Syncopation creates the sensation of groove in synthesized music examples.
In order to better understand the musical properties which elicit an increased sensation of wanting to move when listening to music-groove-we investigate the effect of adding syncopation to simple piano melodies, under the hypothesis that syncopation is correlated to groove. Across two experiments we examine listeners' experience of groove to synthesized musical stimuli covering a range of syncopation levels and densities of musical events, according to formal rules implemented by a computer algorithm that shifts musical events from strong to weak metrical positions. Results indicate that moderate levels of syncopation lead to significantly higher groove ratings than melodies without any syncopation or with maximum possible syncopation. A comparison between the various transformations and the way they were rated shows that there is no simple relation between syncopation magnitude and groove.


Pharmacologic management of cytomegalovirus retinitis: review of current and future therapeutic modalities.
A number of new medications and modes of drug delivery have been introduced for the management of cytomegalovirus (CMV) retinitis in AIDS patients. New modes of treatment have attempted to prolong intervals between dosing and reduce drug-related toxicity in an effort to improve quality of life. The ophthalmic, infectious disease, and pharmacologic literature were reviewed and evaluated for trends and new approaches to the management of CMV retinitis. Ganciclovir and foscarnet have been the mainstays in management of CMV retinitis. Intravenous administration of these drugs is costly, time-consuming, and complicated by numerous toxicities. Changes in the delivery of anti-viral drugs have involved intravitreal injections and implant devices. Other new methods involve liposomal systems to increase drug contact time, use of longer-acting drugs with less-frequent dosing requirements, and methods to improve quality of life by avoiding intravenous drug delivery. A number of strategies have evolved to manage cytomegalovirus retinitis. Patients are living longer with AIDS. With increased survival comes increased risk of CMV retinitis and the need for more-effective treatments to preserve retinal integrity. The optometrist must become aware of the potential of these drugs to control retinitis, protect functional vision, and maintain quality of life.


In vitro and in vivo degradation evaluation of novel iron-bioceramic composites for bone implant applications.
Biodegradable metals such as magnesium, iron and their alloys have been known as potential materials for temporary medical implants. However, most of the studies on biodegradable metals have been focusing on optimizing their mechanical properties and degradation behavior with no emphasis on improving their bioactivity behavior. We therefore investigated the possibility of improving iron biodegradation rate and bioactivity by incorporating various bioactive bioceramics. The iron-based bioceramic (hydroxyapatite, tricalcium phosphate and biphasic calcium phosphate) composites were prepared by mechanical mixing and sintering process. Degradation studies indicated that the addition of bioceramics lowered the corrosion potential of the composites and slightly increased their corrosion rate compared to that of pure iron. In vitro cytotoxicity results showed an increase of cellular activity when rat smooth muscle cells interacted with the degrading composites compared to pure iron. X-ray radiogram analysis showed a consistent degradation progress with that found in vivo and positive tissue response up to 70 days implantation in sheep animal model. Therefore, the iron-based bioceramic composites have the potential to be used for biodegradable bone implant applications.


[Sorption rate equation of 2-mercaptopbenzimidazole chelating cellulose for some heavy metal ions].
Chelating cellulose is of simple preparation, excellent nature and low cost. MBM chelating cellulose (CC-MBM) was prepared with chelating reagent (2-mercaptobenzimidazole) grafted on cotton by indirect etherification method. The approach for separating and preconcentrating trace of Pb, Cd, Cu and Ni has advantages of high exchanging speed, high preconcentration multiple, high selectivity and easy elution. The sorption kinetic properties of CC-MBM for several heavy metal ions have also been studied systematically. It is shown that the sorption rate of CC-MBM is very rapid and the reaching time is short. The relation between the sorption amount and time completely complies with following equation Q/Q infinity = at/(1 + at).


A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2015 Update.
Chronic hepatitis B (CHB) continues to be an important public health problem worldwide, including in the United States. An algorithm for managing CHB was developed by a panel of United States hepatologists in 2004 and subsequently updated in 2006 and 2008. Since 2008, additional data on long-term safety and efficacy of licensed therapies have become available and have better defined therapeutic options for CHB. The evidence indicates that potent antiviral therapy can lead to regression of extensive fibrosis or even cirrhosis, thus potentially altering the natural history of CHB. In addition, appropriate choice of antiviral agent can minimize the risk of resistance. This updated algorithm for managing CHB is based primarily on evidence from the scientific literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy for CHB is durable suppression of serum hepatitis B virus (HBV) DNA to low or undetectable levels. CHB patients who have HBV DNA >2000 IU/mL, elevated alanine aminotransferase level, and any degree of fibrosis should receive antiviral therapy regardless of their hepatitis B e antigen status. CHB patients with HBV DNA >2000 IU/mL and elevated alanine aminotransferase level but no evidence of fibrosis may also be considered for antiviral therapy. Approved antiviral therapies for CHB are interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, telbivudine, and tenofovir, although the preferred first-line treatment choices are peginterferon alfa-2a, entecavir, and tenofovir. In determining choice of therapy, considerations include efficacy, safety, rate of resistance, method of administration, duration, and cost.


Delayed drug hypersensitivity: models of T-cell stimulation.
Drug-induced hypersensitivity reactions can cause a variety of serious diseases by involving drug-specific T-cells. Many of these reactions have been explained by the hapten concept, which postulates that small chemical compounds need to bind covalently to proteins to be recognized by the immune system. Due to their chemical reactivity, haptens stimulate the innate immunity by binding covalently to endogenous proteins and form so called hapten-carrier complexes, which are antigenic and induce T-cell responses. In recent years, a new concept has been developed since drug-induced hypersensitivity reactions were also observed with chemically unreactive drugs. This concept implies direct and reversible interactions of the drug between T-cell receptors (TCR) and major histocompatability complex (MHC) molecules. Therefore it was termed pharmacological interactions with immune receptors (p-i concept). Early observations on drug reacting T-cell clones (TCC) let believe that drugs bind first to the T-cell receptor since HLA molecules could be exchanged without affecting the drug reactivity. However, MHC molecules were always required for full activation of TCC. According to its strong HLA-B*5701 association, recent data on abacavir suggest that a drug could first bind to the peptide binding groove of the MHC molecule. The thereby modified HLA molecule can then be recognized by specific T-cells. Consequently, two types of reactions based on the p-i mechanism may occur: on the one hand, drugs might preferentially bind directly to the TCR, whereas in defined cases with strong HLA association, drugs might bind directly to the MHC molecule.


