Regional Gastrointestinal Transit Times in Patients With Carcinoid Diarrhea: Assessment With the Novel 3D-Transit System.
The paucity of knowledge regarding gastrointestinal motility in patients with neuroendocrine tumors and carcinoid diarrhea re-stricts targeted treatment. 3D-Transit is a novel, minimally invasive, ambulatory method for description of gastrointestinal motility. The system has not yet been evaluated in any group of patients. We aimed to test the performance of 3D-Transit in patients with carcinoid diarrhea and to compare the patients' regional gastrointestinal transit times (GITT) and colonic motility patterns with those of healthy subjects. Fifteen healthy volunteers and seven patients with neuroendocrine tumor and at least 3 bowel movements per day were inves-tigated with 3D-Transit and standard radiopaque markers. Total GITT assessed with 3D-Transit and radiopaque markers were well correlated (Spearman's rho = 0.64, P = 0.002). Median total GITT was 12.5 (range: 8.5-47.2) hours in patients versus 25.1 (range: 13.1-142.3) hours in healthy (P = 0.007). There was no difference in gastric emptying (P = 0.778). Median small intestinal transit time was 3.8 (range: 1.4-5.5) hours in patients versus 4.4 (range: 1.8-7.2) hours in healthy subjects (P = 0.044). Median colorectal transit time was 5.2 (range: 2.9-40.1) hours in patients versus 18.1 (range: 5.0-134.0) hours in healthy subjects (P = 0.012). Median frequency of pansegmental co-lonic movements was 0.45 (range: 0.03-1.02) per hour in patients and 0.07 (range: 0-0.61) per hour in healthy subjects (P = 0.045). Three-dimensional Transit allows assessment of regional GITT in patients with diarrhea. Patients with carcinoid diarrhea have faster than normal gastrointestinal transit due to faster small intestinal and colorectal transit times. The latter is caused by an increased frequency of pansegmental colonic movements.


Characteristics of Carbon Material Formation on SBA-15 and Ni-SBA-15 Templates by Acetylene Decomposition and Their Bioactivity Effects.
Carbon spheres and tubes were formed from acetylene decomposition on SBA-15 and Ni-SBA-15 at 650-850 °C. At 650 °C, the decomposed carbons covered the surface of the support, and no carbon spheres and filament materials were formed. Carbon sphere formation occurred at 750 °C-850 °C; with diameters ranging from 0.8 μm-1.1 μm. For Ni-SBA-15, the diameters of the spheres and filaments were 0.8 μm and 62 nm, respectively, at 650 °C. At 750 °C, the diameter of the ball carbon materials ranged from 0.7 μm-0.8 μm, the diameter of the carbon tubes formed was 120-130 nm, and their pore diameter was 8.0 nm-11 nm. At 850 °C, the diameters of ball carbon materials and carbon tubes were similar to those of the materials at the formation temperature, 750 °C. Si, O and C were the main constituents of SBA-15; Ni-SBA-15 and carbon material formation supports. High-ring PAHs (such as BaP (five rings); IND (six rings); DBA (five rings) and B[ghi]P (six rings)) exist in carbon materials. SBA-15 revealed insignificant cytotoxicity, but Ni-SBA-15 inhibited the proliferation of human lung cancer cells (A549). Less inhibition on cell viability and reactive oxidative species (ROS) generation on A549 were determined for carbon material formation on the Ni-SBA-15 compared to the Ni-SBA-15.


Application of Microdosed Intravenous Omeprazole to Determine Hepatic CYP2C19 Activity.
Omeprazole is an established probe drug to assess cytochrome P450 (CYP) 2C19 activity (phenotyping). Because it has nonlinear pharmacokinetics (PK) after oral administration (autoinhibition of metabolism), the true impact of coadministered perpetrators on CYP2C19 substrates might be underestimated after regular doses. We tested the dose linearity of an intravenous omeprazole microdose of 100 µg and compared it with a 20-mg dose in 4 healthy poor metabolizers (PMs) and 6 extensive metabolizers (EMs) of CYP2C19 in the presence and absence of a strong inhibitor (voriconazole). Without voriconazole, omeprazole exposure was dose-proportional irrespective of the genotype, but in PMs geometric mean ratios (GMRs) of AUC0-∞ were 6.6-fold higher and molar metabolic ratios of 5-OH omeprazole/omeprazole approximately 10-fold lower. Voriconazole increased omeprazole exposure in EMs approximately 5-fold (AUC0-4 GMR after 100 µg omeprazole, 4.61; 90% confidence interval [CI], 2.69-7.89; AUC0-4 GMR after 20 mg omeprazole, 5.5; 90%CI, 1.07-1.46), whereas no clinically significant impact on PK in PMs was observed (GMR AUC0-4 after 100 µg omeprazole, 1.29; 90%CI, 0.81-2.04; GMR AUC0-4 after 20 mg omeprazole, 1.25; 90%CI, 1.07-1.46). Linear regression and Bland-Altman analyses revealed excellent agreement between AUC0-∞ and AUC0-4 of omeprazole (r2 = 0.987; bias, 0.35%; 95%CI, -3.197% to 3.89%) and also the molar metabolic ratio, 5-OH omeprazole/omeprazole (r2 = 0.987; bias, -3.939; 95%CI, -9.06% to -1.18%), suggesting that an abbreviated sampling protocol can be used for intravenous CYP2C19 phenotyping and drug interaction studies. In conclusion, the PK of intravenous omeprazole microdoses closely reflects the changes observed with regular omeprazole doses; however, to avoid autoinhibition of probe drugs, microdosing appears to be the favorable technique.


Studies on interferon induction by infectious bursal disease virus (IBDV). II. Interferon production in White Leghorn chickens infected with an attenuated or pathogenic isolant of IBDV.
Infectious bursal disease virus (IBDV) isolants that differed in virulence for chickens, were compared as to: 1) induction of interferon in serum and tissues; and 2) stimulation of IBDV serum antibody. Specific-pathogen-free chickens were infected at one day and four weeks of age by the subcutaneous and intranasal routes of inoculation. The pathogenic isolant induced a more generalized interferon response than the attenuated isolant, independent of age or route of inoculation. Pathogenic IBDV stimulated interferon in serum, kidney, lung, thymus, spleen, and bursa of Fabricius. The attenuated virus induced interferon only in the bursa. The serum interferon response was greater following inoculation with pathogenic IBDV than with the attenuated virus. Serum interferon titers peaked 2-3 1/2 days after inoculation. The pathogenic and attenuated viruses stimulated similar IBDV-neutralizing antibody responses, which occurred after peak serum interferon activity.


Concise route to 3-arylisoquinoline skeleton by Lewis acid catalyzed C(sp3)-H bond functionalization and its application to formal synthesis of (±)-tetrahydropalmatine.
An expeditious route to furnish an isoquinoline skeleton via hydride shift mediated C-H bond functionalization was developed. In this process, an unusual [1,5]-H shift without the assistance of the adjacent heteroatom took place to produce tetrahydroisoquinoline derivatives in good to excellent chemical yields. The formal synthesis of (±)-tetrahydropalmatine was achieved by exploiting this new transformation.


Treatment of early immunoglobulin A nephropathy by angiotensin-converting enzyme inhibitor.
The treatment of immunoglobulin A (IgA) nephropathy with normal renal function and minimal proteinuria is unknown. We randomly assigned 60 patients with IgA nephropathy, proteinuria <0.5 g/day, normal blood pressure and renal function to ramipril 2.5 mg daily or no treatment. Patients were followed for 5 years for the development of hypertension, proteinuria, or impaired renal function. The blood pressure of the treatment group was marginally lower than the control group throughout the study period. At 60 months, the event-free survival was marginally higher for the treatment group as compared with the control group (81.1% vs 70.5%, P=.27). The proteinuria-free survival was similar at 82.9% and 79.3% for the treatment and control groups, respectively (P=.6); hypertension-free survival was 86.4% and 79.3% (P=.2). After 60 months of follow-up, the estimated glomerular filtration rate (GFR) was 108.1±29.0 mL/min/1.73 m(2) for the treatment group and 105.7±17.7 mL/min/1.73 m(2) for the control group (P=.7), but the difference was not statistically significant. None of the patients developed impaired renal function. The rate of GFR decline was similar between the treatment and control groups (-0.39±2.57 vs -0.59±1.63 mL/min/1.73 m(2) per year, respectively, P=.7). In general, the study medication was well tolerated. Two patients needed to stop prematurely because of cough and dizziness. For early IgA nephropathy patients with minimal proteinuria, normal blood pressure, and normal renal function, treatment with 2.5 mg/daily of ramipril for 5 years does not offer any benefit.


Relative binding affinity of androstane and C-19-nor-androstane-steroids for the estradiol-receptor in human myometrial and mammary cancer tissue.
The relative binding affinity of several androstane- and C-19-nor-androstane-compounds for the estradiol (E2)-receptor in human myometrial and mammary cancer tissue was studied. High speed cytosol was incubated with tritiated E2 alone as well as in the presence of increasing amounts of the compound to be tested. The highest affinity is found for steroids with two hydroxyl-groups at C-3 and C-17 in the beta-position and a double bond at C-4-5 or C-5-6. Saturation of the A-ring decreases the affinity: 5alpha-compounds have less affinity, 5-beta-compounds have less affinity; 5beta-compounds hardly any affinity. The presence of a hydroxyl-group in the 3alpha, 11beta or 16beta-position decreases the affinity, as dose a 3-oxo or 17-oxo-group. Removal of the C-19-methyl-group facilitates the binding. This data led to the concept that flatness of the A-ring in respect to the B-ring of the steroid molecule is a principal requirement for binding to the E2-receptor. The rank order of RBA is identical in myometrium and in mammary cancer tissue, indicating that estrogen-receptors are at least highly similar in both target tissues.


Synthesis and Characterization of a Ditriflate-Bridged, Diiron(II) Complex with Syn-N-Donor Ligands: [Fe(2)(μ-OTf)(2)(PIC(2)DET)(2)](BARF)(2).
The synthesis and characterization of the diiron(II) complex [Fe(2)(μ-OTf)(2)-(PIC(2)DET)(2)](BARF)(2) (2), where PIC(2)DET is a 2,3-diethynyltriptycene-linked dipicolinic methyl ester ligand, are described. The dication in 2, contains, [Fe(2)(μ-OTf)(2)(PIC(2)DET)(2)](2+) two symmetry-equivalent iron atoms with octahedral coordination geometries. Each metal ion has a N(2)O(4) atom donor set that includes four atoms from two picolinic ester N,O chelate rings, as well as two oxygen atoms from the bridging trifluoromethanesulfonate groups. The Fe(2)(μ-OTf)(2) core of 2 is stabilized by two PIC(2)DET ligands that bind the two metal ions in a head-to-head fashion, leading to an Fe···Fe distance of 5.173(1)Å. Molar conductivity data for 2 are consistent with Fe(2)(μ-OTf)(2)(PIC(2)DET)(2)](2+) retaining its identity in acetone solutions, where it behaves as a 2:1 electrolyte. (1)H NMR spectroscopic, solution (d(6)-acetone) and solid-state magnetic susceptibility data all indicate that the iron atoms of 2 are high-spin (S = 2). A fit of the magnetic data (2 - 300K) to a spin-only isotropic exchange Hamiltonian H = -2JS(1)·S(2) are consistent with weak antiferromagnetic coupling between the two iron atoms with J ~ -0.99(2) cm(-1) and g = 2.10(1).


