Distribution, morphology and habenular projections of adenosine deaminase-containing neurons in the septal area of rat.
Adenosine deaminase (ADA) was localized within several types of neurons within the septum and in septal efferent projections to the habenula by immunohistochemical, biochemical, retrograde tracing and lesion methods. Numerous ADA-immunoreactive (ADA-IR) neurons were observed in the septofimbrial nucleus, the triangular septal nucleus and the bed nucleus of the anterior commissure, while considerably fewer numbers were seen in the lateral septal area. Based on their size, shape and dendritic features, 4 morphologically distinct types of ADA-IR neurons were recognized in these septal structures. In addition, fine, non-varicose, ADA-IR fibers appeared to emanate from the postcommissural cell groups and these coalesced within the stria medullaris, continued caudally within this fiber bundle, and gave rise to a dense field of very fine immunoreactive elements within a restricted zone of the dorsal half of the medial habenula. Comparisons of the habenular localization of ADA-IR and enkephalin-IR elements showed that fibers labelled for either ADA or enkephalin occupied distinct, non-overlapping regions within the dorsal half of the medial habenula. After injections of Fluoro-gold (FG) into the medial habenula, the majority of ADA-IR neurons in the septofimbrial nucleus, triangular septal nucleus, and the bed nucleus of the anterior commissure were retrogradely labelled with this fluorescent tracer, whereas no ADA-positive FG-labelled neurons were observed in the lateral septal region. Unilateral transections of the stria medullaris caused substantial depletions of ADA-immunoreactivity and reduced enzymatically determined ADA activity by up to 80% in the medial habenula on the lesioned compared with the contralateral control side. These results demonstrate that ADA-IR neurons in the septum are heterogeneously distributed and that populations of positive neurons within the postcommissural septal nuclei give rise to dense, focal projections to the medial habenula. These projections appear to be restricted to a portion of the medial habenula known to contain substance P-IR neurons and are subregionally segregated from enkephalin-positive septohabenular projections ending within this same portion. In addition to pointing out a unique capacity for adenosine catabolism within some septal neurons, possibly related to purinergic neuromodulation, the results indicate the utility of ADA-immunohistochemistry for the delineation of anatomical relationships between the septum and the medial habenula.


Rac1 GTPase Inhibition Blocked Podocyte Injury and Glomerular Sclerosis during Hyperhomocysteinemia via Suppression of Nucleotide-Binding Oligomerization Domain-Like Receptor Containing Pyrin Domain 3 Inflammasome Activation.
Elevated homocysteine (Hcy) levels have been shown to activate nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome leading to podocyte dysfunction and glomerular injury. However, it remains unclear how this inflammasome activation in podocytes is a therapeutic target for reversal of glomerular injury and ultimate sclerosis. The present study tested whether inhibition of Rac1 GTPase activity suppresses NLRP3 inflammation activation and thereby blocks podocyte injury induced by elevated Hcy. In cultured podocytes, we found that L-Hcy (the active Hcy form) stimulated the NLRP3 inflammasome formation, as shown by increased colocalization of NLRP3 with apoptosis-associated speck-like protein (ASC) or caspase-1, which was accompanied by increased interleukin-1β production and caspase-1 activity, indicating NLRP3 inflammasome activation. Rac1 activator, uridine triphosphate (UTP), mimicked L-Hcy-induced NLRP3 inflammasome activation, while Rac1 inhibitor NSC23766 blocked it. This Rac1 inhibition also prevented L-Hcy-induced podocyte dysfunction. All these effects were shown to be mediated via lipid raft redox signaling platforms with nicotinamide adenine dinucleotide phosphate oxidase subunits and consequent O2- production. In animal studies, hyperhomocysteinemia (hHcy) induced by folate-free diet was shown to induce NLRP3 inflammasome formation and activation in glomeruli, which was also mimicked by UTP and inhibited by NSC23766 to a comparable level seen in Nlrp3 gene knockout mice. These results together suggest that Rac1 inhibition protects the kidney from hHcy-induced podocyte injury and glomerular sclerosis due to its action to suppress NLRP3 inflammasome activation in podocytes.


A comparative study of eight cell lines derived from human testicular teratocarcinoma.
Eight independent cell lines, derived from human testicular germ-cell tumors, were examined for the expression of various markers. These included major histocompatibility and embryonic antigens, chorionic gonadotropin, alpha fetoprotein, alkaline phosphatase, plasminogen activator, and infectivity by SV40. No line consisted primarily of choriocarcinoma or yolk sac cells, but several contained cells resembling murine embryonal carcinoma; some of these lines formed tumors with the distinctive features of embryonal carcinoma when injected into immunosuppressed animals. It is proposed that human embryonal carcinoma cells, unlike those of the mouse, correspond to a preblastocyst stage of development.


Predictors and incidence of sexually transmitted Hepatitis C virus infection in HIV positive men who have sex with men.
Sexual transmission of Hepatitis C virus (HCV) in men who have sex with men (MSM) and its interaction with HIV status, sexually transmitted infections and sexual behaviour is poorly understood. We assessed the incidence and predictors of HCV infection in HIV positive MSM. The electronic medical record and laboratory results from HIV positive MSM in care at a large urban public specialist HIV clinic embedded in a sexual health centre in Melbourne Australia were collected. Patients with two or more HCV antibody tests between January 2008 and March 2016 and with no record of injecting drug use were included. The HCV exposure intervals were the periods between a negative HCV test and the next HCV test. We compared HCV exposure intervals temporally associated with and without newly acquired syphilis or anorectal chlamydia. HCV exposure intervals were also categorised as being before or after HIV virological suppression and by most recent and nadir CD4 cell count. Thirty seven new HCV infections were diagnosed in 822 HIV positive MSM with no history of injecting drug use over 3114 person years (PY) of follow-up. Mean age was 43.1 years (±12.5) and mean CD4 cell count nadir was 362 cells/uL (±186). The incidence of HCV infection in the study population was 1.19/100PY (0.99-1.38). The incidence in exposure periods temporally close to new syphilis infection was 4.72/100PY (3.35-6.08) and to new anorectal chlamydia infection was 1.37/100PY (0.81-1.93). The incidence in men without supressed viral load was 3.19/100PY (1.89-4.49). In the multivariate Cox regression analysis only younger age (aHR 0.67 (0.48-0.92)), exposure periods temporally associated to new syphilis infection (aHR 4.96 (2.46-9.99)) and higher CD4 cell count nadir (aHR 1.26 per 100 cells/uL (1.01-1.58)) were associated with increased risk of HCV infection. During the study period the incidence of syphilis increased dramatically but the incidence of HCV infection remained the same. Incidence of HCV infection is associated with syphilis but not anorectal chlamydia which suggests a biological rather than behavioural risk modification. Rising syphilis incidence may offset declines in HCV transmission through HCV treatment as prevention.


[Growth hormone administration in the treatment of growth retardation in juvenile SLE--case history].
A chronic autoimmune inflammatory process and a long-term steroid therapy seems to underlie growth inhibition in children suffering from juvenile systemic lupus erythematosus (JSLE). The study objective was to assess the effect of one-year GH therapy on the growth rate in a 17-year-old girl with JSLE diagnosed when she was 11. Growth rate slowdown was observed when the girl was eleven (up to the age of 10 the growth was harmonious--50 centile). Since then, the mean gain in body height was approximately 1 cm/year. At the age of 16 (prior to the start of GH therapy), she was 148 cm high (below 3 centile), telarche II degrees, pubarche I degrees. The skeletal age corresponded to approximately 11 years according to the method of Greulich-Pyle. The girl underwent hormonal examinations in the Endocrinology Outpatient Department, including stimulatory tests of pituitary GH reserve, and based on the findings she was qualified for GH therapy, at a weekly dose of 30 IU. Within the 6-month-therapy, the patient grew by 7.5 cm, with the final outcome of 161 cm. The period of treatment was free of JSLE exacerbations or glucose tolerance disturbances. The only side effects included enhanced thirst and transitory oedema of the lower extremities observed in the first week of therapy. At the same time the patient's general feeling improved. During a one-year GH therapy, the girl achieved catch-up growth, which was accompanied by body weight reduction and no significant side effects.


Biophysical characterization of hit compounds for mechanism-based enzyme activation.
Across all families of enzymes, only a dozen or so distinct classes of non-natural small molecule activators have been characterized, with only four known modes of activation among them. All of these modes of activation rely on naturally evolved binding sites that trigger global conformational changes. Among the enzymes that are of greatest interest for small molecule activation are the seven sirtuin enzymes, nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play a central role in the regulation of healthspan and lifespan in organisms ranging from yeast to mammals. However, there is currently no understanding of how to design sirtuin-activating compounds beyond allosteric activators of SIRT1-catalyzed reactions that are limited to particular substrates. Here, we introduce a general mode of sirtuin activation that is distinct from the known modes of enzyme activation. Based on the conserved mechanism of sirtuin-catalyzed deacylation reactions, we establish biophysical properties of small molecule modulators that can in principle result in enzyme activation for diverse sirtuins and substrates. Building upon this framework, we propose strategies for the identification, characterization and evolution of hits for mechanism-based enzyme activating compounds.


Prevalence of hemoplasmas and Bartonella species in client-owned cats in Beijing and Shanghai, China.
A year-round molecular epidemiological survey (2017 to 2018) was conducted on three hemoplasmas and two Bartonella species with zoonotic potential in client-owned cats in Beijing and Shanghai. Among 668 specimens, the overall hemoplasma-positive rate was 4.9% (3.4% for Candidatus Mycoplasma haemominutum, 0.9% for Mycoplasma haemofelis and 1.2% for Candidatus Mycoplasma turicensis). The overall Bartonella-positive rate was 8.5% (4.8% for B. henselae and 4.3% for B. clarridgeiae). Age, breed, ectoparasiticide use and stray history, but not city, season and gender, were significantly associated with the positive rates of one or more pathogens. This is also the first report on the prevalence of Candidatus Mycoplasma turicensis in cats in China.


