrence or contralateral primary was 7.76 years (iqr: 3.68-9.81 years). The adjusted hazard ratio for bca death associated with asm was 0.86 (95% confidence limits: 0.63, 1.16). Annual surveillance mammography was associated with a modestly lowered hazard ratio for bca death.


Quantification of global gross forest cover loss.
A globally consistent methodology using satellite imagery was implemented to quantify gross forest cover loss (GFCL) from 2000 to 2005 and to compare GFCL among biomes, continents, and countries. GFCL is defined as the area of forest cover removed because of any disturbance, including both natural and human-induced causes. GFCL was estimated to be 1,011,000 km(2) from 2000 to 2005, representing 3.1% (0.6% per year) of the year 2000 estimated total forest area of 32,688,000 km(2). The boreal biome experienced the largest area of GFCL, followed by the humid tropical, dry tropical, and temperate biomes. GFCL expressed as the proportion of year 2000 forest cover was highest in the boreal biome and lowest in the humid tropics. Among continents, North America had the largest total area and largest proportion of year 2000 GFCL. At national scales, Brazil experienced the largest area of GFCL over the study period, 165,000 km(2), followed by Canada at 160,000 km(2). Of the countries with >1,000,000 km(2) of forest cover, the United States exhibited the greatest proportional GFCL and the Democratic Republic of Congo the least. Our results illustrate a pervasive global GFCL dynamic. However, GFCL represents only one component of net change, and the processes driving GFCL and rates of recovery from GFCL differ regionally. For example, the majority of estimated GFCL for the boreal biome is due to a naturally induced fire dynamic. To fully characterize global forest change dynamics, remote sensing efforts must extend beyond estimating GFCL to identify proximate causes of forest cover loss and to estimate recovery rates from GFCL.


Feasibility, safety, and efficacy of conservative laparoscopic treatment of borderline ovarian tumors.
To outline the most recent information regarding conservative laparoscopic surgery for young women with borderline ovarian tumors. Review article. Advanced Gynecological Endoscopy Center, Malzoni Medical Center, Avellino, Italy. Young women with low-stage borderline ovarian tumors who wish to preserve their fertility. Conservative laparoscopic surgery with unilateral salpingo-oophorectomy or cystectomy. Recurrence rate and outcomes. Laparoscopic cystectomy may have more chance of preserving a woman's fertility compared with adnexectomy because of the removal of less ovarian tissue. Its greatest danger is the risk of inadvertently leaving behind some malignant cells. Therefore, this procedure should be reserved for patients with previous unilateral salpingo-oophorectomy or when bilateral lesions are present to preserve at least some ovarian tissue. When borderline ovarian tumors are identified at surgery by intraoperative histology, the recommended conservative treatment should be laparoscopic salpingo-oophorectomy. Recurrence can be noted after this type of treatment, but the cases of recurrent disease can be detected with close follow-up and treated accordingly. For these reasons, careful selection of candidates for this kind of treatment is, of course, necessary and close follow-up is required. If these restrictions are rigorously applied, then fertility-sparing surgery may be considered a safe option for this pathology, but all laparoscopic procedures should be reserved for oncologic surgeons trained in extensive laparoscopic procedures.


Effects of tributyltin on placental cytokine production.
Objective Tributyltin (TBT) is a persistent pollutant but its effects on placental function are poorly understood as are its possible interactions with infection. We hypothesized that TBT alters the production of sex hormones and biomarkers for inflammation and neurodevelopment in an infection-dependent manner. Methods Placental explant cultures were treated with 0-5000 nM TBT in the presence and absence of Escherichia coli. A conditioned medium was harvested and concentrations of steroids (progesterone, P4; testosterone, T and estradiol, E2) as well as biomarkers of inflammation [interleukin (IL)-1β (IL-1β), tumor necrosis factor (TNF-α), IL-10, IL-6, soluble glycoprotein 130 (sgp-130) and heme oxygenase-1 (HO-1)], oxidative stress [8-iso-prostaglandin (8-IsoP)] and neurodevelopment [brain-derived neurotrophic factor (BDNF)] were quantified. Results TBT increased P4 slightly but had little or no effect on T or E2 production. IL-1β, IL-6, sgp-130, IL-10 and 8-IsoP production was enhanced by TBT. P4 and IL-6 production was also enhanced by TBT for bacteria-stimulated cultures but TBT significantly inhibited bacteria-induced IL-1β and sgp-130 production. High doses of TBT also inhibited BDNF production. Conclusions TBT increases P4 but has minimal effect on downstream steroids. It enhances the production of inflammatory biomarkers such as IL-1β, TNF-α, IL-10 and IL-6. Inhibition of sgp-130 by TBT suggests that TBT may increase bioactive IL-6 production which has been associated with adverse neurodevelopmental outcomes. Reduced expression of BDNF also supports this possibility.


Pretreatment with dihydroquercetin, a dietary flavonoid, protected against concanavalin A-induced immunological hepatic injury in mice and TNF-α/ActD-induced apoptosis in HepG2 cells.
We have previously demonstrated the hepatoprotective effect of dihydroquercetin (DHQ) against concanavalin A (Con A)-induced immunological hepatic injury in mice. In this study, we investigated the immunoregulatory effects of DHQ on Con A-induced liver injury in mice. DHQ administration significantly decreased the serum levels of alanine transaminase and aspartate transaminase, effectively prevented liver damage, and increased the survival rate of Con A-treated mice. Immunohistochemistry examination revealed that supplementation with DHQ obviously reduced infiltration of CD4+ and CD8+ T cells in the injured liver tissues. Furthermore, DHQ administration resulted in down-regulation of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-2, IL-4, and IL-10), the chemokine osteopontin, apoptosis factors (Fas and FasL), transcription factors that regulate Th cell differentiation (T-bet and GATA-3), perforin, granzyme B, and inducible nitric oxide synthase (iNOS). In vitro, treatment with DHQ protected HepG2 cells against TNF-α/ActD-induced apoptosis by inhibiting the activation of caspase-3, caspase-7, and caspase-8. In addition, DHQ reduced phosphorylation of NF-kB/p65, and inhibited the expressions of pro-apoptotic factors (p53 and Bax), while it up-regulated the expression of the anti-apoptotic factor Bcl-2. Our findings suggest that the immunosuppressive effects of DHQ ameliorated Con A-mediated immunological liver injury by reducing the expression of pro-inflammatory mediators and infiltration of CD4+ and CD8+ T cells in liver tissues, and DHQ protected HepG2 cells against TNF-α/ActD-induced apoptosis possibly via modulation of the caspase and NF-kB pathways.


Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis.
Juvenile polyposis (JP; OMIM 174900) is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. Previous studies have demonstrated a locus for JP mapping to 18q21.1 (ref. 3) and germline mutations in the homolog of the gene for mothers against decapentaplegic, Drosophila, (MADH4, also known as SMAD4) in several JP families. However, mutations in MADH4 are only present in a subset of JP cases, and although mutations in the gene for phosphatase and tensin homolog (PTEN) have been described in a few families, undefined genetic heterogeneity remains. Using a genome-wide screen in four JP kindreds without germline mutations in MADH4 or PTEN, we identified linkage with markers from chromosome 10q22-23 (maximum lod score of 4.74, straight theta=0.00). We found no recombinants using markers developed from the vicinity of the gene for bone morphogenetic protein receptor 1A (BMPR1A), a serine-threonine kinase type I receptor involved in bone morphogenetic protein (BMP) signaling. Genomic sequencing of BMPR1A in each of these JP kindreds disclosed germline nonsense mutations in all affected kindred members but not in normal control individuals. These findings indicate involvement of an additional gene in the transforming growth factor-beta (TGF-beta) superfamily in the genesis of JP, and document an unanticipated function for BMP in colonic epithelial growth control.


Seasonal Arctic sea ice forecasting with probabilistic deep learning.
Anthropogenic warming has led to an unprecedented year-round reduction in Arctic sea ice extent. This has far-reaching consequences for indigenous and local communities, polar ecosystems, and global climate, motivating the need for accurate seasonal sea ice forecasts. While physics-based dynamical models can successfully forecast sea ice concentration several weeks ahead, they struggle to outperform simple statistical benchmarks at longer lead times. We present a probabilistic, deep learning sea ice forecasting system, IceNet. The system has been trained on climate simulations and observational data to forecast the next 6 months of monthly-averaged sea ice concentration maps. We show that IceNet advances the range of accurate sea ice forecasts, outperforming a state-of-the-art dynamical model in seasonal forecasts of summer sea ice, particularly for extreme sea ice events. This step-change in sea ice forecasting ability brings us closer to conservation tools that mitigate risks associated with rapid sea ice loss.


Transcription and microRNA Profiling of Cultured Human Tympanic Membrane Epidermal Keratinocytes.
The human tympanic membrane (TM) has a thin outer epidermal layer which plays an important role in TM homeostasis and ear health. The specialised cells of the TM epidermis have a different physiology compared to normal skin epidermal keratinocytes, displaying a dynamic and constitutive migration that maintains a clear TM surface and assists in regeneration. Here, we characterise and compare molecular phenotypes in keratinocyte cultures from TM and normal skin. TM keratinocytes were isolated by enzymatic digestion and cultured in vitro. We compared global mRNA and microRNA expression of the cultured cells with that of human epidermal keratinocyte cultures. Genes with either relatively higher or lower expression were analysed further using the biostatistical tools g:Profiler and Ingenuity Pathway Analysis. Approximately 500 genes were found differentially expressed. Gene ontology enrichment and Ingenuity analyses identified cellular migration and closely related biological processes to be the most significant functions of the genes highly expressed in the TM keratinocytes. The genes of low expression showed a marked difference in homeobox (HOX) genes of clusters A and C, giving the TM keratinocytes a strikingly low HOX gene expression profile. An in vitro scratch wound assay showed a more individualised cell movement in cells from the tympanic membrane than normal epidermal keratinocytes. We identified 10 microRNAs with differential expression, several of which can also be linked to regulation of cell migration and expression of HOX genes. Our data provides clues to understanding the specific physiological properties of TM keratinocytes, including candidate genes for constitutive migration, and may thus help focus further research.


[Preconception care in 2018; still too many missed opportunities].
Good preconception care does not only benefit the health of the mother to be and her child during pregnancy, but also their health in later life. In the Netherlands, preconception care is not standard care. Preconception care aims to prevent biomedical, behavioural and social risks by taking steps before conception to reduce the likelihood of these risks materialising. It also helps mothers to be to make informed reproductive choices. Caregivers and the public are not aware enough of the extent in which the first 10 weeks of pregnancy affect the health of the infant and of the child later in life. Nowadays, antenatal care often starts around 8 weeks of pregnancy, by which time it is too late to influence potential risks since embryonic development and placentation start immediately after conception. Therefore, all young men and women need to be offered preconception care.


