What drives transient behavior in complex systems?
We study transient behavior in the dynamics of complex systems described by a set of nonlinear ordinary differential equations. Destabilizing nature of transient trajectories is discussed and its connection with the eigenvalue-based linearization procedure. The complexity is realized as a random matrix drawn from a modified May-Wigner model. Based on the initial response of the system, we identify a novel stable-transient regime. We calculate exact abundances of typical and extreme transient trajectories finding both Gaussian and Tracy-Widom distributions known in extreme value statistics. We identify degrees of freedom driving transient behavior as connected to the eigenvectors and encoded in a nonorthogonality matrix T_{0}. We accordingly extend the May-Wigner model to contain a phase with typical transient trajectories present. An exact norm of the trajectory is obtained in the vanishing T_{0} limit where it describes a normal matrix.


Inherited neuropathies: clinical overview and update.
Inherited neuropathy is a group of common neurologic disorders with heterogeneous clinical presentations and genetic causes. Detailed neuromuscular evaluations, including nerve conduction studies, laboratory testing, and histopathologic examination, can assist in identification of the inherited component beyond family history. Genetic testing increasingly enables definitive diagnosis of specific inherited neuropathies. Diagnosis, however, is often complex, and neurologic disability may have both genetic and acquired components in individual patients. The decision of which genetic test to order or whether to order genetic tests is often complicated, and the strategies to maximize the value of testing are evolving. Apart from rare inherited metabolic neuropathies, treatment approaches remain largely supportive. We provide a clinical update of the various types of inherited neuropathies, their differential diagnoses, and distinguishing clinical features (where available). A framework is provided for clinical evaluations, including the inheritance assessment, electrophysiologic examinations, and specific genetic tests.


Field testing and exploitation of genetically modified cassava with low-amylose or amylose-free starch in Indonesia.
The development and testing in the field of genetically modified -so called- orphan crops like cassava in tropical countries is still in its infancy, despite the fact that cassava is not only used for food and feed but is also an important industrial crop. As traditional breeding of cassava is difficult (allodiploid, vegetatively propagated, outbreeding species) it is an ideal crop for improvement through genetic modification. We here report on the results of production and field testing of genetically modified low-amylose transformants of commercial cassava variety Adira4 in Indonesia. Twenty four transformants were produced and selected in the Netherlands based on phenotypic and molecular analyses. Nodal cuttings of these plants were sent to Indonesia where they were grown under biosafety conditions. After two screenhouse tests 15 transformants remained for a field trial. The tuberous root yield of 10 transformants was not significantly different from the control. Starch from transformants in which amylose was very low or absent showed all physical and rheological properties as expected from amylose-free cassava starch. The improved functionality of the starch was shown for an adipate acetate starch which was made into a tomato sauce. This is the first account of a field trial with transgenic cassava which shows that by using genetic modification it is possible to obtain low-amylose cassava plants with commercial potential with good root yield and starch quality.


[ISRAEL NEONATOLOGY: PRESENT AND FUTURE].
The practice of neonatology in Israel debuted in the 1970s as local enterprises by individual hospitals that needed to provide sick and preterm newly born infants with up-to-date and effective care. Descriptions of research and advances in humane and gentle treatment during neonatal care for preterm infants and their families, as well as prevention of neonatal infections, follow-up of preterm infants and care of full-term infants are presented in this issue. The Israel National Very Low Birth Weight (VLBW) Infant database provides an excellent source of knowledge, which has led to multiple scientific publications. Recent international comparisons of the outcome of preterm VLBW infants, made possible by this unique database in Israel, has provided the neonatal community and the Ministry of Health with insights as to the differences in prognosis between Israel and other countries, especially among extremely low birth weight infants. At the border of viability, mortality in Israelis significantly higher than that reported in other countries and proactive steps undertaken to examine these differences and prompt correctional action should be pursued. The Israel Ministry of Health started positive initiatives and should ensure that their steps are implemented at the preterm infant's bedside.


[Value of microbiologic studies for diagnosis of post-enteritis reactive arthritis].
Reactive arthritis may develop within a period of some days until upto 3 weeks after infections with Yersinia enterocolitica, Yersinia pseudotuberculosis, Campylobacter jejuni/coli, Shigella and Salmonella. Intestinal infections with Klebsiella pneumoniae, Clostridium perfringens, Clostridium difficile, Cryptosporidium, Strongyloides stercoralis, Taenia saginata and Schistosoma mansoni are, in some cases, considered to be responsible for reactive arthritis. Detection of pathogenic bacteria in feces is generally most successful in the early stage of the infection. A large spectrum of special tests is required in order to detect all the causative agents and to ensure reliable results. It is therefore necessary that the laboratory is provided with information about the diagnostic object and the tentative diagnosis. The detection of serum antibodies to Y. enterocolitica, Y. pseudotuberculosis, C. jejuni/coli, and Schistosoma may suggest connections between infection and reactive arthritis.


N-nitrosamines in snuff and chewing tobacco on the Swedish market in 1983.
Snuff and chewing tobacco on the Swedish market in 1983 were analysed for tobacco-specific and volatile N-nitrosamines using gas chromatography--thermal energy analysis. All 36 samples of snuff analysed were found to contain detectable levels of N'-nitrosonornicotine, N'-nitrosoanatabine, N'-nitrosoanabasine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Total tobacco-specific N-nitrosamine levels between 2.5 and 51 mg/kg wet weight were found, the mean level being 8.8 mg/kg. Detectable levels of at least two of the four tobacco-specific N-nitrosamines were found in all 18 samples of chewing tobacco analysed. The total concentration of tobacco-specific N-nitrosamines found in chewing tobacco was between 0.1 and 7.8 mg/kg, the mean level being 2.1 mg/kg. The levels of volatile N-nitrosamines found in the 54 samples of snuff and chewing tobacco were very much lower--most of the samples contained less than 10 micrograms/kg and the highest concentration found was 550 micrograms/kg. Since snuff and chewing tobacco contain relatively high levels of carcinogenic N-nitrosamines and there is evidence of an association between the use of these tobacco products and human cancer, snuff and chewing tobacco users should be warned about the possible cancer risk involved in their habit. In addition, efforts should be made to reduce the levels of N-nitrosamines in snuff and chewing tobacco and the formation of these substances in the body from precursors originating from these tobacco products.


High Glucose Downregulates Connexin 43 Expression and Its Gap Junction and Hemichannel Function in Osteocyte-like MLO-Y4 Cells Through Activation of the p38MAPK/ERK Signal Pathway.
Osteocyte network structure correlates with bone material quality. This network is profoundly altered in diabetic mice; however, the underlying mechanisms are unknown. The gap junction protein connexin 43 (Cx43) is necessary for normal osteocyte function and osteocyte network formation. Here, we evaluated Cx43 expression in patients with diabetes, the effect of high glucose on Cx43 expression, and the function of Cx43 gap junctions and hemichannels in osteocyte-like MLO-Y4 (MLO-Y4) cells. Human cortical bone samples were obtained from patients with or without type II diabetes mellitus (T2DM) who underwent arthroplasty surgery to treat osteoporosis-induced femoral neck fracture. Cx43 expression was quantified in human cortical bone samples from both groups of patients and MLO-Y4 cells. The functions of Cx43 gap junctions and hemichannels in MLO-Y4 cells were evaluated using dye transfer and dye uptake assays, respectively. Furthermore, we evaluated levels of membrane Cx43 (mCx43), the functional form, and p38MAPK/ERK1/2 signaling, which is involved in mCx43 internalization, to characterize the mechanism of decreased Cx43 expression and gap junctions and hemichannels function. Osteocyte Cx43 expression was decreased in femoral neck cortical bone samples of patients with T2DM patients compared with the non-diabetic control group. In addition, Cx43 expression was decreased in MLO-Y4 cells treated with high glucose. The functions of Cx43 gap junctions and hemichannels were inhibited in MLO-Y4 cells treated with high glucose. mCx43 expression was decreased in response to activation of p38-MAPK/ERK signaling. Inhibition of the p38-MAPK/ERK pathway partially reversed the decreases in Cx43 hemichannels and gap-junctions function. High glucose dampened Cx43 gap junction and hemichannel function in MLO-Y4 cells by activating the p38MAPK/ERK pathway leading to subsequent mCx43 internalization.


The prevalence of autonomic symptoms in dementia and their association with physical activity, activities of daily living and quality of life.
There is little published data regarding autonomic symptoms in dementia. This study aimed to examine the prevalence and severity of autonomic symptoms in patients with different subtypes of dementia in comparison with healthy controls, and their association with levels of physical activity, depression, quality of life and ability to carry out activities of daily living. Prevalence and severity of autonomic symptoms in Parkinson's disease dementia (PDD, n = 46), dementia with Lewy bodies (DLB, n = 32), vascular dementia (VAD, n = 38), Alzheimer's disease (AD, n = 40) and healthy controls (n = 42) were assessed using a structured symptom scale. The associations between autonomic symptoms and physical activity, Bristol Activities of Daily Living Score, Geriatric and Cornell Depression Scores and quality of life (Medical Outcomes Study 36-Item Short Form Health Survey, SF-36) were examined by multiple linear regressions. Total autonomic symptom scores, urinary symptoms, constipation and postural dizziness were significantly higher in PDD, DLB and VAD patients than either controls or AD patients (all p < 0.05). Higher autonomic symptom scores were associated with poorer outcomes in all measures of physical activity, activities of daily living, depression and quality of life. The burden of autonomic symptoms is high in non-Alzheimer's dementias. The identification of such symptoms is of importance because of the detrimental effect of these symptoms upon physical activity, depression, activities of daily living and quality of life.


Associations between sleep loss and increased risk of obesity and diabetes.
During the past few decades, sleep curtailment has become a very common in industrialized countries. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity and diabetes. Evidence is rapidly accumulating to indicate that chronic partial sleep loss may increase the risk of obesity and diabetes. Laboratory studies in healthy volunteers have shown that experimental sleep restriction is associated with an adverse impact on glucose homeostasis. Insulin sensitivity decreases rapidly and markedly without adequate compensation in beta cell function, resulting in an elevated risk of diabetes. Prospective epidemiologic studies in both children and adults are consistent with a causative role of short sleep in the increased risk of diabetes. Sleep curtailment is also associated with a dysregulation of the neuroendocrine control of appetite, with a reduction of the satiety factor, leptin, and an increase in the hunger-promoting hormone, ghrelin. Thus, sleep loss may alter the ability of leptin and ghrelin to accurately signal caloric need, acting in concert to produce an internal misperception of insufficient energy availability. The adverse impact of sleep deprivation on appetite regulation is likely to be driven by increased activity in neuronal populations expressing the excitatory peptides orexins that promote both waking and feeding. Consistent with the laboratory evidence, multiple epidemiologic studies have shown an association between short sleep and higher body mass index after controlling for a variety of possible confounders.


