Availability and use of rapid diagnostic tests for the management of acute childhood infections in Europe: A cross-sectional survey of paediatricians.
Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability. A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics. There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicians, and the role of diagnostic tests in the management of acute childhood infections.


N-epsilon-(carboxyethyl)lysine, a product of the chemical modification of proteins by methylglyoxal, increases with age in human lens proteins.
Advanced glycation end-products and glycoxidation products, such as Nepsilon-(carboxymethyl)lysine (CML) and pentosidine, accumulate in long-lived tissue proteins with age and are implicated in the aging of tissue proteins and in the development of pathology in diabetes, atherosclerosis and other diseases. In this paper we describe a new advanced glycation end-product, Nepsilon-(carboxyethyl)lysine (CEL), which is formed during the reaction of methylglyoxal with lysine residues in model compounds and in the proteins RNase and collagen. CEL was also detected in human lens proteins at a concentration similar to that of CML, and increased with age in parallel with the concentration of CML. Although CEL was formed in highest yields during the reaction of methylglyoxal and triose phosphates with lysine and protein, it was also formed in reactions of pentoses, ascorbate and other sugars with lysine and RNase. We propose that levels of CML and CEL and their ratio to one another in tissue proteins and in urine will provide an index of glyoxal and methylglyoxal concentrations in tissues, alterations in glutathione homoeostasis and dicarbonyl metabolism in disease, and sources of advanced glycation end-products in tissue proteins in aging and disease.


Prolonged oral vancomycin for secondary prophylaxis of relapsing Clostridium difficile infection.
Clostridium difficile infection (CDI) is an important cause of diarrhea and continues to be a major burden within healthcare institutions and in the community. For a small subset of patients with frequently relapsing CDI who do not have access to fecal microbiota transplantation (FMT), or fail FMT, there are no clear treatment recommendations. We review our experience with prolonged oral vancomycin for secondary prophylaxis of relapsing CDI. We performed a retrospective chart review of cases from the C. difficile consultation service at our institution since 2013. The service had three primary physicians providing consultations and performing over 1000 FMTs over the five-year period. Patients with relapsing CDI who were not candidates for FMT, refused, or relapsed after FMT were treated with vancomycin, followed by long-term oral vancomycin at a dose of 125 mg once daily. Twenty patients received at least 8 weeks of once-daily oral vancomycin for prophylaxis of relapsing CDI. Patients had a median age of 80 years, and experienced a median of four episodes of CDI prior to long-term vancomycin. Most were female and 75% had received FMT. Only a single case of C. difficile relapse occurred while on long-term vancomycin during 200 patient-months of follow-up. Amongst those who stopped long-term vancomycin, 31% relapsed within 6 weeks. No adverse events were observed. For elderly patients with frequently relapsing C. difficile, prolonged vancomycin once daily at a dose of 125 mg orally was effective in preventing further relapse. Vancomycin secondary prophylaxis may be considered in patients who have failed FMT, or in cases where FMT is not available.


Anagliptin Monotherapy for Six Months in Patients With Type 2 Diabetes Mellitus and Hyper-Low-Density Lipoprotein Cholesterolemia Reduces Plasma Levels of Fasting Low-Density Lipoprotein Cholesterol and Lathosterol: A Single-Arm Intervention Trial.
Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been shown to decrease plasma low-density lipoprotein cholesterol (LDL-C) levels. The objective of our study was to elucidate the mechanisms responsible for the anagliptin-mediated improvements in high LDL-C levels (hyper-LDL cholesterolemia). We prospectively examined the effects of anagliptin monotherapy on fasting plasma lathosterol, sitosterol, and campesterol levels in patients with type 2 diabetes mellitus and hyper-LDL cholesterolemia for 6 months. We examined 14 patients who did not use hypoglycemic or lipid-lowering drugs for 4 months before initiating the study. Plasma variables related to glucose and lipid metabolism were measured before and after 6 months of treatment and pre- and postprandially using the cookie-loading test. After treatment, anagliptin monotherapy (n = 14) significantly decreased fasting LDL-C (175.6 to 148.5 mg/dL, mean values before and after the treatment, respectively) and plasma lathosterol levels (3.56 to 2.49 mg/dL), whereas it did not lower fasting sitosterol or campesterol levels. Furthermore, fasting plasma lathosterol levels were negatively correlated with preprandial glucagon-like peptide-1 (GLP-1) levels after anagliptin treatment. Anagliptin monotherapy may have a beneficial effect on lipid metabolism, which could be mediated by the inhibition of hepatic cholesterol synthesis rather than the inhibition of intestinal lipid transport.


Ion beam planarization of diamond turned surfaces with various roughness profiles.
The effectiveness of ion beam planarization (IBP) to reduce surface roughness of diamond turned NiP surfaces was investigated. The surfaces with various spatial wavelengths and depths of turning marks were spray-coated and planarized with broad ion beam. The ion beam planarization was performed at a special angle where the etching rate of photoresist is closely similar to NiP. It is found that the combined process of spray-coating and ion-beam-planarization can effectively reduce the surface roughness of diamond turned NiP. The spatial wavelength and depth of turning marks have limited influence on surface roughness reduction rate. The final surface roughness after ion beam planarization is 30%~40% of the original roughness, irrespective of spatial wavelength and depth of turning marks. Extending planarization time does not alter surface quality after photoresist is etched away. These results show that the IBP is applicable to roughness minimization of diamond turned surfaces.


Carbohydrate mediation of the biological activities of the glycolipoprotein of Pseudomonas aeruginosa.
The glycolipoprotein (GLP) extracted from the surface slime of Pseudomonas aeruginosa produces effects in mice similar to those of the viable cell. The lethal activity has been located in the lipid moiety; however, degradation of the carbohydrate moiety with sodium metaperiodate reduced the antigenicity and abolished the lethality of the GLP. Similar degradation with a phage-induced polysaccharide depolymerase reduced the antigenicity only slightly but reduced the lethality over 60%. The neutral sugar composition of the isolated polysaccharide moiety was shown to be that of the parental GLP. Of the component neutral sugars, mannose and its derivatives were capable of inhibiting the agglutination of erythrocytes coated with GLP. Inhibition also occurred with a soluble mannose polymer from the cell walls of yeast. Antiserum to GLP and to its isolated polysaccharide moiety agglutinated yeast cells, whereas antiserum to a glycolipid fragment of the GLP lacking mannose did not. The lethality of the GLP was reduced by degradation with alpha-mannosidase or by blocking the mannose residues with concanavalin A, and the glycolipid fragment showed less lethality than the native GLP. We conclude that mannose, in addition to being an immunodominant sugar, is an effector sugar in the expression of GLP lethality.


The ceramic coated implant (CCI). Evolution total ankle replacements: a retrospective analysis of 40 ankles with 8 years follow-up.
Diminutive data is available on the outcome of several previously used total ankle replacement implants. The purpose of this study was to investigate the medium-term functional and radiological outcome and implant survival of the CCI Evolution implant. Consecutive series of 40 ankles operated in our hospital with primary TAR using the CCI Evolution implant in 2010-2013 were available for follow-up. The prospective clinical and radiographic data including the Kofoed score, subjective satisfaction and standard radiographs were collected preoperatively and at fixed time-points postoperatively. A CT was obtained in cases where osteolysis or loosening were suspected. The improvement of the Kofoed score and subjective satisfaction were statistically significant (p<0.0001). The implant survival was 97% (95% confidence interval (CI) 81%-100 %) at 5 years, and 81 % (95% confidence interval (CI) 60 %-92%) at 8 years. There were altogether 25 (64%) complications. Overall revision rate was 28% and failure rate 13%. The CCI implant outcome was not acceptable. The malposition of prosthetic components, subsidence, and peri-implant osteolysis were recorded often. Although the patient reported outcome measures improved, mostly due to positive changes in pain severity, overall revision and failure rates were high and comparable with previous findings of the CCI implant.


A Case of Phacomatosis Pigmentokeratotica Associated With Multiple Basal Cell Carcinomas.
Phacomatosis pigmentokeratotica is a recently identified disease characterized by the coexistence of an epidermal nevus with sebaceous differentiation arranged along Blaschko lines and a speckled lentiginous nevus showing a checkerboard pattern, mostly in association with various extracutaneous defects. A 52-year-old man presented with asymptomatic ulcerative plaque on his left side of perioral area. A 2 × 2-cm-sized fleshy colored ulceration on his left perioral area was consistent with basal cell carcinoma with nevus sebaceous. Next to the ulceration, there was a light pinkish to fleshy colored papule on his left cheek that showed syringocystadenoma papilliferum. On his chin area, there was a 2 × 0.3-cm-sized skin colored papule that was consistent with trichilemmoma. Moreover, various sized light brownish macules and dark brownish papules were also located on his left side of the chest wall, back, and arm. Biopsy specimens from macules on the left side of the trunk confirmed the clinical diagnosis of speckled lentiginous nevus and multiple black papules beside that a speckled lentiginous nevus also revealed basal cell carcinomas. Herein, we present a rare case of a patient with phacomatosis pigmentokeratotica who had no extracutaneous abnormalities and who developed basal cell carcinoma, syringocystadenoma papilliferum, and trichilemmoma in nevus sebaceous on the face and speckled lentiginous nevus on the trunk. This syndrome needs adequate follow-up due to the possibility of malignant transformation.