Hydroxypropyl methylcellulose, a viscous soluble fiber, reduces insulin resistance and decreases fatty liver in Zucker Diabetic Fatty rats.
Diets producing a high glycemic response result in exaggerated insulin secretion which induces hepatic lipogenesis, contributing to development of insulin resistance and fatty liver. Viscous dietary fibers blunt the postprandial rise in blood glucose, however their effect on type 2 diabetes and obesity are not entirely known. This study examined the effect of chronic consumption of the viscous, non-fermentable dietary fiber, hydroxypropyl methylcellulose (HPMC), on glucose control, insulin resistance and liver lipids in an obese diabetic rat model. Three groups of Zucker Diabetic Fatty (ZDF) rats were fed diets containing either 5% non-viscous cellulose (control), low viscosity HPMC (LV-HPMC) or high viscosity HPMC (HV- HPMC) for six weeks. Zucker lean littermates consuming cellulose served as a negative control. Markers of glucose control, including oral glucose tolerance test, glycated hemoglobin and urinary glucose, were measured as well as adiposity and the accumulation of liver lipids. The HPMC diets increased the viscosity of the small intestinal contents and reduced the postprandial rise in blood glucose. The food efficiency ratio was greater with HPMC feeding compared to the obese control and urinary excretion of glucose and ketone bodies was reduced. The two HPMC groups had lower glycated hemoglobin and kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Epididymal fat pad weight as percent of body weight was reduced in the HV-HPMC group compared to the obese control group. The HV-HPMC group also had lower concentrations of liver lipid and cholesterol and reduced liver weight. However, HV-HPMC feeding did not affect hepatic gene expression of SREBP-1c or FAS. Muscle concentration of acylcarnitines, a lipid intermediate in fatty acid β-oxidation, was not different between the HPMC groups and obese control, suggesting no change in muscle fatty acid oxidation by HPMC. Consumption of the viscous non-fermentable fiber HPMC decreased diabetic wasting, improved glucose control and reduced insulin resistance and fatty liver in a model of obesity with diabetes.


Impact of a freeway on the dispersal of ticks and Ixodes ricinus-borne pathogens: forested resting areas may become Lyme disease hotspots.
Man-made barriers are well known for their effects on ecosystems. Habitat fragmentation, for instance, is a recognised consequence of modern-day infrastructure. The aim of the present study was to investigate the diversity and abundance of tick species, as well as the risks of acquiring tick-borne infections in habitats adjacent to a freeway. Therefore, ixodid ticks were collected from the vegetation at two-week intervals (in the main tick season, from March to June) in eight habitats of different types (forest, grove, grassland) along both sides of a freeway. Ixodes ricinus females were molecularly screened for three species of tick-borne bacteria. In the study period, 887 ixodid ticks were collected. These included 704 I. ricinus (79.4%), 51 Dermacentor reticulatus (5.7%), 78 D. marginatus (8.8%), 35 Haemaphysalis inermis (3.9%) and 19 H. concinna (2.1%). There was no significant difference in the abundance of tick species between similar habitats separated by the freeway, except for the absence of Dermacentor spp. on one side. In I. ricinus females, the overall prevalence of Anaplasma phagocytophilum was low, and (in part due to this low rate) did not show significant difference between the two sides of the freeway. Rickettsia helvetica had significantly different overall prevalence between two distant habitats along the same side of the freeway (12.3% vs. 31.4%), but not between habitats on the opposite sides. Borrelia burgdorferi s.l. showed significantly different overall prevalence between habitats both on the same and on the opposite sides of the freeway (8.6-35.9%), and the difference was higher if relevant habitats were also separated by the freeway. Importantly, the prevalence rate of the Lyme disease agent was highest in a forested resting area of the freeway, and was significantly inversely proportional to the prevalence of A. phagocytophilum (taking into account all evaluated habitats), apparently related to deer population density. Prevalence rates of these bacteria also differed significantly on single sampling occasions between: (1) closely situated habitats of different types; (2) distant and either similar or different habitat types; and (3) habitats on the opposite sides of the freeway. In conclusion, the findings of the present study show that a fenced freeway may contribute to differences in tick species diversity and tick-borne pathogen prevalence along its two sides, and this effect is most likely a consequence of its barrier role preventing deer movements.


The relationship between chronic lymphocytic thyroiditis and central neck lymph node metastasis in North American patients with papillary thyroid carcinoma.
Several studies have reported that concurrent chronic lymphocytic thyroiditis (CLT) with papillary thyroid carcinoma (PTC) is associated with improved prognosis of the PTC, including decreased lymph node metastasis. We sought to assess the incidence of central nodal metastasis (CNM) in patients with PTC and concurrent CLT. We studied 495 consecutive patients who underwent thyroidectomy with nodal excision for PTC. Pathology reports identified the presence of CLT and the extent of CNM. There were 226 patients (46%) with CLT and 220 (44%) with CNM. Patients with CLT were more often female (88% vs. 71%; P < .001) and had a younger median age (43 vs. 47 years; P = .03), a lesser incidence of CNM (35% vs. 52.4%; P < .001), and a greater incidence of pT1a (40% vs. 25%; P < .001) and pT1b (38% vs. 29%; P < .001) tumors. Multivariate analysis showed that the presence of CLT was associated with a 39% decreased odds of CNM after adjusting for age, gender, tumor size, PTC histopathologic subtype, and presence of lymphovascular invasion (odds ratio, 0.61; 95% confidence interval, 0.38-0.99; P = .046). Predicted probability modeling showed that all females with CLT and no suspicious nodal findings on ultrasonography had a 9-11% risk of CNM with pT1a tumors. Female patients of all ages with CLT and small PTCs have the least incidence of CNM.


The TMEM16A anion channel as a versatile regulator of vascular tone.
The TMEM16A channel represents a key depolarizing mechanism in arterial smooth muscle and contractile pericytes, where it is activated by several endogenous contractile agonists. In this issue of Science Signaling, Mata-Daboin et al. demonstrate a previously unidentified role for TMEM16A in endothelial cells for acetylcholine-mediated vasorelaxation. Collectively, TMEM16A serves as a transducer of vasoactive stimuli to enable fine modulation of vessel tone.