Fibrinogen Kyoto II, a new congenitally abnormal molecule, characterized by the replacement of A alpha proline-18 by leucine.
A new case of heterozygous dysfibrinogenemia characterized by an amino acid replacement in the NH2-terminal region of the fibrin alpha-chain was found in a 27-year-old woman with a bleeding problem. Her one-stage prothrombin time and activated partial thromboplastin time were slightly prolonged, and the purified fibrinogen from this patient had a markedly prolonged thrombin or reptilase time. Release of fibrinopeptides A and B was normal, but the polymerization of fibrin monomers was impaired. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified fibrinogen under the reduced condition showed no abnormalities in the apparent molecular weights of its three chains. Reverse-phase high performance liquid chromatography (HPLC) of the lysylendopeptidase-cleaved purified A alpha-chains showed a decrease in one peptide compared with the normal amount and the appearance of an abnormal peptide peak. These peptides were treated with thrombin and further separated on HPLC. Amino acid sequence analysis of the abnormal peptide indicated that A alpha proline-18, the second residue from the NH2-terminus of the fibrin alpha-chain, was replaced by leucine. The synthetic peptide Gly-Pro-Arg-Pro inhibited both thrombin- and reptilase-induced fibrin aggregation, but Gly-Leu-Arg-Pro showed little or no inhibition under the same conditions. The discovery of this abnormal fibrinogen supports the findings that A alpha proline-18 is important as part of the polymerization site in the NH2-terminus of the fibrin alpha-chain. The propositus' mother had the same abnormal fibrinogen. This unique inherited abnormal fibrinogen was designated as fibrinogen Kyoto II.


Indications, usage, and dosage of the transfer factor.
The transfer factor (TF) was described in 1955 by S. Lawrence. In 1992 Kirkpatrick characterized the specific TF at molecular level. The TF is constituted by a group of numerous molecules, of low molecular weight, from 1.0 to 6.0 kDa. The 5 kDa fraction corresponds to the TF specific to antigens. There are a number of publications about the clinical indications of the TF for diverse diseases, in particular those where the cellular immune response is compromised or in those where there is a deficient regulation of the immune response. In this article we present our clinical and basic experiences, especially regarding the indications, usage and dosage of the TF. Our group demonstrated that the TF increases the expression of IFN-gamma and RANTES, while decreases the expression of osteopontine. Using animal models we have worked with M. tuberculosis, and with a model of glioma with good therapeutic results. In the clinical setting we have worked with herpes zoster, herpes simplex type I, herpetic keratitis, atopic dermatitis, osteosarcoma, tuberculosis, asthma, post-herpetic neuritis, anergic coccidioidomycosis, leishmaniasis, toxoplasmosis, mucocutaneous candidiasis, pediatric infections produced by diverse pathogen germs, sinusitis, pharyngitis, and otits media. All of these diseases were studied through protocols which main goals were to study the therapeutic effects of the TF, and to establish in a systematic way diverse dosage schema and time for treatment to guide the prescription of the TF.


Effects of music intervention on physiological stress response and anxiety level of mechanically ventilated patients in China: a randomised controlled trial.
To examine the effects of music intervention on the physiological stress response and the anxiety level among mechanically ventilated patients in intensive care unit. Despite the fact that previous studies have found music interventions to be effective in stress and anxiety reduction, effects of music on the Chinese population are inconclusive and warranted systematic study to evaluate its effect fully for a different Asian culture. A randomised placebo-controlled trial. A total of 137 patients receiving mechanical ventilation were randomly assigned to either music listening group, headphone group or control group. Outcome measures included the Chinese version of Spielberger State-Trait Anxiety Scale and physiological parameters (heart rate, respiratory rate, saturation of oxygen and blood pressure). Comparison of mean differences (pretest score-posttest score) showed significant differences in heart rate, respiratory rate, systolic blood pressure and diastolic blood pressure as well as the Chinese version of Spielberger State-Trait Anxiety Scale, but not in SaO(2) among the three groups (ranging from p < 0.001 to p = 0.007), of which greater mean differences were found in music listening group. A significant reduction in physiological stress response (heart rate and respiratory rate) over time was found in music listening group (p < 0.001 for both variables) and a significant increase in heart rate and respiratory rate over time in control group (p < 0.001 and p = 0.032), with no significant change over time in headphone group. Within group pretest-posttest comparison of the Chinese version of Spielberger State-Trait Anxiety Scale demonstrated a significant reduction in anxiety for the music listening group (p < 0.001) and headphone group (p < 0.001) but not the control group. Our findings confirm that short-term therapeutic effects of music listening results in substantial reduction in physiological stress responses arising from anxiety in mechanically ventilated patients. Music as a non-pharmacological nursing intervention can be used as complementary adjunct in the care of patients with low-energy states who tire easily, such as those requiring mechanical ventilator support.


Recognising the importance of informal communication events in improving collaborative care.
While the concept of collaboration is highly touted in the literature, most descriptions of effective collaboration highlight formal collaborative events; largely ignored are the informal collaborative events and none focusing on the frequent, 'seemingly' by chance communication events that arise and their role in supporting patient safety and quality care. To identify the types of informal communication events that exist in the inpatient setting and better understand the barriers contributing to their necessity. We undertook a constructivist grounded theory study in an inpatient internal medicine teaching unit in Ontario, Canada. Interview and observational data were collected across two phases; in total, 56 participants were consented for the study. Data collection and analysis occurred iteratively; themes were identified using constant comparison methods. Several types of informal communication events were identified and appeared valuable in three ways: (1) providing a better sense of a patient's baseline function in comparison to their current function; (2) gaining a more holistic understanding of the patient's needs; and (3) generating better insight into a patient's wishes and goals of care. Participants identified a number of organisational and communication challenges leading to the need for informal communication events. These included: scheduling, competing demands and the spatial and temporal organisation of the ward. As a result, nursing staff, allied health professionals and caregivers had to develop strategies for interacting with the physician team. We highlight the importance of informal communication in supporting patient care and the gaps in the system contributing to their necessity. Changes at the system level are needed to ensure we are not leaving important collaborative opportunities to chance alone.


CO-mediated cytoprotection is dependent on cell metabolism modulation.
Carbon monoxide (CO) is a gasotransmitter endogenously produced by the activity of heme oxygenase, which is a stress-response enzyme. Endogenous CO or low concentrations of exogenous CO have been described to present several cytoprotective functions: anti-apoptosis, anti-inflammatory, vasomodulation, maintenance of homeostasis, stimulation of preconditioning and modulation of cell differentiation. The present review revises and discuss how CO regulates cell metabolism and how it is involved in the distinct cytoprotective roles of CO. The first found metabolic effect of CO was its increase on cellular ATP production, and since then much data have been generated. Mitochondria are the most described and studied cellular targets of CO. Mitochondria exposure to this gasotransmitter leads several consequences: ROS generation, stimulation of mitochondrial biogenesis, increased oxidative phosphorylation or mild uncoupling effect. Likewise, CO negatively regulates glycolysis and improves pentose phosphate pathway. More recently, CO has also been disclosed as a regulating molecule for metabolic diseases, such as obesity and diabetes with promising results.


[Cutaneous paresthesia in high-dose intravenous dexamethasone therapy in oncology].
Seventeen oncological patients reported unpleasant but clinically harmless skin sensations directly after intravenous injection of dexamethasone, persisting for 2-4 minutes. In 16 cases, these paraesthesias (tingling, burning, itching, twinging) occurred in the genital or perineal area. In one case, the symptoms started in this area and then extended over the entire truncus integument for a short period. The cause of this obviously drug-induced side effect is unknown.


Altered Gene Expression of the Parasitoid Pteromalus puparum after Entomopathogenic Fungus Beauveria bassiana Infection.
Both parasitoids and entomopathogenic fungi are becoming increasingly crucial for managing pest populations. Therefore, it is essential to carefully consider the potential impact of entomopathogenic fungi on parasitoids due to their widespread pathogenicity and the possible overlap between these biological control tools during field applications. However, despite their importance, little research has been conducted on the pathogenicity of entomopathogenic fungi on parasitoids. In our study, we aimed to address this knowledge gap by investigating the interaction between the well-known entomopathogenic fungus Beauveria bassiana, and the pupal endoparasitoid Pteromalus puparum. Our results demonstrated that the presence of B. bassiana significantly affected the survival rates of P. puparum under laboratory conditions. The pathogenicity of B. bassiana on P. puparum was dose- and time-dependent, as determined via through surface spraying or oral ingestion. RNA-Seq analysis revealed that the immune system plays a primary and crucial role in defending against B. bassiana. Notably, several upregulated differentially expressed genes (DEGs) involved in the Toll and IMD pathways, which are key components of the insect immune system, and antimicrobial peptides were rapidly induced during both the early and late stages of infection. In contrast, a majority of genes involved in the activation of prophenoloxidase and antioxidant mechanisms were downregulated. Additionally, we identified downregulated DEGs related to cuticle formation, olfactory mechanisms, and detoxification processes. In summary, our study provides valuable insights into the interactions between P. puparum and B. bassiana, shedding light on the changes in gene expression during fungal infection. These findings have significant implications for the development of more effective and sustainable strategies for pest management in agriculture.


The web site of the center to advance palliative care.
The web site of the Center to Advance Palliative Care is reviewed. This is an excellent resource containing resources that address financial tutorials and customizable Excel worksheets, development and marketing tools, particularly the decision checklists, satisfaction tools, the information on tracking and reporting outcomes, bereavement tools and a press kit.