GABA(B1a), GABA(B1b) AND GABA(B2) mRNA variants expression in hippocampus resected from patients with temporal lobe epilepsy.
The aim of this study was to investigate the mRNA expression of the two GABA(B1) receptor isoforms and the GABA(B2) subunit, in human postmortem control hippocampal sections and in sections resected from epilepsy patients using quantitative in situ hybridisation autoradiography. Utilising human control hippocampal sections it was shown that the oligonucleotides employed were specific to the receptor. Hippocampal slices from surgical specimens obtained from patients with hippocampal sclerosis and temporal lobe epilepsy were compared with neurologically normal postmortem control subjects for neuropathology and GABA(B) mRNA expression. Neuronal loss was observed in most of the hippocampal subregions, but in the subiculum no significant difference was detected. The localisation of GABA(B1a) and GABA(B1b) isoform mRNAs in human control hippocampal sections supported and extended earlier studies using the GABA(B1) pan probe, which does not distinguish between the two GABA(B1) isoforms. Moreover, the GABA(B2) mRNA location confirmed the heterodimerisation of the receptor. Thus, although there was an apparent correlation between GABA(B1b) and GABA(B2), GABA(B1a) exhibited no such relationship. GABA(B1b) and GABA(B2) showed a similar intensity of expression whilst GABA(B1a) displayed a lower hybridisation signal. Comparison of the expression of the three mRNAs between control and epileptic subjects showed significant decreases or increases in different hippocampal subregions.GABA(B) isoforms and subunit mRNA expression per remaining neuron was significantly increased in the hilus and dentate gyrus. These results demonstrate that altered GABA(B) receptor mRNA expression occurs in human TLE; possibly the observed changes may also serve to counteract ongoing hyperexcitability.


"Why do you stay?": The lived-experience of partners of Australian veterans and first responders with Posttraumatic Stress Disorder.
This study examined the multidimensional nature of experiences of being an intimate partner of an Australian veteran or emergency service first responder (ESFR) with posttraumatic stress disorder (PTSD). Using a qualitative phenomenological approach, inductive thematic analysis was undertaken on data collected in 2017-2018 through individual interviews with a purposive sample of 22 partners of veterans, paramedics, fire and police officers living in Australia. Analysis revealed that the key concern of the participants was to protect their family unit and the intimate relationship, highlighting the ways in which they adapted, managed and coped with the changes that PTSD brought to the relationship. However, lack of understanding by healthcare providers, government, military and emergency service organizations of their daily lives, and of the strength of commitment to their relationship, resulted in a sense of invisibility and was revealed as the key barrier to the support they crave. The findings underscore the importance of recognizing the significance of the intimate relationship in trauma recovery and of responding to the support needs of the intimate partner.


Risk Factors Associated With Infant Deaths From Pertussis: A Case-Control Study.
In the current era, most pertussis deaths occur in infants <3 months of age. Leukocytosis with lymphocytosis and pneumonia are commonly observed among cases of severe pertussis. Risk factors associated with fatal pertussis were identified by comparing fatal pertussis cases among patients <120 days of age occurring from 1 January 1998 through 26 December 2014, matched by age (<120 days), county of residence, and closest symptom onset date with 1-4 nonfatal hospitalized cases. California Department of Public Health surveillance data were reviewed to identify cases; demographics, clinical presentation, and course were abstracted from corresponding birth and medical records. Logistic regression and classification tree analyses were used to examine the risk of fatal pertussis with respect to identified factors. Fifty-three fatal infant pertussis cases were identified and compared with 183 nonfatal hospitalized pertussis cases. Fatal cases had significantly lower birth weight, younger gestational age, younger age at time of cough onset, and higher peak white blood cell (WBC) and lymphocyte counts. Fatal cases were less likely to have received macrolide antibiotics and more likely to have received steroids or nitric oxide and to develop pulmonary hypertension, seizures, encephalitis, and pneumonia. Additionally, exchange transfusion, extracorporeal membrane oxygenation, and intubation occurred significantly more frequently among fatal cases. In multivariate analyses, peak WBC count, birth weight, intubation, and receipt of nitric oxide were predictors of death. Early recognition of pertussis in young infants and treatment with appropriate antibiotic therapy are important in preventing death. Several risk factors are strongly associated with fatal pertussis in infants.


Effect of 17beta-estradiol and progesterone on vitellogenesis in the spotted ray Torpedo marmorata Risso 1810 (Elasmobranchii: Torpediniformes): studies on females and on estrogen-treated males.
The influence of 17beta-estradiol (E(2)) on vertebrate vitellogenesis is well ascertained. The aim of the present paper is to study the involvement of E(2) and progesterone (P) in the induction and regulation of vitellogenesis in females and experimental E(2)-treated males of Torpedo marmorata. We analyzed females in various stages of the reproductive cycle and E(2) experimentally treated males. The presence of vitellogenin was investigated in the plasma and in the liver by western blot and immunohistochemistry; its site of synthesis was investigated by in situ hybridization. The steroid levels in the plasma were measured by Enzyme Immunoassay. In treated males, E(2) induces in the liver the synthesis of VTG which is then secreted into the bloodstream as a 205-kDa polypeptide, the same that is found in the plasma of non-pregnant vitellogenic females. In females, E(2) is naturally present in the plasma and its level is correlated with VTG synthesis in the liver and with the female reproductive cycle. Indeed, large amounts of E(2) are only found in mature vitellogenic females, whose liver is involved in VTG synthesis and secretion. By contrast, small amounts of E(2) are evident in juveniles whose ovaries are lacking in vitellogenic follicles and in females preparing for ovulation. Low titers are also found in gravid females, whose liver is not engaged in VTG synthesis. We show that P, which is absent in untreated males and juvenile females, is evident in the blood serum of E(2)-treated males and sexually mature females. Interestingly, in treated males P appears in the plasma just 24h after the first injection of E(2) and its titer increases; a week after the last injections, the P level is similar to that recorded in non-gravid vitellogenic females. Finally, it is noteworthy that the highest titer of P was recorded in pregnant females. We demonstrate that in Torpedo vitellogenin synthesis, as in other vertebrates, is under the control of E(2) but also that this synthesis is probably under the control of progesterone.


Function of chloride intracellular channel 1 in gastric cancer cells.
To investigate the effect of chloride intracellular channel 1 (CLIC1) on the cell proliferation, apoptosis, migration and invasion of gastric cancer cells. CLIC1 expression was evaluated in human gastric cancer cell lines SGC-7901 and MGC-803 by real time polymerase chain reaction (RT-PCR). Four segments of small interference RNA (siRNA) targeting CLIC1 mRNA and a no-sense control segment were designed by bioinformatics technology. CLIC1 siRNA was selected using Lipofectamine 2000 and transfected transiently into human gastric cancer SGC-7901 and MGC-803 cells. The transfected efficiency was observed under fluorescence microscope. After transfection, mRNA expression of CLIC1 was detected with RT-PCR and Western blotting was used to detect the protein expression. Proliferation was examined by methyl thiazolyl tetrazolium and apoptosis was detected with flow cytometry. Polycarbonate membrane transwell chamber and Matrigel were used for the detection of the changes of invasion and migration of the two cell lines. In gastric cancer cell lines SGC-7901 and MGC-803, CLIC1 was obviously expressed and CLIC1 siRNA could effectively suppress the expression of CLIC1 protein and mRNA. Proliferation of cells transfected with CLIC1 siRNA3 was enhanced notably, and the highest proliferation rate was 23.3% (P = 0.002) in SGC-7901 and 35.55% (P = 0.001) in MGC-803 cells at 48 h. The G2/M phase proportion increased, while G0/G1 and S phase proportions decreased. The apoptotic rate of the CLIC1 siRNA3 group obviously decreased in both SGC-7901 cells (62.24%, P = 0.000) and MGC-803 cells (52.67%, P = 0.004). Down-regulation of CLIC1 led to the inhibition of invasion and migration by 54.31% (P = 0.000) and 33.62% (P = 0.001) in SGC-7901 and 40.74% (P = 0.000) and 29.26% (P = 0.002) in MGC-803. However, there was no significant difference between the mock group cells and the negative control group cells. High CLIC1 expression can efficiently inhibit proliferation and enhance apoptosis, migration and invasion of gastric cancer cells in vitro. CLIC1 might be a promising target for the treatment of gastric cancer.


Front-line ownership: imagine.
When used in a military context, the term front line refers to the interface between enemies in action on the battlefield. In a non-military context, the front line is the site where the core activity defining a particular industry takes place, and those working there are key to successful operations. In healthcare, the need to improve patient safety has become a global imperative, and an armamentarium of strategies, tools and technological approaches have been adapted or developed for this context. Often neglected, however, have been strategies to engage the healthcare workers, those at the front line, in the cause.In order for healthcare to function error free, we must assume the characteristics of high-reliability organizations. In particular, the ability to bounce back, to be resilient in the face of a catastrophe, is of paramount importance. Those working at the front line may have the answers. We need to create an opportunity for them to be heard.`


Use of Pressurized Air Infusion For Pre Descemet's Endothelial Keratoplasty (PDEK) - The Air Pump Assisted PDEK Technique.
To assess the advantages offered by the air pump assisted PDEK technique that utilizes pressurized Anterior Chamber (AC) air infusion. Pressurized air infusion was provided through an anterior chamber maintainer connected to the fluid air exchange system of a posterior vitrectomy machine during surgery. Pressurized air infusion within the AC helped perform Descemetorhexis, prevented bleeding during Peripheral Iridectomy (PI) and synechiolysis, prevented oozing of blood from peripheral corneal neovascularization into the AC and thus helped maintain a non-fibrinous AC environment. In addition, it helped in precise graft manipulation, centration, edge unfolding and unwrinkling after it was floated against the stroma as well as faster graft adhesion. It also prevented AC depth fluctuations during intra-cameral maneuvers and prevented intra-operative as well as post-operative graft detachment. This technique makes several steps of surgery easier and improves graft adhesion.