Individual differences in the ability to access spatial information in lag-clicks.
It may be difficult to determine whether a dichotic lag-click points to the left or right when preceded by a diotic lead-click. Previous research suggests that this loss of spatial information is most prominent at inter-click intervals (ICIs) <10 ms. However, a study by Nilsson, Tirado, and Szychowska [(2019). J. Acoust. Soc. Am. 145, 512-524] found support for loss of spatial information in lag-clicks at much longer ICIs using a stimulus setup differing from those in previous research. The present study used a setup similar to that of the Nilsson, Tirado, and Szychowska study [(2019). J. Acoust. Soc. Am. 145, 512-524] to measure 13 listeners' ability to lateralize (left versus right) and detect (present versus absent) the lag-click in lead-lag click pairs with ICIs of 6-48 ms. The main finding was distinct individual differences in performance. Some listeners could lateralize lag-clicks all the way down to their detection threshold, whereas others had lateralization thresholds substantially higher than their detection thresholds, i.e., they could not lateralize lag-clicks that they could easily detect. Two such listeners trained for 30 days and managed to improve their lateralization thresholds to reach their detection thresholds, but only at longer ICIs (>20 ms), suggesting different mechanisms underlying lag-click lateralization at short versus long ICIs.


Morphology of the seminal vesicle of Calomys callosus submitted to experimental chronic alcoholism.
The objective of the present study was to assess the possible toxic effects of chronic alcohol ingestion on the ultrastructure of the lining epithelium of the seminal vesicle of the rodent Calomys callosus, in order to contribute to the understanding of the consequences of alcohol abuse for the morphology of the male reproductive apparatus. Twenty six adult animals aged three months were divided into two experimental groups. The control group received a solid diet (Purina chow) and tap water, and the alcoholic group received the same solid diet and ethanol P.A. diluted 20% in water (v/v). After 210 days of treatment, all animals were anaesthetised, weighed and sacrificed. At the end of treatment, mean body and seminal vesicle weight did not differ between control and alcoholic animals. The epithelial cells of the alcoholic group showed many alterations such as the presence of lipid droplets of different sizes, nuclei with increased peripheral chromatin and greater electrondensity, megamitochondria, and intense dilatation of the cisterns of the granular endoplasmic reticulum. It was concluded that 20% ethanol provokes marked ultrastructural lesions in the seminal vesicle.


Toward modeling H-NOX domains: a DFT study of heme-NO complexes as hydrogen bond acceptors.
Density functional theory calculations (PW91/STO-TZP, including basis-set superposition error corrections) have been used to evaluate hydrogen bond energies of five- and six-coordinate heme-NO complexes with phenol and imidazole, chosen as models for distal pocket tyrosine and histidine residues. The calculated interaction energies are approximately 2 kcal/mol for phenol and 3-4 kcal/mol for imidazole, which are 2-4 times smaller than the energies calculated for heme-O(2) complexes hydrogen-bonding with a distal histidine. Interestingly, the hydrogen bond energies are found to be very similar for five- and six-coordinate heme-NO complexes, which may be viewed as contrary to the interpretation of a recent observation on a bacterial H-NOX (Heme-Nitric oxide/OXygen-binding) protein with sequence homology to mammalian-soluble guanylate cyclase.


Modulating Wnt Signaling Rescues Palate Morphogenesis in Pax9 Mutant Mice.
Cleft palate is a common birth defect caused by disruption of palatogenesis during embryonic development. Although mutations disrupting components of the Wnt signaling pathway have been associated with cleft lip and palate in humans and mice, the mechanisms involving canonical Wnt signaling and its regulation in secondary palate development are not well understood. Here, we report that canonical Wnt signaling plays an important role in Pax9-mediated regulation of secondary palate development. We found that cleft palate pathogenesis in Pax9-deficient embryos is accompanied by significantly reduced expression of Axin2, an endogenous target of canonical Wnt signaling, in the developing palatal mesenchyme, particularly in the posterior regions of the palatal shelves. We found that expression of Dkk2, encoding a secreted Wnt antagonist, is significantly increased whereas the levels of active β-catenin protein, the essential transcriptional coactivator of canonical Wnt signaling, is significantly decreased in the posterior regions of the palatal shelves in embryonic day 13.5 Pax9-deficent embryos in comparison with control littermates. We show that small molecule-mediated inhibition of Dickkopf (DKK) activity in utero during palatal shelf morphogenesis partly rescued secondary palate development in Pax9-deficient embryos. Moreover, we found that genetic inactivation of Wise, which is expressed in the developing palatal shelves and encodes another secreted antagonist of canonical Wnt signaling, also rescued palate morphogenesis in Pax9-deficient mice. Furthermore, whereas Pax9del/del embryos exhibit defects in palatal shelf elevation/reorientation and significant reduction in accumulation of hyaluronic acid-a high molecular extracellular matrix glycosaminoglycan implicated in playing an important role in palatal shelf elevation-80% of Pax9del/del;Wise-/- double-mutant mouse embryos exhibit rescued palatal shelf elevation/reorientation, accompanied by restored hyaluronic acid accumulation in the palatal mesenchyme. Together, these data identify a crucial role for canonical Wnt signaling in acting downstream of Pax9 to regulate palate morphogenesis.


The influence of iodine on the intensity of the intrathyroidal autoimmune process in Graves' disease.
Several lines of evidence support an etiological role of iodine for the initiation and perpetuation of autoimmune thyroid disease. However, varying relapse rates after increased iodine supplementation have been reported for Graves' disease. Furthermore the effects of iodine on the intensity of human autoimmune thyroiditis have previously only been investigated by indirect parameters and actions of iodine on thyroid function and a possible enhancement of the intrathyroidal autoimmune process in Graves' disease are difficult to separate in previous studies. Moreover lymphocytic thyroiditis in animal models has always been induced by considerably higher iodine doses as those used in in vivo studies. Therefore we investigated the effect of low and high iodine concentrations on the intensity of the intrathyroidal autoimmune process in Graves' disease. The intensity of intrathyroidal infiltration by lymphocytes, memory T cells, plasma cells and antigen presenting cells was determined by quantitative immunohistologic methods in 38 Graves' disease patients. 12 patients received additional preoperative iodine (group II) and 26 were treated with thiourelene antithyroid drugs only (group I). Urinary and intrathyroidal iodine concentrations were determined by a modified cer arsenite method in both groups. Application of high iodine doses in group II induced a significant increase of kappa and lambda positive plasma cells and interdigitating reticulum cells. This was not observed for activated T cells. There was no correlation between the extent of intrathyroidal infiltration by activated T cells, plasma cells and antigen presenting cells, and intrathyroidal or urinary iodine or intrathyroidal iodine concentrations in group I.(ABSTRACT TRUNCATED AT 250 WORDS)


Streptococcus pneumoniae causing septic arthritis with shock and revealing multiple myeloma.
The authors present the case of a 43-year-old male who presented at the emergency department, with a mean arterial pressure of 48 mm of Hg, a sinus tachycardia of 142/min and shallow breathing at 30/min. Two days previously, he started a high-grade fever with a concomitant reddish and painful left knee and right elbow, without any treatment. Septic shock was diagnosed and the patient was started on empiric antibiotics combining ceftriaxone and vancomycin and vasopressors (norepinephrine). The painful knee and elbow joints were aspirated and cultures grew Streptococcus pneumoniae. The patient's clinical condition improved progressively and after investigation, the diagnosis of multiple myeloma was concluded. Pneumococcal septic arthritis, an extraordinary cause of septic arthritis, is a manifestation of an underlying disease and can be responsible for septic shock. Its diagnosis should direct further investigations. It can occur in patients with joint disease but should emphasise the search of systemic immunosuppression.


Exploring the Contributions of Combined Model Regional Medical Education Campuses to the Physician Workforce.
Physician shortages and maldistribution, particularly within family medicine, have led many medical schools worldwide to create regional medical campuses (RMCs) for clerkship training. However, Canadian medical schools have developed a number of RMCs in which all years of training (i.e., a combined model that includes both preclerkship and clinical training) are provided geographically separate from the main campus. This study addresses the question: Are combined model RMC graduates more likely to enter postgraduate training in family medicine and rural-focused programs relative to main campus graduates? The authors used a quasi-experimental research design and analyzed 2006-2016 data from the Canadian Resident Matching Service (CaRMS). Graduating students (N = 26,525) from 16 Canadian medical schools who applied for the CaRMS match in their year of medical school graduation were eligible for inclusion. The proportions of graduates who matched to postgraduate training in (1) family medicine and (2) rural-focused programs were compared for combined model RMCs and main campuses. Of RMC graduates, 48.4% matched to family medicine (95% confidence interval [CI] = 46.1-50.7) compared with 37.1% of main campus graduates (95% CI = 36.5-37.7; P < .001). Of RMC graduates, 23.9% matched to rural-focused training programs (95% CI = 21.8-25.9) compared with 10.4% of main campus graduates (95% CI = 10.0-10.8; P < .001). Subanalyses ruled out a variety of potentially confounding variables. Combined model RMCs, in which all years of training take place away from the medical school's main campus, are associated with greater proportions of medical students entering family medicine postgraduate training and rural-focused training programs. These findings should encourage policymakers, health services agencies, and medical schools to continue seeking complements to academic medical center-based medical education.


Diagnostic performance and costs of contingent screening models for trisomy 21 incorporating non-invasive prenatal testing.
Contingent screening for trisomy 21 using non-invasive prenatal testing has the potential to reduce invasive diagnostic testing and increase the detection of trisomy 21. To describe the diagnostic and economic performance of prenatal screening models for trisomy 21 that use non-invasive prenatal testing as a contingent screen across a range of combined first trimester screening risk cut-offs from a public health system perspective. Using a hypothetical cohort of 300 000 pregnancies, we modelled the outcomes of 25 contingent non-invasive prenatal testing screening models and compared these to conventional screening, offering women with a high-risk (1 > 300) combined first trimester screening result an invasive test. The 25 models used a range of risk cut-offs. High-risk women were offered invasive testing. Intermediate-risk women were offered non-invasive prenatal testing. We report the cost of each model, detection rate, costs per diagnosis, invasive tests per diagnosis and the number of fetal losses per diagnosis. The cost per prenatal diagnosis of trisomy 21 using the conventional model was $51 876 compared to the contingent models which varied from $49 309-66 686. The number of diagnoses and cost per diagnosis increased as the intermediate-risk threshold was lowered. Results were sensitive to trisomy 21 incidence, uptake of testing and cost of non-invasive prenatal testing. Contingent non-invasive prenatal testing models using more sensitive combined first trimester screening risk cut-offs than conventional screening improved the detection rate of trisomy 21, reduced procedure-related fetal loss and could potentially be provided at a lower cost per diagnosis than conventional screening.