Solving shortage in a priceless market: Insights from blood donation.
Shortage is common in many markets, such as those for human organs or blood, but the problem is often difficult to solve through price adjustment, given safety and ethical concerns. In this paper, we study two non-price methods that are often used to alleviate shortage for human blood. The first method is informing existing donors of a current shortage via a mobile message and encouraging them to donate voluntarily. The second method is asking the patient's family or friends to donate in a family replacement (FR) program at the time of shortage. Using 447,357 individual donation records across 8 years from a large Chinese blood bank, we show that both methods are effective in addressing blood shortage in the short run but have different implications for total blood supply in the long run. We compare the efficacy of these methods and discuss their applications under different scenarios to alleviate shortage.


Role of vasoactive substances in active hyperemia in skeletal muscle (38520).
A prolonged, 2-hr period of exercise hyperemia in the canine gracilis muscle was associated with initial increases in the arteriovenous differences for potassium, hydrogen and osmolality. However, that for hydrogen decreased and those for potassium and osmolality became negligible by the 120th min while blood flow remained elevated. Thus, potassium and osmolality do not appear to participate importantly in the maintenance of exercise hyperemia in canine gracilis muscle. A bioassay muscle did not respond with comparable dilation when submaximal, graded levels of exercise hyperemia were induced in an upstream, donor muscle but did respond more comparably in terms of magnitude and time course when the exercise was more severe. Thus, stable vasoactive substances may not entirely account for exercise hyperemia and the study fails to provide evidence that the capillary acts as a significant barrier to the vasoactive substances.


Sunitinib-Containing Carborane Pharmacophore with the Ability to Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, Exhibits Powerful In Vivo Anti-Glioblastoma Activity.
Malignant gliomas are the most common malignant and aggressive primary brain tumors in adults, the prognosis being-especially for glioblastomas-extremely poor. There are no effective treatments yet. However, tyrosine kinase receptor (TKR) inhibitors and boron neutron capture therapy (BNCT), together, have been proposed as future therapeutic strategies. In this sense in our ongoing project of developing new anti-glioblastoma drugs, we identified a sunitinib-carborane hybrid agent, 1, with both in vitro selective cytotoxicity and excellent BNCT-behavior. Consequently, we studied the ability of compound 1 to inhibit TKRs, its promotion of cellular death processes, and its effects on the cell cycle. Moreover, we analyzed some relevant drug-like properties of 1, i.e., mutagenicity and ability to cross the blood-brain barrier. These results encouraged us to perform an in vivo anti-glioblastoma proof of concept assay. It turned out to be a selective FLT3, KIT, and PDGFR-β inhibitor and increased the apoptotic glioma-cell numbers and arrested sub-G1-phase cell cycle. Its in vivo activity in immunosuppressed mice bearing U87 MG human glioblastoma evidenced excellent anti-tumor behavior.


Biological and chemical approaches for the detection and identification of illegal estrogens in water-based solutions.
The continuous introduction of new products used as growth promoters in animal husbandry, for sports doping and as products for body-building requires residue laboratories to initiate research on developing a strategy for the identification of 'unknown' components. In this study, a strategy is presented for elucidating the identity, the structure and the possible effects of illegal estrogenic compounds in an unidentified water-based solution. To obtain complete information on the composition and activity of the unidentified product, a multidisciplinary approach was needed. A case-study is described with a 'solution X' found during a raid. First, in vivo techniques (animal trials with mice, anatomical and histological research) were combined with in vitro techniques (the yeast estrogenic screen (YES)). In a later stage of the investigation, HPLC-fractionation, liquid chromatography-multiple mass spectrometry (LC-MSn) and gas chromatography-multiple mass spectrometry (GC-MSn) were used. Finally, the identity of 'solution X' was confirmed in a very low concentration range (10 ng/L estrone and 400 ng/l ethinyloestradiol).


Epidermal nutrition of the alcyonarian Heteroxenia fuscescens (Ehrb.): absorption of dissolved organic material and lost endogenous photosynthates.
The trophic strategies were studied of Heteroxenia fuscescens living in shallow tropical waters. Structural and physiological adaptations show that particulate food is of less nutritional importance than the uptake of organic material dissolved in the sea, the utilization of assimilates of cytosymbiotic algae (zooxanthellae) and even the symbionts themselves. The external and internal surfaces of the tentacles are enlarged by featherlike pinnules, on the one hand facilitating the epidermal uptake of dissolved organic compounds and on the other offering wellilluminated spaces in which large numbers of zooxanthellae can be 'cultivated'.Zooxanthellae expelled from gastrodermal cells may be taken up by the mesenteric filaments of the dorsal mesenteries, where they are often decomposed and utilized. The transport of photo-assimilates from the gastrodermis to the epidermis through the mesogloea takes place at a low rate. Most of the released assimilates of the symbionts appear in the coelenteron. One fraction of these assimilates is distributed within the gastric channel system and can be taken up by developing stages living there; another fraction reaches the epidermis extracorporally via the pharynx and the sea. Thus both the pharynx and the epidermis absorb these photo-assimilates. The epidermal uptake capacity serves two main purposes: (1) active uptake and incorporation of external organic material dissolved in the sea; (2) reabsorption of internal, self-produced organic material, i.e. reduction of the loss of endogenous compounds escaping from the gastric cavity necessarily due to the polyfunctionality of the coelenteron.


Maxillofacial injuries in Calabar south-south, Nigeria: a 5 year study of jawbone fractures.
The aim of this study is to highlight the overall uniqueness of the pattern of presentation of maxillofacial injuries seen at the Department of Oral and Maxillofacial Surgery of the University of Calabar Teaching Hospital, Calabar south-south Nigeria between January 2000 and December 2004 and to share our experience in terms of occurrence, seasonal fluctuations and the adequacy of treatment methods in our environment. Case notes of all. the 200 maxillofacial trauma patients were retrieved, examined and analyzed with regards to age, gender and cause of injury, socio-demographic data, diagnosis, pattern of presentation, distribution and treatment. A male-to-female ratio of 3.65:1 was obtained. Out of the 200 patients the highest incidence of injury was in the 20-30 year age group 85 (n=85; 42.5%). The major causes of injuries were motorcycle (n=74; 37%), vehicle (n=62; 31.5%) and assault (n=40; 20%). Six (3%) river-related or boat accidents were recorded. Industrial and sports related accidents contributed the least (n=5; 2.5%). Road traffic accident had the highest proportion of the entire maxillofacial injuries with more males affected than females. Seasonal distribution showed a bimodal peak variation of May-June and September-January. This paper calls for the reinforcement of measures for the prevention of automobile accident and the establishment of more maxillofacial specialist centers with modern equipment for effective management of maxillofacial injuries.


What are older people and their families looking for in an aged care services provider?
Choosing an aged care services provider is a complex decision. This study explored the factors older people and their families consider during this decision-making process. Four focus groups (two in rural, two in urban Queensland) included older people using and not using aged care services and family members seeking residential aged care services. Four themes emerged from the analysis of participants' perspectives, with human needs (such as autonomy, caring, respect, certainty) and organisational values (such as person-centredness) viewed as most important. Costs, value for money and regulatory considerations were sometimes perceived to be more important than locality. The perceived significance of facilities, services and amenity needs differed according to age and time of life, although a clear pathway to residential aged care facilities from living in the community was desired. Finding information, planning and choosing providers was seen to be hindered by lack of accessible, quality information. Meeting human needs (such as autonomy, caring, respect, certainty) through organisational values (such as person-centredness) is the most desirable factor according to the perceptions of older people and their families when choosing an aged care services provider.


Isolation of opponent-colour mechanisms at increment threshold.
An experimental examination was made of some paradigms designed to isolate the opponent-colour system at increment threshold. The effectiveness of a uniform white conditioning field spatially coincident with a 1.05-deg uniform test field was assessed by measuring intensity thresholds for simple detection and for colour discrimination. Values were obtained both by a method of adjustment and by a two-interval forced-choice procedure. For sufficiently high luminances of the conditioning field (3000 td or greater) little or no difference was found between simple-detection and colour-discrimination thresholds over the critical test-flash spectral range 520-620 nm, implying that the paradigm produced almost complete isolation of the opponent-colour system at increment threshold. A control experiment in which thresholds were obtained for a conditioning field larger than the test field gave less satisfactory isolation; near 580 nm the luminance system was found to be at least 0.3 log unit more sensitive than the opponent-colour system. A comparison was also made of the spatially coincident field paradigm with a paradigm in which a modified test stimulus of low temporal and spatial frequency content was presented on a large conditioning field. Test spectral sensitivity curves for simple detection obtained by a method of adjustment showed little difference in effectiveness in opponent-colour isolation.


Characteristics of wrist joint receptors in the cat.
A branch of the dorsal interosseous nerve is described, which innervates the dorsal aspect of the wrist joint capsule of the cat. Recordings of the whole wrist joint nerve showed no tonic activity until the wrist was flexed to within 45 degrees of full flexion (about one third of the normal range). There was no tonic activity at full extension or at intermediate postions. 110 single afferents from the wrist joint capsule were isolated from dorsal root filaments. Their responses to movement of the wrist and other mechanical stimuli were examined, and their conduction velocities measured. 31 were slowly adapting, 41 were phasic, 9 were Pacinian corpuscle-like, 7 were weakly activated, and 22 were not activated by the mechanical stimuli which were used. Slowly adapting receptors responded only when the joint was in a flexed position as would be expected from the whole nerve data. Conduction velocities for the 4 classes of responding mechanoreceptors were not significantly different, and fell in the group II range. Fibre diameter histograms of myelinated axons in the wrist joint nerve showed peaks in the group II and group III range. Intravenous injection of succinylcholine showed no increase in whole nerve activity attributable to muscle spindles, and had a negligible effect on identified receptors in the wrist joint capsule.