Prevalent human coxsackie B-5 virus infects porcine islet cells primarily using the coxsackie-adenovirus receptor.
We have previously demonstrated that transplanting porcine encephalomyocarditis virus (EMCV)-infected porcine islet cells (PICs) results in transmission of the virus to recipient mice, which is manifested by acute fatal infection within 5 to 8 days. Here, we determined PIC susceptibility to a related and highly prevalent human picornavirus, coxsackie B-5 virus (CVB-5). PICs were inoculated with CVB-5 in vitro for up to 96 hours and infectivity, level of virus replication, and cellular function determined. Subsequently, monoclonal and polyclonal antibody blocking experiments were used to investigate the receptor CVB-5 uses to enter PICs, and the ability of CVB-5-infected islets to reverse diabetes analyzed in mice. Adult pig islets inoculated with CVB-5 in vitro showed a typical picornaviral replication cycle with a 2-h lag phase followed by a 4-h exponential phase during which the virus titer increased by 4 logs. However, CVB-5 was less cytolytic to PICs than EMCV, resulting in a persistent productive infection lasting for up to 96 h, with minimal evidence of cell lysis. Double immunostaining confirmed the presence of CVB-5 antigens in insulin-producing islets. Infection of PICs in the presence of antibodies against human coxsackie-adenovirus receptor (CAR) resulted in near complete blockage in production of infectious virus particles whereas blocking with anti-porcine decay-accelerating factor (DAF, also called CD55) or anti-porcine membrane cofactor protein (MCP, also called CD46) only slightly decreased the number of infectious CVB-5 particles produced. Immunofluoresence staining showed CAR and MCP expression on the islet surface, but not DAF. Transplanting CVB-5-infected PICs into diabetic C57BL/6 mice resulted in reversal of diabetes. Although PICs are susceptible to human CVB-5, the infection does not appear to affect xenograft function in vitro or in vivo in the short term.


Two-color holography in reduced near-stoichiometric lithium niobate.
We explored a number of factors affecting the properties relevant to holographic optical data storage by using a two-color recording scheme in reduced, near-stoichiometric lithium niobate. Two-color, or photon-gated, recording is achieved by use of 852-nm information-carrying beams and 488-nm gating light. Readout at 852 nm is nondestructive, with a gating ratio of ~10(4). Recording sensitivity, gating ratio, dynamic range, and dark decay were measured for crystals of differing stoichiometry, degree of reduction, wavelength of the gating light, temperature, and optical power density. The two-color sensitivity per incident photon is still somewhat less than that of the one-color process at 488 nm for ~1 W/cm(2) of gating light but is essentially the same in terms of absorbed photons. Two-color recording is an attractive way of achieving nondestructive readout in a read-write material, and it allows selective optical erasure.


[Assessment of needs for care of a schizophrenic patient sample from the Granada Sur Mental Health Care Area].
The assessment of the needs for care for long term severe ill patients has been one of the areas of greatest interest since the community mental health system was established. This study has aimed to describe the needs for care of a group of schizophrenic patients and to know if these needs are met by the public mental health network. A cohort of 83 schizophrenic patients was selected. The diagnosis was confirmed by the SCAN method. The Needs for Care Assessment instrument was used to assess the needs for care of the patients. The positive psychotic symptoms (98%) followed by slowness and underactivity (71%) are the most common clinical problems between the patients of the cohort. In regards to skills and abilities, the most common are those related with work (49%) and house keeping (domestic work, getting meal and domestic shopping, with 42, 41 and 41%, respectively). In regards to the state of the need, 81% of the clinical problems are covered while this is only 40% in the social area. The clinical needs of the schizophrenic patients can be met by the mental health services established, oriented to the community care. However, attending social needs requires more rehabilitation, occupational and residential resources to be developed.


Structural and functional changes of immune system in aging mouse induced by D-galactose.
To investigate the role of D-galactose, especially in the structural and functional changes of the immune system in aging. Serum levels of advanced glycation end-products (AGE) were determined by ELISA method. Ultra-structures of thymus and spleen were detected by transmission electron microscopy. MTT method was used to determine the lymphocyte proliferation. IL-2 activity was determined by bioassay. Northern blot was used to detect the IL-2 mRNA levels. Serum AGE levels of D-galactose- (P < 0.01) and AGE-treated (P < 0.05) mice (n = 8) were increased significantly. The ultra-structures of thymus and spleen in D-galactose- and AGE-treated mice showed regressive changes similar to those in the aged control group. The lymphocyte mitogenesis and IL-2 activity of spleen were also decreased significantly (P < 0.01, n = 8). The change of IL-2 activity shown by Northern blot resulted from the change of mRNA expression. The AGE plus aminoguanidine group, however, showed no significant change in these parameters in comparison with the young control group (P < 0.01 or P < 0.05, n = 8). D-galactose and AGE lead to a mimic regression change of aging in the immune system in vivo.


Inaccurate values for direct bilirubin with some commonly used direct bilirubin procedures.
We compared five methods for the determination of total and direct bilirubins in serum samples from normal controls, subjects with Gilbert's syndrome, and serum pools containing about 50 and 150 mg of total bilirubin per liter. The Kodak Ektachem method and a diazotized sulfanilic acid method with 0.15 mmol/L sodium nitrite concentrations are the only methods that gave accurate direct bilirubin values, as judged by liquid-chromatographic results. The aca method that involved p-nitrobenzene diazonium tetrafluoroborate and another diazotized sulfanilic acid method with a higher concentration of sodium nitrite (0.8 mmol/L) yielded falsely high values for direct bilirubin, which could lead to clinical confusion. The more recently introduced diazotized sulfanilic acid method of the aca gave substantially better results than the p-nitrobenzene diazonium tetrafluoroborate method but was still inaccurate. Systematic investigation of these procedures revealed that the overestimation of direct bilirubin by the diazotized sulfanilic acid method was related to the amount of unconjugated bilirubin present and its ability to react as direct bilirubin in the presence of higher concentrations of sodium nitrite. Inherent properties of p-nitrobenzene diazonium tetrafluoroborate appeared to be responsible for inaccuracies in that method, which could not be corrected by varying reagent concentration or the reaction conditions.


Physiological and Agronomic Performance of the Coffee Crop in the Context of Climate Change and Global Warming: A Review.
Coffee is one of the most important global crops and provides a livelihood to millions of people living in developing countries. Coffee species have been described as being highly sensitive to climate change, as largely deduced from modeling studies based on predictions of rising temperatures and changing rainfall patterns. Here, we discuss the physiological responses of the coffee tree in the context of present and ongoing climate changes, including drought, heat, and light stresses, and interactions between these factors. We also summarize recent insights on the physiological and agronomic performance of coffee at elevated atmospheric CO2 concentrations and highlight the key role of CO2 in mitigating the harmful effects of heat stress. Evidence is shown suggesting that warming, per se, may be less harmful to coffee suitability than previously estimated, at least under the conditions of an adequate water supply. Finally, we discuss several mitigation strategies to improve crop performance in a changing world.


Oxygenated drinking water enhances immune activity in pigs and increases immune responses of pigs during Salmonella typhimurium infection.
It has been considered that drinking oxygenated water improves oxygen availability, which may increase vitality and improve immune functions. The present study evaluated the effects of oxygenated drinking water on immune function in pigs. Continuous drinking of oxygenated water markedly increased peripheral blood mononuclear cell proliferation, interleukin-1β expression level and the CD4(+):CD8(+) cell ratio in pigs. During Salmonella Typhimurium infection, total leukocytes and relative cytokines expression levels were significantly increased in pigs consuming oxygenated water compared with pigs consuming tap water. These findings suggest that oxygenated drinking water enhances immune activity in pigs and increases immune responses of pigs during S. Typhimurium Infection.


Body weight increase and metabolic derangements after tenofovir disoproxil fumarate switch to tenofovir alafenamide in patients with chronic hepatitis B.
Lipid-lowering effect was observed during treatment with tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB). However, the metabolic features in patients switching from TDF to tenofovir alafenamide (TAF) remain unclear. To compare the impacts of switching from TDF to TAF or from entecavir to TAF on body weight and metabolic features in patients with CHB. This was a multi-centre, prospective, observational study in patients with CHB on TDF or entecavir who switched to TAF. Baseline characteristics, lipid profile and sugar profile were determined. This study received IRB approval from each hospital. We enrolled 177 patients on TDF (99) or entecavir (78) and followed them for 48 weeks after the switch to TAF. At baseline, TDF-experienced patients had lower serum triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol than entecavir-experienced patients. The switch from TDF to TAF significantly increased body weight, triglyceride, total cholesterol, HDL, LDL, fasting glucose, glycaemic haemoglobin, insulin and insulin resistance. The switch from entecavir to TAF did not affect these measures. There was no significant difference in atherosclerotic cardiovascular disease risk scores between groups. The switch from TDF to TAF was associated with weight gain, derangements of lipid profile, and increased insulin resistance in patients with CHB. Long-term effects on these metabolic features need further investigation.


'How do you rate us'?
A trust that used to perform poorly in patient surveys has turned itself around by taking a strategic approach to implementing change based on patient feedback and ideas from staff. Carefully placed additional staff have made a big difference to patient care and staff stress levels.


In vivo measurement of aldehyde dehydrogenase-2 activity in rat liver ethanol model using dynamic MRSI of hyperpolarized [1-(13) C]pyruvate.
To date, measurements of the activity of aldehyde dehydrogenase-2 (ALDH2), a critical mitochondrial enzyme for the elimination of certain cytotoxic aldehydes in the body and a promising target for drug development, have been largely limited to in vitro methods. Recent advancements in MRS of hyperpolarized (13) C-labeled substrates have provided a method to detect and image in vivo metabolic pathways with signal-to-noise ratio gains greater than 10 000-fold over conventional MRS techniques. However aldehydes, because of their toxicity and short T1 relaxation times, are generally poor targets for such (13) C-labeled studies. In this work, we show that dynamic MRSI of hyperpolarized [1-(13) C]pyruvate and its conversion to [1-(13) C]lactate can provide an indirect in vivo measurement of ALDH2 activity via the concentration of NADH (nicotinamide adenine dinucleotide, reduced form), a co-factor common to both the reduction of pyruvate to lactate and the oxidation of acetaldehyde to acetate. Results from a rat liver ethanol model (n = 9) show that changes in (13) C-lactate labeling following the bolus injection of hyperpolarized pyruvate are highly correlated with changes in ALDH2 activity (R(2) = 0.76).