[Induced activity of nitrate reductase by nitrate and cloning of nitrate reductase gene].
Excessive nitrate accumulated in plants affects vegetable quality severely and excessive nitrate ingestion would do harm to human health. Assimilatory NADH: nitrate reductase (NR, EC 18.104.22.168), a complex Mo-pterin-, cytochrome b(557)- and FAD-containing protein, catalyzes the regulated and rate-limiting step in the utilization of inorganic nitrogen by higher plants. Enhancing the activity of NR is conducive to reduce the concentration of nitrate in plants. The experiments were conducted to investigate the activity of nitrate reductase in different plant tissues and the relationship between external inducing solution concentration and NR activity (NRA) in plant leaves. Six plant seedlings growing in solution culture were deprived of an external nitrogen (N) supply for 2 weeks. On selected days, three of six plant seedlings were exposed to 50mmol/L NO3- for 0, 2, 5, 8, 11h, and four of the six plant seedlings were exposed to 0, 10, 30, 50mmol/L NO3- for 2h. The NRA was determined in vivo at 538nm using spectrophotometer. The results showed that NRA increased when those plant seedlings were induced by nitrate solution. The change trends of NRA in roots and in leaves of cole, pea and tomato were different during treating time. The NRA in cole leaves was higher than that in its root and in other two plants and increased along with inducing time, but the NRA in bea and tomato was highest when the treating time was 8h and 2h, respectively. The highest NRA in leaves of three kinds of Chinese cabbages and tomato was induced by different concentrations of KNO3 solution. In tomato leaves, the highest NRA was induced by 10 - 30mmol/L KNO3 solution. In three Chinese cabbages, Brassica chinensis L. cv. AJH, XBC and KR-605, the highest NRA was induced by 10, 30, 10mmol/L KNO3 solution, respectively. The results indicated that the response manners of NRA in plants to external nitrate solutions were different. According to these results, the level of NR mRNA in plants could be enhanced by nitrate inducement. The total RNA was isolated from tomato leaves and root which induced by 30mmol/L KNO3 solution for 2h, and NR cDNA was obtained by RT-PCR using the specific primers. The fragments of PCR products were cloned and sequenced. There are 2736 base pairs in the whole cDNA fragment. The deduced protein sequence contains 911 amino acids. The NR gene can be fused to the CaMV 35S promoter, then introduced to higher plants, such as vegetables. It is hoped to decrease drastically the nitrate content of the transgenic plants.


Oligomerization of 1,2-ethanedithiol: an expedient approach to oligothiaethylenethioglycols.
Reactions of ethylenedithioglycol (ETG) with Na(2)CO(3), K(2)CO(3), and Cs(2)CO(3) provided the oligothiaethylenethioglycols (nETG): di- (DETG), tri- (TrETG), tetra- (TETG), and pentathiaethylenethioglycol (PETG), along with higher polymers. The most efficient carbonate was K(2)CO(3) and reactions using DETG and TrETG as starting materials--or their mixtures--were also found to afford similar species. This largely unknown oligomerization process was thoroughly explored and potential pathways were put forward. A convenient conversion of ETG to laboratory quantities of the otherwise scarce and/or expensive DETG, TrETG, TETG, and PETG oligomers, in organic or aqueous media was achieved. Notably, this straightforward reaction takes place without the addition of expensive or toxic metal catalysts and with pure water as the solvent, thereby highlighting its potential as a green chemical reaction. Moreover, the process opens up new approaches to dynamic combinatorial libraries (DCLs) of oligomers and macrocycles with manifolded nETG [(SCH(2)CH(2))(n)S] bridges.


Expression of N19S-SOD1, an SOD1 mutant found in sporadic amyotrophic lateral sclerosis patients, induces low-grade motoneuronal toxicity.
Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease. It has been generally accepted that the proapoptotic property of the familial ALS (FALS)-linked mutant SOD1 genes plays an important role in the pathogenesis of some FALS cases. We found here that expression of N19S-SOD1, a novel SOD1 mutant originally found in a sporadic ALS patient, induces lower grade death in NSC34 cells than FALS-linked mutant SOD1. In agreement, intracytoplasmic aggregate formation and SOD1 polymerization are less prominently induced by ectopic expression of N19S-SOD1 than FALS-linked mutant SOD1. We further found that additional cell stresses, such as inhibition of proteasomal activity or up-regulation of intracellular oxidative stress, enhance N19S-SOD1-induced aggregate formation and polymerization of N19S-SOD1. Such analysis of the intracellular polymerization and the ubiquitination of N19S-SOD1 have further suggested that it is recognized as a misfolded protein, like FALS-linked mutant SOD1, whereas wild-type SOD1 is not. Altogether, it is speculated that the N19S mutation of SOD1 in cooperation with associated cell stresses contributes to the onset of ALS as a risk factor.


[Pharmacokinetics of injected cefozopran hydrochloride in healthy volunteers].
To study the pharmacokinetics of injected cefozopran hydrochloride in healthy volunteers. 24 healthy volunteers were enrolled to receive low (0.5 g), middle (1.0 g), high (2.0 g) doses of single injection and multiple doses (1.0 g) injection of cefozopran hydrochloride in an open randomized study. The plasma concentrations of cefozopran were determined by RP-HPLC. The DAS2.0 was used to fit the concentration-time data and to calculate the pharmacokinetic parameters. The main pharmaeokinetic parameters for a single injection of low, middle and high doses of cefozopran were as follows: Cmax (48.27 +/- 9.84), (77.99 +/- 15.08) and (171.59 +/- 18.27) mg/L; Tmax (0.50 +/- 0.00), (0.51 +/- 0.02) and (0.51 + 0.02) h; AUCo-t (92.43 +/- 24.02), (152.45 +/- 16.26) and (341.03 +/- 44.16) mg x h/L; t1/2beta (1.97 +/- 0.19), (2.44 +/- 0.24) and (2.18 +/- 0.31) h, respectively. The main pharmacokinetic parameters for a multiple doses injection of cefozopran were as follows: Cmax (80.39 +/- 11.86) mg/L; Tmax (0.51 +/- 0.02) h; AUCo-t (159.74 +/- 15.06) mg x h/L; t1/2beta (2.55 +/- 0.55) h. The accumulative rate of cefozopran through urine pathway within 24 h was (89.4 +/- 15.5)%. The statistical analysis showed that Cmax, AUCo-t, and AUCo-infinity increased significantly with increased doses of injection (P < 0.05). Those parameters were linearly correlated with the doses of injection (r = 0.9950, 0.9960, 0.9963). However, dosage did not have an impact on other pharmacokinetic parameters (P > 0.05). No gender differences in the parameters were found (P > 0.05). Cefozopran hydrochloride performs a linear kinetics in healthy volunteers. The main pharmacokinetic parameters have no significant gender differences, and there is no drug accumulated with multiple doses of injection.


Genetic health and prenatal diagnostics in clinical center Brcko District.
We report genetic counseling and prenatal diagnostics in the Obstetrics and Gynecology Department of the Clinical Center Brcko District (BiH) which works for more than 4 years in prevention of giving birth to children with hereditary diseases and congenital malformations. Pregnant women from Brcko District, Tuzla Canton and wider area of BiH underwent genetic counseling. In the period from 2003 to 2007, 1234 pregnant woman underwent amniocentesis and genetic counseling. Among them 27 foetuses with chromosome disorders were discovered (2.19%). There were 9 (0.72%) cases of autosomal numerical aberrations, 9 (0.72%) of numerical anomalies of sex chromosomes and 12 (1.07%) of structural chromosome aberrations. Chordocentesis was performed in 86 pregnant women: 7 foetuses were found carrying chromosome aberrations (8.14%). Frequency of chromosomes in comparison to the Centre of Medicine Genetics in the Children Clinic in Novi Sad (Serbia) indicates that it is significantly higher (1.67% compared to 2.19%), and in both cases the populations are significantly large (12210:1234)--there is a large difference in structural chromosomal aberrations (0.39% -1.07%). This could point to harmful factors of the environment which contribute to induced genome damages. Frequency of chromosomopathies found by prenatal diagnostics is high. The causes for this have to be looked for, but the increase of structural anomalies points to environmental factors.


Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death.
Blockade of fatty acid synthase (FASN), a key enzyme involved in de novo lipogenesis, results in robust death of ovarian cancer cells. However, known FASN inhibitors have proven to be poor therapeutic agents due to their ability to induce cachexia. Therefore, we sought to identify additional targets in the pathway linking FASN inhibition and cell death whose modulation might kill ovarian cancer cells without the attendant side effects. Here, we show that the initiator caspase-2 is required for robust death of ovarian cancer cells induced by FASN inhibitors. REDD1 (also known as Rtp801 or DDIT4), a known mTOR inhibitor previously implicated in the response to FASN inhibition, is a novel caspase-2 regulator in this pathway. REDD1 induction is compromised in ovarian cancer cells that do not respond to FASN inhibition. Inhibition of FASN induced an ATF4-dependent transcriptional induction of REDD1; downregulation of REDD1 prevented orlistat-induced activation of caspase-2, as monitored by its cleavage, proteolytic activity and dimerization. Abrogation of REDD1-mediated suppression of mTOR by TSC2 RNAi protected FASN inhibitor-sensitive ovarian cancer cells (OVCA420 cells) from orlistat-induced death. Conversely, suppression of mTOR with the chemical inhibitors PP242 or rapamycin-sensitized DOV13, an ovarian cancer cell line incapable of inducing REDD1, to orlistat-induced cell death through caspase-2. These findings indicate that REDD1 positively controls caspase-2-dependent cell death of ovarian cancer cells by inhibiting mTOR, placing mTOR as a novel upstream regulator of caspase-2 and supporting the possibility of manipulating mTOR to enhance caspase-2 activation in ovarian cancer.


Brain-wide Organization of Neuronal Activity and Convergent Sensorimotor Transformations in Larval Zebrafish.
Simultaneous recordings of large populations of neurons in behaving animals allow detailed observation of high-dimensional, complex brain activity. However, experimental approaches often focus on singular behavioral paradigms or brain areas. Here, we recorded whole-brain neuronal activity of larval zebrafish presented with a battery of visual stimuli while recording fictive motor output. We identified neurons tuned to each stimulus type and motor output and discovered groups of neurons in the anterior hindbrain that respond to different stimuli eliciting similar behavioral responses. These convergent sensorimotor representations were only weakly correlated to instantaneous motor activity, suggesting that they critically inform, but do not directly generate, behavioral choices. To catalog brain-wide activity beyond explicit sensorimotor processing, we developed an unsupervised clustering technique that organizes neurons into functional groups. These analyses enabled a broad overview of the functional organization of the brain and revealed numerous brain nuclei whose neurons exhibit concerted activity patterns.


Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study.
Recent rodent models of antidepressant response implicate a novel set of genes in mechanisms of antidepressant action. The authors examined variants in four such genes (KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5) for association with remission in a large effectiveness trial of antidepressant treatments. Subjects were drawn from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study, a multicenter, prospective, effectiveness trial in major depressive disorder (MDD). Outpatients with nonpsychotic MDD were initially treated with citalopram for up to 14 weeks; those who did not remit with citalopram were sequentially randomized to a series of next-step treatments, each for up to 12 weeks. Single-nucleotide polymorphisms in four genes were examined for association with remission, defined as a clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C(16)) score < or =5. Of 1554 participants for whom DNA was available, 565 (36%) reached remission with citalopram treatment. No association with any of the four genes was identified. However, among the 751 who entered next-step treatment, variants in KCNK2 were associated with treatment response (Bonferroni-corrected, gene-based empirical p<0.001). In follow-up analyses, KCNK2 was also associated with effects of similar magnitude for third-step treatment among those with unsatisfactory benefit to both citalopram and one next-step pharmacotherapy (n=225). These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response.


Risk factors associated with repair of orbital and lateral skull defects.
To explore the complications and associated risks factors after orbital exenteration and lateral skull base defect repair. Patients who had undergone a reconstruction of their orbital cavity and lateral skull base defects were selected from our departmental database. The outcome of interest was postoperative complications. The risks factors were defined as age, sex, history of radiation therapy, and intracranial involvement (with and without dural involvement). Information was collected on the type of reconstruction used after the orbital cavity repair. The χ(2) test and logistic regression were used to analyze associations between postoperative complications and the various risks factors. Of the 32 identified patients, 19 had intracranial involvement (9 with dural involvement). Twenty-four patients underwent reconstruction with free tissue transfer in the same setting. Reconstruction with free tissue transfer was significantly associated with fewer major postoperative complications (P < .053). There was a trend toward more complications with a history of radiation therapy or intracranial involvement. Reconstruction of the orbital cavity and lateral skull base can be challenging, especially if there is a history of radiation therapy and intracranial involvement. Free tissue transfer is a safe and effective method for reconstruction of such defects.


The homeodomain-interacting protein kinase 2 regulates insulin promoter factor-1/pancreatic duodenal homeobox-1 transcriptional activity.
The homeodomain transcription factor insulin promoter factor (IPF)-1/pancreatic duodenal homeobox (PDX)-1 plays a crucial role in both pancreas development and maintenance of beta-cell function. Targeted disruption of the Ipf1/Pdx1 gene in beta-cells of mice leads to overt diabetes and reduced Ipf1/Pdx1 gene expression results in decreased insulin expression and secretion. In humans, mutations in the IPF1 gene have been linked to diabetes. Hence, the identification of molecular mechanisms regulating the transcriptional activity of this key transcription factor is of great interest. Herein we analyzed homeodomain-interacting protein kinase (Hipk) 2 expression in the embryonic and adult pancreas by in situ hybridization and RT-PCR. Moreover, we functionally characterized the role of HIPK2 in regulating IPF1/PDX1 transcriptional activity by performing transient transfection experiments and RNA interference. We show that Hipk2 is expressed in the developing pancreatic epithelium from embryonic d 12-15 but that the expression becomes preferentially confined to pancreatic endocrine cells at later developmental stages. Moreover, we show that HIPK2 positively influences IPF1/PDX1 transcriptional activity and that the kinase activity of HIPK2 is required for this effect. We also demonstrate that HIPK2 directly phosphorylates the C-terminal portion of IPF1/PDX1. Taken together, our data provide evidence for a new mechanism by which IPF1/PDX1 transcriptional activity, and thus possibly pancreas development and/or beta-cell function, is regulated.


Global phylogenomic novelty of the Cas1 gene from hot spring microbial communities.
The Cas1 protein is essential for the functioning of CRISPR-Cas adaptive systems. However, despite the high prevalence of CRISPR-Cas systems in thermophilic microorganisms, few studies have investigated the occurrence and diversity of Cas1 across hot spring microbial communities. Phylogenomic analysis of 2,150 Cas1 sequences recovered from 48 metagenomes representing hot springs (42-80°C, pH 6-9) from three continents, revealed similar ecological diversity of Cas1 and 16S rRNA associated with geographic location. Furthermore, phylogenetic analysis of the Cas1 sequences exposed a broad taxonomic distribution in thermophilic bacteria, with new clades of Cas1 homologs branching at the root of the tree or at the root of known clades harboring reference Cas1 types. Additionally, a new family of casposases was identified from hot springs, which further completes the evolutionary landscape of the Cas1 superfamily. This ecological study contributes new Cas1 sequences from known and novel locations worldwide, mainly focusing on under-sampled hot spring microbial mat taxa. Results herein show that circumneutral hot springs are environments harboring high diversity and novelty related to adaptive immunity systems.


Topography of connexin32 in rat liver gap junctions. Evidence for an intramolecular disulphide linkage connecting the two extracellular peptide loops.
A range of anti-peptide antibodies directed towards selected amino acid sequences of connexin32 was prepared and characterised. The site-directed antibodies that identified connexin32 were used to study by immunolocalization and by proteolytic treatment of intact and split gap junctions the arrangement of the protein in the membrane. These studies reinforce models of connexin topography in which the polypeptide traverses the junctional membrane four times, with the amino and carboxyl termini cytoplasmically located. The four transmembrane domains were shown to be linked by two extracellular loops with a single intracellular loop connecting the second and third transmembrane domains. Evidence is presented to show that the two extracellular domains of connexin32, which are important for intercellular adhesion and the insulated bridging of the extracellular space by channels allowing cell-cell communication across the gap junction, are connected by disulphide bond(s). The studies lead to a more detailed two-dimensional model of connexin32 in the membrane, incorporating the favoured theoretical arrangement of disulphide bonds at the extracellular domain of connexin32.


The North Atlantic subpolar gyre and the marine migration of Atlantic salmon Salmo salar: the 'Merry-Go-Round' hypothesis.
One model for marine migration of Atlantic salmon Salmo salar proposes that North American and southern European stocks (<62 degrees N) move directly to feeding grounds off west Greenland, then overwinter in the Labrador Sea, whereas northern European stocks (>62 degrees N) utilize the Norwegian Sea. An alternate model proposes that both North American and European stocks migrate in the North Atlantic Subpolar Gyre (NASpG) where S. salar enter the NASpG on their respective sides of the Atlantic, and travel counterclockwise within the NASpG until returning to natal rivers. A review of data accumulated during the last 50 years suggests a gyre model is most probable. Freshwater parr metamorphose into smolts which have morphological, physiological and behavioural adaptations of epipelagic, marine fishes. Former high-seas fisheries were seasonally sequential and moved in the direction of NASpG currents, and catches were highest along the main axis of the NASpG. Marking and discrimination studies indicate mixed continental origin feeding aggregations on both sides of the Atlantic. Marked North American smolts were captured off Norway, the Faroe Islands, east and west Greenland, and adults tagged at the Faroes were recovered in Canadian rivers. Marked European smolts were recovered off Newfoundland and Labrador, west and east Greenland, and adults tagged in the Labrador Sea were captured in European rivers. High Caesium-137 ((137)Cs) levels in S. salar returning to a Quebec river suggested 62.3% had fed at or east of Iceland, whereas levels in 1 sea-winter (SW) Atlantic Canada returnees indicated 24.7% had fed east of the Faroes. Lower levels of (137)Cs in returning 1SW Irish fish suggest much of their growth occurred in the western Atlantic. These data suggest marine migration of S. salar follows a gyre model and is similar to other open-ocean migrations of epipelagic fishes.


Learning from the living to diagnose the dead - parallels between CT findings after survived drowning and fatal drowning.
A case of survived drowning is presented where CT findings of the lungs were in keeping with several findings seen on post-mortem CT (PMCT) examination after fatal drowning. These findings include interlobular septal thickening, peribronichal cuffing, mosaic pattern ground glass opacities, and perivascular nodular ground glass opacities. The absence of confounding normal post-mortem changes allows for a discussion on subtle differences between findings related to aspiration and pulmonary edema after drowning. This case represents a learning opportunity for radiologists and pathologists challenged by the complex lung findings after drowning on PMCT.


Treatment outcomes in patients with extranodal marginal zone B-cell lymphoma of the lung.
To evaluate clinical presentations, treatment modalities, and outcomes of pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma by stage strata. We retrospectively reviewed 51 patients diagnosed with pulmonary MALT lymphoma between January 2003 and December 2015. To compare treatment modalities and outcomes, we stratified the patients into low-stage (IE/IIE) and high-stage (IIIE/IVE) groups using modified Ann Arbor staging. Progression-free survival was estimated using Kaplan-Meier curves, and differences were compared using the log-rank test. A hazard ratio of progression by stage strata, adjusted for other clinical variables, was determined using a Cox adjusted proportional hazards model. The majority of patients had stage IE disease (76.5%; 39 of 51). With advancing stage, patients were more likely to have respiratory and B symptoms and higher International Prognostic Index scores. The most common treatment modality was surgical resection in low-stage patients (33 of 43) and chemotherapy in high-stage patients (7 of 8). At a median follow-up of 40.7 months, progression-free survival was longer for low-stage patients (median, 40.7 months vs 24.9 months; P < .001), and high-stage patients were 9.2 times more likely to progress (hazard ratio, 9.24; 95% confidence interval, 1.93-44.36). Among 30 patients with surgically resected stage IE disease, 8 with central lesions were treated via lobectomy and 22 with peripheral lesions were treated via lobectomy (n = 8) or limited resection (n = 14). One of these patients, with a central lesion, experienced disease recurrence. Our findings suggest that the clinical course of low-stage pulmonary MALT lymphoma, for which the mainstay of treatment is surgical resection, might be indolent.