Automatic early warning of tail biting in pigs: 3D cameras can detect lowered tail posture before an outbreak.
Tail biting is a major welfare and economic problem for indoor pig producers worldwide. Low tail posture is an early warning sign which could reduce tail biting unpredictability. Taking a precision livestock farming approach, we used Time-of-flight 3D cameras, processing data with machine vision algorithms, to automate the measurement of pig tail posture. Validation of the 3D algorithm found an accuracy of 73.9% at detecting low vs. not low tails (Sensitivity 88.4%, Specificity 66.8%). Twenty-three groups of 29 pigs per group were reared with intact (not docked) tails under typical commercial conditions over 8 batches. 15 groups had tail biting outbreaks, following which enrichment was added to pens and biters and/or victims were removed and treated. 3D data from outbreak groups showed the proportion of low tail detections increased pre-outbreak and declined post-outbreak. Pre-outbreak, the increase in low tails occurred at an increasing rate over time, and the proportion of low tails was higher one week pre-outbreak (-1) than 2 weeks pre-outbreak (-2). Within each batch, an outbreak and a non-outbreak control group were identified. Outbreak groups had more 3D low tail detections in weeks -1, +1 and +2 than their matched controls. Comparing 3D tail posture and tail injury scoring data, a greater proportion of low tails was associated with more injured pigs. Low tails might indicate more than just tail biting as tail posture varied between groups and over time and the proportion of low tails increased when pigs were moved to a new pen. Our findings demonstrate the potential for a 3D machine vision system to automate tail posture detection and provide early warning of tail biting on farm.


Primary healthcare system capacities for responding to storm and flood-related health problems: a case study from a rural district in central Vietnam.
As a tropical depression in the East Sea, Vietnam is greatly affected by climate change and natural disasters. Knowledge of the current capacity of the primary healthcare system in Vietnam to respond to health issues associated with storms and floods is very important for policy making in the country. However, there has been little scientific research in this area. This research was to assess primary healthcare system capacities in a rural district in central Vietnam to respond to such health issues. This was a cross-sectional descriptive study using quantitative and qualitative approaches. Quantitative methods used self-administered questionnaires. Qualitative methods (in-depth interviews and focus groups discussions) were used to broaden understanding of the quantitative material and to get additional information on actions taken. 1) Service delivery: Medical emergency services, especially surgical operations and referral systems, were not always available during the storm and flood seasons. 2) Governance: District emergency plans focus largely on disaster response rather than prevention. The plans did not clearly define the role of primary healthcare and had no clear information on the coordination mechanism among different sectors and organizations. 3) Financing: The budget for prevention and control of flood and storm activities was limited and had no specific items for healthcare activities. Only a little additional funding was available, but the procedures to get this funding were usually time-consuming. 4) Human resources: Medical rescue teams were established, but there were no epidemiologists or environmental health specialists to take care of epidemiological issues. Training on prevention and control of climate change and disaster-related health issues did not meet actual needs. 5) Information and research: Data that can be used for planning and management (including population and epidemiological data) were largely lacking. The district lacked a disease early-warning system. 6) Medical products and technology: Emergency treatment protocols were not available in every studied health facility. The primary care system capacity in rural Vietnam is inadequate for responding to storm and flood-related health problems in terms of preventive and treatment healthcare. Developing clear facility preparedness plans, which detail standard operating procedures during floods and identify specific job descriptions, would strengthen responses to future floods. Health facilities should have contingency funds available for emergency response in the event of storms and floods. Health facilities should ensure that standard protocols exist in order to improve responses in the event of floods. Introduction of a computerized health information system would accelerate information and data processing. National and local policies need to be strengthened and developed in a way that transfers into action in local rural communities.


Identification of Cav2-PKCβ and Cav2-NOS1 complexes as entities for ultrafast electrochemical coupling.
Voltage-activated calcium (Cav) channels couple intracellular signaling pathways to membrane potential by providing Ca2+ ions as second messengers at sufficiently high concentrations to modulate effector proteins located in the intimate vicinity of those channels. Here we show that protein kinase Cβ (PKCβ) and brain nitric oxide synthase (NOS1), both identified by proteomic analysis as constituents of the protein nano-environment of Cav2 channels in the brain, directly coassemble with Cav2.2 channels upon heterologous coexpression. Within Cav2.2-PKCβ and Cav2.2-NOS1 complexes voltage-triggered Ca2+ influx through the Cav channels reliably initiates enzymatic activity within milliseconds. Using BKCa channels as target sensors for nitric oxide and protein phosphorylation together with high concentrations of Ca2+ buffers showed that the complex-mediated Ca2+ signaling occurs in local signaling domains at the plasma membrane. Our results establish Cav2-enzyme complexes as molecular entities for fast electrochemical coupling that reliably convert brief membrane depolarization into precisely timed intracellular signaling events in the mammalian brain.


Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy.
Aristolochic acid nephropathy (AAN) is characterized by acute proximal tubule necrosis and immune cell infiltration, contributing to the global burden of chronic kidney disease and urothelial cancer. Although the proximal tubule has been defined as the primary target of aristolochic acids I (AAI), the mechanistic underpinning of gross renal deterioration caused by AAI has not been explicitly explained, prohibiting effective therapeutic intervention. To this point, we employed integrated single-cell RNA-Seq, bulk RNA-Seq, and mass spectrometry-based proteomics to analyze the mouse kidney after acute AAI exposure. Our results reveal a dramatic reduction of proximal tubule epithelial cells, associated with apoptotic and inflammatory pathways, indicating permanent damage beyond repair. We found the enriched development pathways in other nephron segments, suggesting activation of reparative programs triggered by AAI. The divergent response may be attributed to the segment-specific distribution of organic anion channels along the nephron, including OAT1 and OAT3. Moreover, we observed dramatic activation and recruitment of cytotoxic T and macrophage M1 cells, highlighting inflammation as a principal contributor to permanent renal injury. Ligand-receptor pairing revealed that critical intercellular crosstalk underpins damage-induced activation of immune cells. These results provide potentially novel insight into the AAI-induced kidney injury and point out possible pathways for future therapeutic intervention.