Mammalian evolution: timing and implications from using the LogDeterminant transform for proteins of differing amino acid composition.
We explore the tree of mammalian mtDNA sequences, using particularly the LogDet transform on amino acid sequences, the distance Hadamard transform, and the Closest Tree selection criterion. The amino acid composition of different species show significant differences, even within mammals. After compensating for these differences, nearest-neighbor bootstrap results suggest that the tree is locally stable, though a few groups show slightly greater rearrangements when a large proportion of the constant sites are removed. Many parts of the trees we obtain agree with those on published protein ML trees. Interesting results include a preference for rodent monophyly. The detection of a few alternative signals to those on the optimal tree were obtained using the distance Hadamard transform (with results expressed as a Lento plot). One rearrangement suggested was the interchange of the position of primates and rodents on the optimal tree. The basic stability of the tree, combined with two calibration points (whale/cow and horse/rhinoceros), together with a distant secondary calibration from the mammal/bird divergence, allows inferences of the times of divergence of putative clades. Allowing for sampling variances due to finite sequence length, most major divergences amongst lineages leading to modern orders, appear to occur well before the Cretaceous/Tertiary (K/T) boundary. Implications arising from these early divergences are discussed, particularly the possibility of competition between the small dinosaurs and the new mammal clades.


Assisted lipid deposition by reductive electrochemical aryldiazonium grafting and insertion of the antiport NhaA protein in this stable biomimetic membrane.
Quartz crystal microbalance studies have been carried out to monitor the fusion of lipid vesicles (pure 1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC) and mixed vesicles (DMPC and 4-decylaniline). In order to increase the stability of the lipid deposits onto the electrodes, we have developed an original approach involving electrografting of adsorbed mixed vesicles. Aryldiazonium salts generated in situ from 4-decylaniline (4DA) present in adsorbed and fused mixed vesicles at the electrode surface allow their cathodic reduction and subsequent grafting. The stability of the supported lipid deposit has been shown to significantly increase from less than one day for pure DMPC to about two weeks with the lipid deposition assisted by electrochemical grafting. In this stable lipid deposit, the insertion of the sodium/proton antiporter membrane protein (NhaA) or its inactive mutant has been carried out by fusion of proteoliposomes. This has been followed by characterization of the inserted protein activity by cyclic voltammetry onto an electrode previously modified by an adsorbed pH sensor (2-anthraquinone sulfonate). Activation of the protein function by sodium ions leads to a shift of the interfacial pH and confirms the integrity of the immobilized NhaA.


Simultaneously successful transfemoral aortic valve implantation and endovascular repair of thoracic aortic saccular aneurysm.
The prevalence of aortic stenosis (AS) increases in the elderly. They present high surgical risk due to comorbid factors that increase with age. Transcatheter aortic valve implantation (TAVI) is an effective method in patients who present with severe aortic stenosis with a higher surgical risk or who cannot undergo surgical aortic valve replacement (s-AVR). In our case, the presence of saccular thoracic aortic aneurysm with severe AS, which is a vital co-morbidity, requires the treatment of both. The rise in systolic pressure following the TAVI procedure increases the saccular thoracic aneurysm rupture risk and this is why the timing and method of the two treatments become crucial. In this case, which is as far as we know the fi rst and only report in the literature, both TAVI and endovascular thoracic aortic saccular aneurysm repair were applied simultaneously and successfully to the patient via the same transfemoral route. After 1 month, the patient had good functional capacity and there were no complications in control tomography and echocardiography. In this way, we attempted to emphasize with a multidisciplinary study that the patients be assessed carefully before the procedure, and found that even in patients with common peripheral vascular diseases, a transfemoral route could be used together with the proper methods, and that both procedures could be performed simultaneously.


A Multilocus Sequence Typing System (MLST) reveals a high level of diversity and a genetic component to Entamoeba histolytica virulence.
The outcome of an Entamoeba histolytica infection is variable and can result in either asymptomatic carriage, immediate or latent disease (diarrhea/dysentery/amebic liver abscess). An E. histolytica multilocus genotyping system based on tRNA gene-linked arrays has shown that genetic differences exist among parasites isolated from patients with different symptoms however, the tRNA gene-linked arrays cannot be located in the current assembly of the E. histolytica Reference genome (strain HM-1:IMSS) and are highly variable. To probe the population structure of E. histolytica and identify genetic markers associated with clinical outcome we identified in E. histolytica positive samples selected single nucleotide polymorphisms (SNPs) by multiplexed massive parallel sequencing. Profile SNPs were selected which, compared to the reference strain HM-1:IMSS sequence, changed an encoded amino acid at the SNP position, and were present in independent E. histolytica isolates from different geographical origins. The samples used in this study contained DNA isolated from either xenic strains of E. histolytica trophozoites established in culture or E. histolytica positive clinical specimens (stool and amebic liver abscess aspirates). A record of the SNPs present at 16 loci out of the original 21 candidate targets was obtained for 63 of the initial 84 samples (63% of asymptomatically colonized stool samples, 80% of diarrheal stool, 73% of xenic cultures and 84% of amebic liver aspirates). The sequences in all the 63 samples both passed sequence quality control metrics and also had the required greater than 8X sequence coverage for all 16 SNPs in order to confidently identify variants. Our work is in agreement with previous findings of extensive diversity among E. histolytica isolates from the same geographic origin. In phylogenetic trees, only four of the 63 samples were able to group in two sets of two with greater than 50% confidence. Two SNPs in the cylicin-2 gene (EHI_080100/XM_001914351) were associated with disease (asymptomatic/diarrhea p = 0.0162 or dysentery/amebic liver abscess p = 0.0003). This study demonstrated that there are genetic differences between virulent and avirulent E. histolytica strains and that this approach has the potential to define genetic changes that influence infection outcomes.