[Characterization of cytosol and nuclear glucocorticoid receptors from rat liver tissue in hepatocarcinogenesis].
Specific receptors with high affinity for dexamethasone (Kass = 2.03 = 4.04 . 10(8) M-1) were found in liver cytosole of control rats as well as in animals with hepatocarcinogenesis caused by diethylnitrosamine and in cytosole of primary hepatomas. Amount of the binding sites for dexamethasone varied depending on severity of the blastomatous process (3.4 = 0.17 X X 10(-13) M/mg protein). The receptors from liver tissue of control rats, malignant liver and hepatomas were similar in their binding patterns and in chromatigraphic properties. Content of dexamethasone-receptor complexes accepted by chromatin was decreased by 50% in cytosole of malignant liver cells as compared with controls. The same alteration in binding of cytosole-receptor complexes of DNA from malignant liver tissue was found by means of affinity chromatography.


Identification of the needs of elderly people in Northern Ireland.
This paper presents the results of a survey on persons over the age of 65 in Northern Ireland. One of the aims of this research was to identify and measure the needs of the elderly population in order to develop a Programme of Care. It would seem logical that the problems of the elderly tend to increase with age. Since the population is becoming older and given the commitment to community care, this will have serious implications for the National Health and Social Services. The present survey was carried out using a questionnaire to extract details concerning the individuals' mental state, ability for self-care and household duties, mobility, accommodation, social activities, general health, strain imposed on others and current support from the statutory services. The results for each category were then presented for 5 age-groups: 65-69, 70-74, 75-79, 80-84 and 85+. Specific problems in relation to home help provision and social facilities such as day care are also discussed.


Mechanisms for the inhibition of amiloride-sensitive Na+ absorption by extracellular nucleotides in mouse trachea.
Purinergic stimulation of airway epithelial cells induces Cl- secretion and modulates Na+ absorption by an unknown mechanism. To gain insight into this mechanism, we used a perfused micro-Ussing chamber to assess transepithelial voltage (V(te)) and amiloride-sensitive short-circuit current (I(sc-Amil)) in mouse trachea. Exposure to apical ATP or UTP (each 100 micromol/l) caused a large initial increase in lumen negative V(te) and I(sc), corresponding to a transient Cl- secretion, while basolateral application of ATP/UTP induced only a small secretory response. Luminal, but not basolateral, application of nucleotides was followed by a sustained and reversible inhibition of I(sc-Amil) that was independent of extracellular Ca2+ or activation of protein kinase C and was not induced by carbachol (100 micromol/l) or the Ca2+ ionophore ionomycin (1 micromol/l). Removal of extracellular Cl- or exposure to 200 microM DIDS reduced UTP-mediated inhibition of I(sc-Amil) substantially. The phospholipase inhibitor U73122 (10 micromol/l) and pertussis toxin (PTX; 200 ng/ml) both attenuated UTP-induced Cl- secretion and inhibition of I(sc-Amil). Taken together, these data imply a contribution of Cl- conductance and PTX-sensitive G proteins to nucleotide-dependent inhibition of the amiloride-sensitive Na+ current in the mouse trachea.


Evaluation of the toxicity of the dopaminergic neurotoxins MPTP and MPP+ in PC12 pheochromocytoma cells: binding and biological studies.
This study was designed to investigate the toxicity of both MPTP and MPP+ using some simple cell systems, such as PC12 and C6 cultures, as models. Exposure of PC12 cells to 0.5 mM MPTP for 72 h resulted in a 50% cell loss with respect to the control cells, and clorgyline, a MAO-A inhibitor, antagonized this toxic effect. Higher concentrations of MPTP demonstrated only a weak cytostatic effect on C6 cells. Moreover, MPP+ showed a toxic effect which was 100 times more evident than MPTP toxicity in the PC12. We found a single, saturable class of [3H]MPP+ binding sites with a relatively high affinity both in PC12 and C6 cell lines. Moreover, the most susceptible cell line towards the toxic effects of both MPTP and MPP+, i.e. PC12, has the higher number of MPP+ binding sites. Our results suggest that MPTP can be toxic not only via MAO-B, but also via MAO-A activity and we propose PC12 as a model to study the intracellular mechanisms of MPTP and MPP+ toxicity.


Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: Participation of antioxidant, nitrergic and neurotrophic mechanisms.
Oxidative stress has important implications in schizophrenia. Alpha-lipoic acid (ALA) is a natural antioxidant synthesized in human tissues with clinical uses. We studied the effect of ALA or clozapine (CLZ) alone or in combination in the reversal of schizophrenia-like alterations induced by ketamine (KET). Adult male mice received saline or KET for 14 days. From 8th to 14th days mice were additionally administered saline, ALA (100 mg/kg), CLZ 2.5 or 5 mg/kg or the combinations ALA+CLZ2.5 or ALA+CLZ5. Schizophrenia-like symptoms were evaluated by prepulse inhibition of the startle (PPI) and locomotor activity (positive-like), social preference (negative-like) and Y maze (cognitive-like). Oxidative alterations (reduced glutathione - GSH and lipid peroxidation - LP) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) and BDNF in the PFC were also determined. KET caused deficits in PPI, working memory, social interaction and hyperlocomotion. Decreased levels of GSH, nitrite (HC) and BDNF and increased LP were also observed in KET-treated mice. ALA and CLZ alone reversed KET-induced behavioral alterations. These drugs also reversed the decreases in GSH (HC) and BDNF and increase in LP (PFC, HC and ST). The combination ALA+CLZ2.5 reversed behavioral and some neurochemical parameters. However, ALA+CLZ5 caused motor impairment. Therefore, ALA presented an antipsychotic-like profile reversing KET-induced positive- and negative-like symptoms. The mechanism partially involves antioxidant, neurotrophic and nitrergic pathways. The combination of ALA+CLZ2.5 improved most of the parameters evaluated in this study without causing motor impairment demonstrating, thus, that possibly when combined with ALA a lower dose of CLZ is required.


High-performance liquid chromatographic determination of D-amino acid oxidase activity.
A new procedure for the assay of D-amino acid oxidase activity has been developed. alpha-Ketoisovaleric acid, derived from D-valine, was estimated by high-performance liquid chromatography after reaction with o-phenylenediamine to give the corresponding quinoxalinol derivative. alpha-Ketovaleric acid was used as an internal standard to ensure the reproducibility of the method. As an example of application, kidney cortex homogenates were analyzed for their D-amino acid oxidase activity. The advantages of the presented procedure for the determination of the enzymatic activity in biological samples compared with previously reported procedures are discussed.


Evaluation of wastewater toxicity: comparative study between Microtox and activated sludge oxygen uptake inhibition.
Microtox is a frequent toxicity tool for the screening of wastewaters discharged into wastewater treatment plants. There is currently an increasing controversy between this test and others using activated sludge. A Microtox and electrolytic respirometry comparative study for toxicity determination has been performed. Seven organic and five inorganic toxic compounds have been assessed for comparing both methods. Microtox proved to have a higher sensitivity to toxicants but was less representative of effects on activated sludge compared to respirometry. For instance, assays accomplished with LAS, a biodegradable reference surfactant, showed a toxic effect by Microtox but good biodegradability and no toxicity in respirometry. This could be explained by the different nature of the biological material used, as Microtox utilises the seawater Vibrio fischeri, whereas respirometry uses the bacterial consortium in activated sludge. For the evaluation of the potential toxicity of a compound on a WWTP, the preferred biological material be used should be activated sludge itself. Results obtained with any other biological material would be just an approach to reality.


Dual-acting antitumor agents targeting the A2A adenosine receptor and histone deacetylases: Design and synthesis of 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives.
Based on its inhibition by antagonists, the A2A adenosine receptor (A2AAR) has attracted attention as an anti-tumor drug target; however, in preclinical models and clinical trials, A2AAR antagonists have so far shown only limited efficacy as standalone therapies. The design of dual-acting compounds, targeting the A2AAR and histone deacetylases (HDACs), is used here as an approach to the discovery of novel and more potent antitumor agents. Based on the core structures of the A2AAR antagonists V-2006 and CPI-444, novel 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives were designed as such dual-acting compounds. The binding affinities for A2AAR of all the new compounds were tested, and their HDAC inhibitory activity was evaluated. Compounds with balanced A2AAR antagonism and HDAC inhibition were tested for their in vitro anti-proliferative activity and pharmacokinetic properties. One of the compounds, 14c (4-(2-(6-Amino-4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-N-(2-amino-phenyl)benzamide) showed an overall favorable pharmacokinetic profile; in the mouse MC38 xenograft model, it showed potent anti-tumor effects with inhibition rates of 44% (90 mg/kg, po, bid) and 85% (60 mg/kg, ip, bid), respectively.


The sigma1 (sigma1) receptor activation is a key step for the reactivation of cocaine conditioned place preference by drug priming.
Cocaine-seeking behavior can be investigated in rodents using the conditioned place preference (CPP) paradigm, in which the drug-paired environment serves as a conditioned stimulus. Such approach allowed to previously demonstrate the importance of the neuromodulatory sigma1 (sigma1) receptor in acquisition of cocaine-induced CPP. CPP can be extinguished and then reactivated, notably using a cocaine challenge (i.e., priming). In order to examine the role of the sigma1 receptor in reinstatement of Cocaine-seeking, Swiss mice acquired CPP with cocaine (30 mg/kg, i.p.) and then CPP was extinguished. A challenge cocaine priming (15 mg/kg) reactivated CPP up to 140% of the post-conditioning response. Pre-administration of the sigma1 receptor antagonist BD1047 (330 mg/kg, i.p.) or repeated treatment with an antisense probe targeting the sigma1 receptor prevented CPP reactivation. The sigma1 agonist igmesine (1-10 mg/kg, i.p.) or the steroid dehydroepiandrosterone (DHEA, 10-40 mg/kg, s.c.) reactivated CPP, in a BD1047-sensitive manner. Moreover, the in vivo [3H](+)-SKF-10,047 binding levels to the sigma1 receptor were increased after cocaine conditioning in numerous brain structures and these increases subsisted after extinction. Finally, cross-reactivation of cocaine-induced CPP was observed after phencyclidine (PCP), morphine, nicotine and ethanol administration. However, BD1047 blocked reactivation of CPP induced by PCP, morphine and nicotine but not ethanol. Since activation of the sigma1 receptor is not sufficient to sustain CPP in naive animals [Neuropsychopharmacology 26 (2002) 444], it is concluded that sigma1 receptor activation is a key event for relapse to drug seeking. Activation may occur via sensitization due to enhanced in vivo available of receptors.