Temperature Treatment of Highly Porous Zirconium-Containing Metal-Organic Frameworks Extends Drug Delivery Release.
Utilizing metal-organic frameworks (MOFs) as a biological carrier can lower the amount of the active pharmaceutical ingredient (API) required in cancer treatments to provide a more efficacious therapy. In this work, we have developed a temperature treatment process for delaying the release of a model drug compound from the pores of NU-1000 and NU-901, while taking care to utilize these MOFs' large pore volume and size to achieve exceptional model drug loading percentages over 35 wt %. Video-rate super-resolution microscopy reveals movement of MOF particles when located outside of the cell boundary, and their subsequent immobilization when taken up by the cell. Through the use of optical sectioning structured illumination microscopy (SIM), we have captured high-resolution 3D images showing MOF uptake by HeLa cells over a 24 h period. We found that addition of a model drug compound into the MOF and the subsequent temperature treatment process does not affect the rate of MOF uptake by the cell. Endocytosis analysis revealed that MOFs are internalized by active transport and that inhibiting the caveolae-mediated pathway significantly reduced cellular uptake of MOFs. Encapsulation of an anticancer therapeutic, alpha-cyano-4-hydroxycinnamic acid (α-CHC), and subsequent temperature treatment produced loadings of up to 81 wt % and demonstrated efficacy at killing cells beyond the burst release effect.


A descriptive analysis of child-relevant systematic reviews in the Cochrane Database of Systematic Reviews.
Systematic reviews (SRs) are considered an important tool for decision-making. There has been no recent comprehensive identification or description of child-relevant SRs. A description of existing child-relevant SRs would help to identify the extent of available child-relevant evidence available in SRs and gaps in the evidence base where SRs are required. The objective of this study was to describe child-relevant SRs from the Cochrane Database of Systematic Reviews (CDSR, Issue 2, 2009). SRs were assessed for relevance using pre-defined criteria. Data were extracted and entered into an electronic form. Univariate analyses were performed to describe the SRs overall and by topic area. The search yielded 1666 SRs; 793 met the inclusion criteria. 38% of SRs were last assessed as up-to-date prior to 2007. Corresponding authors were most often from the UK (41%). Most SRs (59%) examined pharmacological interventions. 53% had at least one external source of funding. SRs included a median of 7 studies (IQR 3, 15) and 679 participants (IQR 179, 2833). Of all studies, 48% included only children, and 27% only adults. 94% of studies were published in peer-reviewed journals. Primary outcomes were specified in 72% of SRs. Allocation concealment and the Jadad scale were used in 97% and 25% of SRs, respectively. Adults and children were analyzed separately in 12% of SRs and as a subgroup analysis in 14%. Publication bias was assessed in only 14% of SRs. A meta-analysis was conducted in 68% of SRs with a median of 5 trials (IQR 3, 9) each. Variations in these characteristics were observed across topic areas. We described the methodological characteristics and rigour of child-relevant reviews in the CDSR. Many SRs are not up-to-date according to Cochrane criteria. Our study describes variation in conduct and reporting across SRs and reveals clinicians' ability to access child-specific data.


Calcitonin for osteoporosis and bone pain.
Calcitonin has been approved for the treatment of osteoporosis and other diseases involving accelerated bone turnover for approximately 25 years. The most commonly studied and prescribed form is salmon calcitonin, which has a greater efficacy in clinical use. A wealth of well-controlled clinical studies have demonstrated that calcitonin preserves or increases bone mineral density (BMD) and reduces the risk of vertebral fractures in osteoporosis. Recent studies have indicated that while a low BMD is correlated with an increase in fracture risk, increases in BMD alone do not explain the antifracture efficacy of antiresorptive therapies such as calcitonin. Therapies that moderately increase BMD may reduce fracture risk by reducing the rate of bone turnover and maintaining the integrity of the trabecular architecture, resulting in the preservation of bone strength and quality in osteoporotic patients. An advantage of calcitonin that is not shared by other antiresorptive therapies is its direct analgesic effect on bone pain. Calcitonin has been demonstrated to be clinically useful in improving pain, not only from the acute vertebral fractures of osteoporosis, but also in Paget's disease, bone malignancies, and other sources of musculoskeletal pain. Drugs containing calcitonin may be approved for additional indications in the near future, and as more convenient routes of administration such as the oral route become available, the demand for the calcitonin peptide is expected to increase.


Diesel engine exhaust and lung cancer risks - evaluation of the meta-analysis by Vermeulen et al. 2014.
Vermeulen et al. 2014 published a meta-regression analysis of three relevant epidemiological US studies (Steenland et al. 1998, Garshick et al. 2012, Silverman et al. 2012) that estimated the association between occupational diesel engine exhaust (DEE) exposure and lung cancer mortality. The DEE exposure was measured as cumulative exposure to estimated respirable elemental carbon in μg/m(3)-years. Vermeulen et al. 2014 found a statistically significant dose-response association and described elevated lung cancer risks even at very low exposures. We performed an extended re-analysis using different modelling approaches (fixed and random effects regression analyses, Greenland/Longnecker method) and explored the impact of varying input data (modified coefficients of Garshick et al. 2012, results from Crump et al. 2015 replacing Silverman et al. 2012, modified analysis of Moehner et al. 2013). We reproduced the individual and main meta-analytical results of Vermeulen et al. 2014. However, our analysis demonstrated a heterogeneity of the baseline relative risk levels between the three studies. This heterogeneity was reduced after the coefficients of Garshick et al. 2012 were modified while the dose coefficient dropped by an order of magnitude for this study and was far from being significant (P = 0.6). A (non-significant) threshold estimate for the cumulative DEE exposure was found at 150 μg/m(3)-years when extending the meta-analyses of the three studies by hockey-stick regression modelling (including the modified coefficients for Garshick et al. 2012). The data used by Vermeulen and colleagues led to the highest relative risk estimate across all sensitivity analyses performed. The lowest relative risk estimate was found after exclusion of the explorative study by Steenland et al. 1998 in a meta-regression analysis of Garshick et al. 2012 (modified), Silverman et al. 2012 (modified according to Crump et al. 2015) and Möhner et al. 2013. The meta-coefficient was estimated to be about 10-20 % of the main effect estimate in Vermeulen et al. 2014 in this analysis. The findings of Vermeulen et al. 2014 should not be used without reservations in any risk assessments. This is particularly true for the low end of the exposure scale.