Role of residual kidney function and convective volume on change in beta2-microglobulin levels in hemodiafiltration patients.
Removal of beta2-microglobulin (beta2M) can be increased by adding convective transport to hemodialysis (HD). The aim of this study was to investigate the change in beta2M levels after 6-mo treatment with hemodiafiltration (HDF) and to evaluate the role of residual kidney function (RKF) and the amount of convective volume with this change. Predialysis serum beta2M levels were evaluated in 230 patients with and 176 patients without RKF from the CONvective TRAnsport STudy (CONTRAST) at baseline and 6 mo after randomization for online HDF or low-flux HD. In HDF patients, potential determinants of change in beta2M were analyzed using multivariable linear regression models. Mean serum beta2M levels decreased from 29.5 +/- 0.8 (+/-SEM) at baseline to 24.3 +/- 0.6 mg/L after 6 mo in HDF patients and increased from 31.9 +/- 0.9 to 34.4 +/- 1.0 mg/L in HD patients, with the difference of change between treatment groups being statistically significant (regression coefficient -7.7 mg/L, 95% confidence interval -9.5 to -5.6, P < 0.001). This difference was more pronounced in patients without RKF as compared with patients with RKF. In HDF patients, beta2M levels remained unchanged in patients with GFR >4.2 ml/min/1.73 m2. The beta2M decrease was not related to convective volume. This study demonstrated effective lowering of beta2M levels by HDF, especially in patients without RKF. The role of the amount of convective volume on beta2M decrease appears limited, possibly because of resistance to beta2M transfer between body compartments.


Toward a high-performance management system in health care, Part 5: How high-performance work practices facilitate speaking up in health care organizations.
Employees' reluctance to speak up about problems and/or make suggestions for improvement is a noted barrier to quality and patient safety improvement in health care organizations. High-performance work practices (HPWPs) offer a framework for considering how management practices can encourage speaking up in these organizations. We aimed to explore how implementation of HPWPs in U.S. health care organizations could facilitate or remove barriers to speaking up. We were interested in improving understanding of how HPWPs could influence manager behavior and organizational policies and practices to encourage, support, and foster speaking up among employees. We examined case study data from five health care organizations purposely selected for their use of HPWPs. Interview transcripts from 67 key informants were inductively and deductively analyzed to explore how speaking up was characterized. We found that speaking up was recognized as an important factor impacting quality improvement and/or patient safety initiatives across all five organizations. Management efforts to facilitate speaking up included both direct practices, such as using structured communication processes and reporting systems, and complementary practices that supported speaking up. Both direct and complementary practices were aligned with the HPWP model, with sites showing evidence of supporting the frontline, engaging staff, developing talent, and having effective leaders fostering efforts to encourage employees to speak up. Both conceptual evidence and qualitative evidence supporting the applicability of HPWPs as a management model for systematically facilitating speaking up in health care organizations were presented in this study. Application of an evidence-based framework enabled consideration of an organizational rather than employee perspective and provided examples of specific management practices that have been successfully implemented to facilitate speaking up. This research furthers the growing body of evidence supporting the applicability of HPWP implementation as a valuable strategy for impacting quality and safety in health care organizations.


Genetic targeting of an adenovirus vector via replacement of the fiber protein with the phage T4 fibritin.
The utility of adenovirus (Ad) vectors for gene therapy is restricted by their inability to selectively transduce disease-affected tissues. This limitation may be overcome by the derivation of vectors capable of interacting with receptors specifically expressed in the target tissue. Previous attempts to alter Ad tropism by genetic modification of the Ad fiber have had limited success due to structural conflicts between the fiber and the targeting ligand. Here we present a strategy to derive an Ad vector with enhanced targeting potential by a radical replacement of the fiber protein in the Ad capsid with a chimeric molecule containing a heterologous trimerization motif and a receptor-binding ligand. Our approach, which capitalized upon the overall structural similarity between the human Ad type 5 (Ad5) fiber and bacteriophage T4 fibritin proteins, has resulted in the generation of a genetically modified Ad5 incorporating chimeric fiber-fibritin proteins targeted to artificial receptor molecules. Gene transfer studies employing this novel viral vector have demonstrated its capacity to efficiently deliver a transgene payload to the target cells in a receptor-specific manner.


Early detection and prognosis of ovarian cancer using serum YKL-40.
YKL-40 is a secreted glycoprotein (chitinase family). We compared YKL-40 with two ovarian cancer serum markers, CA125 and CA15-3, for the detection of early-stage ovarian cancer. Serum YKL-40 levels were assayed by enzyme-linked immunosorbent assay for 46 healthy subjects, 61 high-risk individuals, 33 patients with benign gynecologic processes, and 50 preoperative patients subsequently diagnosed with predominantly early-stage ovarian cancer. Serum CA125 and CA15-3 values were obtained. Median YKL-40 level was 28 ng/mL (range, 15 to 166 ng/mL) for healthy subjects, 36 ng/mL (range, 9 to 69 ng/mL) for high-risk individuals without prior cancer, 44.5 ng/mL (range, 5 to 133 ng/mL) for high-risk patients with prior breast cancer, and 38 ng/mL (range, 5 to 67 ng/mL) for individuals with benign gynecologic processes (P = NS). Median preoperative YKL-40 level for ovarian cancer patients was 94 ng/mL (range, 17 to 517 ng/mL; P <.0001 compared with normal and high-risk). YKL-40 was elevated (>/= 62 ng/mL) in 36 (72%) of 50 patients compared with 23 (46%) of 50 and 13 (26%) of 50 patients for CA125 and CA15-3 (P <.008). Twenty (65%) of 31 early-stage patients had elevated serum YKL-40 levels compared with 11 (35%) of 31 and four (13%) of 31 patients for CA125 and CA15-3 (P =.039). YKL-40 levels increased with stage (P <.005), regardless of grade, histology, or patient age. Patients with early-stage tumors with YKL-40 values more than 80 ng/mL had a worse prognosis (71% recurrence v no recurrence [P =.034]). YKL-40 may represent a novel marker for the detection of early-stage ovarian cancer. YKL-40 levels in early-stage patients may also predict disease recurrence and survival. The utility of YKL-40 in detection of early-stage ovarian cancer deserves further investigation.


Opioid Policy and Chronic Pain Treatment Access Experiences: A Multi-Stakeholder Qualitative Analysis and Conceptual Model.
Patients on long-term opioid therapy (LTOT) for pain have difficulty accessing primary care clinicians who are willing to prescribe opioids or provide multimodal pain treatment. Recent treatment guidelines and statewide policies aimed at reducing inappropriate prescribing may exacerbate these access issues, but further research is needed on this issue. This study aimed to understand barriers to primary care access and multimodal treatment for chronic pain from the perspective of multiple stakeholders. Qualitative, semi-structured phone interviews were conducted with adult patients with chronic pain, primary care clinicians, and clinic office staff in Michigan. Interview questions covered stakeholder experiences with prescription opioids, opioid-related policies, and access to care for chronic pain. Interviews were coded using inductive and deductive methods for thematic analysis. A total of 25 interviews were conducted (15 patients, 7 primary care clinicians, and 3 office staff). Barriers to treatment access were attributed to six themes: (1) reduced clinic willingness to manage prescribed opioids for new patients; (2) lack of time and reimbursement for quality opioid-related care; (3) paucity of multimodal care and coordination between providers; (4) fear of liability and use of new guidelines to justify not prescribing opioids; (5) delayed prescription receipt due to prior authorization and pharmacy issues; and (6) poor availability of effective non-opioid treatments. Issues of policy, logistics, and clinic-level resources converge to disrupt treatment access for patients with chronic pain, as many clinics both do not offer multimodal pain care and are unwilling to prescribe LTOT. The resulting conceptual model can inform the development of policy interventions to help mitigate these access barriers.


[Principles of hormone replacement therapy in climacteric].
With age-specific diminished and excluded ovarian function and estrogen deficiency, 60% of females may develop various systemic disorders (the menopausal syndrome, urogenital and cardiovascular diseases, osteoporosis). In the past 10-15 years, hormone replacement treatment regimens have been developed for climacteric females. Numerous epidemiological surveys have indicated that hormone replacement therapy shows a 50% reduction in the incidence of stroke, myocardial infarction, bone fractures. Therefore, post-menopausal hormone therapy is indicated both for therapeutical and prophylactic purposes, which may increase female longevity.


Relationship between Cortical Thickness and Neuropsychological Performance in Normal Older Adults and Those with Mild Cognitive Impairment.
Mild cognitive impairment (MCI) has been extensively investigated in recent decades to identify groups with a high risk of dementia and to establish effective prevention methods during this period. Neuropsychological performance and cortical thickness are two important biomarkers used to predict progression from MCI to dementia. This study compares the cortical thickness and neuropsychological performance in people with MCI and cognitively healthy older adults. We further focus on the relationship between cortical thickness and neuropsychological performance in these two groups. Forty-nine participants with MCI and 40 cognitively healthy older adults were recruited. Cortical thickness was analysed with semiautomatic software, Freesurfer. The analysis reveals that the cortical thickness in the left caudal anterior cingulate (p=0.041), lateral occipital (p=0.009) and right superior temporal (p=0.047) areas were significantly thinner in the MCI group after adjustment for age and education. Almost all neuropsychological test results (with the exception of forward digit span) were significantly correlated to cortical thickness in the MCI group after adjustment for age, gender and education. In contrast, only the score on the Category Verbal Fluency Test and the forward digit span were found to have significant inverse correlations to cortical thickness in the control group of cognitively healthy older adults. The study results suggest that cortical thinning in the temporal region reflects the global change in cognition in subjects with MCI and may be useful to predict progression of MCI to Alzheimer's disease. The different pattern in the correlation of cortical thickness to the neuropsychological performance of patients with MCI from the healthy control subjects may be explained by the hypothesis of MCI as a disconnection syndrome.


RAD21 cooperates with pluripotency transcription factors in the maintenance of embryonic stem cell identity.
For self-renewal, embryonic stem cells (ESCs) require the expression of specific transcription factors accompanied by a particular chromosome organization to maintain a balance between pluripotency and the capacity for rapid differentiation. However, how transcriptional regulation is linked to chromosome organization in ESCs is not well understood. Here we show that the cohesin component RAD21 exhibits a functional role in maintaining ESC identity through association with the pluripotency transcriptional network. ChIP-seq analyses of RAD21 reveal an ESC specific cohesin binding pattern that is characterized by CTCF independent co-localization of cohesin with pluripotency related transcription factors Oct4, Nanog, Sox2, Esrrb and Klf4. Upon ESC differentiation, most of these binding sites disappear and instead new CTCF independent RAD21 binding sites emerge, which are enriched for binding sites of transcription factors implicated in early differentiation. Furthermore, knock-down of RAD21 causes expression changes that are similar to expression changes after Nanog depletion, demonstrating the functional relevance of the RAD21--pluripotency transcriptional network association. Finally, we show that Nanog physically interacts with the cohesin or cohesin interacting proteins STAG1 and WAPL further substantiating this association. Based on these findings we propose that a dynamic placement of cohesin by pluripotency transcription factors contributes to a chromosome organization supporting the ESC expression program.