Commercial glucocorticoid formulations and skin dryness. Could it be caused by the vehicle?
Eczema craquelé can be induced by repeated open application of a topical glucocorticoid, viz. 0.05% clobetasole 17-propionate cream. This might not be invariably due to the active component. Comparison of the skin surface roughness as assessed by profilometry and as expressed by RZDIN showed a decrease after repeated open application of 0.1% betamethasone 17-valerate cream and 0.25% prednicarbate cream, but an increase following the vehicle of the latter preparation. Thus commercial oil-in-water emulsion preparations seem to be potentially injurious to human skin, though this may be masked when a glucocorticoid is added.


Microfluidic Patterning of Metal Structures for Flexible Conductors by In Situ Polymer-Assisted Electroless Deposition.
A low-cost, solution-processed, versatile, microfluidic approach is developed for patterning structures of highly conductive metals (e.g., copper, silver, and nickel) on chemically modified flexible polyethylene terephthalate thin films by in situ polymer-assisted electroless metal deposition. This method has significantly lowered the consumption of catalyst as well as the metal plating solution.


Identifying and quantifying main components of physiological noise in functional near infrared spectroscopy on the prefrontal cortex.
Functional Near-Infrared Spectroscopy (fNIRS) is a promising method to study functional organization of the prefrontal cortex. However, in order to realize the high potential of fNIRS, effective discrimination between physiological noise originating from forehead skin haemodynamic and cerebral signals is required. Main sources of physiological noise are global and local blood flow regulation processes on multiple time scales. The goal of the present study was to identify the main physiological noise contributions in fNIRS forehead signals and to develop a method for physiological de-noising of fNIRS data. To achieve this goal we combined concurrent time-domain fNIRS and peripheral physiology recordings with wavelet coherence analysis (WCA). Depth selectivity was achieved by analyzing moments of photon time-of-flight distributions provided by time-domain fNIRS. Simultaneously, mean arterial blood pressure (MAP), heart rate (HR), and skin blood flow (SBF) on the forehead were recorded. WCA was employed to quantify the impact of physiological processes on fNIRS signals separately for different time scales. We identified three main processes contributing to physiological noise in fNIRS signals on the forehead. The first process with the period of about 3 s is induced by respiration. The second process is highly correlated with time lagged MAP and HR fluctuations with a period of about 10 s often referred as Mayer waves. The third process is local regulation of the facial SBF time locked to the task-evoked fNIRS signals. All processes affect oxygenated haemoglobin concentration more strongly than that of deoxygenated haemoglobin. Based on these results we developed a set of physiological regressors, which were used for physiological de-noising of fNIRS signals. Our results demonstrate that proposed de-noising method can significantly improve the sensitivity of fNIRS to cerebral signals.


Activation time of myocardial oxidative phosphorylation in creatine kinase and adenylate kinase knockout mice.
Our goal was to determine whether mice genetically altered to lack either creatine kinase (M/MtCK(-/-)) or adenylate kinase (AK(-/-)) show altered properties in the dynamic regulation of myocardial oxygen consumption (MVO(2)). We measured contractile function, oxygen consumption, and the mean response time of oxygen consumption to a step increase in heart rate [i.e., mitochondrial response time (t(mito))] in isolated Langendorff-perfused hearts from wild-type (n = 6), M/MtCK(-/-) (n = 6), and AK(-/-) (n = 4) mice. Left ventricular developed pressure was higher in M/MtCK(-/-) hearts (88.2 +/- 6.8 mmHg) and lower in AK(-/-) hearts (46.7 +/- 9.4 mmHg) compared with wild-type hearts (60.7 +/- 10.1 mmHg) at the basal pacing rate. Developed pressure fell slightly when heart rate was increased in all three groups. Basal MVO(2) at 300 beats/min was 19.1 +/- 2.4, 19.4 +/- 1.5, and 16.3 +/- 1.9 micromol x min(-1) x g dry wt(-1) for M/MtCK(-/-), AK(-/-), and wild type, respectively, which increased to 25.5 +/- 3.7, 25.4 +/- 2.6, and 22.0 +/- 2.6 micromol. min(-1) x g(-1), when heart rate was increased to 400 beats/min. The t(mito) was significantly faster in M/MtCK(-/-) hearts: 3.0 +/- 0.3 versus 7.3 +/- 0.6 and 8.0 +/- 0.4 s for M/MtCK(-/-), AK(-/-), and wild-type hearts, respectively. Our results demonstrate that MVO(2) of M/MtCK(-/-) hearts adapts more quickly to an increase in heart rate and thereby support the hypothesis that creatine kinase acts as an energy buffer in the cytosol, which delays the energy-related signal between sites of ATP hydrolysis and mitochondria.


Why the AMA is (now) worth joining.
The AMA is partnering with several public health-oriented organizations, including the Centers for Disease Control and Prevention, to reach out to individuals with diabetes, cardiovascular disease, and cardiac risk factors to promote primary and secondary prevention strategies at a population level.


Gastric cancer recognized by metastasis to the ureter.
Although ureteral obstruction is rarely noted in patients with gastric cancer at an advanced stage or at autopsy, the condition caused by authentic ureteral metastasis of gastric cancer is extremely rare. We experienced a case of gastric cancer in a 51-year-old woman who showed bilateral ureteral metastasis. The patient initially complained of right flank pain, caused by right ureteral obstruction, and was referred to our hospital, where she underwent a right nephroureterectomy, with suspicion of primary ureteral neoplasm. Histopathological examination of the resected specimen showed that metastatic growth of adenocarcinoma in the ureteral wall had caused the obstruction, and the subsequent extensive search for the primary lesion revealed asymptomatic gastric cancer. Soon after the nephroureterectomy, the patient developed left hydronephrosis, possibly caused by left ureteral metastasis, and a left percutaneous nephrostomy was performed. She then received chemotherapeutic reagents. However, she finally developed peritoneal carcinomatosis, and died of the disease about 1 year after the onset of the disease. In this report, we also review true ureteral metastasis from the stomach, and discuss the clinicopathologic features.


Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease.
The TAFRO clinical subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO) is a rare hematologic illness involving episodic disease flares of thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly (TAFRO) and progressive multiple organ dysfunction. We previously showed that the mTOR signaling pathway is elevated in lymph nodes of iMCD-TAFRO patients and that an mTOR inhibitor is effective in a small cohort of patients. However, the upstream mechanisms, cell types, and mediators involved in disease pathogenesis remain unknown. Here, we developed a targeted approach to identify candidate cellular drivers and mechanisms in iMCD-TAFRO through cellular and transcriptomic studies. Using paired iMCD-TAFRO PBMC samples collected during flare and remission, we identified T cell activation and alterations in NK cell and monocyte subset frequencies during iMCD-TAFRO flare. These changes were associated with increased Type I IFN (IFN-I) response gene signatures across CD8+ T cells, NK cells, and monocytes. Finally, we found that IFN-β stimulation of monocytes and T cells from iMCD-TAFRO patient remission samples induced increased mTOR activation compared with healthy donors, and this was abrogated with either mTORC1 or JAK1/2 inhibition. The data presented here support a potentially novel role for IFN-I signaling as a driver of increased mTOR signaling in iMCD-TAFRO.


Value of diagnostic procedures in rectovaginal endometriosis.
Rectovaginal endometriosis has the potential to infiltrate into the rectal wall. The recognition of infiltration prior to surgery is of utmost importance since only infiltrative disease should be treated by partial or complete rectal resection. This study compares different imaging procedures in rectovaginal endometriosis cases in an everyday clinical setting. Seventy nine consecutive women diagnosed with rectovaginal endometriosis were included in this prospective study. Preoperatively, all women had a rectovaginal gynaecological examination and transvaginal sonography. Furthermore, MRI or rectal endosonography imaging procedures together with a rectosigmoidoscopy and estimation of a serum Ca125 were undertaken. Sensitivity and specificity of all diagnostic tools were compared with the intraoperative findings. The procedure with the highest accuracy was bimanual rectovaginal gynaecological examination (sensitivity: 0.92/specificity: 0.32). Rectal endosonography obtained a sensitivity of 0.44 and a specificity of 0.77. All other diagnostic procedures such as Ca125 (sensitivity: 0.42/specificity: 0.81), MRI (sensitivity: 0.41/specificity: 0.83), transvaginal sonography (sensitivity: 0.2/ specificity: 0.79) and rectosigmoidoscopy (sensitivity: 0.03/specificity: 0.92) were only of limited value. The diagnostic method with the highest sensitivity to detect bowel infiltration in an everyday clinical setting is the gynaecological examination. It is followed by rectal endosonography. However, none of the currently available preoperative diagnostic tools can predict infiltrative growth of rectovaginal endometriosis with any certainty. Hence, infiltrative growth still needs to be verified by operative assessment.


Induction of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) by Glycyrrhiza Species Used for Women's Health: Differential Effects of the Michael Acceptors Isoliquiritigenin and Licochalcone A.
For the alleviation of menopausal symptoms, women frequently turn to botanical dietary supplements, such as licorice and hops. In addition to estrogenic properties, these botanicals could also have chemopreventive effects. We have previously shown that hops and its Michael acceptor xanthohumol (XH) induced the chemoprevention enzyme, quinone oxidoreductase 1 (NQO1), in vitro and in vivo. Licorice species could also induce NQO1, as they contain the Michael acceptors isoliquiritigenin (LigC) found in Glycyrrhiza glabra (GG), G. uralensis (GU), G. inflata (GI), and licochalcone A (LicA) which is only found in GI. These licorice species and hops induced NQO1 activity in murine hepatoma (Hepa1c1c7) cells; hops ≫ GI > GG ≅ GU. Similar to the known chemopreventive compounds curcumin (turmeric), sulforaphane (broccoli), and XH, LigC and LicA were active dose-dependently; sulforaphane ≫ XH > LigC > LicA ≅ curcumin ≫ liquiritigenin (LigF). Induction of the antioxidant response element luciferase in human hepatoma (HepG2-ARE-C8) cells suggested involvement of the Keap1-Nrf2 pathway. GG, GU, and LigC also induced NQO1 in nontumorigenic breast epithelial MCF-10A cells. In female Sprague-Dawley rats treated with GG and GU, LigC and LigF were detected in the liver and mammary gland. GG weakly enhanced NQO1 activity in the mammary tissue but not in the liver. Treatment with LigC alone did not induce NQO1 in vivo most likely due to its conversion to LigF, extensive metabolism, and its low bioavailability in vivo. These data show the chemopreventive potential of licorice species in vitro could be due to LigC and LicA and emphasize the importance of chemical and biological standardization of botanicals used as dietary supplements. Although the in vivo effects in the rat model after four-day treatment are minimal, it must be emphasized that menopausal women take these supplements for extended periods of time and long-term beneficial effects are quite possible.