Reversed-phase high-performance liquid chromatography of virus proteins and other large hydrophobic proteins in formic acid containing solvents.
The excellent dissolving capacity of formic acid together with a propanol-2 gradient is utilized in a new system for reversed-phase high-performance liquid chromatographic separation of poliovirus polypeptides and a variety of large proteins. Differences in elution characteristics were detected between reduced and non-reduced proteins containing disulphide bridges as well as proteins modified at cysteinyl residues. The retention coefficients of single amino acids were used to calculate those of proteins. The correlation of calculated coefficients with actual retention times indicates that some proteins are bound via their full, unfolded length to the reversed-phase support, whereas others partly preserved their secondary structure. Treatment of proteins with sodium dodecyl sulphate prior to injection dissociates these structural elements and leads to an increase in retention times. The high resolution of the system described should be applicable to the isolation and characterization of components of mixtures of proteins, particularly those of water-insoluble proteins of membranes or viruses, on the analytical and semi-preparative scales.


Ethical issues in disasters.
A disaster is a situation that overwhelms the local population's capacity to respond, thus necessitating a request for assistance from outside the impacted area. In these circumstances, needs usually outweigh resources. The objective of response is to do the greatest good for the greatest number of people (the utilitarian principle). As such, some unique ethical considerations will arise that are not seen in day-to-day practice.The adoption of medical ethics principles is important in such situations, but certain provisions must be accepted. In large-scale, complex disasters, it may be impossible to provide optimal care to each patient. This paper will discuss some of the challenges for healthcare personnel at "ground zero", how training in preventive ethics may help, and what principles can be applied when working in disaster-affected areas or when responding to disasters.


Six years follow-up of the levels of TNF-alpha and IL-6 in patients with complex regional pain syndrome type 1.
In an earlier study, levels of the proinflammatory cytokines TNF-alpha and IL-6 are higher in blisters fluid from the complex regional pain syndrome type 1 (CRPS1) side obtained at 6 and 30 months (median) after the initial event. The aim of this follow-up study is to determine the involvement of these cytokines in long lasting CRPS1. Twelve CRPS1 patients, with median disease duration of 72 months, participated. The levels of TNF-alpha and IL-6 were measured in blister fluid; disease activity was reevaluated by measuring pain and differences in temperature, volume, and mobility between both extremities. Differences in levels of IL-6 and TNF-alpha and mobility between both sides were significantly decreased. Pain and differences in temperature and volume were not significantly altered. No correlation was found between the cytokines and the disease characteristics. These results indicate that IL-6 and TNF-alpha are only partially responsible for the signs and symptoms of CRPS1.


Release of prostaglandin E(2) and nitric oxide from spinal microglia is dependent on activation of p38 mitogen-activated protein kinase.
The spinal release of prostaglandins (PGs), nitric oxide (NO), and cytokines has been implicated in spinal nociceptive processing. Microglia represent a possible cell of origin for these proexcitatory mediators. Spinal microglia possess Toll-like receptor 4 (TLR4) and neurokinin 1 (NK1) receptors, and both receptors play a significant role in peripheral nerve injury- and inflammation-induced spinal sensitization. Accordingly, we examined the properties of the cascades activated by the respective targets, which led to the release of PGE(2) and an increase in nitrite (NO(2)(-)) (a marker of NO) from cultured rat spinal microglia. Spinal microglia isolated from Sprague-Dawley neonatal rats were cultured with lipopolysaccharide (LPS) or substance P (SP) alone, with LPS in combination with SP, and with LPS in the presence of each inhibitor of cyclooxygenase (COX), NO synthase 2 (NOS2) or p38 mitogen-activated protein kinase (p38), or minocycline for 24 hours and 48 hours. Concentrations of PGE(2) and NO(2)(-) in culture supernatants were measured using an enzyme immunoassay and a colorimetric assay, respectively. Application of LPS (a TLR4 ligand, 0.1 to 10 ng/mL) to cultured microglia produced a dose- and time-dependent increase in PGE(2) and NO(2)(-) production, whereas no effects were observed after incubation with SP (an NK1 agonist, up to 10(-5) M) alone or in combination with LPS. Antagonist studies with SC-560 (COX-1 inhibitor) and SC-236 (COX-2 inhibitor) showed that LPS-induced PGE(2) release was generated from both COX-1 and COX-2. LPS-induced NO release was suppressed by 1400W, an inhibitor of NOS2. Minocycline, an agent blocking microglial activation, and SB203580, an inhibitor of p38, both attenuated the LPS-induced PGE(2) and NO release. The 1400W, at the doses that suppressed NO release, also blocked increased PGE(2) release. Our findings suggest that (a) activation of spinal microglia via TLR4 but not NK1 receptors produces PGE(2) and NO release from these cells; (b) the evoked PGE(2) release is generated by both COX-1 and COX-2, and (c) the COX-PGE(2) pathway is regulated by p38 and NOS2. Taken together with our previous in vivo work, the current findings emphasize that p38 in spinal microglia is a key player in regulating production of pronociceptive molecules, such as PGE(2) and NO.


Activities of the Vastus Lateralis and Vastus Medialis Oblique Muscles during Squats on Different Surfaces.
[Purpose] The purpose of the present study was to examine the effects of squat exercises performed on different surfaces on the activity of the quadriceps femoris muscle in order to provide information on support surfaces for effective squat exercises. [Subjects and Method] Fourteen healthy subjects performed squat exercises for five seconds each on three different support surfaces: hard plates, foam, and rubber air discs. Their performance was measured using electromyography. As the subjects performed the squat exercises on each surface, data on the activity of the vastus medialis oblique and the vastus lateralis, and the vastus medials oblique/vastus lateralis ratio, were collected. [Results] The activity of the vastus medialis oblique and the vastus medialis oblique/vastus lateralis ratio were found to be statistically significantly higher on rubber air discs than when the squats were performed on hard plates or foam. [Conclusion] To activate the vastus medialis obilique, and to enhance the vastus medialis oblique/vastus lateralis ratio, unstable surfaces that are highly unstable should be selected.


Mental representation of number in different numerical forms.
How are numerical operations implemented within the human brain? It has been suggested that there are at least three different codes for representing number: a verbal code that is used to manipulate number words and perform mental numerical operations (e.g., multiplication), a visual code that is used to decode frequently used visual number forms (e.g., Arabic digits), and an abstract analog code that may be used to represent numerical quantities. Furthermore, each of these codes is associated with a different neural substrate. We extend these studies using dense-sensor event-related EEG recording techniques to investigate the temporal pattern of notation-specific effects observed in a parity judgement (odd versus even) task in which single numbers were presented in one of four different numerical notations. Contrasts between different notations demonstrated clear modulations in the visual evoked potentials (VEP) recorded. We observed increased amplitudes for the P1 and N1 components of the VEP that were specific to Arabic numerals and to dot configurations but differed for random and recognizable (die-face) dot configurations. These results demonstrate clear, notation-specific differences in the time course of numerical information processing and provide electrophysiological support for the triple-code model of numerical representation.


Risk Factors for Hepatitis B Virus Transmission in Oman.
Hepatitis B virus (HBV) is a major public health problem worldwide. The prevalence of HBV is dependent on the modes of transmission. Chronic hepatitis B (CHB) infection can progress to liver cirrhosis and hepatocellular carcinoma. Oman is regarded as an intermediate endemic region and has had a neonatal vaccine against HBV since 1990. However, little research has been conducted regarding risk factors for HBV transmission. Our study aimed to identify the prevalence of major risk factors for acquiring HBV in Oman. We conducted a retrospective chart review of all adult Omani patients diagnosed with CHB at two tertiary hospitals in Oman, Sultan Qaboos University Hospital and Armed Forces Hospital, between February 2009 and July 2013. The prevalence of major risk factors was identified by interviewing CHB patients using a standard questionnaire during their follow-up visits to the hepatology clinic at both hospitals. The risk factor frequency was stratified by age, gender, and educational level. A total of 274 patients were interviewed; 52.2% of the participants were males. The median age for men was 35.9 years and 35.1 years for women, with 75.5% aged 20-39 years old. The antenatal screening was the most common means of identifying HBV infection in females, and pre-blood donation screening was the most common in males. Intra-familial contact with HBV infected persons and behavioral risks such as body piercing (females) and barber shaving (males) were more common than nosocomial risk factors. Knowledge about HBV infection was scarce among our participants. More than half of the participants had a positive family history of HBV infection. There was a significant association between HBV infection and age groups, and educational levels (p < 0.050 and p < 0.001, respectively). Among those who were infected due to intra-familial contact or behavioral risk, there was a significant difference between the two sexes (p < 0.020) and between the three age groups (< 23, 23-28, >28) of HBV positive mothers (33.3%, 14.3%, and 6.6%, respectively; p < 0.050). There was also a statistically significant difference among different educational levels (p < 0.050). Direct contact of infected individuals within a family and exposure to high-risk behaviors such as piercing and barber shaving are the main reported risk factors for HBV infection in Omani patients. Reducing the vertical and horizontal transmission of HBV in Oman could be improved by implementing routine antenatal screening of pregnant women and a greater focus on contact screening, respectively.


Evaluation of Maternal, Embryo, and Placental Effects in CD-1 Mice following Gestational Exposure to Perfluorooctanoic Acid (PFOA) or Hexafluoropropylene Oxide Dimer Acid (HFPO-DA or GenX).
Perfluorooctanoic acid (PFOA) is a poly- and perfluoroalkyl substance (PFAS) associated with adverse pregnancy outcomes in mice and humans, but little is known regarding one of its replacements, hexafluoropropylene oxide dimer acid (HFPO-DA, referred to here as GenX), both of which have been reported as contaminants in drinking water. We compared the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placenta units, with a specific focus on the placenta as a hypothesized target. Pregnant CD-1 mice were exposed daily to PFOA (0, 1, or 5mg/kg) or GenX (0, 2, or 10mg/kg) via oral gavage from embryonic day (E) 1.5 to 11.5 or 17.5 to evaluate exposure effects on the dam and embryo-placenta unit. Gestational weight gain (GWG), maternal clinical chemistry, maternal liver histopathology, placental histopathology, embryo weight, placental weight, internal chemical dosimetry, and placental thyroid hormone levels were determined. Exposure to GenX or PFOA resulted in increased GWG, with increase in weight most prominent and of shortest latency with 10mg/kg/d GenX exposure. Embryo weight was significantly lower after exposure to 5mg/kg/d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5mg/kg/d PFOA and 10mg/kg/d GenX) and lower doses (1mg/kg/d PFOA and 2mg/kg/d GenX), including higher maternal liver weights, changes in liver histopathology, higher placental weights and embryo-placenta weight ratios, and greater incidence of placental abnormalities relative to controls. Histopathological features in placentas suggested that PFOA and GenX may exhibit divergent mechanisms of toxicity in the embryo-placenta unit, whereas PFOA- and GenX-exposed livers shared a similar constellation of adverse pathological features. Gestational exposure to GenX recapitulated many documented effects of PFOA in CD-1 mice, regardless of its much shorter reported half-life; however, adverse effects toward the placenta appear to have compound-specific signatures. https://doi.org/10.1289/EHP6233.