Physical Demands of Representative Match-Play in Adolescent Rugby Union.
Read, DB, Jones, B, Phibbs, PJ, Roe, GAB, Darrall-Jones, J, Weakley, JJS, and Till, K. Physical demands of representative match-play in adolescent rugby union. J Strength Cond Res 31(5): 1290-1296, 2017-The purpose of this study was to quantify the physical demands of representative adolescent rugby union match-play and investigate the difference between playing positions and age groups. Players (n = 112) were classified into 6 groups by playing position (forwards and backs) and age group (U16, U18, and U20). The physical demands were measured using microsensor-based technology and analyzed using magnitude-based inferences to assess practical importance. Backs had a greater relative distance (except U16s) and a greater high-speed running distance per minute than forwards, with the magnitude of difference between the positions becoming larger in older age groups. Forwards had higher values of PlayerLoad (PL) per minute (accumulated accelerations from the 3 axes of movement) and PL slow per minute (accumulated accelerations from the 3 axes of movement where velocity is <2 m·s) than backs at all age groups. Relative distance, low-, and high-speed running per minute all had a trend to be lower in older age groups for both positions. PlayerLoad per minute was greater in U18 than that in U16 and U20 for both positions. PlayerLoad slow per minute was greater for older age groups besides the U18 and U20 comparisons, which were unclear. The contrasts in physical demands experienced by different positions reinforce the need for greater exposure to sprinting and collision-based activity for backs and forwards, respectively. Given PL metrics peak at U18 and locomotor demands seem to be lower in older ages, the demands of representative adolescent rugby union do not seem to be greater at U20 as expected.


Conceptual understanding of social capital in a First Nations community: a social determinant of oral health in children.
Objectives. The purpose of the study was: (a) to better understand the concept of social capital and its potential role in oral health of children in a First Nations community and (b) to identify the strengths and resources in terms of social capital and a health promotion model that the community has at its disposal to address its oral health issues. Methods. In this qualitative case study, participants were purposively selected in a First Nations community: Seven individual interviews and two focus groups involving 18 parents/care givers were selected. Putnam's concept of social capital guided all the interviews. The interviews were recorded and transcribed verbatim. Thematic analysis was employed using the NVivo software. Results. The community was close-knit and seemed to have strong moral fibre, which encouraged members to help each other. A strong bonding social capital was also found among the members, especially inside the clans (families). A need for improvement in bridging social capital that would help the community to reach external resources was observed. While members of the community were actively involved in religious rituals and cultural ceremonies, more efforts seemed to be required to recruit volunteers for other events or programs. Active engagement of community members in any program requires that members be given a voice as well as some ownership of the process. Mobilizing or building community's social capital can play a role when planning future interventions. Conclusions. A better understanding of social capital may enhance the community's investment and efforts by reinforcing healthy oral behaviours and improving access to external resources. With more dynamic collaboration, it may be possible to create more sustainable community-based oral health promotion programs.


Molecular cartography in acute Chlamydia pneumoniae infections--a non-targeted metabolomics approach.
Infections with Chlamydia pneumoniae cause several respiratory diseases, such as community-acquired pneumonia, bronchitis or sinusitis. Here, we present an integrated non-targeted metabolomics analysis applying ultra-high-resolution mass spectrometry and ultra-performance liquid chromatography mass spectrometry to determine metabolite alterations in C. pneumoniae-infected HEp-2 cells. Most important permutations are elaborated using uni- and multivariate statistical analysis, logD retention time regression and mass defect-based network analysis. Classes of metabolites showing high variations upon infection are lipids, carbohydrates and amino acids. Moreover, we observed several non-annotated compounds as predominantly abundant after infection, which are promising biomarker candidates for drug-target and diagnostic research.


ELECTROCONVULSIVE SHOCK, RETROACTIVE AMNESIA, AND THE SINGLE-SHOCK METHOD.
If electroconvulsive shock is given immediately after a learning session, retroactive amnesia for that response occurs. Such results may be due to production of aversive responses or to interference with consolidation of the neural engram, or to both. Aversive responses or competing responses are not adequate explanations for retroactive amnesia. Consolidation theory provides the most plausible explanation. The single-shock method is an appropriate approach for studying the relationships between electroconvulsive shock and retroactive amnesia.


Pregnancy and risk of renal cell cancer: a population-based study in Sweden.
Epidemiological findings indicate that hormonal influences may play a role in the etiology of renal cell cancer (RCC). The possible effect of childbearing remains enigmatic; while some investigators have reported a positive association between number of births and renal cell cancer risk, others have not. A case-control study, nested within a nation-wide Fertility Register covering Swedish women born 1925 and later, was undertaken to explore possible associations between parity and age at first birth and the risk of renal cell cancer. Among these women a total of 1465 cases of RCC were identified in the Swedish Cancer Register between 1958 and 1992 and information on the number of live childbirths and age at each birth was obtained by linkage to the Fertility Database. For each case, five age-matched controls were randomly selected from the same register. Compared to nulliparous women, ever-parous women were at a 40% increased risk of RCC (Odds Ratio [OR]=1.42; 95% CI 1.19-1.69). The corresponding OR for women of high parity (five or more live births) was 1.91 (95% CI 1.40-2.62). After controlling for age at first birth among parous women, each additional birth was associated with a 15% increase in risk (OR=1.15; 95% CI 1.08-1.22). The observed positive association between parity and renal cell cancer risk is unlikely to be fully explained by uncontrolled confounding, but warrants further evaluation in large studies, with allowance for body mass index.


[A simple technic of true pyroloclasia: crushing with a rubber-sheathed clamp].
For more than 10 years the authors have been using a pyloroclasia derived from the Hivet and Lagadec technique of digital dilatation, in place of gastric drainage pyloroplasty. The procedure is simple, effective and easily reproducible. It only requires a rubber sheathed clamp to crush the anterior part of the pyloric annulus; the pyloroclasia is then confirmed by digital exploration. This technique has been used regularly without any per-operative problem and post-operative complications ascribable to pyloroclasia. The long-term results have been satisfactory with complete absence of gastric stasis or biliary reflux. When performed, post-operative radiography and fibroscopy have shown adequate gastric emptying and little changes in pyloric morphology. Pyloroclasia is simpler and less septic than pyloroplasty, and it reduces the incidence of dumping syndrome. Pyloroclasia with a rubber sheathed clamp is simpler and more reproducible than digital pyloroclasia. In view of its regularly good results it can certainly be recommended.