Neutron autoradiography to study boron compound microdistribution in an oral cancer model.
We previously reported the therapeutic efficacy of Sequential Boron Neutron Capture Therapy (Seq-BNCT), i.e., BPA (boronophenylalanine) - BNCT followed by GB-10 (decahydrodecaborate) - BNCT 1 or 2 days later, in the hamster cheek pouch oral cancer model. We have utilized the neutron autoradiography methodology to study boron microdistribution in tissue. The aim was to use this method to evaluate if the distribution of GB-10 is altered by prior application of BPA-BNCT in Sequential BNCT protocols. Extensive qualitative and quantitative autoradiography analyses were performed in the following groups: G1 (animals without boron); G2 (animals injected with BPA); G3 (animals injected with GB-10); G4 (same as G3, 24 h after BPA-BNCT); and G5 (same protocol as G4, 48 h interval). A detailed study of boron localization in the different tissue structures of tumor, premalignant and normal tissue in the hamster cheek pouch was performed. GB-10 accumulated preferentially in non-neoplastic connective tissue, whereas for BPA neoplastic cells showed the highest boron concentration. Boron distribution was less heterogeneous for GB-10 than for BPA. In premalignant and normal tissue, GB-10 and BPA accumulated mostly in connective tissue and epithelium, respectively. BPA-BNCT could alter boron microlocalization of GB-10 administered subsequently. Boron targeting homogeneity is essential for therapeutic success.


SALpingectomy for STERilisation (SALSTER): study protocol for a Swedish multicentre register-based randomised controlled trial.
Salpingectomy is currently suggested as an alternative to tubal ligation for sterilisation. Precursor lesions of ovarian carcinoma can be found in the fallopian tubes; thus, salpingectomy could possibly reduce the incidence. Most of the existing trials on safety are small, on caesarean section and report on surrogate ovarian function measures. Randomised trials in laparoscopy are lacking. Well-designed trials are needed to evaluate safety of laparoscopic opportunistic salpingectomy. In SALSTER, a national register-based randomised controlled non-inferiority trial, 968 women <50 years, wishing laparoscopic sterilisation will be randomised to either salpingectomy or tubal ligation. The Swedish National Quality Register of Gynecological Surgery (GynOp) will be used for inclusion, randomisation and follow-up. Primary outcomes are any complication up to 8 weeks postoperatively, and age at menopause. Both outcomes are measured with questionnaires, complications are also assessed by a gynaecologist. In a nested trial, ovarian function will be evaluated comparing the mean difference of anti-Müllerian hormone (AMH), assessed preoperatively and 1 year after surgery. Performing salpingectomy for sterilisation has become increasingly common, despite the unclear risk-benefit balance. SALSTER studies the safety of salpingectomy compared with tubal ligation. Regardless of the result, SALSTER will provide gynaecologists with high quality evidence to inform women to decide on salpingectomy or not. The central ethical review board of Gothenburg, Sweden (Dnr. 316-18) approved the trial in 2018. Results will be presented at scientific congresses and published in peer-reviewed scientific journals. The results will be communicated through professional organisations and research networks. NCT03860805.


Impact of chemical cleaning and air-sparging on the critical and sustainable flux in a flat sheet membrane bioreactor for municipal wastewater treatment.
The paper discusses the experimental optimisation of both chemical and mechanical cleaning procedures for a flat-sheet submerged membrane bioreactor fed with municipal wastewater. Fouling was evaluated by means of the critical flux concept, which was experimentally measured by short-term flux-stepping tests. By keeping constant most important parameters of the biological process (MLSS, sludge age), two different chemical cleaning protocols (2,000 mg L(-1) NaOCl and 200 mg L(-1) NaOCl) were applied with different frequency and, after approximately 9 months of operation, the criticality threshold was determined under different values of SAD(m) (specific aeration demand per unit of membrane surface area). The weaker and more frequent chemical cleaning regime (200 mg L(-1), monthly) proved much more effective than the stronger and less frequent strategy (2,000 mg L(-1), once every three months). The improvement of performances was quantified by two TMP-based parameters, the fouling rate and the DeltaTMP (difference between TMP values during the increasing and decreasing phase of hysteresis). The best performing configuration was then checked over a longer period by running four long-term trials showing an exponential trend of the sub-critical fouling rate with the imposed flux.


Osteopontin promotes host defense during Klebsiella pneumoniae-induced pneumonia.
Klebsiella pneumoniae is a common cause of nosocomial pneumonia. Osteopontin (OPN) is a phosphorylated glycoprotein involved in inflammatory processes, some of which is mediated by CD44. The aim of this study was to determine the role of OPN during K. pneumoniae-induced pneumonia. Wild-type (WT) and OPN knockout (KO) mice were intranasally infected with 10⁴ colony forming units of K. pneumoniae, or administered Klebsiella lipopolysaccharides (LPS). In addition, recombinant OPN (rOPN) was intranasally administered to WT and CD44 KO mice. During Klebsiella pneumonia, WT mice displayed elevated pulmonary and plasma OPN levels. OPN KO and WT mice showed similar pulmonary bacterial loads 6 h after infection; thereafter, Klebsiella loads were higher in lungs of OPN KO mice and the mortality rate in this group was higher than in WT mice. Early neutrophil recruitment into the bronchoalveolar space was impaired in the absence of OPN after intrapulmonary delivery of either Klebsiella bacteria or Klebsiella LPS. Moreover, rOPN induced neutrophil migration into the bronchoalveolar space, independent from CD44. In vitro, OPN did not affect K. pneumoniae growth or neutrophil function. In conclusion, OPN levels were rapidly increased in the bronchoalveolar space during K. pneumoniae pneumonia, where OPN serves a chemotactic function towards neutrophils, thereby facilitating an effective innate immune response.


Theoretical Rationalization of Self-Assembly of Cellulose Nanocrystals: Effect of Surface Modifications and Counterions.
The hierarchical self-assembly of cellulose nanocrystals (CNCs) is an important phenomenon occurring naturally in plant cell walls. Utilization of this assembly for advanced applications requires a fundamental theoretical understanding of interactions between the CNCs, which is still incomplete. Hence, in this work, we used molecular dynamics simulations to study the effect of surface modification on the interactions between the CNCs and the resulting bundling process. We consider two types of common surface modifications of native CNCs, sulfated CNCs (SCNCs) and TEMPO-oxidized CNCs (TCNCs), in the presence of two types of counterions, Na+ and Ca2+, in solution. We used the umbrella sampling method to calculate the potential of the mean force (PMF), and we found that the strength of interaction between the modified CNCs decreases, compared with the native CNCs. The strength of interaction for TCNCs is almost similar to that for SCNCs at the same level of surface substitution, whereas the type of counterion has a strong effect on the PMF with a higher interaction energy between the CNCs in the presence of a divalent counterion as compared to a monovalent counterion. Finally, we studied the self-assembly of CNCs into a hexagonal bundle for the native CNCs and sulfated CNCs focusing on the twist of the bundle, bound water inside the bundle, inter-CNC gap, and interaction energy between the CNCs in the bundle, and the effect of the counterions on the morphology of the bundle. The equilibrium spacing of the CNCs within the bundle is found to be consistent with the results of PMF calculations for the minimum separation distance between the respective crystal surfaces.


Different time scales in wave function intensity statistics.
Unstable periodic orbits scar wave functions in chaotic systems. The local short term dynamics also influences the associated spectra that follow the otherwise universal Porter-Thomas intensity distribution. We show here how this deviation extends to other longer periodic orbits sharing some common dynamical characteristics. This indicates that the quantum mechanics of the system can be described quite simply with few orbits, up to the resolution associated with the corresponding lengths.


Inpatient Occupational Therapy Management for a Pediatric Patient With COVID-19 and Multisystem Inflammatory Syndrome in Children: A Case Report.
This case report describes the distinct value of occupational therapy services in the treatment of a pediatric patient with coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children in an acute care setting. Practice-based evidence was used to design the treatment plan for this patient throughout the course of his hospital stay. Interventions addressed range of motion, strength, functional endurance, activities of daily living (ADLs), instrumental activities of daily living (IADLs), and functional cognition. Occupational therapy goals focused on the progression toward return to baseline functioning and participation in ADLs and IADLs.


[Identification of Ixodes persulcatus and Ixodes pavlovskyi occidentalis (Ixodidae) by the analysis of the gene fragment COXI (cytochrome oxidase subunit I)].
Ticks of the genus Ixodes were collected in 2010 in the lowland part of Toguchinsk district of Novosibirsk Province (Russia) and in the forest-park area of Novosibirsk Scientific Centre and its outskirts (Sovetskiy district of Novosibirsk), and identified as Ixodes persulcatus (Schulze, 1930) (18 females and 13 males) and Ixodes pavlovskyi (13 females and 10 males). Ten specimens of each sex from each collecting site were examined. The following nine characters were used: the length and width of the scutum (conscutum) and of the gnathosoma in ventral view; the length of palpal segments II-III; the width of the hypostome; the length of idiosoma with scapula, of leg I, of the medial spur on fore coxa (Taiga..., 1985; Filippova, Musatov, 1996; Filippova, Panova, 1998). According to morphometric characters, specimens of Ixodes pavlovskyi collected in the forest-park area of the Novosibirsk Scientific Centre were identified as the subspecies I. p. occidentalis Filippova et Panova, 1998. Nucleotide sequences of the COI mitochondrial gene fragment were determined for 56 ticks. Phylogenetic analysis of the COI gene fragment in representatives of the persulcatus-ricinus species-group dwelling in Asia demonstrated high degree of conservatism. Molecular-genetic methods allow reliable identification of morphologically similar species I. pavlovskyi and I. persulcatus, pathogenic for humans.


A trivalent antigen for the detection of type I avian adenovirus precipitin.
A double immunodiffusion antigen prepared from cell-culture-propagated CELO virus was not capable of detecting precipitin directed against all of the type I avian adenovirus (fowl adenoviruses) isolates tested. However, an antigen pool containing CELO-4, B-3, and IBH-2 (Tipton) fowl adenovirus isolates detected precipitin directed against representative isolates of 10 type I serotypes. Additionally, this antigen pool markedly improved detection of adenovirus field exposure.