Indole analogues decreasing the virulence of Vibrio campbellii towards brine shrimp larvae.
Indole signalling has been proposed as a potential target for the development of novel virulence inhibitors to control bacterial infections. However, the major structural features of indole analogues that govern antivirulence activity remain unexplored. Therefore, we investigated the impact of 26 indole analogues on indole-regulated virulence phenotypes in Vibrio campbellii and on the virulence of the bacterium in a gnotobiotic brine shrimp model. The results demonstrated that 10 indole analogues significantly increased the fluorescence of indole reporter strain Vibrio cholerae S9149, 21 of them decreased the swimming motility of V. campbellii, and 13 of them significantly decreased the biofilm formation of V. campbellii. Further, we found that 1-methylindole, indene, 2,3-benzofuran, thianaphthene, indole-3-acetonitrile, methyl indole-3-carboxylate, 3-methylindole, and indole-2-carboxaldehyde exhibited a significant protective effect on brine shrimp larvae against V. campbellii infection, resulting in survival rates of challenged brine shrimp above 80%. The highest survival of shrimp larvae (98%) was obtained with indole-3-acetonitrile, even at a relatively low concentration of 20 μM. Importantly, the indole analogues did not affect bacterial growth, both in vitro and in vivo. These results indicate the potential of indole analogues in applications aiming at the protection of shrimp from vibriosis.


Malignant change in benign cystic teratoma of the ovary.
In a clinico-pathological study of malignant disease of the ovary in the former North East Metropolitan Region, malignant transformation of benign cystic teratoma has emerged as the commonest malignancy of "germ cell" origin. The clinical and pathological details of 12 patients are reported.


Recognition of melting of nanoparticle catalysts with cubically shaped Co3O4 nanoparticles.
Cubically shaped cobalt oxide nanoparticle catalysts were used for the first time to investigate the melting of the nanoparticle catalysts responsible for the synthesis of silica nanocoils at 1050 degrees C and straight nanowires at 1100 degrees C. Cobalt nanoparticles remained morphologically highly anisotropic after the growth of nanocoils at 1050 degrees C, whereas they became predominately spherical after straight nanowires were made at 1100 degrees C. These results strongly indicated that cobalt nanoparticles responsible for the synthesis of straight nanowires were completely molten and that melting occurred to these nanoparticles between 1050 and 1100 degrees C.


LIPG: an inflammation and cancer modulator.
Endothelial lipase (LIPG/EL) performs fundamental and vital roles in the human body, including cell composition, cytokine expression, and energy provision. Since LIPG predominantly functions as a phospholipase as well as presents low levels of triglyceride lipase activity, it plays an essential role in lipoprotein metabolism, and involves in the metabolic syndromes such as inflammatory response and atherosclerosis. Cytokines significantly affect LIPG expression in endothelial cells in many diseases. Recently, it is suggested that LIPG contributes to cancer initiation and progression, and LIPG attached increasing importance to its potential for future targeted therapy.


Hsa_circ_0015382 is involved in the pathogenesis of preeclampsia by mediating THBS2 expression.
Preeclampsia (PE) is a hypertensive disorder of pregnancy that causes significant maternal and perinatal morbidity and mortality. Circular RNA (circRNA) hsa_circ_0015382 is associated with the pathogenesis of PE, but its underlying regulatory mechanism remains to be explored. Relative RNA levels of hsa_circ_0015382, microRNA-616-3p and thrombospondin-2 (THBS2) were detected by quantitative reverse transcription-polymerase chain reaction. In vitro regulatory effects of hsa_circ_0015382 on the proliferation, migration, invasion and angiogenesis of trophoblasts were evaluated by CCK-8, flow cytometry for cell cycle, EdU, transwell, wound healing and HUVEC tube formation assays, respectively. Targeting interaction was verified by dual-luciferase reporter and RNA immunoprecipitation assays. Hsa_circ_0015382 was highly expressed in placental tissues from PE patients. Upregulation of hsa_circ_0015382 repressed trophoblast proliferation, migration, invasion and lowered trophoblast-induced HUVEC tube formation. Hsa_circ_0015382 was validated as a miR-616-3p sponge and miR-616-3p targeted THBS2. Hsa_circ_0015382 could mediate trophoblast proliferation, migration, invasion and regulate trophoblast-induced HUVEC tube formation by sponging miR-616-3p and regulating THBS2 expression. Hsa_circ_0015382 is associated with the pathogenesis of PPE by regulating the miR-616-3p/THBS2 axis. Hsa_circ_0015382 is overexpressed in preeclampsia patients. Hsa_circ_0015382 inhibits trophoblast proliferation, migration, invasion and decreases trophoblast-induced HUVEC tube formation. Hsa_circ_0015382 interacts with miR-616-3p to regulate THBS2 expression.


The neurobehavioural consequences of petrol (gasoline) sniffing.
This review will introduce petrol (gasoline) sniffing as a specific form of substance abuse. Petrol sniffing is associated with dysfunctions that range in severity from subtle cognitive impairment to encephalopathy and death, and these are discussed with respect to their specific neurological and cognitive bases. Morbidity and mortality rates will also be presented that suggest severe central nervous system damage occurs as a result of petrol sniffing. The neuropharmacological actions of tetraethyl lead and volatile hydrocarbons, the components within petrol, and their contributions to the effects of sniffing petrol are investigated. Reports of human occupational or recreational exposure to either lead additives or volatile hydrocarbons (i.e. inhalants) have provided evidence of the neurological and cognitive effects that may also occur with petrol sniffing. Petrol sniffing causes a progressive decline of cognitive function that eventually leads to permanent neurological changes.


Magnetocardiography in the evaluation of fetuses at risk for sudden cardiac death before birth.
We hypothesized that fetuses at risk for sudden death may have abnormal conduction or depolarization, ischemia, or abnormal heart rate variability (HRV) detectable by magnetocardiography. Using a 37-channel biomagnetometer, we evaluated 3 groups of fetuses at risk for sudden death: group 1, critical aortic stenosis (AS); group 2, arrhythmias; and group 3, heart failure and in utero demise. Five to 10 recordings of 10-minute duration were recorded, and signal was averaged to determine rhythm, conduction intervals, HRV, and T-wave morphology. In group 1, 2 of 3 had atrial and ventricular strain patterns. In (n = 53) group 2, 15% had prolonged QTc and 17% had T-wave alternans (TWA). Of 23 group 2 fetuses with atrioventricular block, 74% had ventricular ectopy, 21% had junctional ectopic tachycardia, and 29% had ventricular tachycardia. Group 3 (n = 2) had abnormal HRV and TWA. Repolarization abnormalities, unexpected arrhythmias, and abnormal HRV suggest an arrhythmogenic mechanism for "sudden cardiac death before birth."


Ballistic reactions under different motor sets.
In preparation for performing task specific ballistic movements, subjects may choose among different possibilities for setting up their motor apparatus, ranging from quiet resting to different types of muscle activation. In the study presented here, we investigated whether differences in the motor set modify either the reaction time or the kinematic characteristics of the movement. Subjects wearing surface EMG recording electrodes in the wrist extensor (WE) and wrist flexor (WF) muscles were requested to react to the presentation of a visual stimulus by performing a ballistic wrist extension movement of an amplitude of about 50 degrees in the following experimental conditions: resting quietly, which was considered as the control condition (CC); isometric contraction (IC), in which subjects were required to activate WE and WF muscles isometrically; rapid oscillations (RO), in which subjects were requested to make a fast oscillatory wrist movement; and slow oscillations (SO), in which subjects were maintaining a slow oscillatory motion of the wrist. To constrain the movement to the wrist joint and limit the action of postural muscles, the subject's forearm and hand were attached to joined non-resistive metallic platforms, allowing for free non-frictional displacement. In the EMG recordings, we measured the size of the EMG bursts in agonist and antagonist muscles, and the inter-burst intervals. In movement recordings, we measured movement onset latency and the velocity profile. Movement onset was delayed in SO with respect to all other conditions. Conversely, peak velocity was larger in all test conditions in comparison to CC. There were no differences in the size of the first EMG burst of the agonist muscle, but significant changes occurred in the subsequent bursts recorded in the agonist and antagonist muscles. Our study indicates that the motor program used to execute a ballistic voluntary movement is influenced by the conditions of the motor system. The configuration of the motor set should be specifically considered in the search for improving the speed of the reaction and the kinematics of ballistic movements.


Meso-dihydroguaiaretic acid and licarin A of Machilus thunbergii protect against glutamate-induced toxicity in primary cultures of a rat cortical cells.
1 We previously reported that four lignans isolated from the bark of Machilus thunbergii Sieb. et Zucc. (Lauraceae) protected primary cultures of rat cortical neurons from neurotoxicity induced by glutamate. 2 Among the lignans, meso-dihydroguaiarectic acid (MDGA) and licarin A significantly attenuated glutamate-induced neurotoxicity when added prior to or right after the excitotoxic glutamate challenge. 3 The neuroprotective activities of two lignans appeared to be more effective in protecting neurons against neurotoxicity induced by NMDA than that induced by kainic acid. 4 MDGA and licarin A diminished the calcium influx that routinely accompanies with the glutamate-induced neurotoxicity, and inhibited the subsequent overproduction of cellular nitric oxide and peroxide to the level of control cells. They also preserved cellular activities of antioxidative enzymes such as superoxide dismutase, glutathione peroxidase and glutathione reductase reduced in the glutamate-injured neuronal cells. 5 Thus, our results suggest that MDGA and licarin A significantly protect primary cultured neuronal cells against glutamate-induced oxidative stress, via antioxidative activities.


Diagnosis of O. volvulus infection via skin exposure to diethylcarbamazine: clinical evaluation of a transdermal delivery technology-based patch.
Elimination of onchocerciasis in Africa is now regarded as an achievable goal in many areas. This makes monitoring changes in infection prevalence a key component of control programmes. Monitoring is currently based on determining the presence of O. volvulus microfilariae in skin snips, an invasive, labour-intensive method. The Onchocerciasis Control Programme (OCP) had established procedures to detect O. volvulus infections via the localized skin reaction induced by killing of microfilariae upon skin exposure to diethylcarbamazine via a patch (OCP-patch). Large scale OCP - patch use is difficult due to labour-intensive patch preparation. At the request of TDR, a manufacturer specialized in transdermal-delivery systems developed a ready-to-use diethylcarbamazine (DEC) containing patch (LTS-2 patch). To qualify this patch for large scale studies of its sensitivity and specificity, this study evaluated its ease of application, ability to detect infection and DEC exposure related adverse reactions compared to the OCP-patch in 30 infected individuals. Each participant with 0.2-36.8 O. volvulus microfilariae/mg skin received the OCP-patch and 4 days later the LTS-2 patch at the left and right iliac crest, respectively, for 24 h. Presence and characteristics of local skin reactions were assessed at patch removal and 6 h later. Skin reaction and Mazzotti reaction rates were compared with Fisher's exact and a paired t-test, respectively. The LTS-2 patch could be applied within 10 s. Mild itching occurred at 63.3 % of OCP-patch (duration 8.9 ± 11.8 h) and 26.7 % of LTS-2 patch sites (duration 1.0 ± 2.5 h) and was the most frequent Mazzotti reaction. At patch removal after 24 h, a diagnostic local skin reaction was present under 90 % of OCP-patches and 83 % of LTS-2 patches; 6 h later, it was present at 93 % of OCP-patch and 100 % of LTS-2 patch sites. The data suggest that safety, tolerability and ability to detect infections of the LTS-2 patch are comparable to those of the OCP-patch. They qualify the LTS-2 patch for field studies to determine LTS-2 patch sensitivity, specificity and utility during large scale use and thus to inform use of the LTS-2 patch by onchocerciasis control programmes to determine prevalence of infection. Current controlled Trials ISRCTN76875372 .