4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes modified for extended conjugation and restricted bond rotations.
Five new, constrained, aryl-substituted 4,4-difluoro-4-bora-3a, 4a-diaza-s-indacene (BODIPY) dyes (3f,g and 4h-j) were prepared and investigated to see if they have more favorable fluorescence characteristics than the unconstrained systems 2 that were prepared in previous studies. Dye types 3 and 4 have relatively rigid conformations caused by the heteroatom (3f and 3g) or ethylene bridge (4h-j) linkers that preclude free rotation of the substituted-benzene molecular fragments. In the event, the new dye types 3 and 4 have longer lambda(max abs) (620-660 nm) and lambda(max)(fluor) (630-680 nm) values than compounds 2. They also exhibit higher extinction coefficients (>100 000 M(-1) cm(-1), except for 3g). Their fluorescent quantum yields are high (up to 0.72 for 4j), with the exception of compound 3g, which has a quantum yield of only 0.05. The redox properties of dyes 3 and 4 have also been examined.


Central Pancreatectomy with Pancreaticojejunostomy for an Insulinoma: A Case Report with Literature Review.
Background: Insulinomas are a rare entity commonly treated by resection. Central pancreatectomy represents an uncommon type of resection for pancreatic lesions. Case Presentation: A 77-year-old female underwent a central pancreatectomy with Roux-en-Y pancreaticojejunostomy and pancreatic stump oversew after presenting with symptoms of hypoglycemia concerning for an insulinoma. Her hospital course was uncomplicated and her symptoms resolved after resection. Conclusion: Resection of insulinomas is the preferred approach of treatment, and resection by central pancreatectomy is a safe option for benign lesions in the neck of the pancreas.


Polarized sorting in epithelial cells: raft clustering and the biogenesis of the apical membrane.
Polarized cells establish and maintain functionally distinct surface domains by an elaborate sorting process, which ensures accurate delivery of biosynthetic cargo to different parts of the plasma membrane. This is particularly evident in polarized epithelial cells, which have been used as a model system for studies of sorting mechanisms. The clustering of lipid rafts through the oligomerization of raft components could be utilized for segregating apical from basolateral cargo and for the generation of intracellular transport carriers. Besides functioning in polarized sorting in differentiated cells, raft clustering might also play an important role in the biogenesis of apical membrane domains during development.


Autosomal dominant mutation causing the dorsal ridge predisposes for dermoid sinus in Rhodesian ridgeback dogs.
To define the mode of inheritance of the dorsal ridge and investigate if the ridge predisposes to the congenital abnormality dermoid sinus in the Rhodesian ridgeback. Segregation analysis was performed, including 87 litters (n=803) produced in Sweden between 1981 and 2002. Data were corrected to avoid bias in the segregation ratio. Chi-squared analysis was performed including 402 litters (n=3598) for the evaluation of a possible genetic correlation between the ridge and dermoid sinus. The ridge is inherited in an autosomal dominant mode and predisposes for dermoid sinus. The frequency of ridgeless offspring in the Swedish Rhodesian ridgeback population is estimated to be 5.6 per cent. Rhodesian ridgeback dogs that carry the ridge trait are predisposed to dermoid sinus.


Association between DNA repair-deficiency and high level of p53 mutations in melanoma of Xeroderma pigmentosum.
Xeroderma pigmentosum (XP) is an inheritable disease characterized by sun-sensitivity and a high frequency of skin cancers including melanoma. We have analyzed two different groups of XP: the XP complementation group C (XP-C), deficient in global nucleotide excision repair but proficient in transcription-coupled repair and associated with a very early onset of skin cancers; and the XP variant (XPV), deficient in the bypass of DNA photoproducts. To get new insights into the biology of melanoma in XP patients, we studied 20 melanomas from four XP-C and two XPV patients in terms of pathology, immunohistochemistry of p53, mutations in exons 4-9 of the p53 gene, and polymorphisms of the p53 gene at codon 72. All statistical tests were two-sided. The majority of the XP melanomas were of the lentigo maligna melanoma (LMM) type, as found in the elderly. p53 point mutations were found in 60% of XP-C melanomas and in only 10% of XPV melanomas, this latter frequency being similar to what has been reported in the general population. Mutations show the specific UV-signature because the majority were CC to tandem and C to T transitions located at the bipyrimidine sites known to be hotspots of UV-induced DNA lesions. All DNA lesions giving rise to mutations in XP-C melanomas were located on the nontranscribed strand of the p53 gene, demonstrating that these patients' cells were able to carry out preferential repair in vivo. The LMMs found in XP-C are associated with an accumulation of unrepaired DNA lesions and may represent a good model for the LMM induction in the elderly.


The role of particle composition on the association between PM2.5 and mortality.
Although the association between exposure to particulate matter (PM) mass and mortality is well established, there remains uncertainty about which chemical components of PM are most harmful to human health. A hierarchical approach was used to determine how the association between daily PM2.5 mass and mortality was modified by PM2.5 composition in 25 US communities. First, the association between daily PM2.5 and mortality was determined for each community and season using Poisson regression. Second, we used meta-regression to examine how the pooled association was modified by community and season-specific particle composition. There was a 0.74% (95% confidence interval = 0.41%-1.07%) increase in nonaccidental deaths associated with a 10 microg/m3 increase in 2-day averaged PM2.5 mass concentration. This association was smaller in the west (0.51% [0.10%-0.92%]) than in the east (0.92% [0.23%-1.36%]), and was highest in spring (1.88% [0.23%-1.36%]). It was increased when PM2.5 mass contained a higher proportion of aluminum (interquartile range = 0.58%), arsenic (0.55%), sulfate (0.51%), silicon (0.41%), and nickel (0.37%). The combination of aluminum, sulfate, and nickel also modified the effect. These species proportions explained residual variability between the community-specific PM2.5 mass effect estimates. This study shows that certain chemical species modify the association between PM2.5 and mortality and illustrates that mass alone is not a sufficient metric when evaluating health effects of PM exposure.


Trophoblastic growths: morphologic aspects and taxonomy.
The hydatidiform mole-gestational choriocarcinoma complex constitutes a graft qua tumor whose natural invasion, rejection and resolution share features of normal pregnancy and of neoplasms of other tissues. Trophoblastic neoplasms sometimes arise from morphogenetically abnormal chorions, notably the "partial mole," among others. Thus, they provide another demonstration of the association of teratogenic and carcinogenic events. Gestational choriocarcinoma is a complication of pregnancy, not a sequel to it. Although these tumors may arise from the trophoblast of any pregnancy, presenting symptoms during gestation or following it, they are much rarer than the innocuous conditions, normal and abnormal, with which they may be confused. A bone fide malignant neoplasm is less likely to be misdiagnosed as a banal phenomenon than is the reverse. Morphologically, the trophoblast is the key, and emphasis should be placed on its behavior. Taxonomy should follow suit, employing the simple, explicit terms chorioma and choriocarcinoma, graded to express the neoplastic attributes of the constituent epithelium.