Stepwise charge separation and charge recombination in ferrocene-meso,meso-linked porphyrin dimer-fullerene triad.
A meso,meso-linked porphyrin dimer [(ZnP)(2)] as a light-harvesting chromophore has been incorporated into a photosynthetic multistep electron-transfer model for the first time, including ferrocene (Fc), as an electron donor and fullerene (C(60)) as an electron acceptor to construct the ferrocene-meso,meso-linked porphyrin dimer-fullerene system (Fc-(ZnP)(2)-C(60)). Photoirradiation of Fc-(ZnP)(2)-C(60) results in photoinduced electron transfer from the singlet excited state of the porphyrin dimer [(1)(ZnP)(2)] to the C(60) moiety to produce the porphyrin dimer radical cation-C(60) radical anion pair, Fc-(ZnP)(2)(*+)-C(60)(*-). In competition with the back electron transfer from C(60)(*-) to (ZnP)(2)(*+) to the ground state, an electron transfer from Fc to (ZnP)(2)(*+) occurs to give the final charge-separated (CS) state, that is, Fc(+)-(ZnP)(2)-C(60)(*-), which is detected as the transient absorption spectra by the laser flash photolysis. The quantum yield of formation of the final CS state is determined as 0.80 in benzonitrile. The final CS state decays obeying first-order kinetics with a lifetime of 19 micros in benzonitrile at 295 K. The activation energy for the charge recombination (CR) process is determined as 0.15 eV in benzonitrile, which is much larger than the value expected from the direct CR process to the ground state. This value is rather comparable to the energy difference between the initial CS state (Fc-(ZnP)(2)(*+)-C(60)(*-)) and the final CS state (Fc(+)-(ZnP)(2)-C(60)(*-)). This indicates that the back electron transfer to the ground state occurs via the reversed stepwise processes,that is, a rate-limiting electron transfer from (ZnP)(2) to Fc(+) to give the initial CS state (Fc-(ZnP)(2)(*+)-C(60)(*-)), followed by a fast electron transfer from C(60)(*-) to (ZnP)(2)(*+) to regenerate the ground state, Fc-(ZnP)(2)-C(60). This is in sharp contrast with the extremely slow direct CR process of bacteriochlorophyll dimer radical cation-quinone radical anion pair in bacterial reaction centers.


Advanced extrauterine pregnancy: description of 38 cases with literature survey.
An analysis is presented of 38 patients with advanced extrauterine pregnancy. First three typical cases are described that emphasize the marked differentiation of clinical symptoms which these patients present to the doctor. The first patient was referred for induction because of a suspected intrauterine death. The second patient presented an intraligamentous pregnancy with a living fetus. In the third case, the patient was admitted to hospital after 32 weeks of pregnancy because of a persistent oblique lie. At 34 weeks, a normal living fetus was born. In all three cases, ultrasound examination was able to visualize the separate uterus. A literature survey is given with special attention to the specific "clinic" and the problems concerning diagnosis and treatment. It is obvious that sonography is the most important diagnostic technique at present. The decision to remove the placenta by means of a laparotomy is brought up for discussion.


The extent and distribution of skeletal muscle necrosis after graded periods of complete ischemia.
The management of an acutely ischemic extremity requires knowledge of the response of skeletal muscle (the largest component of the lower limb) to prolonged periods of complete normothermic ischemia. We have used the canine gracilis muscle model to evaluate the extent and distribution of ischemic necrosis after 3 and 5 hours of ischemia and 48 hours of reperfusion. Each muscle was cut into six slices, and the extent and distribution of postischemic necrosis identified by means of nitroblue tetrazolium staining and 99mTc pyrophosphate uptake. After 3, 4, and 5 hours of ischemia the extent of necrosis was 2.0% +/- 0.9%, 30.3% +/- 6.0%, and 90.1% +/- 3.5% (mean +/- SEM), respectively. A statistically significant correlation exists between the extent of necrosis and the uptake of 99mTc pyrophosphate uptake per gram of tissue (y = 1574.9x - 8.4, r = 0.84, p less than 0.001). Most necrosis was centrally located and found in the thickest portion of the muscle. We conclude that there is a graded response in the extent of skeletal muscle necrosis related to the length of ischemic stress rather than an "all-or-none" phenomenon. This central distribution of necrosis makes the usual external evaluation of ischemic damage clinically unreliable. In addition, since there was no enveloping fascia in this model, a compartment release alone may not prevent the development of skeletal muscle necrosis. This knowledge of the response of skeletal muscle to ischemia may lead to an improved clinical approach to an extremity suffering a prolonged ischemic insult.


Markers of endothelial damage in organ dysfunction and sepsis.
To review the literature on direct and indirect markers of endothelial activation and damage in patients with sepsis and systemic inflammation and to assess their clinical usefulness for diagnosis and outcome. Various markers derived from or activated by endothelial cells are described, such as adhesion molecules, thrombomodulin, von Willebrand factor, parameters of the coagulation system, and interleukin-6. Furthermore, the association of these markers with the severity of sepsis, systemic inflammation, and outcome is evaluated. Published research and review articles related to these parameters, with special emphasis on clinical studies. Endothelial activation and damage occur early during sepsis and play a major role in the pathophysiology of systemic inflammation. Various markers of endothelial activation are increased during sepsis and systemic inflammation, and in most studies, the level of markers such as soluble intercellular adhesion molecule, vascular cell adhesion molecule, and E selectin correlate well with the severity of inflammation and the course of the disease. However, to date, it remains unclear whether adhesion molecules and coagulation parameters are superior in this respect to interleukin-6 and procalcitonin, as direct comparisons are lacking. In addition, it is evident that markers of endothelial activation and coagulation parameters lack specificity for infection-induced endothelial damage and organ dysfunction.


A Column-Generation and Branch-and-Cut Approach to the Bandwidth-Packing Problem.
The telecommunications problem of assigning calls with point to point demand to a capacitated network where each call can be assigned to at most one path has been called the Bandwidth-Packing Problem. For a given network, with specified arc costs and arc capacities, one wishes to route calls (defined by a starting and ending point) through the network to maximize the profit from the calls routed. Each such call is single path routed and not all calls will be routed. We propose a branch-and-cut methodology coupled with column generation to optimally solve such problems. We examine the alternative approaches in the literature and explain how this new method takes the best of all components of methods suggested previously. The method we suggest is new in that it includes a linear programming-based heuristic for obtaining good lower bounds, uses lifted minimal covers that take into account special-ordered set constraints, and dynamically choose among three alternative branching strategies. In addition, whenever a new column is generated, it is lifted into all existing cuts. We also discuss the need to generate all tied optimal linear optimization solutions if one wishes to assure that the solution obtained is optimal. Our computational results provide solutions to problems previously unsolvable.


Regulation of the leucocyte chemoattractant receptor FPR in glioblastoma cells by cell differentiation.
The G protein-coupled formylpeptide receptor (FPR), known to mediate phagocytic leucocyte chemotaxis in response to bacterial- and host-derived agonists, was expressed by tumor cells in specimens of surgically removed more highly malignant human gliomas. In human glioblastoma cell lines, FPR activation increased cell motility, tumorigenicity and production of angiogenic factors. In studies of the mechanistic basis for the selective expression of FPR in more highly malignant gliomas, we found that the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (Aza), while promoting the differentiation of human glioblastoma cells, downregulated FPR expression. Aza also reduced the global methylation levels in glioblastoma cells and activated the pathway of p53 tumor suppressor. Methylation-specific polymerase chain reaction revealed that Aza treatment of tumor cells reduced the methylation of p53 promoter, which was accompanied by increased expression of p53 gene and protein. In addition, overexpression of p53 in glioblastoma cells mimicked the effect of Aza treatment as shown by increased cell differentiation but reduction in FPR expression, the capacity of tumor sphere formation in soft agar and tumorigenesis in nude mice. Furthermore, Aza treatment or overexpression of the wild-type p53 in glioblastoma cells increased the binding of p53 to FPR promoter region shown by chromatin immunoprecipitation. These results indicate that increased methylation of p53 gene retains human glioblastoma cells at a more poorly differentiated phase associated with the aberrant expression of FPR as a tumor-promoting cell surface receptor.


Delusional gross replacement of inanimate objects.
Three cases of a misidentification syndrome are presented. In this syndrome, which may be Capgras' or a new syndrome that we refer to as delusional gross replacement of inanimate objects, patients believe that their new possessions are replaced by inferior copies of the original objects by identified individuals. The patients believe that these individuals want to enhance themselves at the patients' expense, and feel persecuted by them.


Hydrothermal deposition as a novel method for the preparation of Co-Mn mixed oxide catalysts supported on stainless steel meshes: application to VOC oxidation.
The aim of this work was to develop a novel method for the preparation of structured Co-Mn mixed oxide catalysts: deposition on stainless steel meshes by hydrothermal synthesis. The use of meshes enabled the deposition of a thin layer of the active phase, which significantly suppressed the influence of internal diffusion. Consequently, the prepared catalysts exhibited from 48 to 114 times higher catalytic activity in ethanol oxidation than the commercial pelleted Co-Mn-Al catalyst. Moreover, we have shown that their catalytic activity correlated with the proportion of surface oxygen vacancies determined by XPS. Finally, the outstanding activity of the catalyst with Co:Mn ratio of 0.5 was ascribed to the mutual effect of high number of oxygen vacancies and exceptional redox properties.


A change of Plasmodium species infecting children in Karachi over the last decade.
Febrile children of both sexes, aged between 0-15 years coming to the Civil Hospital over the last 12 years had their blood tested for malarial parasite. Five hundred and twenty-six slides positive for Plasmodium were analysed for species and stage identification. Of the total 59.3% children with malaria were between 5-15 years of age. Applying the test of proportion, Plasmodium vivax was the predominant species (P < 0.01) between 1981-1985 and plasmodium falciparum between 1986-1990. This trend persisted upto 1992. As malaria due to Plasmodium falciparum is more severe with multiple complications accurate and easier methods of its diagnosis are needed at primary health care level.