Patient-centred care and patient autonomy: doctors' views in Chinese hospitals.
Patient-centred care and patient autonomy is one of the key factors to better quality of service provision, hence patient outcomes. It enables the development of patients' trusts which is an important element to a better doctor-patient relationship. Given the increasing number of patient disputes and conflicts between patients and doctors in Chinese public hospital, it is timely to ensure patient-centred care is fully and successfully implemented. However, limited studies have examined the views and practice in different aspects of patient-centred care among doctors in the Chinese public hospitals. A quantitative approach was adopted by distributing paper-based questionnaires to doctors and patients in two hospitals (Level III and Level II) in Jinan, Shandong province, China. In total, 614 doctors from the surgical and internal medicine units of the two hospitals participated in the survey yielding 90% response rates. The study confirmed the inconsistent views among doctors in terms of their perception and practice in various aspects patient-centred care and patient autonomy regardless of the hospital where they work (category II or category III), their unit speciality (surgical or non-surgical), their gender or seniority. The high proportion of doctors (more than 20%) who did not perceive the importance of patient consultation prior to determining diagnostic and treatment procedure is alarming. This in in part due to the belief held by more than half of the doctors that patients were unable to make rational decisions and their involvement in treatment planning process did not necessarily lead to better treatment outcomes. The study calls for the development of system level policy and organisation wide strategies in encouraging and enabling the practice of patient-centred care and patient autonomy with the purposes of improving the quality of the service provided to patients by Chinese hospitals.


Sequence-specific binding of androgen-receptor complexes to prostatic binding protein genes.
Prostatic binding protein is a complex glycoprotein comprising three components, C1, C2 and C3, organized into two different heterodimers (C1-C3 and C2-C3). The rat ventral prostate genes encoding all three constituent polypeptides are expressed under androgenic control. Analysis of genomic fragments containing the genes and flanking sequences revealed in each case one androgen receptor-binding region upstream of or within the promoter and another in the first intron. The effect of androgens on the expression of these genes may, therefore, be mediated by these direct receptor-DNA interactions. The genomic fragments which contain androgen receptor-binding regions all contain nucleotide sequences reminiscent of glucocorticoid response elements (GRE). Mutations in these sequences in restriction fragments and in synthetic oligonucleotides significantly decreased their affinity for androgen-receptor complexes and their introduction into nonspecific sequences conferred affinity for androgen-receptor complexes. Based on these data, a consensus sequence for putative androgen response elements (ARE) is proposed. However, despite the specific recognition of these sequences by the androgen receptor in vitro, only the C3(1) intronic fragment could confer significant androgen responsiveness on a heterologous promoter. While this could be due to the fact that the GRE-like sequences present in the other fragments are not strong AREs, alternative hypotheses are being investigated currently. Not least of these is that the similar localization of the binding sites in each gene might underlie a more complex androgen regulation mechanism.


An endobronchial recurrence of resected lung adenocarcinoma.
We report a rare case of endobronchial metastasis arising from peripheral lung adenocarcinoma 12 months after its complete resection. A 69-year old man underwent left upper lobectomy and lymph node dissection. A year after surgery, a bronchial nodule was identified at the left main bronchus through a computed tomography study. A bronchoscope examination showed that the bronchial nodule in the cartilage was located apart from the stump of the upper bronchus. Thus, bronchoscopic resection was performed. The pathological diagnosis was papillary adenocarcinoma, which was identical to the pathology of the previously resected lung cancer. Endobronchial metastasis from the primary lung cancer was confirmed. The present case highlights that clinicians should pay more attention to this rare recurrence pattern of lung cancer.


Prognostic value of circumferential radial margin involvement in esophagectomy for esophageal cancer: a case series.
Residual tumor at the proximal or distal margin after esophagectomy is associated with worse survival outcomes; however, the significance of the circumferential resection margin (CRM) remains controversial. In this study, we sought to evaluate the prognostic significance of the CRM in patients with esophageal cancer undergoing resection. We identified patients who underwent esophagectomy for pathologic T3 esophageal cancer from 2000 to 2019. Patients were divided into three groups: CRM- (residual tumor >1 mm from the CRM), CRM-close (residual tumor >0 to 1 mm from the CRM), and CRM+ (residual tumor at the surgical CRM). CRM was also categorized and analyzed per the Royal College of Pathologists (RCP) and College of American Pathologists (CAP) classifications. Of the 519 patients included, 351 (68%) had CRM-, 132 (25%) had CRM-close, and 36 (7%) had CRM+. CRM+ was associated with shorter disease-free survival [DFS; CRM+ vs. CRM-: hazard ratio (HR), 1.53 [95% CI, 1.03-2.28]; P =0.034] and overall survival (OS; CRM+ vs. CRM-: HR, 1.97 [95% CI, 1.32-2.95]; P <0.001). Survival was not significantly different between CRM-close and CRM-. After adjustment for potential confounders, CAP+ was associated with poor oncologic outcomes (CAP+ vs. CAP-: DFS: HR, 1.47 [95% CI, 1.00-2.17]; P =0.050; OS: HR, 1.93 [95% CI, 1.30-2.86]; P =0.001); RCP+ was not (RCP+ vs. RCP-: DFS: HR, 1.21 [95% CI, 0.97-1.52]; P =0.10; OS: HR, 1.21 [95% CI, 0.96-1.54]; P =0.11). CRM status has critical prognostic significance for patients undergoing esophagectomy: CRM+ was associated with worse outcomes, and outcomes between CRM-close and CRM- were similar.


Thermal responses of Durum wheat Triticum durum to early water stress. Consequence on leaf and flower development.
Drought can alter stem apex temperature and plant phenological development and it can then have an effect on the duration of the durum wheat stages. Thermal responses of plants to water stress are tentatively analysed as regards microclimate conditions by applying three different water treatments. Apex temperature measurements showed that they are related to radiation and that acceleration of apex development could be related to their increase.


Baseline levels and trimestral variation of triiodothyronine and thyroxine and their association with mortality in maintenance hemodialysis patients.
Conflicting evidence exists with regard to the association of thyroid hormones and mortality in dialysis patients. This study assesses the association between basal and trimestral variation of thyroid stimulating hormone, triiodothyronine, and thyroxine and mortality. In 210 prevalent hemodialysis patients, serum triiodothyronine, thyroxine, thyroid stimulating hormone, and interleukin-6 were measured 3 months apart. Cardiovascular and non-cardiovascular deaths were registered during follow-up. Based on fluctuations along tertiles of distribution, four trimestral patterns were defined for each thyroid hormone: persistently low, decrease, increase, and persistently high. The association of baseline levels and trimestral variation with mortality was investigated with Kaplan-Meier curves and Cox proportional hazard models. During follow-up, 103 deaths occurred. Thyroid stimulating hormone levels did not associate with mortality. Patients with relatively low basal triiodothyronine concentrations had higher hazards of dying than patients with high levels. Longitudinally, patients with persistently low levels of triiodothyronine during the 3-month period had higher mortality hazards than those having persistently high levels. These associations were mainly attributable to cardiovascular-related mortality. The association between thyroxine and mortality was not altered after adjustment for triiodothyronine. Hemodialysis patients with reduced triiodothyronine or thyroxine levels bear an increased mortality risk, especially due to cardiovascular causes. This was true when considering both baseline measurements and trimestral variation patterns. Our longitudinal design adds observational evidence supporting the hypothesis that the link may underlie a causal effect.


A formulation of the foundations of genetics and evolution.
This paper proposes a formulation of theories of the foundations of genetics and evolution that can be used to mathematically simulate phenotype expression, reproduction, mutation, and natural selection. It will be shown that Mendelian inheritance can be mathematically simulated with expressions involving matrices and that these expressions can also simulate phenomena that are modifications to Mendel's basic principles, like alleles that give rise to quantitative effects and traits that are the expression of multiple alleles and/or multiple genetic loci.


Potassium attenuates zinc-induced death of cultured cortical astrocytes.
Transient global ischemia induces CA1 hippocampal neuronal death without astrocyte death, perhaps mediated in part by the toxic translocation of zinc from presynaptic terminals to postsynaptic neurons. We tested the hypothesis that cellular depolarization, which occurs in the ischemic brain due to increased extracellular potassium and energy failure, might contribute to astrocyte resistance to zinc-induced death. We previously reported that neurons in mixed cortical neuronal-astrocyte cultures were more vulnerable to a 5-15-min exposure to Zn(2+) than astrocytes in the same cultures. In the present report, we show that (1) neurons in isolation or in conjunction with astrocytes were 2-3-fold more sensitive to a 15-min nondepolarizing Zn(2+) exposure than are glia; (2) KCl-induced depolarization attenuated glial vulnerability to zinc toxicity but potentiated neuronal vulnerability to zinc toxicity; (3) Zn(2+)-induced glial death was attenuated by T-type Ca(2+) channel blockade, as well as compounds that increase NAD(+) levels; and (4) both astrocytic (65)Zn(2+) accumulation and the increase in astrocytic [Zn(2+)](i) induced by Zn(2+) exposure were also attenuated by depolarization or T-type Ca(2+) channel blockers. Zn(2+)-induced cell death in astrocytes was at least in part apoptotic, as caspase-3 was activated, and the caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone partially attenuated Zn(2+)-induced death. The levels of peak [Zn(2+)](i) achieved in astrocytes during this toxic nondepolarizing Zn(2+) exposure (250 nM) were substantially greater than those achieved in neurons (40 nM). In glia, exposure to 400 microM Zn(2+) induced a 13-mV depolarization, which can activate T-type Ca(2+) channels. This Zn(2+)-induced astrocyte death, like neuronal death, was attenuated by the addition of pyruvate or niacinamide to the exposure medium.