Choroid plexus carcinoma. Report of a case with immunohistochemical and ultrastructural observations.
A choroid plexus carcinoma from the lateral ventricle of a ten-month-old boy was examined by light and electron microscopy. The neoplasm exhibited papillary and solid areas, invasion of adjacent brain, cytologic anaplasia, and necrosis. Intra- and extracellular PAS positive droplets were present, but no pigment was observed. No glial fibrillary acidic protein was detected within neoplastic cells. Ultrastructural examination revealed irregular nuclei with large nucleoli and occasional intranuclear filamentous rods. Cytoplasmic organelles included a moderate number of free ribosomes, rough endoplasmic reticulum, Golgi complexes, and microtubules. In some areas, numerous mitochondria filled the cytoplasm. Surface specializations included zonulae adherentes, microvilli, and clusters of cilia with a 9 + 0 microtubular pattern. Clusters of basal bodies with prominent basal feet and striated rootlets were present within the cytoplasm. Normal choroid plexus from this patient also had 9 + 0 cilia. In contrast, choroid plexus papillomas from two other infants had cilia with a 9 + 2 pattern. These observations demonstrate that both differentiated and anaplastic choroid plexus neoplasms have the potential to form cilia, and that the microtubular structure of such cilia may deviate from the usual 9 + 2 pattern.


Bug22p, a conserved centrosomal/ciliary protein also present in higher plants, is required for an effective ciliary stroke in Paramecium.
Centrioles, cilia, and flagella are ancestral conserved organelles of eukaryotic cells. Among the proteins identified in the proteomics of ciliary proteins in Paramecium, we focus here on a protein, Bug22p, previously detected by cilia and basal-body high-throughput studies but never analyzed per se. Remarkably, this protein is also present in plants, which lack centrioles and cilia. Bug22p sequence alignments revealed consensus positions that distinguish species with centrioles/cilia from plants. In Paramecium, antibody and green fluorescent protein (GFP) fusion labeling localized Bug22p in basal bodies and cilia, and electron microscopy immunolabeling refined the localization to the terminal plate of the basal bodies, the transition zone, and spots along the axoneme, preferentially between the membrane and the microtubules. RNA interference (RNAi) depletion of Bug22p provoked a strong decrease in swimming speed, followed by cell death after a few days. High-speed video microscopy and morphological analysis of Bug22p-depleted cells showed that the protein plays an important role in the efficiency of ciliary movement by participating in the stroke shape and rigidity of cilia. The defects in cell swimming and growth provoked by RNAi can be complemented by expression of human Bug22p. This is the first reported case of complementation by a human gene in a ciliate.


Comparison of the thicknesses of the transversus abdominis and internal abdominal obliques during plank exercises on different support surfaces.
[Purpose] This study applied variable plank exercises on a stable surface consisting of a mat, on an unstable surface consisting of a dynamic cushion placed under the upper extremities and lower extremities. [Subjects] Forty-three healthy male and female subjects in their 20s voluntarily consented to participate in this study. [Methods] The subjects performed the plank exercises on the three support surfaces. Ultrasound imaging was conducted while they carried out plank exercises. [Results] The changes in the thicknesses of both the transversus abdominis and internal abdominal obliques were statistically more significant for LEDCP than for MatP. In addition, the changes in the thickness of the transversus abdominis were statistically more significant for LEDCP than for UEDCP. [Conclusion] Therefore, applying an unstable condition to the lower limbs using a dynamic cushion is considered more effective during plank exercises.


The degree of stability in motor performance in preschool children and its association with child-related variables.
Understanding the stability of individual differences in motor performance during the early years of life, despite normative age-related growth in motor performance, has important implications for identification of motor coordination difficulties and subsequently, early remediation. Therefore, the aims of the present study were to examine the degree of rank-order and individual-level stability in motor performance in young children with different levels of motor skill proficiency. Subsequently, we explored the influence of child variables (i.e., age, gender, and behavioural self-regulation) on different aspects of stability. In this longitudinal study, a community sample of 68 participants (49% girls) with a mean age of 3 years and 11 months (SD = 7 months) were assesses in three six-monthly waves. The total standard score of the Movement Assessment Battery for Children-2 (MABC-2) was used as the measure of motor performance. Rank-order stability was examined with zero-order Pearson correlations. Individual-level stability was examined by means of stability in classifications (at risk for motor coordination difficulties versus typically developing). In addition to examining stability in group classification, the Reliable Change Index (RCI) was calculated to examine if the difference in a child's scores over time exceeded (increased or decreased relative to) the expected change. The results showed moderate to high rank-order stability between time points. No significant differences in degree of rank-order stability were found between boys and girls and between 3-year old and 4-year old children. In terms of stability of classification, it was shown that for ~50% of the children with motor coordination difficulties and ~ 90% of typically developing the classification based on the cut-off score on the MABC-2 was stable. Based on the RCI, over 90% showed individual-level stability. The level of behavioural self-regulation at T1 (as measured with the Head-Toes-Knees-Shoulders task) was not significantly related to individual-level stability in motor performance. In conclusion, our findings highlight the importance of a careful choice of stability measures and a reflection on the implications of their results. More research is needed to understand which child and environmental variables impact on stability.


Heterosexual and homosexual transmission of hepatitis C virus: relation with hepatitis B virus and human immunodeficiency virus type 1.
A seroprevalence study was carried out on 1757 outpatients consecutively seen in a sexually transmitted disease (STD) clinic in order to evaluate the sexual transmission of hepatitis C virus (HCV). A total of 1442 consenting patients were tested for hepatitis C, hepatitis B and human immunodeficiency virus type 1 (HCV, HBV, HIV-1) antibodies. The relations between anti-HCV, anti-HBc and anti-HIV-1 were studied. Of 73 anti-HCV positive reactions, 45 (61.6%) were confirmed by the recombinant immunoblot assay (RIBA). The proportion of individuals with anti-HCV was higher in outpatients with a history of sexually transmitted disease than without. It was 2.8% in non drug user heterosexuals and 2.9% in non drug user homosexuals. Intravenous drug users (IDU) had higher anti-HCV prevalence when a history of STD was taken into account (42.3% in subjects with STD versus 36.7% in subjects without STD). Among non drug user heterosexuals an association was found between anti-HCV and anti-HBc. These data suggest that sexual transmission of HCV occurs, although it seems to be less efficient than other parenteral modes of transmission. When a more sensitive and specific marker of HCV infection become available, a more accurate estimate of the frequency and efficiency of the sexual transmission will be possible.


What's new in benign lung tumours?
While lung cancer is one of the most common malignancies routinely encountered by pathologists, benign pulmonary neoplasms are quite rare. However, it is important for pathologists to be familiar with the typical diagnostic features of benign lung tumors to avoid confusing them with malignant morphological mimics. There have also been intriguing discoveries in the genetics of benign pulmonary neoplasms in the past decade. This review will cover several of the most common benign lung tumors, including the diagnostic categories of pulmonary adenomas, bronchial papillomas, and benign mesenchymal tumors, with discussion of the current classification, differential diagnosis, and current knowledge regarding genetic drivers.


Membrane guanylyl cyclase complexes shape the photoresponses of retinal rods and cones.
In vertebrate rods and cones, photon capture by rhodopsin leads to the destruction of cyclic GMP (cGMP) and the subsequent closure of cyclic nucleotide gated ion channels in the outer segment plasma membrane. Replenishment of cGMP and reopening of the channels limit the growth of the photon response and are requisite for its recovery. In different vertebrate retinas, there may be as many as four types of membrane guanylyl cyclases (GCs) for cGMP synthesis. Ten neuronal Ca(2+) sensor proteins could potentially modulate their activities. The mouse is proving to be an effective model for characterizing the roles of individual components because its relative simplicity can be reduced further by genetic engineering. There are two types of GC activating proteins (GCAPs) and two types of GCs in mouse rods, whereas cones express one type of GCAP and one type of GC. Mutant mouse rods and cones bereft of both GCAPs have large, long lasting photon responses. Thus, GCAPs normally mediate negative feedback tied to the light-induced decline in intracellular Ca(2+) that accelerates GC activity to curtail the growth and duration of the photon response. Rods from other mutant mice that express a single GCAP type reveal how the two GCAPs normally work together as a team. Because of its lower Ca(2+) affinity, GCAP1 is the first responder that senses the initial decrease in Ca(2+) following photon absorption and acts to limit response amplitude. GCAP2, with a higher Ca(2+) affinity, is recruited later during the course of the photon response as Ca(2+) levels continue to decline further. The main role of GCAP2 is to provide for a timely response recovery and it is particularly important after exposure to very bright light. The multiplicity of GC isozymes and GCAP homologs in the retinas of other vertebrates confers greater flexibility in shaping the photon responses in order to tune visual sensitivity, dynamic range and frequency response.