Factors controlling the size of graphene oxide sheets produced via the graphite oxide route.
We have studied the effect of the oxidation path and the mechanical energy input on the size of graphene oxide sheets derived from graphite oxide. The cross-planar oxidation of graphite from the (0002) plane results in periodic cracking of the uppermost graphene oxide layer, limiting its lateral dimension to less than 30 μm. We use an energy balance between the elastic strain energy associated with the undulation of graphene oxide sheets at the hydroxyl and epoxy sites, the crack formation energy, and the interaction energy between graphene layers to determine the cell size of the cracks. As the effective crack propagation rate in the cross-planar direction is an order of magnitude smaller than the edge-to-center oxidation rate, graphene oxide single sheets larger than those defined by the periodic cracking cell size are produced depending on the aspect ratio of the graphite particles. We also demonstrate that external energy input from hydrodynamic drag created by fluid motion or sonication, further reduces the size of the graphene oxide sheets through tensile stress buildup in the sheets.


Aging or disease? Cardiovascular reactivity in Finnish men over the middle years.
Cardiovascular responses to psychological events may mediate the influence of stress on cardiovascular disease. In this study the authors asked whether cardiovascular responses to psychological challenge changed with age and whether such changes were intrinsic to aging or could be attributed to the influence of disease and medications. Cardiovascular reactivity to mental challenge was examined in 902 men ranging in age from 46 to 64 years who participated in the Kuopio Ischemic Heart Disease Risk Factor Study. A battery of 4 tasks was used to induce cardiovascular responses. Current disease status, age, and medication use were entered into hierarchical regression analyses to assess their relation with measures of cardiovascular reactivity. Age and hypertension contributed independent, approximately equal, but small amounts of variance in the cardiac and vascular reactivity indexes. Medications also influenced reactivity independently of age and disease. Performance on the tasks was more consistently altered by age than by disease or medication. Cardiac and vascular reactivity increased with increasing age and the presence of hypertension. The authors conclude that both age and disease state must be considered when examining cardiovascular reactivity as a risk factor for disease.


Non-Hodgkin's lymphoma and membranous nephropathy in mixed connective tissue disease.
A 60-year-old woman with a diagnosis of poorly differentiated lymphocytic lymphoma presented with nephrotic syndrome. Her clinical picture and serological studies were consistent with the diagnosis of mixed connective tissue disease (MCTD). Renal biopsy demonstrated the changes of membranous nephropathy by light, immunofluorescence and electron microscopy. Treatment with corticosteroids and cyclophosphamide had no effect on the proteinuria, and she demonstrated progression of renal failure. This patient demonstrates that the lymphadenopathy associated with MCTD may be of a separate malignant origin. The treatment of MCTD may not alter the course of renal disease, and renal failure may ensue in patients with MCTD.


Cardiac resynchronization therapy: double cannulation approach to coronary venous lead placement via a prominent thebesian valve.
We report identification of a prominent Thebesian valve by cardiovascular computed tomography (CT) angiography impeding cannulation of the coronary sinus, with subsequent successful coronary venous lead placement with cannulation of the coronary sinus ostium via a transvenous femoral vein approach and subsequent cannulation of the ostium with the coronary venous lead with a left subclavian approach. A 57-year-old man with nonischemic dilated cardiomyopathy, New York Heart Association Class III heart failure, left bundle branch block, and an ejection fraction of 15%, underwent an attempted cardiac resynchronization therapy implantable cardiac defibrillator (ICD). As the coronary sinus ostium could not be cannulated, a dual chamber ICD was placed. The patient subsequently underwent cardiovascular CT angiography, which identified a prominent Thebesian valve at the coronary sinus ostium as the anatomic obstacle to cannulation. Reattempted transvenous cardiac resynchronization therapy was accomplished successfully with a double cannulation approach: cannulation of the coronary sinus ostium with a catheter via a transvenous femoral vein approach and subsequent cannulation with the coronary venous lead via a left subclavian approach. When a prominent Thebesian valve is identified as an obstacle to transvenous left ventricular lead placement, cannulation of the coronary sinus by an alternate venous approach may allow for a coronary venous route rather than necessitate an epicardial approach.


Should Bilateral Internal Thoracic Artery Grafting Be Used in Patients After Recent Myocardial Infarction?
Bilateral internal thoracic artery grafting (BITA) is associated with improved survival. However, surgeons do not commonly use BITA in patients after myocardial infarction (MI) because survival is good with single internal thoracic artery grafting (SITA). We aimed to compare the outcomes of BITA with those of SITA and other approaches in patients with multivessel disease after recent MI. In total, 938 patients with recent MI (<3 months) who underwent BITA between 1996 and 2011 were compared with 682 who underwent SITA. SITA patients were older and more likely to have comorbidities (diabetes mellitus, chronic obstructive pulmonary disease, chronic renal failure, peripheral vascular disease), to be female, and to have had a previous MI. Acute MI and 3-vessel disease were more prevalent in the BITA group. Operative mortality of BITA patients was lower (3.0% versus 5.8%, P=0.01), and sternal infections and strokes were similar. Median follow-up was 15.21 years (range: 0-21.25 years). Survival of BITA patients was better (70.3% versus 52.5%, P<0.001). Propensity score matching was used to account for differences in preoperative characteristics between groups. Overall, 551 matched pairs had similar preoperative characteristics. BITA was a predictor of better survival in the matched groups (hazard ratio: 0.679; P=0.002; Cox model). Adjusted survival of emergency BITA and SITA patients was similar (hazard ratio: 0.883; P=0.447); however, in the nonemergency group, BITA was a predictor of better survival (hazard ratio: 0.790; P=0.009; Cox model). This study suggests that survival is better with BITA compared with SITA in nonemergency cases after recent MI, with proper patient selection.