Antibacterial assay guided isolation of a novel hydroxy-substituted pentacyclo ketonic compound from Pseudomonas aeruginosa MBTDCMFRI Ps04.
Antimicrobial compounds from the natural source have gained greater relevance because of their wide spectrum of possible applications, especially in the aquaculture industry where pathogenic threat and antibacterial resistance are serious concerns. In this regard, Pseudomonas aeruginosa MBTDCMFRI Ps04 (P. aeruginosa Ps04) strain isolated from the tropical estuarine habitats of Cochin was evaluated for its antibacterial potential against major aquaculture pathogens. The physiological conditions for the maximum production of the active metabolite were also optimized. An activity-guided approach was employed further to isolate and characterize the secondary metabolite responsible for the inhibitory potential. It was found that the cell free supernatant (CFS) of P. aeruginosa Ps04 exhibited strong antibacterial activity against major aquaculture pathogens belonging to the genus Vibrio and Aeromonas and retained its potential even at 30% (v/v) dilution. The highest antibacterial activity was detected from 3rd day culture, grown in glycerol alanine media (1% each) as carbon and nitrogen source, respectively, at 30 °C, pH 7.0 and at a salinity of 20 parts per thousand (ppt). The activity of the antagonistic principle was found to be stable against variations in pH (pH 2-pH 12), temperature (up to 120 °C) and enzymatic treatments. Bioassay-guided purification followed by spectroscopic characterization of active fractions of P. aeruginosa Ps04 revealed that the compound 4-Hydroxy-11-methylpentacyclo [11.8.0.02,3.011, 12.016,17]henicosa-1,3,5,8(9),17-penten-14-one is responsible for its major antibacterial activity. The results of this study indicated that P. aeruginosa Ps04 has beneficial antibacterial properties which could be used in developing novel antimicrobial therapeutics against a variety of aquaculture pathogens.


Forecasting Brassica napus production under climate change with a mechanistic species distribution model.
Brassica napus, a versatile crop with significant socioeconomic importance, serves as a valuable source of nutrition for humans and animals while also being utilized in biodiesel production. The expansion potential of B. napus is profoundly influenced by climatic variations, yet there remains a scarcity of studies investigating the correlation between climatic factors and its distribution. This research employs CLIMEX to identify the current and future ecological niches of B. napus under the RCP 8.5 emission scenario, utilizing the Access 1.0 and CNRM-CM5 models for the time frame of 2040-2059. Additionally, a sensitivity analysis of parameters was conducted to determine the primary climatic factors affecting B. napus distribution and model responsiveness. The simulated outcomes demonstrate a satisfactory alignment with the known current distribution of B. napus, with 98% of occurrence records classified as having medium to high climatic suitability. However, the species displays high sensitivity to thermal parameters, thereby suggesting that temperature increases could trigger shifts in suitable and unsuitable areas for B. napus, impacting regions such as Canada, China, Brazil, and the United States.


Effects of cadmium, mercury, and selenium on reproductive indices in male lesser scaup (Aythya affinis) in the western Boreal forest.
Combined lesser scaup (Aythya affinis) and greater scaup (A. marila) populations decreased from the 1980s to the 1990s and have not recovered. Factors limiting reproduction, including effects of contaminants and trace elements, have been highlighted as a concern in female scaup, but no studies have examined possible effects on male scaup. We examined the effects of cadmium, mercury, selenium, and corticosterone on pair status and on male reproductive indices, including testosterone, testes mass, and seminiferous tubule diameter, in male lesser scaup collected in the western boreal forest near Yellowknife, Northwest Territories, May and June, during 2004 and 2005. Male scaup that were larger in size (p = 0.048) and with better body condition (p = 0.038) were more likely to be paired. No relations were observed between independent variables and testosterone and testes mass. However, results suggested that seminiferous tubule diameter is influenced by a complex array of biologic and toxicologic parameters, which differ depending on pair status. Tubule diameters of paired male scaup were negatively influenced by hormones, whereas contaminants influenced diameter in unpaired male scaup. The effects of selenium were attenuated when bound with cadmium but not mercury. When selenium concentrations were high (greater than median value), there was a positive effect of cadmium on tubule diameter (R(2) = 0.30, n = 10, p = 0.007) but a negative relation with mercury (R(2) = 0.15, n = 10, p = 0.09). Seminiferous tubule diameter may be a sensitive indicator of sublethal effects of contaminants. This study showed contaminant and trace element effects at concentrations lower than threshold levels associated with major toxic effects. This study also demonstrated the complex nature of biologic systems and the importance of considering interactions to accurately characterize effects of metals.


Aflatoxin B1 induces microglia cells apoptosis mediated by oxidative stress through NF-κB signaling pathway in mice spinal cords.
Many studies have shown that aflatoxin B1 (AFB1) can cause cytotoxicity in numerous cells and organs induced by oxidative stress. However, the toxic effects and related mechanism of AFB1 on the microglia cells in the spinal cords have not been studied yet. Our results showed that AFB1 significantly reduced the number of microglia cells, increased the oxidants (malonaldehyde and hydrogen peroxide) but decreased the anti-oxidants (superoxide dismutase and total antioxidant capacity) in a dose dependent manner in mice spinal cords. In addition, AFB1 significantly increased the oxidative stress, promoted apoptosis and cell cycle arrest in G2-M phase, and activated NF-κB phosphorylation in BV2 microglia cells. However, the addition of active oxygen scavenger N-acetylcysteine can significantly reduce the ROS production, improve cell cycle arrest, reduce apoptosis, and the expression of phosphorylated NF-κB in BV2 microglia cells. These results indicate that AFB1 induces microglia cells apoptosis through oxidative stress by activating NF-κB signaling pathway.


Direct inhibition of smooth muscle myosin light chain kinase by arachidonic acid in a purified system.
The direct effect of arachidonic acid (AA) on the phosphorylation of smooth muscle myosin light chain (SMLC) by smooth muscle myosin light chain kinase (SMLCK) was assessed in a purified system. AA inhibited the phosphorylation of SMLC by SMLCK in a dose dependent manner. Increasing the amount of calmodulin (59 nM and 590 nM) did not reverse this inhibition. Linoleic acid and oleic acid also inhibited the phosphorylation. The inhibitory potency of these unsaturated fatty acids paralleled the number of cis double bonds. These results show that SMLCK is directly inhibited by unsaturated fatty acids including AA.


Factors associated with women's approval on intimate partner violence in Bangladesh: A cross-sectional analysis of latest demographic and health survey 2017-18.
In Bangladesh, intimate partner violence (IPV) is high among women faced by their husband. Regrettably, IPV is often justified by the women themselves, resulting in poor social and health outcomes among them. In this paper, we explored the factors that influence the approval of IPV among the women by their husband in Bangladesh. The present used the data from the most recent Bangladesh Demographic and Health Survey (BDHS) 2017-18. The BDHS 2017-18 followed a two-stage stratified random sampling techniques and the present analysis was carried out among a weighted sample of 20,127 women. Multivariate logistic regression was used to identify the demographic and socio-economic factors associated with the approval of IPV among the women. Overall, one in five women (20.5%) approved at least one form of violence by their husband. In adjusted analysis, women who completed secondary education were 57% less likely [AOR = 0.43, 95% CI: 0.34-0.54] to approve IPV compared to those who had no formal education. Similarly, women who belonged to Hinduism and other religious group were 42% less likely [AOR = 0.58, 95% CI: 0.45-0.74] to approve IPV compared to those who practiced Islam. Moreover, women who were exposed to television, participated in the decision on household purchase and moving outside home had 14%, 19%, and 21% less chance for approving IPV by the husband for at least one reason (p < 0.05). This study highlighted that many women in Bangladesh approve violence by their husband which could be a major obstacle to the reduction of violence from society. Behavior change intervention should be implemented, particularly targeting the less-educated Muslim women to increase the awareness on IPV in Bangladesh.


Author Correction: Novel Imidazole and Methoxybenzylamine Growth Inhibitors Affecting Salmonella Cell Envelope Integrity and its Persistence in Chickens.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Genome-wide identification and characterization of SnRK family genes in Brassica napus.
Sucrose non-fermenting 1 related protein kinases (SnRK) play crucial roles in responding to biotic and abiotic stresses through activating protein phosphorylation pathways. However, little information of SnRK genes was available in Brassica napus, one of important oil crops. Recently, the released sequences of the reference genome of B.napus provide a good chance to perform genome-wide identification and characterization of BnSnRK gene family in the rapeseed. Totally 114 SnRK genes distributed on 19 chromosomes were identified in the genome of B.napus and classified into three subfamilies on the basis of phylogenetic analysis and the domain types. According to gene structure and motif composition analysis, the BnSnRK sequences showed obvious divergence among three subfamilies. Gene duplication and synteny between the genomes of the rapeseed and Arabidopsis were also analyzed to provide insights into the evolutionary characteristics of BnSnRK family genes. Cis-element analysis revealed that BnSnRKs may response to diverse environmental stresses. Moreover, the expression patterns of BnSnRKs in various tissues and under diverse abiotic stresses were distinct difference. Besides, Single Nucleotide Polymorphisms (SNP) distribution analysis suggests the function disparity of BnSnRK family genes in different genotypes of the rapeseed. We examined genomic structures, evolution features, expression patterns and SNP distribution of 114 BnSnRKs. The results provide valuable information for functional characterization of BnSnRK genes in future studies.


Detection of oligoclonal IgG kappa and IgG lambda bands in cerebrospinal fluid and serum with Hevylite™ antibodies. comparison with the free light chain oligoclonal pattern.
Oligoclonal IgG bands in cerebrospinal fluid that are absent in serum indicate intrathecal IgG synthesis and are a sensitive marker of CNS inflammatory diseases, in particular multiple sclerosis. It may be of interest to determine whether these bands are predominantly IgGκ or IgGλ. We have used Hevylite™ antibodies and developed a technique for detection of oligoclonal IgGκ and IgGλ bands by means of isoelectric focusing followed by immunoblotting. The same technique was used for oligoclonal free κ and free λ detection. Among several techniques tested, affinity immunoblotting appears to be the most sensitive; it can detect less than 1 ng of IgGκ or IgGλ paraprotein. We compared oligoclonal IgG profiles with those of oligoclonal IgGκ and IgGλ. There was good agreement concerning the presence or absence of intrathecal synthesis. We observed the ratios between oligoclonal IgGκ and IgGλ bands, and they did not always match the ratios between free κ and free λ bands. We were also able to detect antigen-specific CSF-restricted oligoclonal IgGκ and IgGλ bands in neuroborreliosis. It remains to be determined subsequently by a clinically-oriented prospective study, whether predominant IgGκ/IgGλ or free κ/free λ can be observed more frequently in particular diseases with oligoclonal IgG synthesis. Very sensitive detection of oligoclonal IgGκ and IgGλ bands in cerebrospinal fluid with Hevylite antibodies is feasible; detection of antigen-specific IgGκ or IgGλ is possible as well. In particular situations, e.g. when difficulties arise in distinguishing between oligoclonal and monoclonal pattern, the test may be of considerable clinical value.