Characterization of canine MDR1 mRNA: its abundance in drug resistant cell lines and in vivo.
Overexpression of the MDR1 gene often contributes to antineoplastic drug resistance. The purpose of this study was to characterize the canine MDR1 mRNA homologue and evaluate its expression in both canine cell lines and lymphomas. The abundance of the canine MDR1 transcript was assessed in three resistant cell lines and in pretreatment canine lymphoma using semi-quantitative RT/PCR. Canine transcript was 4.5 Kb with 93% sequence homology to human MDR1, and 90% homology to mouse and hamster equivalent genes. Increase in MDR1 transcript levels was observed in three progressively resistant canine cell lines. De novo MDR1 transcript expression was independent of response to therapy in dogs with lymphoma. We conclude that the canine MDR1 mRNA homologue is structurally similar to the human transcript. Expression of MDR1 mRNA correlates with in vitro drug sensitivity but does not correlate with in vivo doxorubicin sensitivity in canine lymphoma.


Chemical Synthesis of Glycoproteins with the Specific Installation of Gradient-Enriched 15 N-Labeled Amino Acids for Getting Insights into Glycoprotein Behavior.
Elucidating the effects of oligosaccharides on glycoprotein properties, such as local conformational changes, stability, and dynamics, has still been challenging. In this paper, a novel partial 15 N-labeling method for the amide backbone of a synthetic glycoprotein is proposed. Using solid-phase peptide synthesis (SPPS) and native chemical ligation (NCL), thirteen 15 N-labeled amino acids were inserted at specific positions of the protein backbone, while intentionally varying the enrichment of 15 N atoms. This idea discriminated even the same type of amino acid based on the intensities of 1 H-15 N HSQC signals, combined with classic homonuclear TOCSY and NOESY methods, thus allowing for understanding the dynamics of the local conformation of a synthetic homogeneous glycoprotein. Results suggested that the attachment of an oligosaccharide of either a bi-antennary complex-type or a high-mannose-type did not disturb protein conformation. However, T1 values suggested that the oligosaccharide influenced dynamics at the local conformation. Temperature-varied circular dichroism (CD) spectra and T1 values clearly indicated that oligosaccharides appeared to inhibit protein fluctuation or, in other words, stabilize protein structure. This insight into oligosaccharide behavior suggests some further effects on binding affinity between a glycoprotein and its receptor.


Liver transplantation for metabolic liver diseases in adults: indications and outcome.
Orthotopic liver transplantation is the preferred treatment for many patients with complications of end-stage liver disease. For metabolic liver diseases liver transplantation does not only replace the diseased organ, but also can potentially correct the metabolic defect. Results of liver transplantation for metabolic diseases have been encouraging. In Wilson's disease liver transplantation is considered an effective treatment for the fulminant form and for end-stage liver disease, associated with an excellent long-term outcome. However, it is still a matter of controversy whether liver transplantation should be considered in Wilson's disease patients with severe neurological impairment. Liver transplantation for hereditary haemochromatosis is relatively uncommon and is associated with a decreased post-transplantation patient survival, most likely due to infections and cardiac complications. Reduction of iron overload prior to liver transplantation in patients with hereditary haemochromatosis might be associated with a better outcome.


Changes in dietary intake following a culturally adapted lifestyle intervention among Iraqi immigrants to Sweden at high risk of type 2 diabetes: a randomised trial.
To investigate the effectiveness of a culturally adapted lifestyle intervention for changing dietary intake, particularly energy, fat and fibre intakes, in the intervention group (IG) compared with the control group (CG). Randomised controlled trial. IG (n 50) and CG (n 46). The IG was offered seven group sessions, including one cooking class, over a period of 4 months. The participants filled out 4 d food diaries at the start, mid and end of the study. Iraqi-born residents of Malmö, Sweden, at increased risk for developing diabetes. At baseline, participants' fat intake was high (40 % of total energy intake (E%)). The predefined study goals of obtaining <30 E% from fat and ≥15 g fibre/4184 kJ (1000 kcal) were met by very few individuals. In the IG v. the CG, the proportion of individuals obtaining <40 E% from fat (48·4 v. 34·6 %, P=0·65), <10 E% from saturated fat (32·3 v. 11·5 %, P=0·14) and ≥10 g fibre/4184 kJ (45·2 v. 26·9 %, P=0·46) appeared to be higher at the last visit, although the differences were statistically non-significant. A trend towards decreased mean daily intakes of total energy (P=0·03), carbohydrate (P=0·06), sucrose (P=0·02) and fat (P=0·02) was observed within the IG. Differences in changes over time between the groups did not reach statistical significance. Although no significant differences were observed in the two groups, our data indicate that this culturally adapted programme has the potential to modify dietary intake in Middle Eastern immigrants. The high fat intake in this group should be addressed.


Family planning and contraception in Islamic countries: a critical review of the literature.
The population of the world reached seven billion in 2012. Pakistan's population stands at more than 180 million, is growing rapidly, and has the highest unmet need for family planning (FP) in isolated rural areas. The low usage of contraception in the rural areas of Pakistan correlates with the level of isolation, poverty, illiteracy, and to a large extent, religious misinterpretations/misconceptions. Almost 25% of couples who desired FP services were not receiving them for a variety of reasons of which religion could be one, especially in the rural remote areas where the media is still not reaching and influencing mind-sets. In this scenario, the role of social marketing in bringing about attitudinal and behavioural change among users in underserved areas and gatekeepers and opinion makers in society must not be neglected. The work in promoting FP, contraception and birth spacing requires authentic evidence from similar sociocultural contexts and this endeavour of compiling case studies from various Islamic countries on their FP initiatives is a good step. Governments around the world, including many in the Islamic world, support FP programmes to enable individuals and couples to choose the number and timing of their children. This paper is a review of secondary data accessed through PubMed and Google Scholar. It provides an overview of Islamic countries' policies on, and support for FP and modern contraception. For this purpose, literature from Afghanistan, Bangladesh, Egypt, Indonesia, Iran, Jordan, Kuwait, Malaysia, Morocco, Nigeria, Pakistan, and Turkey was included. There are significant internal social and economic reasons to focus on FP in the Muslim world. Thus, arguments by religious scholars who see FP as an external western conspiracy aimed at curtailing the growth and strength of the Islamic world appear to be uninformed of both the socio-political and demographic realities in many Muslim countries, as well as the historical permissibility of contraception within the Islamic legacy. In fact, it can be argued that given the profound socio-economic and political difficulties in various parts of the Muslim world, a lack of FP and increasing populations would weaken and curtail the pace of overall development. Private institutions and the government must collaborate in leveraging initiatives and bridging gaps for more robust advocacy with clergymen and religious scholars to support the larger cause of FP and birth spacing i.e. improving infant and maternal health in Pakistan.


Influence of leukemia inhibitory factor (LIF) on the survival, proliferation and differentiation of human erythroid progenitor cells. In vitro studies under serum free conditions.
Different inflammatory cytokines are involved in the pathogenesis of the anemia of chronic disease (ACD), by inhibiting the proliferation of erythroid progenitors. Leukemia inhibitory factor (LIF), is an important inflammatory cytokine, and the purpose of this study was to evaluate its effect on the proliferation and viability of human erythroid progenitors. We have found that LIF slightly increased the survival of human early progenitor cells cultured under serum free conditions. LIF also slightly costimulated in vitro growth of human erythroid colonies. This last effect seems to be a direct one, because we found that LIF receptor (LIF-R) is expressed in cells isolated from growing in vitro human erythroid BFU-E colonies. These data, and the data reported by others in in vivo models, where LIF administration to experimental animals did not change the values of erythropoietic parameters, demonstrate that this inflammatory cytokine itself is not involved in the pathogenesis of ACD.


A unique case of free-floating gastric band tubing causing intraabdominal sepsis in a patient with locked-in syndrome secondary to Guillain-Barré syndrome.
Laparoscopic adjustable gastric banding is a known bariatric procedure that has largely fallen out of favor in our modern surgical era. Several case reports describe various complications secondary to gastric band slippage. Here we present a unique complication not related to gastric band slippage, but intraabdominal sepsis secondary to free-floating gastric band tubing after removal of the subcutaneous port in a patient with locked-in syndrome secondary to Guillain-Barré syndrome.


Portal vein embolisation prior to extended right-sided hepatic resection.
To determine whether preoperative portal vein embolisation improves the operative outcome of patients undergoing extended right-sided hepatic resection for hepatobiliary malignancy. Prospective non-randomised study. University teaching hospital, Hong Kong. Ninety-two patients underwent extended right-sided hepatic resection for hepatobiliary malignancy during a 45-month period (January 2000 to September 2003). Among them, 15 (16%) underwent portal vein embolisation via a percutaneous ipsilateral approach (n=9) or through the ileocolic vein with a mini-laparotomy (n=6). The remaining 77 (84%) patients underwent hepatic resection without portal vein embolisation. Operative morbidity and mortality. Patients undergoing portal vein embolisation were older (69 years vs 55 years; P=0.009), and had significantly worse preoperative renal function (creatinine, 96 micromol/L vs 86 micromol/L; P=0.039) and liver function (bilirubin, 23 micromol/L vs 12 micromol/L; P<0.001). Portal vein embolisation resulted in an increase in the future liver remnant of 9% (interquartile range, 7-13%) of the estimated standard liver volume. The operating time for patients receiving portal vein embolisation was significantly longer (medium, 660 min vs 420 min; P<0.001) with more complicated surgery performed in terms of concomitant caudate lobectomy and hepaticojejunostomy. There was no hospital mortality in patients who underwent portal vein embolisation whereas five without the treatment died (P=0.587). The operative morbidity of patients who underwent portal vein embolisation and those who did not was 20% and 30%, respectively (P=0.543). In older patients who have worse preoperative liver and renal functions, portal vein embolisation enhances the possibility to perform extended right-sided hepatic resection for hepatobiliary malignancies with potentially lower operative mortality and morbidity.


Peritonitis following percutaneous gastrostomy in children: management guidelines.
To establish the incidence, timing and outcome of peritonitis following percutaneous gastrostomy (PEG) insertion in children. Patients developing peritonitis after PEG insertion during a 5-year period (1990-95) were identified. Variables analysed included clinical presentation, management, operative findings and outcome. One hundred and twenty paediatric patients received 130 PEG in the 5-year period. Eight children developed peritonitis: 4 within 24 h of PEG insertion and 4 following routine PEG tube change (3-18 months later). All four patients developing early peritonitis underwent laparotomy in whom three had sustained major damage to adjacent viscera. The fourth patient had a negative laparotomy, but died from continued overwhelming sepsis. All four patients who developed peritonitis after a routine tube change underwent a tube contrast study. In two children a gastrocolic fistula was identified and surgically repaired. Contrast studies in two patients detected an intraperitoneal leak. This problem resolved with conservative management in both cases. Peritonitis immediately following PEG insertion is rarely due to the air leakage during insertion (benign pneumoperitoneum) and warrants early laparotomy to identify and correct the likely associated visceral trauma. Following PEG tube change peritonitis may result from stomal separation or tube malposition and an urgent study is indicated to identify the cause.