Adipose Stem Cells (ASCs) and Stromal Vascular Fraction (SVF) as a Potential Therapy in Combating (COVID-19)-Disease.
A recent and interesting study reported improved respiratory activity after intravenous administration of mesenchymal stem cells (MSCs) into patients affected by coronavirus disease 2019 (COVID-19). These outcomes displayed that intravenous infiltration of MSCs is a safe and efficacy treatment for COVID-19 pneumonia, a severe acute respiratory illness caused by the coronavirus 2 (SARS-CoV-2). Only 7 patients were treated, but with extraordinary results, opening a new strategy in COVID-19 therapy. Currently, no specific therapies against SARS-CoV-2 are available. The MSCs therapy outcomes reported, are striking, as these cells inhibit the over-activation of the immune system, promoting endogenous repair, by improving the lung microenvironment after the SARS-CoV-2 infection. The MSCs could represent an effective, autologous and safe therapy, and therefore, sharing these published results, here is reported the potential use possibilities in COVID-19 of the most common MSCs represented by Adipose Stem Cells (ASCs).


Water use, water use efficiency and drought resistance among warm-season turfgrasses in shallow soil profiles.
As the available water supply for urban turfgrass management is becoming limited in Australia, it will be crucial to identify drought-resistant turfgrass species and water-saving management strategies. Eight (pre-)commercial turfgrasses grown in Australia, two each of four species including the bermudagrasses (Cynodon dactylon L.), the Queensland blue couches (Digitaria didactyla Willd), the seashore paspalums (Paspalum vaginatum Swartz.) and St Augustinegrasses (Stenotaphrum secundatum (Walt.) Kuntze) were evaluated in two lysimeter experiments. Shallow lysimeters (28 and 40cm) were used to represent shallow soil profiles typical of urban environments. We measured gravimetric water use for the eight cultivars and calculated water use efficiency (WUE, clipping yield to water use ratio) and WUEr (ratio of WUE under drought to that under irrigated conditions). WUEr measured in both experiments correlated strongly with survival period and this relationship was not affected by soil type or cutting height. Using survival period as the criterion for drought resistance, the best were the bermudagrasses and the worst were the seashore paspalums and Queensland blue couches. The bermudagrass genotypes had the lowest water use, highest WUE and WUEr and the Queensland blue couches and seashore paspalums had the greatest water use, lowest WUE and WUEr. The possible mechanisms of drought resistance included lower water use and lower stomatal conductance as indicated by higher canopy temperature in the early stage of water deficit.


Long non-coding RNAs in leukemia: biology and clinical impact.
Over the last years, long non-coding RNAs (lncRNAs) have emerged as putative regulators of malignant hematopoietic development. Here, we review recent literature on the involvement of lncRNAs in leukemia, including their role in driving or sustaining disease and their potential impact on diagnosis, classification, and prognosis. Leukemogenesis is a complex process resulting from the accumulation of multiple genetic alterations. Over the last years, advances in high-throughput sequencing and transcriptome profiling have enabled the identification of lncRNAs involved in leukemia development. lncRNAs are able to distinguish different subtypes of human leukemia and several reports have identified specific patterns of lncRNA expression associated with clinical patient characteristics. Although functional studies on the actual role of these lncRNAs during transformation remain scarce, emerging evidence suggests that complex interactions between coding and non-coding transcript are truly involved in leukemia development. Introduction of lncRNAs as an additional layer of complexity in human leukemia might provide new molecular genetic insights in the biology of this disease and could create unique opportunities for the identification of novel drug targets and diagnostic or prognostic biomarkers.


Therapy and outcome in 51 children with mesoblastic nephroma: a report of the National Wilms' Tumor Study.
Mesoblastic nephroma is a distinctive pathologic renal tumor with unique clinical, therapeutic, and prognostic patterns. This report reviews 51 patients (2.8% of 1905 patients submitted to NWTS with renal tumors) with this diagnosis from the NWTS contrasting this disease entity with Wilms' tumor. There were 33 males and 18 females, predominantly term babies born after uncomplicated pregnancies. The mean age at tumor excision was 3.44 +/- 0.6 mo (one child 9 yr). A palpable mass was the predominant presentation in 48 patients and in addition hematuria (9), hypertension (2), vomiting (3), and jaundice (1) were noteworthy. Diagnostic studies included IVP (49 positive, 2 negative) and ultrasound (15 positive, 1 negative). Adequate operative excision was achieved in 43 of 51 patients while 8 children had local extension and 10 had tumor spillage. Operation alone (23), predominantly since 1978, surgery plus chemotherapy (24), prior to 1978, and surgery, chemotherapy, and radiation therapy (4), prior to 1976, were the modes of therapy. The follow-up ranges from 4 mo to 11.5 yr. Survival was excellent; 50 patients survive (98%), only 1 dying of sepsis. These data suggest that mesoblastic nephroma contrasts with Wilms' tumor in that it occurs in a younger age group, has a benign biologic behavior, and a more favorable outcome. Aggressive multimodal treatment though utilized in the early years of the study is not essential to achieve this outcome.


Patient education: a potential marketing tool for the private physician.
To keep pace with increasing competition, the private physician is encouraged to consider a patient education program as a marketing tool. Meeting the educational needs of patients is presented as an opportunity to create a trusting environment in the practice, enhance the doctor-patient relationship, and increase the active role of the patient in the health care process. A management model is proposed for successfully planning, organizing, staffing, leading, and controlling the patient education program.


A Case Study on A University-Community Partnership to Eliminate Racial Disparities in Infant Mortality: Effective Strategies and Lessons Learned.
This case study discusses the implementation framework, effective strategies, and lessons learned of a university-community partnership addressing racial disparities in infant mortality. The partnership was successful at enhancing coordination within service delivery systems for maternal and child health programs. Results: the elimination of waiting list for services, maximizing federal and state reimbursement, the adoption of culturally-appropriate intervention practices, increasing racial diversity in the workforce, diffusing silos, and facilitating healthier relationships among service providers. Key lessons: activating the collective strengths among a network of diverse community stakeholders with shared interests, prioritizing black voices in the change process, and capacity building opportunities.


High Seebeck Coefficient from Screen-Printed Colloidal PbSe Nanocrystals Thin Film.
Thin-film thermoelectrics (TEs) with a thickness of a few microns present an attractive opportunity to power the internet of things (IoT). Here, we propose screen printing as an industry-relevant technology to fabricate TE thin films from colloidal PbSe quantum dots (QDs). Monodisperse 13 nm-sized PbSe QDs with spherical morphology were synthesized through a straightforward heating-up method. The cubic-phase PbSe QDs with homogeneous chemical composition allowed the formulation of a novel ink to fabricate 2 μm-thick thin films through robust screen printing followed by rapid annealing. A maximum Seebeck coefficient of 561 μV K-1 was obtained at 143 °C and the highest electrical conductivity of 123 S m-1 was reached at 197 °C. Power factor calculations resulted in a maximum value of 2.47 × 10-5 W m-1 K-2 at 143 °C. To the best of our knowledge, the observed Seebeck coefficient value is the highest reported for TE thin films fabricated by screen printing. Thus, this study highlights that increased Seebeck coefficients can be obtained by using QD building blocks owing to quantum confinement.


Inter- and intra-rater reproducibility of quantitative dynamic contrast enhanced MRI using TWIST perfusion data in a uterine fibroid model.
To determine the reproducibility of TWIST-derived (Time-Resolved Angiography with Interleaved Stochastic Trajectories) quantitative dynamic contrast enhanced (DCE) MRI in a uterine fibroid model. The institutional review board approved this retrospective study. Dynamic contrast-enhanced TWIST datasets from 15 randomly selected 1.5 Tesla pelvic MR studies were postprocessed. Five readers recorded kinetic parameters (K(trans) [volume transfer constant], ve [extracellular extravascular space volume], kep [flux rate constant], iAUC [initial area under the gadolinium-time curve]) of the largest uterine fibroid using three region-of-interest (ROI) selection methods. Measurements were randomized and repeated three times, and measures of reproducibility were calculated. The intra-rater coefficients of variation (CVs, brackets indicate 95% confidence intervals) varied from 4.6% to 7.6% (K(trans) 7.6% [6.1%, 9.1%], kep 7.2% [5.9%, 8.5%], ve 4.6% [3.8%, 5.4%], and iAUC 7.2% [6.1%, 8.3%]). ve was the most reproducible (P < 0.05). Inter-rater reproducibility was significantly (P < 0.05) greater for the large ROI method (range of intraclass correlation coefficients [ICCs] = 0.80-0.98 versus 0.48-0.63 [user-defined ROI] versus 0.41-0.69 [targeted ROI]). The uterine fibroid accounted for the greatest fraction of variance for the large ROI method (range across kinetic parameters: 83-98% versus 56-69% [user-defined ROI] versus 47-74% [targeted ROI]). The reader accounted for the greatest fraction of variance for the user-defined ROI method (0.4-14.1% versus 0.1-3.0% [large ROI] versus <0.1-1.5% [targeted ROI]). Changes in TWIST-derived DCE-MRI kinetic parameters of up to 9-15% may be attributable to measurement error. Large DCE-MRI regions of interest are the most reproducible across multiple readers.


Central nervous system (CNS)-resident natural killer cells suppress Th17 responses and CNS autoimmune pathology.
Natural killer (NK) cells of the innate immune system can profoundly impact the development of adaptive immune responses. Inflammatory and autoimmune responses in anatomical locations such as the central nervous system (CNS) differ substantially from those found in peripheral organs. We show in a mouse model of multiple sclerosis that NK cell enrichment results in disease amelioration, whereas selective blockade of NK cell homing to the CNS results in disease exacerbation. Importantly, the effects of NK cells on CNS pathology were dependent on the activity of CNS-resident, but not peripheral, NK cells. This activity of CNS-resident NK cells involved interactions with microglia and suppression of myelin-reactive Th17 cells. Our studies suggest an organ-specific activity of NK cells on the magnitude of CNS inflammation, providing potential new targets for therapeutic intervention.