Properties of BK(Ca) channels formed by bicistronic expression of hSloalpha and beta1-4 subunits in HEK293 cells.
Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels are sensitive to both voltage and internal [Ca(2+)] and are found in many tissues. Their physiological roles range from causing relaxation of smooth muscle to regulating the frequency of action potential firing. There is considerable variation between different tissues in their Ca(2+)- and voltage-dependence. Much of this variation results from the association of the pore-forming alpha subunit (hSloalpha) with different beta subunits leading to altered channel properties. Since hSloalpha alone produces functional BK(Ca) channels, we have used a bicistronic expression method to ensure that both alpha and beta subunits are expressed, with the beta subunit being in excess. Using this method we have investigated the effect of four beta subunits (beta1 to beta4) on cloned BK(Ca) channels. The four beta subunits were individually cloned into a vector that had hSloalpha cDNA inserted downstream of an internal ribosome entry site. The constructs were transiently transfected into HEK293 cells together with a construct that expresses green fluorescent protein, as a marker for transfection. Fluorescent cells expressed BK(Ca) channels whose currents were recorded from inside-out or outside-out patches. The currents we measured using this expression system were similar to those expressed in Xenopus oocytes by Brenner et al. (Brenner, R., Jegla, T.J., Wickenden, A., Liu, Y., Aldrich, R.W. 2000. Cloning and functional expression of novel large-conductance calcium-activated potassium channel beta subunits, hKCNMB3 and hKCNMB4. J. Biol. Chem.275:6453-6461.)


Prediction of response of blood lead to airborne and dietary lead from volunteer experiments with lead isotopes.
To predict the response of blood lead to airborne and dietary lead requires knowledge of the rate of uptake of lead into the body from lung and gut, its subsequent partitioning between compartments, the stay time in those compartments, and its redistribution or excretion. Tracer studies with volunteers have shown no differences in systemic distribution of inorganic lead between tissues whether it is taken by inhalation, ingestion or injection. Lead is rapidly transferred from plasma to red cells, and there is slower movement thence into liver and other soft tissues, to bone, and to excreta. Work at Harwell and elsewhere with 203Pb has shown that the initial rapid distribution leaves rather over half the assimilated lead attached to red cells. The result is remarkably consistent, and applies also to dogs and baboons. The renal clearance (Vu) (ratio of U to CB, or daily urinary output expressed as mass of blood having the same lead content), and also the endogenous faecal clearance excretion rate (Vf), have been measured on human subjects with 203Pb. The results are consistent with Vu, as measured with stable lead, with many results giving Vu about 0.1 kg d-1. However, there is evidence that Vu increases when CB is elevated above the normal. This may explain the nonlinear relation between uptake of lead and the corresponding CB, which has been observed in humans exposed to environmental lead. Vf is about half Vu, and a similar result applies to calcium. The clearance rate Va of 203Pb from blood to bone has been measured, and a variety of human and animal data in the literature has been reviewed to support this result. Combined with bone turnover rates (from data on 90Sr), the postulated inputs to bone give estimates of skeletal burdens which agree with post-mortem results. The results are combined in a compartment model. The retention of lead aerosol in the lung, and uptake from the gut are then considered, with use made of radioactive tracer (203Pb), stable isotopic tracer (204Pb) and total lead measurements. Here there is great diversity of results. Particle size affects the fractional lung retention and the site of retention, which in turn affects the fractional uptake to blood. Presence or absence of food in the stomach when lead is ingested greatly affects the fractional gut uptake. Finally, a limited selection of results of volunteer exposures to stable lead in air or diet are reviewed.(ABSTRACT TRUNCATED AT 400 WORDS)


Water permeability and particle aggregates in ADH-, cAMP-, and forskolin-treated toad bladder.
Osmotic water flow was used to evaluate total tissue water permeability (Ptissue), and luminal membrane particle aggregates, presumed sites for transmembrane water movement, were quantified to assess luminal membrane water permeability, in bladders treated with maximally stimulating concentrations of antidiuretic hormone (ADH), adenosine 3',5'-cyclic monophosphate (cAMP), and forskolin. Aggregates were as numerous and occupied the same fractional area of the luminal membrane in response to cAMP treatment (10 mM) as treatment with ADH (20 mU/ml). Ptissue in cAMP-treated tissues, however, was only half of that induced by ADH (P less than 0.001). A similar disparity in the relationship between aggregates and Ptissue occurred for additional bladders treated with 50 microM forskolin, which is known to increase endogenous cAMP to levels much greater than caused by maximally stimulating concentrations of ADH. Although Ptissue achieved with forskolin was the same in paired bladders treated with ADH, aggregates were far more numerous (P less than 0.05) and occupied much more membrane area (P less than 0.05) with forskolin. These observations are consistent with the view that aggregate appearance in the luminal membrane is a function of intracellular cAMP. The finding that the hydrosmotic response of toad bladder to both cAMP and forskolin compared with ADH stimulation is reduced relative to measured changes in luminal membrane aggregates suggests that the effect of ADH in altering water permeability involves additional regulation via a non-cAMP-mediated mechanism. This latter event would appear to be by an effect of ADH on the permeability of a resistance at a postluminal membrane site and/or possibly on the permeability of aggregates in the luminal membrane.


The use of homeopathic products in childhood: data generated over 8.5 years from the Avon Longitudinal Study of Parents and Children (ALSPAC).
Very little is known about the use of homeopathic products (HP) in children. The Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based cohort in the South-West of England, has collected homeopathic data through self-completion questionnaires posted to the mother at regular time points throughout childhood. The aim of this article is to describe the use of these products in a large cohort of children from birth to 8.5 years of age. Questions asked about the use of HP within a preceding time period at seven time points from birth to 8.5 years of age. Additional questions at 18 and 81 months asked about the conditions treated and at 81 months who had prescribed the HP. Eleven and eight-tenths percent (11.8%) of this cohort used a HP at least once up to 8.5 years of age. Chamomilla for teething and Arnica for soft-tissue bruising were the most commonly used products. The most frequently prescribed products were for common self-limiting infantile conditions such as colic, cuts and bruises, and teething. Parents were most likely at 81 months to prescribe HP for their children (46.3% of all prescription sources) and 10% of products were prescribed by general practitioners. Confusion about what constituted a HP was present in nearly 10% of answers. No other study, to our knowledge, has been able to map the use of HP over such a long time period in such a large cohort of children. The amount of HP use reflects a significant minority of the population who use complementary and alternative medicine treatments to manage the health of their family. Health care professionals should be aware of the confusion surrounding HP and have knowledge around some of the more commonly used HP. Parents and carers are using homeopathy wisely with appropriate remedies consistently used for acute problems. Research could focus on greater information delivery to the community and monitoring of potential health and cost benefits, or side-effects of the use of HP for acute and chronic conditions in children.


Incidence and significance of early recurrences of atrial fibrillation after cryoballoon ablation: insights from the multicenter Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP AF) Trial.
Early recurrence of atrial fibrillation (ERAF) is common after radiofrequency catheter ablation for AF. We sought to determine the incidence and prognostic significance of ERAF after cryoballoon ablation. Moreover, the benefit of early reablation for ERAF after cryoballoon ablation is undetermined. The Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP AF) trial randomized 245 patients with paroxysmal AF to medical therapy versus cryoballoon-based pulmonary vein ablation. Patients were followed for 12 months. ERAF was defined as any recurrence of AF >30 seconds during the first 3 months of follow-up. Late recurrence (LR) was defined as any recurrence of AF >30 seconds between 3 and 12 months. Of the 163 patients randomized to cryoablation, 84 patients experienced ERAF (51.5%). The only significant factor associated with ERAF was male sex (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.03-4.61; P=0.041). LR was observed in 41 patients (25.1%), and was significantly related to ERAF (55.6% LR with ERAF versus 12.7% without ERAF; P<0.001). Among patients with ERAF, only current tobacco use (HR, 3.84; 95% CI, 1.82-8.11; P<0.001) was associated with LR. Conversely, early reablation was associated with greater freedom from LR (3.3% LR with early reablation versus 55.6% without; HR, 0.04; 95% CI, 0.01-0.32; P=0.002). ERAF after cryoballoon ablation occurs in ≈50% of patients and is strongly associated with LR. Early reablation for ERAF is associated with excellent long-term freedom from recurrent AF.


The development of medicines for children. Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni.
The lack of availability of appropriate medicines for children is an extensive and well known problem. As a consequence off label or unlicensed administration of medicinal products in every day paediatric practice is frequent. A variety of obstacles hinder the development of paediatric indications for drugs primarily intended for the adult market. The barriers to proper research on children's drug development include several complex factors, such as the limited commercial interest, lack of suitable infrastructure and competence for conducting paediatric clinical trials, difficulties in trial design, ethical worries and many others. Medicinal products used to treat children should be subjected to ethical research of high quality and be explicitly authorised for use in children as it happens in adults. Conducting adequate clinical trials in children is challenging and demanding. Identification of paediatric medical needs, extrapolation from adult data, modelling and simulation, specific clinical trial methodology are important features in the development of drugs intended for children. Market forces alone have proven insufficient to stimulate adequate research aimed at specific authorisation of medicinal products for the paediatric population, and for that reason, following the US experience, the European Paediatric Regulation has been amended in January 2007 by the European Commission. The objective of the Paediatric Regulation is to improve the development of high quality and ethically researched medicines for children aged 0 to 17 years, to facilitate the availability of information on the use of medicines for children, without subjecting children to unnecessary trials, or delaying the authorisation of medicines for use in adults. The impact of the Paediatric Regulation reflects in an increase in the number of paediatric studies to be performed, even if a significant number of these studies have not started yet. The objective of this review is to describe the main regulatory and scientific features which play a role in the complex issue of paediatric drug development.


Video Head Impulse Test (vHIT): The Role of Corrective Saccades in Identifying Patients With Vestibular Loss.
1) Characterize corrective saccades (CS) in normal controls, and 2) examine the sensitivity of the video head impulse test (vHIT) for identifying vestibular loss using both gain and CS. Prospective combined with retrospective review. Tertiary referral center. Seventy subjects with normal vestibular function served as controls (mean age, 44.1 yr; range, 10-78) and data from 49 patients with unilateral and bilateral vestibular loss was retrospectively reviewed (mean age, 50; range, 7-81). vHIT; individual horizontal head impulses were then analyzed in MATLAB. Horizontal vHIT gain, CS peak velocity, frequency, and latency. There was not an age effect for CS velocity or latency, and only a weak relationship between CS frequency and age in the control group. Gain and CS latency were the only parameters affected by impulse side, demonstrating higher gain and longer latency on the right. The group with vestibular loss had significantly lower mean vHIT gain, higher mean CS frequency, higher mean CS velocity, earlier CS latency, and smaller mean CS standard deviations of the latency compared with the control group.When all factors were analyzed separately by logistic regression, vHIT gain provided the best classification (83.8%), closely followed by CS frequency (83.1%). Using a two variable approach (both gain and CS frequency) yielded the best diagnostic accuracy (overall classification = 84.6%). Along with gain, incorporating CS frequency in interpreting vHIT improves diagnostic accuracy. A repeatable CS (>81.89%) and/or low gain (<0.78) indicate vestibular loss.