Imaging of disease dynamics during meningococcal sepsis.
Neisseria meningitidis is a human pathogen that causes septicemia and meningitis with high mortality. The disease progression is rapid and much remains unknown about the disease process. The understanding of disease development is crucial for development of novel therapeutic strategies and vaccines against meningococcal disease. The use of bioluminescent imaging combined with a mouse disease model allowed us to investigate the progression of meningococcal sepsis over time. Injection of bacteria in blood demonstrated waves of bacterial clearance and growth, which selected for Opa-expressing bacteria, indicating the importance of this bacterial protein. Further, N. meningitidis accumulated in the thyroid gland, while thyroid hormone T4 levels decreased. Bacteria reached the mucosal surfaces of the upper respiratory tract, which required expression of the meningococcal PilC1 adhesin. Surprisingly, PilC1 was dispensable for meningococcal growth in blood and for crossing of the blood-brain barrier, indicating that the major role of PilC1 is to interact with mucosal surfaces. This in vivo study reveals disease dynamics and organ targeting during meningococcal disease and presents a potent tool for further investigations of meningococcal pathogenesis and vaccines in vivo. This might lead to development of new strategies to improve the outcome of meningococcal disease in human patients.


[THE EFFECTIVENESS OF THE MODERN IMMUNOACTIVE PREPARATION IMMUNOFAN FOR MEDICAL REHABILITATION OF PATIENTS WITH NONALCOHOLIC STEATOHEPATITISIS AGAINST NEUROCIRCULATORY DYSTONIA, AFTER INFECTIOUS MONONUCLEOSIS].
The presence of the expressed changes of cellular immunity, namely T-lymphopenia, disbalance of subpopulation structure of T-lymphocytes with primary downstroke T-helpers/inductor (CD4+), decrease immunoregulatory index CD4/CD8, and functional activity of T-cells is characteristic for the patients with nonalcoholic steatohepatitis, against neurocirculatory dystonia, after infectious mononucleosis. Including in a medical rehabilitation of such patients immunofan promoted practically full correction of the revealed infringements on the part of a cellular link of immunity.


Celastrol ameliorates acetaminophen-induced oxidative stress and cytotoxicity in HepG2 cells.
Acetaminophen (APAP) is the most commonly used analgesic and antipyretic drug in the world. However, hepatotoxicity caused by APAP overdose is the most frequent cause of acute liver failure worldwide and oxidative stress involved in the pathogenesis of APAP hepatotoxicity. Celastrol is a natural triterpenoid derived from Tripterygium wilfordii Hook F. that exhibits antioxidant, anti-inflammatory, and antitumor activities. In this study, we aimed to investigate the potential ameliorative effects of celastrol against APAP-induced cytotoxicity and oxidative stress. Human hepatocellular carcinoma cells (HepG2) were incubated with 20 mM of APAP for 24 h and posttreated with 50 nM, 100 nM, or 200 nM of celastrol for a further 24 h. The methylthiazolyldiphenyl-tetrazolium bromide, lactate dehydrogenase, and neutral red uptake assays showed celastrol posttreatments recovered cell viability and cell membrane integrity in a concentration-dependent manner. Celastrol posttreatments exerted a significant increase in the glutathione content and a decrease in the malondialdehyde and protein carbonylation levels. Also, celastrol posttreatments attenuated the APAP-induced oxidative stress by raising glutathione peroxidase, glutathione reductase, and catalase activities. However, superoxide dismutase activity did not change. In conclusion, celastrol treatment may improve cell viability and increase cellular antioxidant defense in HepG2 cells. These results suggest that celastrol may have the potential to ameliorate the APAP-induced oxidative stress and cytotoxicity.


Quantitative assessment of gustatory function in a clinical context using impregnated "taste strips".
Assessment of gustatory sensitivity in a clinical setting is the prerequisite for correct diagnosis and adequate treatment of taste dysfunction. Despite of this, no taste test has been established for the routine clinical testing. The aim of the present study was to create a protocol which is easy to administer. The presently used technique is based on strips made from filter paper which were impregnated with different taste solutions (four concentrations each for sweet, sour, salty and bitter). These strips are placed on the tongue and subjects are asked to identify the taste quality. After establishing the concentration range of the taste solutions, the test was tried in 69 subjects. Each subject received eighteen taste strips (four concentrations of each taste quality plus two blanks) in a pseudo-randomized sequence. Results from this new procedure correlated significantly with the results of the well established extensive three-drop-technique (r69 = 0.67). Repeated measures indicated good reproducibility of the results for the taste strips (r69 = 0.68). These data suggest the usefulness of this new technique in routine clinical practice. Major advantages are long shelf-life, convenience of administration, short time needed for testing (approximately 8 min), and the possibility to test each side of the tongue separately.


Remodeling of the lung in bleomycin-induced pulmonary fibrosis in the rat. An immunohistochemical study of laminin, type IV collagen, and fibronectin.
Intratracheal injection of bleomycin in rats results in the development of patchy pulmonary fibrosis. We investigated events associated with remodeling of lung structure by light and electron microscopic immunolocalization of fibronectin, laminin, and type IV collagen. Animals were studied from 2 to 60 days after injection of bleomycin. In the acute phase of injury, staining of fibronectin was prominent in fibrinous exudates, whereas during healing it was mainly associated with the surface of fibroblasts. The early accumulation of fibronectin in alveolar exudates is probably the result of leakage of plasma. During the reparative phase, fibronectin may be synthesized locally since it is selectively associated with the fibroblast surface. Staining with antibodies to type IV collagen and laminin identified the basal lamina and also helped to define the tissue boundaries despite the presence of intense exudation. It highlighted two processes in the acutely injured lung that lead to abnormal lung architecture: collapse of alveoli and invasion of air spaces by fibroblasts. In some healed lesions at 20 and 60 days, the immunostaining still outlined atelectatic lung. Electron microscopy of these lesions showed collagenous synechiae between approximated alveolar walls. We suggest that alveolar collapse and intraalveolar fibrosis in areas of collapse play an important role in bleomycin-induced pulmonary fibrosis and probably other types of fibrosis. They readily explain the loss of lung volume and compliance characteristic of fibrotic lung.


Silica dust and lung cancer: results from the Nordic occupational mortality and cancer incidence registers.
Autopsy studies of the relationship between silicosis and lung cancer have been mainly negative; but recent epidemiologic studies have indicated a positive association, and an excess lung cancer risk has been observed in some occupational groups with exposure to silica dust. For the further shedding of light on the possible association between silica dust and lung cancer, analysis was made on mortality and cancer incidence data available in census-based record linkage studies from the Nordic countries for males in occupational groups with potential exposure to silica dust. The study showed an excess lung cancer risk for foundry workers in all the Nordic countries and for miners in Sweden. These results were consistent with findings from previous in-depth epidemiologic studies. The lung cancer risk did not differ significantly from that of the respective national populations for males working in excavation; stone quarries; sand and gravel pits; and glass, porcelain, ceramic, and tile manufacture. Stonecutters, who are probably not exposed to known lung carcinogens at the workplace but in some places to high concentrations of silica dust, showed a significant excess lung cancer risk in both Finland and Denmark. Excess lung cancer risks furthermore were seen for Finish miners, for Finnish males in excavation work, and for Danish glassworkers.