9-O-butyl-13-(4-isopropylbenzyl)berberine, KR-72, is a potent antifungal agent that inhibits the growth of Cryptococcus neoformans by regulating gene expression.
In this study we explored the mode of action of KR-72, a 9-O-butyl-13-(4-isopropylbenzyl)berberine derivative previously shown to exhibit potent antifungal activity against a variety of human fungal pathogens. The DNA microarray data revealed that KR-72 treatment significantly changed the transcription profiles of C. neoformans, affecting the expression of more than 2,000 genes. Genes involved in translation and transcription were mostly upregulated, whereas those involved in the cytoskeleton, intracellular trafficking, and lipid metabolism were downregulated. KR-72 also exhibited a strong synergistic effect with the antifungal agent FK506. KR-72 treatment regulated the expression of several essential genes, including ECM16, NOP14, HSP10 and MGE1, which are required for C. neoformans growth. The KR-72-mediated induction of MGE1 also likely reduced the viability of C. neoformans by impairing cell cycle or the DNA repair system. In conclusion, KR-72 showed antifungal activity by modulating diverse biological processes through a mode of action distinct from those of clinically available antifungal drugs such as polyene and azole drugs.


The A-Z of Zika drug discovery.
Despite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A-Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond.


Mononuclear subsets in the peripheral blood of multiple sclerosis patients in relation to results of brain gadolinium- enhancing imaging.
Very little is known about processes which are leading to the development of new multiple sclerosis (MS) plaques. Therefore, the problem of correlating immunological disequilibrium in MS patients with the onset of a relapse and with other markers of the disease seems to be of great importance. In our studies we have evaluated the mononuclear subsets in the peripheral blood of multiple sclerosis patients in relation to results of brain gadolinium-enhancing imaging. A positive magnetic resonance imaging (MRI) gadolinium enhancement indicates an ongoing inflammation and activity of the MS process, whereas gadolinium (Gd) negative imaging should be considered as a sign of stabilization of the MS process. Peripheral blood was taken from 70 MS patients, fulfilling the criteria of McDonald et al [8]. Brain MRI was performed using a Magneton Impact 1.0 T (Siemens) machine. Enhanced T1 images were obtained after administration of 0.1 mmol/kg gadolinium - DTPA. Lymphocyte subsets were analyzed by flow cytometry with the aid of specific monoclonal antibodies. The relative percentage of the white blood cell count as well as the absolute number of mononuclears and of CD3+ lymphocyte were significantly lowered only in the group of gadolinium negative MS cases. The CD4+ relative percentage was significantly higher both in the total as well as in gadolinium positive and negative subgroups. The ratio of CD4/CD8 was significantly higher in MS patients. The absolute number of CD4 lymphocytes was the lowest in gadolinium negative MS cases. An appropriate regulation of the Th /T helper/ cells seems to be critical in the control and prevention of diverse states of the disease. In the course of an acute process, gadolinium positive imaging as well as immunological events, represented by mononuclear subsets in the peripheral blood may proceed and change very quickly, whereas gadolinium negative findings reflecting a stabilization of processes, are changing more slowly and therefore may be detected more easily in peripheral blood cell counts.


The role of ADP-ribosylation in regulating DNA double-strand break repair.
ADP-ribosylation is the post translational modification of proteins catalysed by ADP-ribosyltransferases (ARTs). ADP-ribosylation has been implicated in a wide variety of cellular processes including cell growth and differentiation, apoptosis and transcriptional regulation. Perhaps the best characterised role, however, is in DNA repair and genome stability where ADP-ribosylation promotes resolution of DNA single strand breaks. Although ADP-ribosylation also occurs at DNA double strand breaks (DSBs), which ARTs catalyse this reaction and the molecular basis of how this modification regulates their repair remains a matter of debate. Here we review recent advances in our understanding of how ADP-ribosylation regulates DSB repair. Specifically, we highlight studies using the genetic model organism Dictyostelium, in addition to vertebrate cells that identify a third ART that accelerates DSB repair by non-homologous end-joining through promoting the interaction of repair factors with DNA lesions. The implications of these data with regards to how ADP-ribosylation regulates DNA repair and genome stability are discussed.


Comparison of a Novel Handheld Telehealth Device with Stand-Alone Examination Tools in a Clinic Setting.
Background and Objective: Research demonstrates that telemedicine is effective in pediatric settings but little is published to validate the quality of the data acquired by remote peripheral examination devices to accurately inform clinical decision-making.Introduction: The primary aim was to compare a novel Food and Drug Administration (FDA)-cleared multifunctional remote examination device (Tyto) with other stand-alone digital examination devices. The secondary aim was to ascertain whether either device produced images or sounds better able to provide clinical information to clinicians caring for children.Materials and Methods: Otoscopic images and heart and lung sounds from 50 patients of ages 2-18 years were acquired using the novel device and a stand-alone digital otoscope and stethoscope. Data were stored on a secure server for review by physicians (two pulmonary faculty, two general faculty, two cardiology faculty, and two cardiology fellows). Reviewers were blinded and they reviewed images and audio files in a randomized manner. Images and sounds were scored in terms of quality using a Likert scale. Means and standard deviations (and t-tests to compare those means) were calculated. Individual (heart sounds, lung sounds, and otoscopic images) and aggregate scores were compared.Results: The novel device provided higher sound and image quality with less chance of an inability to make a diagnosis than the stand-alone devices. The novel device had a superior mean comparative diagnostic score with a high intra- and inter-reliability of cardiac, pulmonary, and otoscopic diagnosis.Discussion and Conclusions: The novel device outperformed the stand-alone digital stethoscope and otoscope and was better able to provide usable data to support a clinical encounter.


Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model.
The bisphosphonate, zoledronic acid (ZOL), can inhibit osteoclasts leading to decreased osteoclastogenesis and osteoclast activity in bone. Here, we used a mixed osteolytic/osteoblastic murine model of bone-metastatic prostate cancer, RM1(BM), to determine how inhibiting osteolysis with ZOL affects the ability of these cells to establish metastases in bone, the integrity of the tumour-bearing bones and the survival of the tumour-bearing mice. The model involves intracardiac injection for arterial dissemination of the RM1(BM) cells in C57BL/6 mice. ZOL treatment was given via subcutaneous injections on days 0, 4, 8 and 12, at 20 and 100 µg/kg doses. Bone integrity was assessed by micro-computed tomography and histology with comparison to untreated mice. The osteoclast and osteoblast activity was determined by measuring serum tartrate-resistant acid phosphatase 5b (TRAP 5b) and osteocalcin, respectively. Mice were euthanased according to predetermined criteria and survival was assessed using Kaplan Meier plots. Micro-CT and histological analysis showed that treatment of mice with ZOL from the day of intracardiac injection of RM1(BM) cells inhibited tumour-induced bone lysis, maintained bone volume and reduced the calcification of tumour-induced endochondral osteoid material. ZOL treatment also led to a decreased serum osteocalcin and TRAP 5b levels. Additionally, treated mice showed increased survival compared to vehicle treated controls. However, ZOL treatment did not inhibit the cells ability to metastasise to bone as the number of bone-metastases was similar in both treated and untreated mice. ZOL treatment provided significant benefits for maintaining the integrity of tumour-bearing bones and increased the survival of tumour bearing mice, though it did not prevent establishment of bone-metastases in this model. From the mechanistic view, these observations confirm that tumour-induced bone lysis is not a requirement for establishment of these bone tumours.


Mycetoma (Madura Foot) in Israel: Recent Cases and a Systematic Review of the Literature.
AbstractMycetoma is a chronic soft tissue infection caused by fungal or bacterial pathogens, and is endemic in tropical and subtropical regions. Cases in developed countries outside the mycetoma belt are rare and usually imported by immigrants. Sporadic cases have been reported in Israel. Unpublished cases in the participating medical centers are reported. In addition, a systematic review of the literature was performed. All published mycetoma cases diagnosed in Israel were included with relevant variables collected. Twenty-one cases of mycetoma were diagnosed in Israel between 1942 and 2015, including four unpublished cases and 17 published cases. The mean age at diagnosis was 42 years (range 23-73), and 16 of the patients were male. The foot was the primary involved organ. Fifteen patients were immigrants from Yemen, Ethiopia, and Sudan. Five cases were autochthonous. One case was travel related. Among patients who developed symptoms after immigration, the mean time from exposure to symptom onset was 5.6 years (range 1-10 years). The mean time from symptom onset to diagnosis was 6.6 years (range 0.2-35 years). The autochthonous cases demonstrate that Israel is endemic of mycetoma. The immigrant population represents two distinct waves of immigration to Israel in the past century. Two unpublished cases of Ethiopian immigrants are the first reported cases of mycetoma acquired in Ethiopia. The diagnostic and therapeutic challenges along with the epidemiological data emphasize the need of raising the awareness of physicians to this devastating condition even in developed countries.


Distinct receptor domains determine subtype-specific coupling and desensitization phenotypes for human beta1- and beta2-adrenergic receptors.
Human beta1- and beta2-adrenergic receptor (beta1 AR and beta2 AR) coupling and desensitization characteristics were compared in defined heterologous expression systems. Significant differences in the coupling efficacies of the two subtypes were found in both Chinese hamster fibroblasts and murine Ltk- fibroblasts, which were used as surrogate cell lines. At the maximal level of stimulation with the nonselective beta-adrenergic agonist isoproterenol, beta1 AR-mediated adenylyl cyclase activation represented 70% and 20% of that mediated by beta2 AR in Chinese hamster and murine Ltk- fibroblasts, respectively. Sustained (15 min) stimulation with subsaturating concentration of isoproterenol (< 10% of receptor occupancy) led to identical desensitization of the beta-adrenergic-stimulated adenylyl cyclase activity for both beta1 AR and beta2AR-expressing cells. In contrast, when a nearly saturating concentration of isoproterenol (> 90% of receptor occupancy) was used to promote desensitization, the extent of desensitization observed for beta2 AR-expressing cells was 1.7-2-fold higher than that of the beta1 AR. The carboxyl domain of several G protein-coupled receptors has been shown to play important roles in both coupling efficacy and agonist-promoted desensitization. Therefore, we examined the contribution of this receptor domain in the subtype-selective phenotypes described above. A chimeric receptor composed of the first six transmembrane domains of the beta1 AR and of the seventh transmembrane domain and carboxyl tail of the beta2 AR maintained a coupling efficacy characteristic of the beta1 AR, whereas the extent of desensitization resulting from high receptor occupancy was identical to that of the beta2 AR. These results therefore suggest that the carboxyl portion of the beta1 AR and beta2 AR determines their subtype-selective desensitization patterns but not their respective coupling efficacies.