Mitochondrial beta-oxidation in Aspergillus nidulans.
Beta-oxidation (beta-ox) occurs exclusively in the peroxisomes of Saccharomyces cerevisiae and other yeasts, leading to the supposition that fungi lack mitochondrial beta-ox. Here we present unequivocal evidence that the filamentous fungus Aspergillus nidulans houses both peroxisomal and mitochondrial beta-ox. While growth of a peroxisomal beta-ox disruption mutant (DeltafoxA) was eliminated on a very long-chain fatty acid (C(22:1)), growth was only partially impeded on a long-chain fatty acid (C(18:1)) and was not affected at all on short chain (C4-C6) fatty acids. In contrast, growth of a putative enoyl-CoA hydratase mutant (DeltaechA) was abolished on short-chain and severely restricted on long- and very long-chain fatty acids. Furthermore fatty acids inhibited growth of the DeltaechA mutant but not the DeltafoxA mutant in the presence of an alternate carbon source (lactose). Disruption of echA led to a 28-fold reduction in 2-butenoyl-CoA hydratase activity in a preparation of organelles. EchA was also required for growth on isoleucine and valine. The subcellular localization of the FoxA and EchA proteins was confirmed through the use of red and green fluorescent protein fusions.


Crystal structures of the human adiponectin receptors.
Adiponectin stimulation of its receptors, AdipoR1 and AdipoR2, increases the activities of 5' AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR), respectively, thereby contributing to healthy longevity as key anti-diabetic molecules. AdipoR1 and AdipoR2 were predicted to contain seven transmembrane helices with the opposite topology to G-protein-coupled receptors. Here we report the crystal structures of human AdipoR1 and AdipoR2 at 2.9 and 2.4 Å resolution, respectively, which represent a novel class of receptor structure. The seven-transmembrane helices, conformationally distinct from those of G-protein-coupled receptors, enclose a large cavity where three conserved histidine residues coordinate a zinc ion. The zinc-binding structure may have a role in the adiponectin-stimulated AMPK phosphorylation and UCP2 upregulation. Adiponectin may broadly interact with the extracellular face, rather than the carboxy-terminal tail, of the receptors. The present information will facilitate the understanding of novel structure-function relationships and the development and optimization of AdipoR agonists for the treatment of obesity-related diseases, such as type 2 diabetes.


Dietary habits of Greek adults and serum total selenium concentration: the ATTICA study.
The trace element selenium is an essential micronutrient for human health, and its low levels in serum are implicated in the pathogenesis of several chronic diseases. The determination of total serum selenium levels may contribute to the assessment of the health status of all populations. Since the serum selenium levels are highly affected by diet, we assessed its association with the dietary habits of Greek adults. Serum selenium levels were determined with inductively coupled plasma mass spectrometry in a cohort of 506 participants (men: 296, women: 210) aged 18-75 from the ATTICA study. Food consumption was evaluated with a validated food-frequency questionnaire. Evaluation of the relationship between serum total selenium with major food groups and beverages by multi-adjusted analysis revealed that serum selenium was positively correlated with the consumption of red meat (2.37 ± 0.91, p = 0.01) while the consumption of other selenium-containing foods (i.e., fish, cereals, dairy products, vegetables) did not demonstrate such a relationship. Moreover, principal component analysis revealed that the adoption of a vegetarian type of diet is inversely correlated with total selenium (-3.94 ± 2.28, p = 0.08). Among the dietary habits that were examined, red meat seems to be the major determinant of serum selenium in Greek adults.


Radiation-induced sarcomas of the head and neck.
The aim of this study was to report our experience on the management of radiation-induced sarcomas (RISs). A retrospective study from 1994 to 2003 was done at our institution reviewing the medical records of 5 patients who had RISs. Five patients diagnosed of head and neck cancer received irradiation to treat their diseases. Later on, these patients developed new neoplasms in the irradiation fields (3 malignant fibrous histiocytoma, 1 osteosarcoma, and 1 angiosarcoma). The mean period of latency between irradiation and diagnosis of new tumors was 13 years. Early symptoms included neck or face swelling, odynophagia, or trigeminal hypoesthesia. All of the patients underwent surgical treatment. In 4 cases, regional and free flaps for head and neck reconstruction were required. Three patients also needed neoadjuvant chemotherapy. In the follow-up, 2 patients are alive and free of disease. Wide excision is the treatment of choice for RISs. Previous radiation therapy limits the dose that can be administered to the involved area, and the response rate to the chemotherapy is always poor.


Echocardiography, spirometry, and systemic acute-phase inflammatory proteins in smokers with COPD or CHF: an observational study.
Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) may coexist in elderly patients with a history of smoking. Low-grade systemic inflammation induced by smoking may represent the link between these 2 conditions. In this study, we investigated left ventricular dysfunction in patients primarily diagnosed with COPD, and nonreversible airflow limitation in patients primarily diagnosed with CHF. The levels of circulating high-sensitive C-reactive protein (Hs-CRP), pentraxin 3 (PTX3), interleukin-1β (IL-1 β), and soluble type II receptor of IL-1 (sIL-1RII) were also measured as markers of systemic inflammation in these 2 cohorts. Patients aged ≥ 50 years and with ≥ 10 pack years of cigarette smoking who presented with a diagnosis of stable COPD (n=70) or stable CHF (n=124) were recruited. All patients underwent echocardiography, N-terminal pro-hormone of brain natriuretic peptide measurements, and post-bronchodilator spirometry. Plasma levels of Hs-CRP, PTX3, IL-1 β, and sIL-1RII were determined by using a sandwich enzyme-linked immuno-sorbent assay in all patients and in 24 healthy smokers (control subjects). Although we were unable to find a single COPD patient with left ventricular dysfunction, we found nonreversible airflow limitation in 34% of patients with CHF. On the other hand, COPD patients had higher plasma levels of Hs-CRP, IL1 β, and sIL-1RII compared with CHF patients and control subjects (p < 0.05). None of the inflammatory biomarkers was different between CHF patients and control subjects. In conclusion, although the COPD patients had no evidence of CHF, up to one third of patients with CHF had airflow limitation, suggesting that routine spirometry is warranted in patients with CHF, whereas echocardiography is not required in well characterized patients with COPD. Only smokers with COPD seem to have evidence of systemic inflammation.


Interference of secretory immunoglobulin A with sorption of oral bacteria to hydroxyapatite.
The potential of secretory immunoglobulin A (S-IgA) to interfere with the initial phase of dental plaque formation was studied by using an in vitro method which permits the quantitative determination of the sorption of radiolabeled oral bacterial cells to hydroxyapatite (HA) beads. The importance of specific S-IgA antibodies was evaluated by a comparison of the effect of pure preparations of colostral S-IgA, polymeric myeloma IgA, or preabsorbed S-IgA. Specific antibody molecules bound at the HA surface significantly enhanced the sorption of two Streptococcus sanguis strains. In contrast, HA-bound S-IgA antibodies inhibited the sorption of Streptococcus mitior and Streptococcus salivarius. The same was true for Streptococcus mutans cells, but only when they were propagated in the absence of sucrose. Suspended in saliva, cells of all streptococcal species adhered in significantly lower numbers to HA. Comparative experiments with bacteria suspended in solutions of various preparations of IgA or immunoglobulin-deficient salivas with S-IgA or myeloma IgA added indicated that the adherence inhibition seen with S. Sanguis, S. mitior, S. salivarius, and glucose-grown S. mutans was partly attributable to functions of S-IgA antibodies. Under the in vitro conditions of the study, S-IgA antibodies had no effect on the sorption of sucrose-grown S. mutans, Actinomyces viscosus, and Actinomyces naeslundii to HA. The results indicated that S-IgA can interfere with the sorption of some oral bacteria to HA by several different functions.


[Clinical signs of endothelial disorders in patients with severe sepsis].
A clinical-experimental study was carried out. The objective was to find some regularities in endothelial disorder progression in patients with severe sepsis and to evaluate clinical efficacy of some methods of hepatic protection. Experimental part of work was carried out on 59 mice with induced peritonitis. Obtained data shows early emergence of lung disorders that precede changes in hepatic tissue. Clinical part of work included 181 patient with severe sepsis. It was noted that acute respiratory distress syndrome symptoms occurred earlier than hepatic dysfunction, if the latter joints, it aggravates the patients status and worsens the prognosis. Use of Heptral (Ademetionine) and Ketamine in order to protect liver is a clinically effective method which makes possible to decrease the lethality.


TRPM5.
TRPM5 is a Ca(2+)-activated cation channel that mediates signaling in taste and other chemosensory cells. Within taste cells, TRPM5 is the final element in a signaling cascade that starts with the activation of G protein-coupled receptors by bitter, sweet, or umami taste molecules and that requires the enzyme PLCβ2. PLCβ2 breaks down PIP2 into DAG and IP3, and the ensuing release of Ca(2+) from intracellular stores activates TRPM5. Since its initial discovery in the taste system, TRPM5 has been found to be distributed in sparse chemosensory cells located throughout the digestive track, in the respiratory system, and in the olfactory system. It is also found in pancreatic islets, where it contributes to insulin secretion. This review highlights recent work on the mechanisms of the activation of the TRPM5 channel and its regulation by voltage, phosphoinositides, temperature, and pH. The distribution of the channel in the body and its functional contribution to various sensory and nonsensory processes are discussed.