Ubiquitous Neocortical Decoding of Tactile Input Patterns.
Whereas functional localization historically has been a key concept in neuroscience, direct neuronal recordings show that input of a particular modality can be recorded well outside its primary receiving areas in the neocortex. Here, we wanted to explore if such spatially unbounded inputs potentially contain any information about the quality of the input received. We utilized a recently introduced approach to study the neuronal decoding capacity at a high resolution by delivering a set of electrical, highly reproducible spatiotemporal tactile afferent activation patterns to the skin of the contralateral second digit of the forepaw of the anesthetized rat. Surprisingly, we found that neurons in all areas recorded from, across all cortical depths tested, could decode the tactile input patterns, including neurons of the primary visual cortex. Within both somatosensory and visual cortical areas, the combined decoding accuracy of a population of neurons was higher than for the best performing single neuron within the respective area. Such cooperative decoding indicates that not only did individual neurons decode the input, they also did so by generating responses with different temporal profiles compared to other neurons, which suggests that each neuron could have unique contributions to the tactile information processing. These findings suggest that tactile processing in principle could be globally distributed in the neocortex, possibly for comparison with internal expectations and disambiguation processes relying on other modalities.


Temporal Trends and Outcomes of Left Ventricular Aneurysm After Acute Myocardial Infarction.
There are limited data on the prevalence and an outcome of left ventricular (LV) aneurysms following acute myocardial infarction (AMI). Using the National Inpatient Sample during 2000 to 2017, a retrospective cohort of AMI admissions was evaluated for LV aneurysms. Complications included ventricular arrhythmias, mechanical, cardiac arrest, pump failure, LV thrombus, and stroke. Outcomes of interest included in-hospital mortality, temporal trends, complications, hospitalization costs, and length of stay. A total 11,622,528 AMI admissions, with 17,626 (0.2%) having LV aneurysms were included. The LV aneurysm cohort was more often female, with higher comorbidity, and admitted to large urban hospitals (all p < 0.001). In 2017, compared with 2000, there was a slight increase in LV aneurysms prevalence in those with (adjusted odds ratio [aOR] 1.57 [95% confidence interval {CI} 1.41 to 1.76]) and without (aOR 1.13 [95% CI 1.00 to .127]) ST-segment-elevation AMI (p < 0.001 for trend). LV aneurysms were more commonly noted with anterior ST-segment-elevation AMI (31%) compared with inferior (12.3%) and other (7.9%). Ventricular arrhythmias (17.6% vs 8.0%), mechanical complications (2.6% vs 0.2%), cardiac arrest (7.1% vs 5.0%), pump failure (26.3% vs 16.1%), cardiogenic shock (10.0% vs 4.8%) were more common in the LV aneurysm cohort (all p < 0.001). Those with LV aneurysms had comparable in-hospital mortality compared with those without (7.4% vs 6.2%; aOR 1.02 [95% CI 0.90 to 1.14]; p = 0.43). The LV aneurysm cohort had longer length of hospital stay, higher hospitalization costs, and fewer discharges to home. In conclusion, LV aneurysms were associated with higher morbidity, more frequent complications, and greater in-hospital resource utilization, without any differences in in-hospital mortality in AMI.


C2 crossing laminar screws: cadaveric morphometric analysis.
C2 screw fixation through the pars or pedicle involves a small but finite risk of vertebral artery injury. Recently, C2 crossing laminar screws were described as a method for rigid fixation of the axis. This technique, confined to the dorsal aspect of C2, presents minimal chance of injury to the neighboring neural or vascular structures. Morphometric analysis was performed on 38 cadaveric spines obtained from the Keck School of Medicine at the University of Southern California. Critical measurements were determined for screw entry points, trajectories, and lengths for application of the technique, as described by Wright, using 3.5 and 4.0 mm screws. The average maximal screw length was 32 mm with a range of 27 to 37 mm. The minimal total laminar cross sectional area averaged 75 mm2, and the cancellous bone cross sectional area averaged 39 mm2. The minimal laminar cross sectional diameter was determined to be too small to accommodate a 3.5-mm diameter screw, assuming a 1 mm tolerance on each side, in 16 sides of 14 specimens, and to be too small to accommodate a 4.0 mm diameter screw, assuming a 1 millimeter tolerance, in 32 sides of 18 specimens. C2 laminar screw placement is straightforward and carries little risk of injury to the neural and vascular structures as long as the implants remain intraosseous. However, the highly variable thickness of the C2 lamina necessitates preoperative computed tomographic scanning to ensure that the patient's anatomy can accommodate screws entirely within the bone.


Understandings, Attitudes, and Barriers About Diabetes Care: Analysis of Factors Influencing Community Pharmacists in China.
Diabetes mellitus (DM) has been known as a major chronic health problem in China. Suboptimal management of diabetic patients may incur serious complications, even death. The quality of post-hospital care has a good relationship with community pharmacists. However, data describing the current situation from care between community pharmacists and patients in China are lacking. Our article is to investigate community pharmacists' activities, evaluate their attitudes towards providing diabetes care, assess their understandings, and identify perceived barriers. A survey divided into four parts was carried out randomly in China. The part of basic characteristics, understandings, and pharmacists' perceived barriers was rated with a few listed choices scales, while the Likert scale was used to identify on the part of attitudes. Quantitative data were shown in frequency and valid percent. One-way analysis of variance (ANOVA) and non-parametric test conducted on data. A P-value ≤0.05 was considered statistically significant. A total of 737 surveys were collected. The respondent pharmacists maintained a simply moderate understanding of diabetes care and the pharmaceutical services provided met basic needs rather than clinical ones, though they showed a good momentum towards providing better service. The respondent pharmacists considered patients lacking knowledge on self-management, shortage of funds as the main barriers. Efforts are supposed to make to expand pharmacists' scope of practice, lessen patients' reluctance, and create platforms for pharmacists receiving further education.