Diverse effects of prostacyclin on angiogenesis-related processes in the porcine endometrium.
Angiogenesis is important for endometrial remodeling in mature females. The endometrium synthesizes high amounts of prostacyclin (PGI2) but the role of PGI2 in angiogenesis-related events in this tissue was not fully described. In the present study, porcine endometrial endothelial (pEETH) cells and/or a swine umbilical vein endothelial cell line (G1410 cells) were used to determine the regulation of PGI2 synthesis and PGI2 receptor (PTGIR) expression by cytokines and to evaluate the effect of PGI2 on pro-angiogenic gene expression, intracellular signaling activation, cell proliferation and migration, cell cycle distribution, and capillary-like structure formation. We found that IL1β, IFNγ, and/or TNFα increased PGI2 secretion and PTGIR expression in pEETH cells. Iloprost (a PGI2 analogue) acting through PTGIR enhanced the transcript abundance of KDR, FGFR2, and ANGPT2 and increased proliferation of pEETH cells. This latter was mediated by PI3K and mTOR activation. In support, transfection of G1410 cells with siRNA targeting PGI2 synthase decreased pro-angiogenic gene expression and cell proliferation. Furthermore, iloprost accelerated the gap closure and promoted cell cycle progression. Intriguingly, the formation of capillary-like structures was inhibited but not completely blocked by iloprost. These findings point to a complex pleiotropic role of PGI2 in angiogenesis-related events in the porcine uterus.


Bronchial allergen challenges in children - safety and predictors.
In allergic asthma, the diagnosis of house dust mite (HDM) allergy is mainly based on the patient's history, allergy testing by the skin prick test (SPT) or the levels of allergen-specific IgE. We retrospectively analysed data from 350 bronchial provocations with HDM and related it to the following parameters: specific IgE, bronchial hyperresponsiveness (BHR) to methacholine testing (MCT) and exhaled NO (eNO). Approximately 350 patients (5-18 yr of age) with allergic asthma and a positive SPT to HDMs were included. To define the sensitivity and specificity for the detection method of an early asthmatic response (EAR), a receiver-operating characteristic (ROC) curve was plotted. The accuracy was measured by the area under the ROC curve (AUC). A logistic regression model was used to predict the individual probability of a positive challenge. The results of the regression model were validated in a prospective group of n = 75 patients. The following cut-off values showed the best combination of sensitivity and specificity: specific IgE Dermatophagoides farinae 19.6 kU/l (AUC, 0.88), PD(20) FEV(1) 0.13 mg methacholine (AUC, 0.73) and eNO 20.1 ppb (AUC, 0.71). The following equation predicted the individual probability of a positive challenge in the retrospective and prospective group: p = 1(.) [1 + exp[-(-1.78 + 2.46.(10) log D. far - 1.25(.10) logPD(20) metha)]](-1) , (AUC = 0.88). The value of using the specific IgE and MCT as predictors was confirmed in a large number of patients. We also showed, for the first time, that the eNO predicted the EAR. The logistic regression model is repeatable with a good accuracy.


Relationship between blood culture collection method and proportion of contaminated cultures in neonates.
This study aims to document methods of blood culture collection used in our neonatal unit and to determine whether or not the proportion of contaminated cultures varied according to method of collection. Two specific comparisons of interest were the proportion of contaminated cultures in samples collected via (i) preferred versus non-preferred methods, and (ii) peripheral cannulae at the time of insertion versus separate arterial or venous puncture. Data were collected on every blood culture taken in the Grantley Stable Neonatal Unit of the Royal Brisbane and Women's Hospital over a 12-month period. The method used to collect blood for culture was recorded, and the proportion of contaminated cultures taken by each method was calculated. Blood was collected via peripheral cannulae at the time of insertion in 63.1% of cultures, umbilical catheters at the time of insertion in 18.1%, peripheral arterial or venous puncture in 7.7%, and indwelling lines in 2.1%, and the method was unknown in 9.0%. The proportion of contaminated blood cultures was 11.5% with collection via peripheral vascular puncture, 11.1% via indwelling lines, 2.1% via peripheral cannulae at the time of insertion and 1.1% via umbilical catheters at the time of insertion. There was no significant difference in the proportion of contaminated cultures taken via preferred and non-preferred methods. The proportion of contaminated cultures taken via peripheral cannulae at the time of insertion was significantly less than when samples were taken via a separate arterial or venous puncture. In our unit, blood cultures are frequently collected via peripheral cannulae at the time of insertion. Blood cultures taken in this manner are less likely to be contaminated than cultures collected via separate vascular puncture.


1,25(OH)2-vitamin D3 signal transduction in chick myoblasts involves phosphatidylcholine hydrolysis.
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) rapidly stimulates the biphasic formation of diacylglycerol (DAG) in chick myoblasts. Neomycin (0.5 mM), an inhibitor of phosphoinositide hydrolysis, abolished the first phase (1 min) but had no effect on the second 1,25(OH)2D3-induced DAG peak (5 min). In myoblasts prelabeled with [3H]choline, 1,25(OH)2D3 increased the release of [3H]choline (maximally at 5 min), with a concomitant decrease in phosphatidylcholine and the absence of significant changes in phosphocholine. 1,25(OH)2D3 caused a significant increase in phosphatidylethanol (PEt) formation in myoblasts in the presence of 1.5% ethanol. The effects of 1,25(OH)2D3 were time- and dose-dependent (10(-11) to 10(-8) M) and specific as 25OHD3 and 24,25(OH)2D3 failed to accumulate PEt. 12-O-Tetradecanoylphorbol-13-acetate failed to accumulate PEt. 12-O-Tetradecanoylphorbol-13-acetate also stimulated PEt formation. The combination of 1,25(OH)2D3 and 12-O-tetradecanoylphorbol-13- acetate was more effective than either compound alone. Neither the PKC inhibitor H7 nor PKC down-regulation blocked the hormone-induced increase in PEt. The effects of 1,25(OH)2D3 were, however, inhibited in the absence of extracellular Ca2+ (+EGTA) and by nifedipine and verapamil, whereas the Ca2+ ionophore A23187 also increased PEt generation. The data support the notion that 1,25(OH)2D3 triggers the hydrolysis of phosphatidylcholine in myoblasts through a Ca(2+)-dependent, PKC-independent, phospholipase D-catalyzed mechanism.


The laboratory identification of serum antinuclear antibody in the dog.
An indirect immunofluorescence test with sections of rat liver as a substrate, proved useful in detecting antinuclear antibodies (ANA) in the dog. A specific anti-canine IgG reagent conjugated with fluorescein isothiocyanate was used. A proportion of normal dogs gave positive reactions at low titres. The presence of ANA was one of the criteria used to diagnose canine systemic lupus erythematosus. Some dogs within a general hospital population were also positive for the auto-antibody. The indirect immunofluorescence test with Trypanosoma brucei as a substrate was insensitive. The LE-cell test was laborious and insensitive. A commercial latex slide agglutination test used for detecting ANA in man gave false positive and false negative results in the dog. A commercial radioimmunoassay used in man gave many false positive results. A similar assay with synthetic DNA gave encouraging results and is worthy of further study.


Comparative studies of the polysaccharides from species of the genus Ramalina-lichenized fungi-of three distinct habitats.
Several structurally different glucans (alpha- and beta-) and galactomannans were characterized as components of four species of the genus Ramalina, namely R. dendriscoides, R. fraxinea, R. gracilis and R. peruviana. Freeze-thawing treatment of hot aqueous extracts furnished as precipitates (PW) linear alpha-D-glucans of the nigeran type, with regularly distributed (1-->3)- and (1-->4)-linkages in a 1:1 ratio. The supernatants (SW) contained alpha-D-glucans with (1-->3)- and (1-->4)-linkages in a molar ratio of 3:1. The lichen residues were then extracted with 2% aq. KOH, and the resulting extracts submitted to the freeze-thawing treatment, giving rise to precipitates (PK2) of a mixture of alpha-glucan (nigeran) and beta-glucan, which were suspended in aqueous 0.5% NaOH at 50 degrees C, dissolving preferentially the beta-glucan. These were linear with (1-->3)-linkages (laminaran). The mother liquor of the KOH extractions (2% and 10% aq. KOH) was treated with Fehling's solution to give precipitates (galactomannans). The galactomannans are related, having (1-->6)-linked alpha-D-mannopyranosyl main chains, substituted at O-4 and in a small proportion at O-2,4 by beta-D-galactopyranosyl units. Despite the different habitats of these lichenized fungi, all species studied in this investigation have a similar pool of polysaccharides.


Study of steroidogenesis in pupae of the forensically important blow fly Protophormia terraenovae (Robineau-Desvoidy) (Diptera: Calliphoridae).
Protophormia terraenovae is a forensically important fly whose development time is studied by forensic entomologists to establish the time elapsed since death (post-mortem interval, PMI). Quantity and nature of ecdysteroid hormones present in P. terraenovae pupae were analysed in order to determine if they could be correlated to the age of pupae found on corpses and thereby could give information on the PMI. Ecdysteroid levels were quantified during the pupal-adult development of synchronised animals using enzyme immunoassay (EIA), a sensitive method allowing acurate quantification in one pupa. Two types of pupae were compared: "fresh" pupae, kept frozen until analysis and "experimentally dried" pupae, which were left for several weeks at ambient temperature. A peak of ecdysteroids was detected between 36 and 96 h after pupariation in fresh animals. It was not observed in "experimentally dried" pupae. High-pressure liquid chromatography (HPLC) analyses combined with EIA showed that 20-hydroxyecdysone (20E) was the major free ecdysteroid at various pupal ages. Enzymatic hydrolysis experiments revealed the presence of apolar conjugates at all ages tested. However, neither qualitative nor quantitative difference was detected between early and late pupae. This study gives precise information on the nature and quantity of ecdysteroids in the course of pupal development of a calliphorid fly. The limits of using ecdysteroid measurement as a tool in forensic entomology are discussed.


Inequality in mortality by occupation related to economic crisis from 1980 to 2010 among working-age Japanese males.
The mortality rate for Japanese males aged 30-59 years in managerial and professional spiked in 2000 and remains worse than that of other occupations possibly associated with the economic downturn of the 1990s and the global economic stagnation after 2008. The present study aimed to assess temporal occupation-specific mortality trends from 1980 to 2010 for Japanese males aged 30-59 years for major causes of death. We obtained data from the Occupation-specific Vital Statistics. We calculated age-standardized mortality rates for the four leading causes of death (all cancers, suicide, ischaemic heart disease, and cerebrovascular disease). We used a generalized estimating equation model to determine specific effects of the economic downturn after 2000. The age-standardized mortality rate for the total working-age population steadily declined up to 2010 in all major causes of death except suicide. Managers had a higher risk of mortality in all leading causes of death compared with before 1995. Mortality rates among unemployed people steadily decreased for all cancers and ischaemic heart disease. Economic downturn may have caused the prolonged increase in suicide mortality. Unemployed people did not experience any change in mortality due to suicide and cerebrovascular disease and saw a decline in cancer and ischemic heart disease mortality, perhaps because the basic properties of Japan's social welfare system were maintained even during economic recession.


Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis.
Galectin (Gal)-3 is a profibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small-molecule inhibitor of Gal-3.A randomised, double-blind, multicentre, placebo-controlled, phase 1/2a study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF. Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15-50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once-daily doses of TD139 (0.3-10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side-effects. TD139 was rapidly absorbed, with mean time taken to reach maximum plasma concentration (C max) values ranging from 0.6 to 3 h and a plasma half-life (T 1/2) of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 and 10 mg dose groups compared with placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (platelet-derived growth factor-BB, plasminogen activator inhibitor-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.


Performance, clinical utility, and cost-effectiveness of selective use of staging investigations in early breast cancers.
International guidelines do not recommend routine staging of EBCs. However, most clinicians still perform staging investigations (SI) selectively for several reasons. We examined our practice of selective use of SI to determine its performance, clinical utility, and cost-effectiveness. We performed this retrospective study on patients who had treatment for AJCC stage I or stage II breast cancer through Eastern health Breast and cancer centre, Melbourne, for 50 months from January 2012. Our practice of selective use resulted in SI in 41% of all EBCs (95% CI 37-46%). Overall yield was 3% (95% CI 0.4-5.4%) with a false positive rate of 22% (95% CI 1628%) and a false-negative rate of 45% (95% CI 11-79%). The sensitivity of SI is 55% (95% CI 21-89%) with a negative predictive value of 97% (95% CI 94.8-99.9%). None of the treatment components was found to be significantly changed based on findings on SI. There was no significant difference in all-cause mortality or new distant recurrence in the staged and non-staged groups. Identification of six new metastases cost at least 422 021 AUD. The approximate cost to stage one EBC is 2069 AUD. 'Number needed to scan' to detect one new metastasis is 34 at the expense of 70337AUD. Selective use of SI results in better yield. However, the clinical utility of these results is not significant. It is debatable if this level of expenditure is cost-effective. Our results point to a need for change in practice.


Digital camera assessment for detection of cervical intraepithelial neoplasia in rural El Salvador.
To explore the feasibility of digital photography for primary cervical cancer screening in a low-resource setting in El Salvador. Three independent examiners performed Pap test, visual inspection, digital camera assessment and colposcopy on each subject. Lesions were detected in 99 of 504 patients (20%) by visual inspection, 72/504 (14%) by DART and 90/504 (18%) by colposcopic impression. Seven of 504 patients (1.3%) had CIN on histology. Pap detected 2 of 7 subjects (29% sensitivity) (C.I. 4%, 56%), visual inspection detected 5 of 7 (71% sensitivity, C.I. 34%, 95%), digital assessment detected 6 of 7 (86% sensitivity C. I. 45%, 99%), and colposcopic impression detected 5 of 7 (71% sensitivity, C.I. 34%, 95%). This small pilot trial demonstrates the potential value and feasibility of performing digital camera assessment of the reproductive tract on women in a developing country setting.


Skeletal muscle-secreted myokine interleukin-6 induces white adipose tissue conversion into beige adipose tissue in myostatin gene knockout pigs.
Myostatin (MSTN) is primarily expressed in skeletal muscle and plays an important role in the regulation of muscle growth and development as well as fat deposition; however, little is known about the molecular mechanism through which MSTN regulates body fat deposition. Therefore, in this study, we sought to identify the signaling pathways through which MSTN regulates fat accumulation in pigs. MSTN knockout (MSTN-/-) pigs showed increased muscle mass, decreased fat mass, and a leaner body composition. In this study, we found that the adipose tissue of MSTN-/- pigs exhibits the characteristics of beige adipose tissue, and the mRNA expression levels of beige adipose marker genes, including UCP3, Cidea, and CD137, were significantly increased. Remarkably, the observed beige phenotype was not adipocyte autonomous but rather caused by muscle-secreted myokine interleukin (IL)-6. This occurrence results in increased AMP-activated protein kinase (AMPK) phosphorylation in adipose tissue, which subsequently activates peroxisome proliferator-activated receptor gamma coactivator 1α and the conversion of white adipocytes to beige in pigs. Therefore, we concluded that MSTN deficiency leads to increased IL-6 secretion in skeletal muscle and activates AMPK in adipocytes, thereby increasing the beige adipose tissue in MSTN-/- pigs.


Impact of Gene Biomarker Discovery Tools Based on Protein-Protein Interaction and Machine Learning on Performance of Artificial Intelligence Models in Predicting Clinical Stages of Breast Cancer.
Breast cancer, as one of the most common diseases threatening the women's life, has attracted serious attention of the clinical and biomedical researchers worldwide. The genome-based studies along with their registered GEO datasets are frequent in the literature. Since several methodologies have been developed for analyzing and identifying gene biomarkers, it is necessary to evaluate their robustness. In this study, three well-known biomarker identification methods (i.e., ClusterOne, MCODE, and BioDiscML) were employed in order to identify the potential biomarkers. Then, the methods were ranked and evaluated using nonlinear classification models developed based on the identified sets of biomarkers. A combined BC microarray dataset consisting of GSE124647, GSE124646, and GSE15852 was used as training set, and two test datasets, GSE15852 and GSE25066, were used for the performance measurement of the trained models. The validation of the proposed models was carried out internally (leave-one-out, fivefold and tenfold cross-validation, random sampling, test on training set) and externally (test on test set). The results showed that ClusterOne, MCODE, and BioDiscML tools ranked first, second, and third, respectively, based on the area under the curve (AUC), accuracy, F1 score, precision, and recall metrics. Overall, it can be concluded that the descriptive values of gene biomarkers in terms of their biological aspects that have been determined by a given methodology and the predictive power of the models developed based on the identified gene biomarkers should be considered simultaneously while validating the biomarker identification approaches.


Tuning the nanostructure of DODAB/nickel tetrasulfonated phthalocyanine bilayers in LbL films.
Nanostructured films of dioctadecyldimethylammonium bromide (DODAB) and nickel tetrasulfonated phthalocyanine (NiTsPc) were layer-by-layer (LbL) assembled to achieve a synergistic effect considering the distinct properties of both materials. Prior to LbL growth, the effect of NiTsPc on the structure of DODAB vesicles in aqueous medium was investigated by differential scanning calorimetry (DSC). Therefore, DODAB/NiTsPc LbL films were prepared using NiTsPc at concentrations below and above the limit concentration of vesicle formation according to our DSC experiments. As a result, LbL films with distinct nanostructures were obtained, which were studied at micro and nanoscales by micro-Raman and atomic force microscopy, respectively. A linear growth of the LbL films was observed by ultraviolet-visible absorption spectroscopy. However, the bilayer thickness and the surface morphology of the LbL films were radically affected depending on NiTsPc concentration. The electrostatic interaction between DODAB and NiTsPc was identified via Fourier transform infrared (FTIR) absorption spectroscopy as the main driving force responsible for LbL growth. Because LbL films have been widely applied as transducers in sensing devices, DODAB/NiTsPc LbL films having distinct nanostructures were tested as proof-of-principle in preliminary sensing experiments toward dopamine detection using impedance spectroscopy (e-tongue system). The real capacitance vs. dopamine concentration curves were treated using Principal Component Analysis (PCA) and an equivalent electric circuit, revealing the role played by the LbL film nanostructure and the possibility of building calibration curves.


Treatment of functional diarrhea.
Functional diarrhea (FD), one of the functional gastrointestinal disorders, is characterized by chronic or recurrent diarrhea not explained by structural or biochemical abnormalities. The treatment of FD is intimately associated with establishing the correct diagnosis. First, FD needs to be distinguished from diarrhea-predominant irritable bowel syndrome (IBS), in which, unlike in FD, abdominal pain is a primary diagnostic criterion. Next, FD must be differentiated from the myriad organic causes of chronic diarrhea. Unlike IBS, in which a positive diagnosis can be made with an acceptable level of confidence using symptom-based criteria and minimal testing, the diagnosis of FD is still primarily a diagnosis of exclusion. Thus, the onus is on the physician to eliminate potential underlying causes, both common and uncommon, in the proper clinical setting. Once the diagnosis has been established, the clinician and patient should first focus on identifying, eliminating, and/or treating aggravating factors. These may include physiologic factors (eg, small bowel bacterial overgrowth), psychological factors (eg, stress and anxiety), and dietary factors (eg, carbohydrate malabsorption). Thereafter, appropriate treatment for functional diarrhea may be instituted. Treatment options include dietary and lifestyle modification, pharmacologic therapies, and alternative modalities. Although many of these strategies have been studied in IBS, almost none of them has been examined specifically in FD. Furthermore, given the poorly understood pathophysiologic basis of FD, these treatments primarily target a patient's symptoms and presumed altered physiology rather than underlying etiologic mechanisms. Therefore, we stress that treatment must be approached in an individualized manner and that dietary and pharmacologic therapies should be part of a comprehensive therapeutic approach in which education and reassurance form the foundation. In general, we attempt to remove dietary triggers and recommend increased fiber intake. We then add anticholinergic, antispasmodic, antimotility, and antidiarrheal agents as the first line of pharmacotherapy. Should a patient not respond to these, and for patients who have a significant degree of psychological dysfunction, central acting agents, including antidepressants and/or anxiolytics, may be beneficial. During the treatment period, we also recommend that physicians keep an open mind. If signs or symptoms that suggest an ongoing or previously unrecognized organic process develop, then a re-evaluation of the clinical picture is indicated.


The validity and reliability of ratings of dental and facial attractiveness for epidemiologic use.
A method to obtain indices of dental and facial attractiveness for epidemiologic survey work has been evaluated. A two-person panel was constituted to make ratings of photographic records under standardized conditions by means of a visual analogue recording scale. The method proved to be convenient and rapid in operation and its validity was upheld. Good reliability was established and there is scope for further improvement by increasing the size of the panel.


Two different primary tumours of the brain in a patient with breast cancer.
Some reports on multiple primary brain tumours have been published. When one or more tumours are found in brain scintigraphy they are often supposed to be metastases. Further investigations may thus be given up, especially if the patient has or has had a malignant tumour in some other part of the body. In this report a case is described where the patient began to have cerebral symptoms two years after she had been operated for breast cancer. In the scintigraphy a tumour was found in both brain hemispheres. The tumours were regarded as metastases. But when the patient died in a geriatric hospital it was recognized from the autopsy that one tumour was a meningioma and the other a glioblastoma multiforme.