Light and scanning electron microscopy of nasal biopsy material from patients with naturally acquired common colds.
As our knowledge of the histopathology of common colds is very limited, we have undertaken a blind quantitative examination by scanning electron microscopy and light microscopy of 56 nasal biopsies, taken from 29 volunteers with naturally acquired colds. In agreement with earlier reports we found evidence of sloughing of epithelial cells, but in contrast to in vitro experiments, this did not result in a destruction of the epithelial lining, which by and large remained continuous, with structurally normal cell borders. There was a significant increase in the number of neutrophils, both in epithelium and in lamina propria, already on the 2nd day of the disease, and the hypothesis is advanced that the virus infection itself is the cause of the local neutrophilia. The only other abnormality demonstrated was an increased number of extracellular erythrocytes in the acute stage. The histological picture was not suggestive of an involvement of epithelial mast cells in the inflammation.


Ultrafast Relaxation Dynamics of Photoexcited Zinc-Porphyrin: Electronic-Vibrational Coupling.
Cyclic tetrapyrroles are the active core of compounds with crucial roles in living systems, such as hemoglobin and chlorophyll, and in technology as photocatalysts and light absorbers for solar energy conversion. Zinc-tetraphenylporphyrin (Zn-TPP) is a prototypical cyclic tetrapyrrole that has been intensely studied in past decades. Because of its importance for photochemical processes the optical properties are of particular interest, and, accordingly, numerous studies have focused on light absorption and excited-state dynamics of Zn-TPP. Relaxation after photoexcitation in the Soret band involves internal conversion that is preceded by an ultrafast process. This relaxation process has been observed by several groups. Hitherto, it has not been established if it involves a higher lying "dark" state or vibrational relaxation in the excited S2 state. Here we combine high time resolution electronic and vibrational spectroscopy to show that this process constitutes vibrational relaxation in the anharmonic S2 potential.


Large diameter metal on metal total hip replacement for femoral neck fractures with neurological conditions: A retrospective assessment.
Patients with Parkinson's disease and poliomyelitis can have a femoral neck fracture; yet, the optimal methods of treatment for these hips remains controversial. Many constrained or semi-constrained prostheses, using constrained liners (CLs) with a locking mechanism to capture the femoral head, were used to treat femoral neck fractures in patients with neurological disorders. We retrospectively studied a group of patients with Parkinson's disease and poliomyelitis who sustained femoral neck fractures and were treated by total hip arthroplasty using an L-MoM prosthesis. We retrospectively reviewed 12 hips in 12 patients who underwent large-diameter metal-on-metal (L-MoM) total hip replacement between May 2007 and October 2009. Eight of the 12 patients (8 hips; 66.7%) had Parkinson's disease and 4 patients (4 hips; 33.3%) were affected with poliomyelitis. The followup time was 5.2 years (range 3.6-6.0 years). At the latest followup, all the patients showed satisfactory clinical and radiographic results, with pain relief. No complications, such as dislocation or aseptic loosening occurred. We believe the use of L-MoM can diminish the rate of instability or dislocation, after operation. The L-MoM is an option for patients with Parkinson's disease and poliomyelitis with femoral neck fracture.


Primary prevention of atherosclerotic cardiovascular disease: controversies and clinical considerations.
A new guideline for the treatment of blood cholesterol was recently released by the American College of Cardiology (ACC) and the American Heart Association (AHA), serving as an update to the National Cholesterol Education Program's (NCEP) Adult Treatment Panel III cholesterol guideline first released in 2001. With significant changes to key definitions, treatment strategy, and therapy selection, the guideline has transformed the treatment of blood cholesterol and also created controversy within the health care community. This controversy is largely focused on appropriate identification and treatment of patients for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Whereas statins play an integral role in the treatment and secondary prevention of ASCVD, their use for primary prevention is less clearly defined. It is imperative that health care providers are well versed in the concepts and controversies of the new guideline recommendations for primary prevention of ASCVD and can effectively assess the risks and benefits of statin therapy in this patient population.


Purification and characterization of a new family of polypeptide neurotoxins from the heteronemertine Cerebratulus lacteus (Leidy).
Mucus secreted from the integument of the marine heteronemertine Cerebratulus lacteus (Leidy) contains two major types of polypeptide neurotoxin: the A toxins (11,000 daltons) which are lethal to a variety of animal species including mammals, and the B toxins (6,000 daltons) which appear to be selectively toxic for crustaceans. Both types of toxin were readily obtained from live worms by stimulation and collection of mucus with 1% acetic acid followed by batch adsorption of the basic polypeptide fraction upon CM-cellulose. Separate A and B toxin fractions were obtained by gel chromatography. Four toxins were purified from the B toxin fraction by CM-cellulose gradient elution chromatography. Each consists of a single polypeptide chain with NH2-terminal alanine and three (B-I) or four (B-II, B-III, B-IV) intrachain disulfide bonds. All four B toxins contain large proportions of lysine and exhibit identical gel electrophoretic mobilities at neutral pH. The B toxins lack cysteine and reducing sugar moieties. Toxin B-I differs considerably from the others in its amino acid composition and its shorter chain length (49 instead of 53 or 54 residues). The other three toxins have similar compositions, but lack proline, methionine, and phenylalanine. All four polypeptides show crustacean-selective toxicities which vary over a 30-fold range; B-II possesses the highest toxicity. As a working hypothesis it is suggested that the Cerebratulus B toxins are isotoxins which act via a common receptor present in crustacean axon membranes.


Visualization of through-plane blood flow measurements obtained from phase-contrast MRI.
The purpose of this work was to develop a visualization method for concurrent observation of both velocity and magnitude data obtained from through-plane velocity measurements using phase-contrast magnetic resonance imaging. Magnitude and velocity images were combined using an opacity transfer function (OTF) where the opacity was a function of a velocity range defined by the velocity encoding (v (enc)) parameter. Measured velocities were color-coded according to a predefined color scale and then combined into one image with the gray-scale magnitude image according to the OTF. In the combined images, simultaneous information of velocity and anatomy was presented. The proposed visualization method facilitated the understanding of how the measured blood flow was related to the underlying anatomy. Results are shown where the method is used to visualize blood flow measurements in the ascending aorta and the aortic valve. Adjustments of the OTF render possible identification of the peak velocities and their localization. Forward and backward blood flow is easily shown when applying appropriate OTF and color-coding. An advantage when using the proposed method is the ability of developing standardized protocol settings since the velocity information is quantitative and not relative as is the case for data obtained from the magnitude images. The intended application of the visualization method is the analysis of common flow studies used in the diagnosis of different cardiovascular diseases.


Influence of Cilostazol on Changes in Cyclin D1 Expression in Cerebral Cortex of Rats with Chronic Cerebral Ischemia.
The influence of cilostazol on learning and memory, and cyclin D1 expression in the cerebral cortex of rats with chronic cerebral ischemia were investigated. A chronic cerebral ischemia model was established using the permanent bilateral common carotid artery occlusion method (2VO), learning and memory capacity was detected using the Morris water maze, and expression changes in apoptosis regulating gene cyclin D1 were tested by RT-PCR. Results of the Morris water maze indicated that significant extensions were found in the escape latent period and swimming path of rats in the ischemia group (2VO group), learning and memory results in the cilostazol group was obviously superior compared to the 2VO group (P<0.05), and the expression of cyclin D1 was observed to increase in both the ischemia and cilostazol intervention groups at the 9th week of ischemia. A significant difference was observed, compared with the sham operation group (P<0.05), the expression level decreased in the ischemia group compared with the cilostazol group, and a significant difference was identified compared with the ischemia group (P<0.05). Cilostazol can reduce nerve function impairment and improve learning and memory functions by affecting changes in apoptosis regulating genes.


Bacterial expression system with tightly regulated gene expression and plasmid copy number.
A new Escherichia coli host/vector system has been engineered to allow tight and uniform modulation of gene expression and gamma origin (ori) plasmid copy number. Regulation of gamma ori plasmid copy number is achieved through arabinose-inducible expression of the necessary Rep protein, pi, whose gene was integrated into the chromosome of the host strain under control of the P(BAD) promoter. gamma ori replication can be uniformly modulated over 100-fold by changing the concentration of l-arabinose in the growth medium. This strain avoids the problem of all-or-nothing induction of P(BAD) because it is deficient in both arabinose uptake and degradation genes. Arabinose enters the cell by a mutant LacY transporter, LacYA177C, which is expressed from the host chromosome. Although this strain could be compatible with any gamma ori plasmid, we describe the utility of a gamma ori expression vector that allows especially tight regulation of gene expression. With this host/vector system, it is possible to independently modulate gene expression and gene dosage, facilitating the cloning and overproduction of toxic gene products. We describe the successful use of this system for cloning a highly potent toxin, Colicin E3, in the absence of its cognate immunity protein. This system could be useful for cloning genes encoding other potent toxins, screening libraries for potential toxins, and maintaining any gamma ori vector at precise copy levels in a cell.


Streptomycin and alternative agents for the treatment of tularemia: review of the literature.
Because of the recent lack of availability of streptomycin--currently considered the drug of choice for the treatment of tularemia--we reviewed the literature on alternative drugs that have been used for this purpose. In addition, we reviewed data on the in vitro susceptibility of Francisella tularensis to a wide variety of agents. The rate of cure for streptomycin was 97%, with no relapses. For gentamicin and tetracycline, respectively, the rates of cure were 86% and 88%, the rates of relapse were 6% and 12%, and the rates of failure were 8% and 0. The duration of therapy with gentamicin and a delay in its initiation may have affected outcome in severe cases. For chloramphenicol and tobramycin, cure rates were 77% and 50%, respectively; relapse rates were 21% and 0; and failure rates were 2% and 33%, respectively. Treatment with imipenem/cilastatin was successful in one case, and that with ciprofloxacin or norfloxacin was successful in six cases; in contrast, therapy with ceftriaxone was ineffective in eight cases. On the basis of this review, we conclude that gentamicin is an acceptable alternative to streptomycin for the treatment of tularemia.