Is the Duration of Spa Cure Treatment Important in Knee Osteoarthritis? A Randomized Controlled Study.
Spa therapies are applied in varying durations. Today, the duration of spa therapy may be long for people with active lives. How should we determine the duration of treatment in order to minimize therapy costs and loss of labor force? Does the duration of treatment have an impact on pain, functional status, and quality of life of patients? Our aim was to investigate the role of application time on the efficacy of spa therapy in individuals undergoing the same treatment protocol. This was a randomized, controlled, single-blind clinical trial design. Sixty individuals were divided into two groups: 3 weeks of therapy (group 1) and 2 weeks of therapy (group 2). Pretreatment, posttreatment, and 30-day posttreatment findings were recorded using a visual analog scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Nottingham Health Profile (NHP). The measurements revealed significant improvement after treatment compared to those observed prior to the treatment in both groups, except for the social isolation subgroup. When the groups were compared to each other, significant improvement was observed in pain (VAS, WOMAC, NHP) in favor of group 1 at all measurement times. Our results suggest that spa therapy has positive effects on pain, physical activity, and quality of life in patients, and 15 sessions of therapy had even better effects on pain. We believe that the duration of therapy should be determined considering the efficacy of the therapy on pain as well as the functional situation and quality of life of patients regarding therapy costs.


Some guidelines for structural equation modelling in cognitive neuroscience: the case of Charlton et al.'s study on white matter integrity and cognitive ageing.
Charlton et al. (2008) (Charlton, R.A., Landua, S., Schiavone, F., Barrick, T.R., Clark, C.A., Markus, H.S., Morris, R.G.A., 2008. Structural equation modelling investigation of age-related variance in executive function and DTI-measured white matter change. Neurobiol. Aging 29, 1547-1555) presented a model that suggests a specific age-related effect of white matter integrity on working memory. We illustrate potential pitfalls of structural equation modelling by criticizing their model for (a) its neglect of latent variables, (b) its complexity, (c) its questionable causal assumptions, (d) the use of empirical model reduction, (e) the mix-up of theoretical perspectives, and (f) the failure to compare alternative models. We show that a more parsimonious model, based solely on the well-established general factor of cognitive ability, fits their data at least as well. Importantly, when modelled this way there is no support for a role of white matter integrity in cognitive aging in this sample, indicating that their conclusion is strongly dependent on how the data are analysed. We suggest that evidence from more conclusive study designs is needed.


Exploring the views of nurses on the cardiometabolic health nurse in mental health services in australia.
People with serious mental illness experience premature death due to higher rates of cardiometabolic conditions (e.g. cardiovascular disease, diabetes) than the general population. Mental health services often do not provide sufficient cardiometabolic clinical care to address these risks. The cardiometabolic health nurse (CHN) role has been suggested as a strategy for ensuring integrated care is provided and sustained. The views of nurses in mental health would be essential in informing the viability and development for this initiative. This paper presents the findings of open-ended comments from a cross-sectional online survey of nurses working in mental health in Australia (n = 643) eliciting views about the possible introduction of the cardiometabolic nurse. Thematic analysis was undertaken, of 133 open comments on this topic. The findings suggest that nurses see the specialist role as suitable and valuable for mental health services. Some nurses voiced concern about specialisation leading to fragmentation (e.g. in responsibilities for physical health, division of mental and physical health care, and less emphasis on equipping all nurses with comprehensive care skills), especially for settings where generalist nursing was seen as already available. The findings suggest this role is viewed favourably by nurses, provided that it is consistent with holistic and comprehensive care. Empirical research is needed to see whether this role increases holism (as valued by consumers and nurses) and cardiometabolic outcomes.


Evaluation of a self-management patient education program for patients with fibromyalgia syndrome: study protocol of a cluster randomized controlled trial.
Fibromyalgia syndrome (FMS) is a complex chronic condition that makes high demands on patients' self-management skills. Thus, patient education is considered an important component of multimodal therapy, although evidence regarding its effectiveness is scarce. The main objective of this study is to assess the effectiveness of an advanced self-management patient education program for patients with FMS as compared to usual care in the context of inpatient rehabilitation. We conducted a multicenter cluster randomized controlled trial in 3 rehabilitation clinics. Clusters are groups of patients with FMS consecutively recruited within one week after admission. Patients of the intervention group receive the advanced multidisciplinary self-management patient education program (considering new knowledge on FMS, with a focus on transfer into everyday life), whereas patients in the control group receive standard patient education programs including information on FMS and coping with pain. A total of 566 patients are assessed at admission, at discharge and after 6 and 12 months, using patient reported questionnaires. Primary outcomes are patients' disease- and treatment-specific knowledge at discharge and self-management skills after 6 months. Secondary outcomes include satisfaction, attitudes and coping competences, health-promoting behavior, psychological distress, health impairment and participation. Treatment effects between groups are evaluated using multilevel regression analysis adjusting for baseline values. The study evaluates the effectiveness of a self-management patient education program for patients with FMS in the context of inpatient rehabilitation in a cluster randomized trial. Study results will show whether self-management patient education is beneficial for this group of patients. German Clinical Trials Register, DRKS00008782 , Registered 8 July 2015.


Serum levels of neopterin during antimicrobial treatment for Mycobacterium ulcerans infection.
Neopterin is closely associated with activation of the cellular immune system. Neopterin levels differed between controls and patients with Buruli ulcer disease. No differences between patients with or without paradoxical responses were observed. Therefore, neopterin has no value in detecting paradoxical responses among patients with limited Buruli ulcer disease. Neopterin levels were lower in patients receiving clarithromycin. This finding might indicate a slower cellular immune recovery, with possible consequences in future therapy with clarithromycin.