Diagnosis and management of brain metastasis from gestational trophoblastic disease.
Significant advances have been made since the introduction of methotrexate towards the improvement of long-term survival in patients with brain metastases from gestational trophoblastic disease. Early diagnosis via computed tomography of the head and beta-hCG serum testing along with aggressive, multiagent intervention have greatly improved patient prognosis from this once highly fatal condition. Although toxicity is commonly associated with this treatment, death from sepsis or drug reactions is unusual. Surgery has been found useful only to relieve intracranial pressure and is discouraged as part of diagnosis.


Spatial Mechano-Signaling Regulation of GTPases through Non-Degradative Ubiquitination.
Blood flow produces shear stress exerted on the endothelial layer of the vessels. Spatial characterization of the endothelial proteome is required to uncover the mechanisms of endothelial activation by shear stress, as blood flow varies in the vasculature. An integrative ubiquitinome and proteome analysis of shear-stressed endothelial cells demonstrated that the non-degradative ubiquitination of several GTPases is regulated by mechano-signaling. Spatial analysis reveals increased ubiquitination of the small GTPase RAP1 in the descending aorta, a region exposed to laminar shear stress. The ubiquitin ligase WWP2 is identified as a novel regulator of RAP1 ubiquitination during shear stress response. Non-degradative ubiquitination fine-tunes the function of GTPases by modifying their interacting network. Specifically, WWP2-mediated RAP1 ubiquitination at lysine 31 switches the balance from the RAP1/ Talin 1 (TLN1) toward RAP1/ Afadin (AFDN) or RAP1/ RAS Interacting Protein 1 (RASIP1) complex formation, which is essential to suppress shear stress-induced reactive oxygen species (ROS) production and maintain endothelial barrier integrity. Increased ROS production in endothelial cells in the descending aorta of endothelial-specific Wwp2-knockout mice leads to increased levels of oxidized lipids and inflammation. These results highlight the importance of the spatially regulated non-degradative ubiquitination of GTPases in endothelial mechano-activation.


Children's vulnerability to toxic chemicals: a challenge and opportunity to strengthen health and environmental policy.
A key policy breakthrough occurred nearly twenty years ago with the discovery that children are far more sensitive than adults to toxic chemicals in the environment. This finding led to the recognition that chemical exposures early in life are significant and preventable causes of disease in children and adults. We review this knowledge and recommend a new policy to regulate industrial and consumer chemicals that will protect the health of children and all Americans, prevent disease, and reduce health care costs. The linchpins of a new US chemical policy will be: first, a legally mandated requirement to test the toxicity of chemicals already in commerce, prioritizing chemicals in the widest use, and incorporating new assessment technologies; second, a tiered approach to premarket evaluation of new chemicals; and third, epidemiologic monitoring and focused health studies of exposed populations.


Development and Evaluation of a Multiplex Quantitative Real-Time Polymerase Chain Reaction for Hookworm Species in Human Stool.
Hookworm disease caused by Necator americanus, Ancylostoma duodenale, and Ancylostoma ceylanicum affects half a billion people worldwide. The prevalence and intensity of infection of individual hookworm species are vital for assessing morbidity and generating targeted intervention programs for their control. The present study aims to evaluate a multiplex real-time quantitative PCR (qPCR) assay to determine the prevalence and egg intensity of all three hookworm species and compare this with standard microscopy and published genus-based conventional and real-time multiplex qPCRs. Performance of the diagnostic assays was evaluated using DNA extracted from 192 fecal samples collected as part of a soil-transmitted helminth (STH) survey in northern Cambodia. The prevalence of hookworms as detected by the multiplex hookworm qPCR of 84/192 (43.8%) was significantly higher than that using microscopy of 49/192 (25.5%). The hookworm multiplex qPCR showed very good agreement for the detection of both N. americanus (Kappa 0.943) and Ancylostoma spp. (Kappa 0.936) with a multiplex STH qPCR. A strong and moderate quantitative correlation between cycle threshold and eggs per gram (EPG) feces was obtained for the hookworm qPCR for seeded DNA egg extracts (R 2 ≥ 0.9004) and naturally egg-infected individuals (R 2 = 0.6848), respectively. The newly developed hookworm quantitative multiplex qPCR has the potential for application in anthelmintic efficacy trials and for monitoring the success of mass deworming programs targeting individual species of anthroponotic and zoonotic hookworms.


Changing urbanization patterns in US lung cancer mortality, 1950-2007.
This study examined disparities in lung cancer mortality rates among US men and women in metropolitan and non-metropolitan areas from 1950 through 2007. Annual age-adjusted mortality rates were calculated for men and women in metropolitan and non-metropolitan areas, and differences in mortality rates were tested for statistical significance. Log-linear regression was used to model annual rates of change in mortality over time, while Poisson regression was used to estimate relative risk after adjusting for age, sex, deprivation, and urbanization levels. Urbanization patterns in lung cancer mortality changed dramatically between 1950 and 2007. Compared to men in metropolitan areas, men aged 25-64 years in non-metropolitan areas had significantly lower lung cancer mortality rates from 1950 to 1977 and men aged ≥65 years in non-metropolitan areas had lower mortality rates from 1950 to 1985. Differentials began to reverse and widen by the mid-1980s for men and by the mid-1990s for younger women. In 2007, compared to their metropolitan counterparts, men aged 25-64 and ≥65 years in non-metropolitan areas had 49 and 19% higher lung cancer mortality and women aged 25-64 and ≥65 years in non-metropolitan areas had 32 and 4% higher lung cancer mortality, respectively. Although adjustment for deprivation levels reduced excess lung cancer mortality risk among those in non-metropolitan areas, significant rural-urban differences remained. Rural-urban patterns reversed because of faster and earlier reductions in lung cancer mortality among men and women in metropolitan areas. Temporal trends in rural-urban disparities in lung cancer mortality appear to be consistent with those in smoking.


Field experiments find no evidence that chimpanzee nut cracking can be independently innovated.
Cumulative culture has been claimed a hallmark of human evolution. Yet, the uniqueness of human culture is heavily debated. The zone of latent solutions hypothesis states that only humans have cultural forms that require form-copying social learning and are culture-dependent. Non-human ape cultural behaviours are considered 'latent solutions', which can be independently (re-)innovated. Others claim that chimpanzees, like humans, have cumulative culture. Here, we use field experiments at Seringbara (Nimba Mountains, Guinea) to test whether chimpanzee nut cracking can be individually (re-)innovated. We provided: (1) palm nuts and stones, (2) palm fruit bunch, (3) cracked palm nuts and (4) Coula nuts and stones. Chimpanzee parties visited (n = 35) and explored (n = 11) the experiments but no nut cracking occurred. In these experiments, chimpanzees did not individually (re-)innovate nut cracking under ecologically valid conditions. Our null results are consistent with the hypothesis that chimpanzee nut cracking is a product of social learning.


Architecture of the yeast origin recognition complex bound to origins of DNA replication.
In many organisms, the replication of DNA requires the binding of a protein called the initiator to DNA sites referred to as origins of replication. Analyses of multiple initiator proteins bound to their cognate origins have provided important insights into the mechanism by which DNA replication is initiated. To extend this level of analysis to the study of eukaryotic chromosomal replication, we have investigated the architecture of the Saccharomyces cerevisiae origin recognition complex (ORC) bound to yeast origins of replication. Determination of DNA residues important for ORC-origin association indicated that ORC interacts preferentially with one strand of the ARS1 origin of replication. DNA binding assays using ORC complexes lacking one of the six subunits demonstrated that the DNA binding domain of ORC requires the coordinate action of five of the six ORC subunits. Protein-DNA cross-linking studies suggested that recognition of origin sequences is mediated primarily by two different groups of ORC subunits that make sequence-specific contacts with two distinct regions of the DNA. Implications of these findings for ORC function and the mechanism of initiation of eukaryotic DNA replication are discussed.


Amniotic fluid embolism.
Amniotic fluid embolism remains one of the most devastating conditions in obstetric practice with an incidence of approximately 1 in 40,000 deliveries and a reported mortality rate ranging from 20% to 60%. The pathophysiology appears to involve an abnormal maternal response to fetal tissue exposure associated with breaches of the maternal-fetal physiologic barrier during parturition. This response and its subsequent injury appear to involve activation of proinflammatory mediators similar to that seen with the classic systemic inflammatory response syndrome. Progress in our understanding of this syndrome continues to be hampered by a lack of universally acknowledged diagnostic criteria, the clinical similarities of this condition to other types of acute critical maternal illness, and the presence of a broad spectrum of disease severity. Clinical series based on population or administrative databases that do not include individual chart review by individuals with expertise in critical care obstetrics are likely to both overestimate the incidence and underestimate the mortality of this condition by the inclusion of women who did not have amniotic fluid embolism. Data regarding the presence of risk factors for amniotic fluid embolism are inconsistent and contradictory; at present, no putative risk factor has been identified that would justify modification of standard obstetric practice to reduce the risk of this condition. Maternal treatment is primarily supportive, whereas prompt delivery of the mother who has sustained cardiopulmonary arrest is critical for improved newborn outcome.


A hypertension control program in Yu-Chi, Taiwan: preliminary results.
The purpose of this study was to evaluate the feasibility and effectiveness of a community approach to hypertension control in both high risk and general populations in an agricultural district with limited medical and community resources. It was conducted in Yu-Chi district of Nan-Tou county in central Taiwan from 1993 to 1994. The study included blood pressure screening, follow-up, health education, village-based campaigns, and program evaluation after 6 months of intervention. Two villages each were randomly assigned to intervention and control groups. Intervention comprised visits by trained volunteers to measure blood pressure and body weight, and education related to hypertension. All residents 40 years of age and older were enrolled. A total of 471 residents from the intervention villages and 426 residents from the control villages completed the study. Overall, for the intervention and control groups, the knowledge and behavior related to hypertension improved significantly 6 months after the baseline survey. The improvement was greater in the subgroup of hypertensives in the intervention group than in the controls. The educational intervention also significantly improved the status of awareness, treatment, and the control of hypertension, and reduced blood pressure in the hypertensive subjects. We conclude that a hypertension control program that relies solely on limited community resources is feasible and effective.