Wolbachia in the Genus Bicyclus: a Forgotten Player.
Bicyclus butterflies are key species for studies of wing pattern development, phenotypic plasticity, speciation and the genetics of Lepidoptera. One of the key endosymbionts in butterflies, the alpha-Proteobacterium Wolbachia pipientis, is affecting many of these biological processes; however, Bicyclus butterflies have not been investigated systematically as hosts to Wolbachia. In this study, we screen for Wolbachia infection in several Bicyclus species from natural populations across Africa as well as two laboratory populations. Out of the 24 species tested, 19 were found to be infected, and no double infection was found, but both A- and B-supergroup strains colonise this butterfly group. We also show that many of the Wolbachia strains identified in Bicyclus butterflies belong to the ST19 clonal complex. We discuss the importance of our results in regard to routinely screening for Wolbachia when using Bicyclus butterflies as the study organism of research in eco-evolutionary biology.


Pathophysiology of abdominal aortic aneurysms: insights from the elastase-induced model in mice with different genetic backgrounds.
Abdominal aortic aneurysms (AAAs) represent a complex degenerative disorder involving chronic aortic wall inflammation and destructive remodeling of structural connective tissue. Studies using human AAA tissues have helped identify a variety of molecular mediators and matrix-degrading proteinases, which contribute to aneurysm disease, thereby providing a sound foundation for understanding AAAs; however, these human tissue specimens represent only the "end stage" of a long and progressive disease process. Further progress in understanding the pathophysiology of AAAs is therefore dependent in part on the development and application of effective animal models that recapitulate key aspects of the disease. Based on original studies in rats, transient perfusion of the abdominal aorta with porcine pancreatic elastase has provided a reproducible and robust model of AAAs. More recent applications of this model to mice have also opened new avenues for investigation. In this review, we summarize investigations using the elastase-induced mouse model of AAAs including results in animals with targeted deletion of specific genes and more general differences in mice on different genetic backgrounds. These studies have helped us identify genes that are essential to the development of AAAs (such as MMP9, IL6, and AT1R) and to reveal other genes that may be dispensable in aneurysm formation. Investigations on mice from different genetic backgrounds are also beginning to offer a novel approach to evaluate the genetic basis for susceptibility to aneurysm development.


Crossing the quasi-threshold manifold of a noise-driven excitable system.
We consider the noise-induced escapes in an excitable system possessing a quasi-threshold manifold, along which there exists a certain point of minimal quasi-potential. In the weak noise limit, the optimal escaping path turns out to approach this particular point asymptotically, making it analogous to an ordinary saddle. Numerical simulations are performed and an elaboration on the effect of small but finite noise is given, which shows that the ridges where the prehistory probability distribution peaks are located mainly within the region where the quasi-potential increases gently. The cases allowing anisotropic noise are discussed and we found that varying the noise term in the slow variable would dramatically raise the whole level of quasi-potentials, leading to significant changes in both patterns of optimal paths and exit locations.


Association between genetic polymorphisms and ovarian cancer risk.
The etiology of ovarian cancer is not fully understood. Polymorphisms in low penetrance genes involved in carcinogen and estrogen metabolism are hypothesized to play a role in the initiation of carcinogenesis. A case-control study was conducted to investigate the role of these polymorphisms in ovarian cancer risk. The participants were genotyped for eleven polymorphisms in seven genes involved in estrogen and xenobiotic metabolism (CYP1A1, CYP1B1, COMT, GSTP1, NAT2, estrogen receptor ESR, and progesterone receptor PGR). The odds ratios for ovarian cancer risk were 2.02 (95% confidence interval [CI] = 1.14-3.56) in the NAT2 intermediate acetylators and 4.07 (95% CI = 1.30-12.70) in the slow acetylators. At least three cumulative high-risk genotypes increased ovarian cancer risk, but not significantly. More studies are needed in order to define genetic ovarian risk factors.


AGA Clinical Practice Update on Evaluation and Management of Belching, Abdominal Bloating, and Distention: Expert Review.
Belching, bloating, and abdominal distention are all highly prevalent gastrointestinal symptoms and account for some of the most common reasons for patient visits to outpatient gastroenterology practices. These symptoms are often debilitating, affecting patients' quality of life, and contributing to work absenteeism. Belching and bloating differ in their pathophysiology, diagnosis, and management, and there is limited evidence available for their various treatments. Therefore, the purpose of this American Gastroenterological Association (AGA) Clinical Practice Update is to provide best practice advice based on both controlled trials and observational data for clinicians covering clinical features, diagnostics, and management considerations that include dietary, gut-directed behavioral, and drug therapies. This Expert Review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. These best practice advice statements were drawn from a review of the published literature based on clinical trials, the more robust observational studies, and from expert opinion. Because systematic reviews were not performed, these best practice advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Clinical history and physical examination findings and impedance pH monitoring can help to differentiate between gastric and supragastric belching. BEST PRACTICE ADVICE 2: Treatment options for supragastric belching may include brain-gut behavioral therapies, either separately or in combination, such as cognitive behavioral therapy, diaphragmatic breathing, speech therapy, and central neuromodulators. BEST PRACTICE ADVICE 3: Rome IV criteria should be used to diagnose primary abdominal bloating and distention. BEST PRACTICE ADVICE 4: Carbohydrate enzyme deficiencies may be ruled out with dietary restriction and/or breath testing. In a small subset of at-risk patients, small bowel aspiration and glucose- or lactulose-based hydrogen breath testing may be used to evaluate for small intestinal bacterial overgrowth. BEST PRACTICE ADVICE 5: Serologic testing may rule out celiac disease in patients with bloating and, if serologies are positive, a small bowel biopsy should be done to confirm the diagnosis. A gastroenterology dietitian should be part of the multidisciplinary approach to care for patients with celiac disease and nonceliac gluten sensitivity. BEST PRACTICE ADVICE 6: Abdominal imaging and upper endoscopy should be ordered in patients with alarm features, recent worsening symptoms, or an abnormal physical examination only. BEST PRACTICE ADVICE 7: Gastric emptying studies should not be ordered routinely for bloating and distention, but may be considered if nausea and vomiting are present. Whole gut motility and radiopaque transit studies should not be ordered unless other additional and treatment-refractory lower gastrointestinal symptoms exist to warrant testing for neuromyopathic disorders. BEST PRACTICE ADVICE 8: In patients with abdominal bloating and distention thought to be related to constipation or difficult evacuation, anorectal physiology testing is suggested to rule out a pelvic floor disorder. BEST PRACTICE ADVICE 9: When dietary modifications are needed (eg, low-fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet), a gastroenterology dietitian should preferably monitor treatment. BEST PRACTICE ADVICE 10: Probiotics should not be used to treat abdominal bloating and distention. BEST PRACTICE ADVICE 11: Biofeedback therapy may be effective for bloating and distention when a pelvic floor disorder is identified. BEST PRACTICE ADVICE 12: Central neuromodulators (eg, antidepressants) are used to treat bloating and abdominal distention by reducing visceral hypersensitivity, raising sensation threshold, and improving psychological comorbidities. BEST PRACTICE ADVICE 13: Medications used to treat constipation should be considered for treating bloating if constipation symptoms are present. BEST PRACTICE ADVICE 14: Psychological therapies, such as hypnotherapy, cognitive behavioral therapy, and other brain-gut behavior therapies may be used to treat patients with bloating and distention. BEST PRACTICE 15: Diaphragmatic breathing and central neuromodulators are used to treat abdominophrenic dyssynergia.


Intestinal Flora Composition Determines Microglia Activation and Improves Epileptic Episode Progress.
In response to environmental stimuli, immune memory mediates the plasticity of myeloid cells. Immune training and immune tolerance are two aspects of plasticity. Microglia that are immunologically trained or immunologically tolerant are endowed with a tendency to differentiate into alternative dominant phenotypes (M1/M2). Male C57BL/6 mice (immune-training group, immune-tolerant group, and control group) were used to establish the kainic acid epilepsy model. The seizure grade, duration, latency, hippocampal potential, and energy density were used to evaluate seizures, and the changes in the polarization of microglia were detected by western blot. 16S rDNA sequencing showed that the abundance of Ruminococcus in the immune-tolerant group was the dominant flora. Our research connections Intestinal microorganisms, brain immune status, and epilepsy behavior together. Pro-inflammatory M1 phenotype and anti-inflammatory M2 phenotype mediate and enhance and suppress subsequent inflammation, respectively. We conclude that intestinal microorganisms influence the occurrence and development of epilepsy by regulating the polarization of microglia.


Climate Change Research in View of Bibliometrics.
This bibliometric study of a large publication set dealing with research on climate change aims at mapping the relevant literature from a bibliometric perspective and presents a multitude of quantitative data: (1) The growth of the overall publication output as well as (2) of some major subfields, (3) the contributing journals and countries as well as their citation impact, and (4) a title word analysis aiming to illustrate the time evolution and relative importance of specific research topics. The study is based on 222,060 papers (articles and reviews only) published between 1980 and 2014. The total number of papers shows a strong increase with a doubling every 5-6 years. Continental biomass related research is the major subfield, closely followed by climate modeling. Research dealing with adaptation, mitigation, risks, and vulnerability of global warming is comparatively small, but their share of papers increased exponentially since 2005. Research on vulnerability and on adaptation published the largest proportion of very important papers (in terms of citation impact). Climate change research has become an issue also for disciplines beyond the natural sciences. The categories Engineering and Social Sciences show the strongest field-specific relative increase. The Journal of Geophysical Research, the Journal of Climate, the Geophysical Research Letters, and Climatic Change appear at the top positions in terms of the total number of papers published. Research on climate change is quantitatively dominated by the USA, followed by the UK, Germany, and Canada. The citation-based indicators exhibit consistently that the UK has produced the largest proportion of high impact papers compared to the other countries (having published more than 10,000 papers). Also, Switzerland, Denmark and also The Netherlands (with a publication output between around 3,000 and 6,000 papers) perform top-the impact of their contributions is on a high level. The title word analysis shows that the term climate change comes forward with time. Furthermore, the term impact arises and points to research dealing with the various effects of climate change. The discussion of the question of human induced climate change towards a clear fact (for the majority of the scientific community) stimulated research on future pathways for adaptation and mitigation. Finally, the term model and related terms prominently appear independent of time, indicating the high relevance of climate modeling.