Preliminary development of an ultrabrief two-item bedside test for delirium.
Delirium is common, morbid, and costly, yet is greatly under-recognized among hospitalized older adults. To identify the best single and pair of mental status test items that predict the presence of delirium. Diagnostic test evaluation study that enrolled medicine inpatients aged 75 years or older at an academic medical center. Patients underwent a clinical reference standard assessment involving a patient interview, medical record review, and interviews with family members and nurses to determine the presence or absence of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition defined delirium. Participants also underwent the three-dimensional Confusion Assessment Method (3D-CAM), a brief, validated assessment for delirium. Individual items and pairs of items from the 3D-CAM were evaluated to determine sensitivity and specificity relative to the reference standard delirium diagnosis. Of the 201 participants (mean age 84 years, 62% female), 42 (21%) had delirium based on the clinical reference standard. The single item with the best test characteristics was "months of the year backwards" with a sensitivity of 83% (95% confidence interval [CI]: 69%-93%) and specificity of 69% (95% CI: 61%-76%). The best 2-item screen was the combination of "months of the year backwards" and "what is the day of the week?" with a sensitivity of 93% (95% CI: 81%-99%) and specificity of 64% (95% CI: 56%-70%). We identified a single item with >80% and pair of items with >90% sensitivity for delirium. If validated prospectively, these items will serve as an initial innovative screening step for delirium identification in hospitalized older adults.


Genetic Analysis of mcr-1-Carrying Plasmids From Gram-Negative Bacteria in a Dutch Tertiary Care Hospital: Evidence for Intrapatient and Interspecies Transmission Events.
The role of plasmids in the complex pandemic of antimicrobial resistance is increasingly being recognized. In this respect, multiple mobile colistin resistance (mcr) gene-carrying plasmids have been described. However, the characteristics and epidemiology of these plasmids within local healthcare settings are largely unknown. We retrospectively characterized the genetic composition and epidemiology of plasmids from mcr-1-positive bacterial isolates identified from patients from a large academic hospital in the Netherlands. Clinical Gram-negative bacteria with an MIC > 2 μg/mL for colistin, obtained from patients hospitalized at the Erasmus MC University Medical Center Rotterdam during the years 2010-2018, were screened for presence of the mcr-1 gene. Extracted plasmids from mcr-1-positive isolates were sequenced using a combination of short- and long-read sequencing platforms, characterized by incompatibility type and genetic composition and compared to publicly available mcr-1-carrying plasmid sequences. In 21 isolates from 14 patients, mcr-1 was located on a plasmid. These plasmids were of diverse genetic background involving Inc types IncX4, IncI2(delta), IncHI2, as well as double Inc types IncHI2/IncN and IncHI2/IncQ. mcr-1-carrying plasmids were found in Escherichia coli, Klebsiella pneumoniae, and Kluyvera georgiana, and within the chromosome of an ST147 K. pneumoniae isolate. In depth analysis indicated intrapatient, interpatient, and interspecies transmission events of mcr-1-carrying plasmids. In addition, our results show that the mcr-1 gene resides in a rich environment full of other (mcr-1 negative) plasmids and of many different Inc types, enabling interplasmidal transfer events and facilitating widespread dissemination of the mcr-1 gene. Multiple mcr-1-carrying plasmid transmission events had likely occurred among isolates from hospitalized patients. Recognition and identification of plasmid transmission events within hospitals is necessary in order to design and implement effective infection control measures.


Tristatic high resolution Doppler lidar to study winds and turbulence in the troposphere.
The implementation of a high resolution Doppler lidar (HRDL) to measure tropospheric winds and turbulence using a high resolution Fabry-Perot optical interferometer is considered. The Fabry-Perot detector system we have chosen is based on the one developed for passive wind measurements on board the Dynamics Explorer satellite. This is a stable high resolution system consisting of an optically contacted plane étalon and a multiring anode detector to scan spatially the image plane of the Fabry-Perot. The Doppler lidar proposed here consists of two transmitters and a receiver in a collinear arrangement. This system enables measurement of a horizontal and the vertical components of the wind in a common volume in space. The volume is determined by the intersection of the field of view of the receiver and the divergence of the laser beam.


Persistent, Consistent, and Extensive: The Trend of Increasing Pain Prevalence in Older Americans.
Assess trends in pain prevalence from 1992 to 2014 among older U.S. adults and by major population subgroups, and test whether the trends can be explained by changes in population composition. Health and Retirement Study data include information on any pain, pain intensity, and limitations in usual activities due to pain. Average annual percent change in prevalence is calculated for any and for 2 levels of pain-mild/moderate and nonlimiting and severe and/or limiting-across demographic and socioeconomic characteristics, and for those with and without specific chronic conditions. Generalized linear latent and mixed models examine trends adjusting for covariates. Linear and extensive increases in pain prevalence occurred across the total population and subgroups. The average annual percent increase was in the 2%-3% range depending upon age and sex. Increases were consistent across subgroups, persistent over time, and not due to changes in population composition. Without increases in educational attainment over time, pain prevalence increases would be even higher. The increases in pain prevalence among older Americans are alarming and potentially of epidemic proportions. Population-health research must monitor and understand these worrisome trends.


Diabetes and renal disease in veterans.
To describe the frequency and sequelae of diabetic renal disease in veterans who receive health care from the Veterans Administration (VA). Veterans with a diagnosis of diabetes, diabetic nephropathy, other kidney diseases, and end-stage renal disease (ESRD) were identified by diagnosis codes from national VA databases for FY1998. Data were obtained and analyzed for prevalence of renal disease, comorbid conditions, and 1-year mortality. A total of 44,671 (10.7%) of the 415,910 veterans with diabetes had a concomitant diagnosis of any renal disease. The average age was 67 years; 98% were male and 60% were white. The prevalence of diabetic nephropathy was 6.0% (n = 25,263). ESRD secondary to diabetes was present in 4.2% (17,636) of subjects. The age-standardized prevalence of diabetes and any renal disease was 72.6/1,000 persons and differed by race (white 76.1/1,000, black 103.4/1,000 persons). Diabetes-associated ESRD prevalence was higher among black versus white veterans and male versus female veterans. One-year age-standardized mortality was 10.7%. Nephropathy is prevalent in veterans with diabetes. Greater mortality is observed among those with renal disease compared with those without renal disease. Additional surveillance is needed to identify persons likely to progress to diabetic nephropathy and to plan for appropriate and timely health care for these individuals.