Disruption of Rab3-calmodulin interaction, but not other effector interactions, prevents Rab3 inhibition of exocytosis.
Rab GTPases regulate membrane traffic between the cellular compartments of eukaryotic cells. Rab3 is associated with secretory vesicles of neuronal and endocrine cells and controls the Ca(2+)-triggered release of neurotransmitters and hormones. To clarify the mode of action of Rab3 we generated mutants of the GTPase that do not interact efficiently with its putative effectors Rabphilin and RIM. Surprisingly, these mutants transfected in PC12 cells were still capable of inhibiting Ca(2+)-evoked secretion. Rab3 was shown previously to bind to calmodulin in a Ca(2+)-dependent manner. By replacing two arginines conserved between Rab3 isoforms, we generated a mutant with a reduced affinity for calmodulin. This mutant retained the capacity to interact with the Rab3 regulatory proteins, Rabphilin, RIM, Mss4 and RabGDI, and was correctly targeted to dense-core secretory granules. However, replacement of the two arginines abolished the ability of the GTP-bound form of Rab3 to inhibit exocytosis of catecholamine- and insulin-secreting cells. We propose that a Rab3-calmodulin complex generated by elevated Ca(2+) concentrations mediated at least some of the effects of the GTPase and limited the number of exocytotic events that occurred in response to secretory stimuli.


Discriminatory performance of adiponectin and leptin in the identification of impaired glucose tolerance: The Guangzhou Biobank Cohort Study - Cardiovascular Disease Subcohort.
To evaluate the additional discriminatory performance of adiponectin, leptin, and their ratio in the identification of impaired glucose tolerance (IGT) in men and women without diabetes on top of conventional risk factors. A total of 698 subjects underwent an oral glucose tolerance test (oGTT) and adipocytokine measurements. A comprehensive stepwise selection procedure was performed, followed by c-statistics and integrated discrimination improvement (IDI) analysis. In males, adiponectin levels were significantly lower in the IGT group compared to the non-IGT group (Whitney U test, p < 10-4), whereas leptin levels were significantly higher (p = 0.009) in IGT group. In females, adiponectin and leptin levels were not significantly different between groups (Mann-Whitney U test, p = 0.073 and p = 0.08, respectively). Adjusting for the most informative, sex-specific, clinical and biochemical factors, adiponectin, leptin and their ratio were not found to be significant predictors of the response to the glucose load, when modelled as continuous terms or tertiles. In males, the area-under-the-curve (AUC) for adiponectin was estimated at 0.620 (95% CI: 0.558-0.682) and the addition of adiponectin into the basic model provided a ΔAUC benefit of 0.004, showing no additional discriminatory benefit on top of conventional risk factors (IDI p-value: 0.27), nor did the addition of leptin or their ratio. The results were similar in females. In Chinese individuals without diabetes, no significant evidence for the potential discriminatory value of adiponectin, leptin or their ratio in the identification of IGT on top of conventional risk factors was observed.


Community shift of ammonia-oxidizing bacteria along an anthropogenic pollution gradient from the Pearl River Delta to the South China Sea.
The phylogenetic diversity and abundance of ammonia-oxidizing beta-proteobacteria (beta-AOB) was analyzed along an anthropogenic pollution gradient from the coastal Pearl River Delta to the South China Sea using the ammonia monooxygenase subunit A (amoA) gene. Along the gradient from coastal to the open ocean, the phylogenetic diversity of the dominant genus changed from Nitrosomonas to Nitrosospira, indicating the niche specificity by these two genera as both salinity and anthropogenic influence were major factors involved. The diversity of bacterial amoA gene was also variable along the gradient, with the highest in the deep-sea sediments, followed by the marshes sediments and the lowest in the coastal areas. Within the Nitrosomonas-related clade, four distinct lineages were identified including a putative new one (A5-16) from the different sites over the large geographical area. In the Nitrosospira-related clade, the habitat-specific lineages to the deep-sea and coastal sediments were identified. This study also provides strong support that Nitrosomonas genus, especially Nitrosomonas oligotropha lineage (6a) could be a potential bio-indicator species for pollution or freshwater/wastewater input into coastal environments. A suite of statistical analyses used showed that water depth and temperature were major factors shaping the community structure of beta-AOB in this study area.


Screening for cognitive impairment in an Australian aged care assessment team as part of comprehensive geriatric assessment.
Accurate detection of mild cognitive impairment (MCI) is important to stratify and address risk. Yet, few short cognitive screening instruments are validated for this. . In Australia, all clients referred to an Aged Care Assessment Team (ACAT) receive comprehensive geriatric assessment (CGA) including the Standardized Mini-Mental State Examination (SMMSE). We compared the accuracy of the quick mild cognitive impairment (Qmci) screen to the SMMSE in 283 participants: 195 with dementia, 47 with MCI, and 41 with subjective cognitive decline (SCD) in an Australian community-based ACAT. Both had similar accuracy in identifying dementia, AUC of 0.86 for the Qmci versus 0.93 for the SMMSE (p = 0.10), but the Qmci was more accurate than the SMMSE in differentiating MCI from SCD, AUC of 0.84 versus 0.71, respectively, p = 0.046. These suggest that the new, short (3-5 min) Qmci screenis appropriate for use in an ACAT or other units conducting CGA.


Distinct Transcriptional Profiles in the Different Phenotypes of Neurofibroma from the Same Subject with Neurofibromatosis 1.
Neurofibromatosis 1 is a prevalent hereditary neurocutaneous disorder. Among the clinical phenotypes of neurofibromatosis 1, cutaneous neurofibroma (cNF) and plexiform neurofibroma (pNF) have distinct clinical manifestations, and pNF should be closely monitored owing to its malignant potential. However, the detailed distinct features of neurofibromatosis 1 phenotypes remain unknown. To determine whether the transcriptional features and microenvironment of cNF and pNF differ, single-cell RNA sequencing was performed on isolated cNF and pNF cells from the same patient. Six cNF and five pNF specimens from different subjects were also immunohistochemically analyzed. Our findings revealed that cNF and pNF had distinct transcriptional profiles even within the same subject. pNF is enriched in Schwann cells with characteristics similar to those of their malignant counterpart, fibroblasts, with a cancer-associated fibroblast-like phenotype, angiogenic endothelial cells, and M2-like macrophages, whereas cNF is enriched in CD8 T cells with tissue residency markers. The results of immunohistochemical analyses performed on different subjects agreed with those of single-cell RNA sequencing. This study found that cNF and pNF, the different neurofibromatosis phenotypes in neurofibromatosis 1, from the same subject are transcriptionally distinct in terms of the cell types involved, including T cells.


A Case Report of Avian Malaria (Plasmodium spp.) in Pen-Reared Pigeons (Columba livia).
One dead 6-wk-old male racing pigeon (Columba livia) was submitted for postmortem evaluation after presenting with weight loss, anorexia, dry shanks, dehydration, and lethargy. The bird belonged to a confined flock with 12 other pigeons raised by a hobbyist. Two pigeons in the flock reportedly had died with a history of similar clinical signs. On gross examination, the liver and the spleen were diffusely dark brown to black. Histopathology revealed moderate to large amounts of anisotropic, intracytoplasmic black pigment, compatible with hemozoin, in the spleen, liver, lung, and kidneys, with small amounts in the heart and meninges of the brain. Marked plasmacytic infiltrates were observed in liver, lungs, heart, and kidneys. Blood smears from a clinically affected concomitant pigeon from the flock revealed numerous light-blue, round to oval, intraerythrocytic trophozoites and meronts suggestive of Plasmodium spp. PCR and sequencing tests were performed from spleen and ceca with fragments of the 18S ribosomal RNA and the mitochondrial cytochrome b (cytB) genes. Sequencing results confirmed the presence of Plasmodium in the affected pigeon. Although an exact genetic match could not be determined, the most similar species to the isolate from this study are Plasmodium relictum, Plasmodium matutinum, Plasmodium lutzi, and Plasmodium homocircumflexum.


Disruption of the medical curriculum in a developing country: The need for medical students to be stronger than ever.
This article was migrated. The article was marked as recommended. Being a medical student from a low to moderate income country comes with its challenges particularly in moments where the world is facing with an uncharted territory; the COVID-19 pandemic. With no face to face interactions with lecturers, halt of clinical postings and uncertainty of when exams will be held, final year medical students are facing an unprecedented situation. Being a final year student, this personal view is aimed at describing the current situation of medical students in Mauritius, the numerous challenges that are being encountered and the coping strategies being adopted.


Localized and sustained release of brain-derived neurotrophic factor from injectable hydrogel/microparticle composites fosters spinal learning after spinal cord injury.
Damaged axons in the adult mammalian central nervous system (CNS), including those of the spinal cord, have extremely limited endogenous capacity to regenerate. This is the result of both the intrinsic and extrinsic inhibitory factors that limit the regeneration of adult neurons. Despite attempts to limit or eliminate the extrinsic inhibitory components, regeneration of adult neurons in the CNS is still limited. Therefore, additional factors that can further enhance the intrinsic plasticity of adult neurons need to be considered. Herein, we examine the effects of brain-derived neurotrophic factor (BDNF), a known growth factor for neuronal survival and plasticity, using an in vivo delivery method for a localized and sustained delivery to the spinal cord. A highly versatile injectable biomaterial platform for the sustained delivery of BDNF was developed using a physical blend of hyaluronic acid (HA) and methylcellulose (MC), in combination with poly-lactic-co-glycolic acid (PLGA) microparticles. Contemporary studies examining the plasticity of the CNS suggest that the spinal cord is an important site for activity-dependent learning that can mediate motor function after injury or disease. Here we utilized such a learning paradigm in combination with local and sustained BDNF application (at L3-S2) to foster spinal learning after complete spinal cord injury in rodents. Our data suggest that composite biomaterial systems such as the one described herein can be utilized for the sustained and localized delivery of therapeutics following damage to the spinal cord.