Satisfaction with information and quality of life in patients undergoing chemotherapy for cancer. The role of individual differences in information preference.
Earlier studies have shown that patients are dissatisfied with the information they receive from doctors and nurses. The purpose of this study was to analyze satisfaction with information and quality of life in patients with cancer undergoing chemotherapy, considering the patient's information preference. Data were collected during interviews with 30 consecutive patients undergoing chemotherapy for cancer. The subject of the interviews was the satisfaction of patients with the information they received, and additional measures used were the Miller Behavioral Styles Scale and EORTC-QLQ-30. The results showed that 21 of 30 patients were satisfied with the information they received from health care. Married patients or cohabitants were satisfied more often than single patients. No significant differences in quality of life could be found between satisfied and dissatisfied patients. Regarding information preferences, the dissatisfied patients reported more information-avoiding behavior than those who were satisfied. The results must be interpreted cautiously because of the study's limitations, but one clinical implication can be stated: There is value in being aware of patients' information-seeking/avoiding behavior before starting to inform them.


Effect of a natural supplement containing glucosinolates, phytosterols and citrus flavonoids on body weight and metabolic parameters in a menopausal murine model induced by bilateral ovariectomy.
To evaluate the effect of a herbal preparation containing glucosinolates, phytosterols and citrus flavonoids (supplement) on body weight and metabolic parameters usually impaired by menopause. A pre-clinical experimental study carried out in twenty-five Swiss strain mice (Mus musculus) randomly distributed (1:1:1:1:1 ratio) to five groups to receive for ten weeks: (1) oral gelatinized maca extract 0.5625 mg/kg/day + bilateral ovariectomy (Maca + OVX); (2) oral supplement 0.5625 mg/kg/day + bilateral ovariectomy (S1 + OVX); (3) oral supplement 1.6875 mg/kg/day + bilateral ovariectomy (S2 + OVX); (4) oral saline 100 µl/kg/day + bilateral ovariectomy (OVX); and (5) oral saline 100 µl/kg/day + sham surgery (sham). The primary endpoint was change in body weight gain from baseline to final. Secondary endpoints were uterine weight and cholesterol, triglyceride, glucose, and glucose/triglycerides index values at the end of the study. A modified intention-to-treat analysis was performed through linear regression models and using the Bonferroni method to penalized p-values by multiple comparisons. Twenty-three animals completed the study. There was a significant average difference in weight gain, with a greater reduction in the S2 + OVX group compared to the OVX group (difference= -3.5; 95% CI (-5.27; -1.74); p < .001). S2 + OVX group also displayed a significant average reduction of total blood cholesterol (difference: -16.94; 95% CI (-33.73; -0.15); p = .037). No significant effects of the supplement were found on other secondary endpoints. In this murine menopausal model, triple oral supplement dose resulted in an average reduction of weight gain and total cholesterol levels, suggesting that the compound could have a potential effect at regulating menopausal altered metabolism.


A pipeline for automated annotation of yeast genome sequences by a conserved-synteny approach.
Yeasts are a model system for exploring eukaryotic genome evolution. Next-generation sequencing technologies are poised to vastly increase the number of yeast genome sequences, both from resequencing projects (population studies) and from de novo sequencing projects (new species). However, the annotation of genomes presents a major bottleneck for de novo projects, because it still relies on a process that is largely manual. Here we present the Yeast Genome Annotation Pipeline (YGAP), an automated system designed specifically for new yeast genome sequences lacking transcriptome data. YGAP does automatic de novo annotation, exploiting homology and synteny information from other yeast species stored in the Yeast Gene Order Browser (YGOB) database. The basic premises underlying YGAP's approach are that data from other species already tells us what genes we should expect to find in any particular genomic region and that we should also expect that orthologous genes are likely to have similar intron/exon structures. Additionally, it is able to detect probable frameshift sequencing errors and can propose corrections for them. YGAP searches intelligently for introns, and detects tRNA genes and Ty-like elements. In tests on Saccharomyces cerevisiae and on the genomes of Naumovozyma castellii and Tetrapisispora blattae newly sequenced with Roche-454 technology, YGAP outperformed another popular annotation program (AUGUSTUS). For S. cerevisiae and N. castellii, 91-93% of YGAP's predicted gene structures were identical to those in previous manually curated gene sets. YGAP has been implemented as a webserver with a user-friendly interface at http://wolfe.gen.tcd.ie/annotation.


Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors.
Deregulation of androgen receptor (AR) splice variants has been implicated to play a role in prostate cancer development and progression. To understand their functions in prostate, we established a transgenic mouse model (AR3Tg) with targeted expression of the constitutively active and androgen-independent AR splice variant AR3 (a.k.a. AR-V7) in prostate epithelium. We found that overexpression of AR3 modulates expression of a number of tumor-promoting autocrine/paracrine growth factors (including Tgfβ2 and Igf1) and expands prostatic progenitor cell population, leading to development of prostatic intraepithelial neoplasia. In addition, we showed that some epithelial-mesenchymal transition-associated genes are up-regulated in AR3Tg prostates, suggesting that AR3 may antagonize AR activity and halt the differentiation process driven by AR and androgen. This notion is supported by our observations that the number of Ck5(+)/Ck8(+) intermediate cells is increased in AR3Tg prostates after castration, and expression of AR3 transgene in these intermediate cells compromises prostate epithelium regeneration upon androgen replacement. Our results demonstrate that AR3 is a driver of prostate cancer, at least in part, through modulating multiple tumor-promoting autocrine/paracrine factors.