Mucormycosis in hematologic malignancies: an emerging fungal infection.
In recent years pulmonary mucormycosis has been reported in patients with leukemia and lymphoma and bone marrow transplant recipients. It carries an extremely poor prognosis. We report our experience of clinical findings, diagnostic procedures, treatment and outcome of mucormycosis diagnosed in neutropenic patients affected by hematologic neoplasms admitted to our Department. From November 1987 to July 1999 we observed 13 cases of Mucor. Their median age was 61 years (range 20-75), and they were predominantly in the aplastic post-chemotherapy period (12/13), affected by acute myeloid leukemia (11 cases ) or non-Hodgkin's lymphoma (2 cases). Six patients (all with leukemia) were receiving inductionEth consolidation therapy, 7 had progressive hematologic disease. At the onset of infection all patients were neutropenic (N < 0.5x10(9)/L). No patients had diabetes mellitus. Two patients had been receiving steroid therapy for 5 and 7 days. The lung was involved in all cases (13/13); disseminated disease was present in 8/13 patients. All cultures (blood, sputum, nasal swabs and bronchoalveolar lavage) were negative. In 3 patients a histologic diagnosis was made in vivo: in 1 patient by percutaneous pulmonary biopsy, in 1 patient by pulmonary lobectomy, and in the last patient by percutaneous pulmonary biopsy confirmed by excision of a cerebellar abscess. In the remaining 10 cases diagnosis was made post-mortem. Five patients were not treated, 2 because of poor clinical condition and 3 because fungal infection was not suspected. Amphotericin B (1 mg/kg/day) was given empirically to 6 patients and 2 responded to treatment. The remaining 2 patients with neurologic symptoms at the onset of infection were treated with liposomal amphotericin, Ambisome, one with 3 and one with 5 mg/kg/day; of these two patients the first died in 4 days; the second, with both pulmonary and cerebellar localizations, was treated successfully with 5 mg/kg/day for 4 weeks and then with 3 mg/kg/day, and excision of a brain abscess at neutrophil recovery (total dose of Ambisome: 12,000 mg). The 3 surviving leukemic patients were able to complete subsequent consolidation therapy using amphotericin B or liposomal amphotericin as secondary prophylaxis during aplasia. In neutropenic hematologic patients Mucor is rarely suspected. In our patients infection was often characterized by disseminated disease and a rapidly fatal course; only early aggressive amphotericin B (or Ambisome) treatment together with neutrophil recovery appeared to improve the outcome. Diagnosis is very important for programming antifungal therapy and secondary prophylaxis with amphotericin B, because Mucor is usually resistant to itraconazole.


Early Career Experience of Pediatric Orthopaedic Fellows: What to Expect and Need for Their Services.
A dramatic increase in the number of pediatric orthopaedic fellows being trained has led to concerns that there may be an oversupply of pediatric orthopaedists. The purpose of this study was to determine whether this perception is accurate and whether the practice expectations of recent pediatric fellowship graduates are being met by surveying recent pediatric fellowship graduates about their early practice experiences. A 36-question survey approved by the Pediatric Orthopaedic Society of North America (POSNA) leadership was electronically distributed to 120 recent graduates of pediatric orthopaedic fellowships; 81 responses were ultimately obtained (67.5% response rate). Almost all (91%) of the respondents were very or extremely satisfied with their fellowship experience. Half of the respondents had at least 1 job offer before they entered their fellowships. After completion of fellowships, 35% received 1 job offer and 62.5% received ≥2 job offers; only 2.5% did not receive a job offer. Most reported a practice consisting almost entirely of pediatric orthopaedics, and 93.5% thought this was in line with their expectations; 87% indicated satisfaction with their current volume of pediatric orthopaedics, and 85% with the complexity of their pediatric orthopaedic cases. Despite the high employment percentages and satisfaction with practice profiles, nearly a third (28%) of respondents replied that too many pediatric orthopaedists are being trained. Positive messages from this survey include the satisfaction of graduates with their fellowship training, the high percentage of graduates who readily found employment, and the satisfaction of graduates with their current practice environments; this indicates that the pediatric orthopaedic job environment is not completely saturated and there are continued opportunities for graduating pediatric fellows despite the increased number of fellows being trained. Although not determined by this study, it may be that the stable demand for pediatric orthopaedic services is being driven by the expansion of the scope of practice as well as subspecialization within the practice of pediatric orthopaedics.


Characterization of antichemotactic factor extracted from the gastric mucosa of rats.
The gastric mucosa of normal rats exhibits no detectable inflammation or visible damage. We examined the effect of the gastric mucosal extract of rats on neutrophil chemotaxis and tried to purify antichemotactic factor. The chemotaxis of neutrophils was examined by the modified Boyden's method. After mucosal layer was scraped and then homogenized and centrifuged at 20,000 x g for 30 min, the supernatant was used as rat gastric mucosal extract (RGME). Prior exposure of neutrophils to the gastric mucosal extract caused a dose-dependent reduction in the neutrophil migration induced by formyl-methionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4) and interleukin 8 (IL-8) without affecting the cell viability. The antichemotactic factor was partially purified by lectin affinity chromatography on wheat germ lectin (WGL)-Sepharose, anion exchange chromatography on Mono-Q and gel filtration on Superose 12. The molecular weight of the antichemotactic factor was estimated to be around 60 k by gel filtration. The activity was markedly abolished by boiling for 5 min, heating at 60 degrees C for 30 min, and treatment with 1% acetic acid, 0.1 M Na2CO3 or trypsin. Furthermore, the FMLP-induced migration of neutrophils pretreated with the antichemotactic factor for 5 min followed by washing with fresh medium was inhibited, although the factor was not added to the chamber. These results suggest that the gastric mucosa of rats intrinsically generates an antichemotactic factor which might play a crucial role in maintenance of the integrity of the gastric mucosa.


Protein-arginine deiminase 2 suppresses proliferation of colon cancer cells through protein citrullination.
Expression of the gene for protein-arginine deiminase 2 (PADI2) has been shown to be downregulated in colon cancer, with such downregulation being indicative of a poor prognosis in individuals with this disease. We have now examined the expression of PADI2 in matched colon cancer and normal colon tissue specimens as well as in colon cancer cell lines. We found that isoform 1 of PADI2 is the predominant isoform in colon tissue and is downregulated during colon carcinogenesis. Immunohistochemical analysis showed that PADI2 is expressed in normal colonic epithelial cells. Overexpression of PADI2 isoform 1 suppressed the proliferation of colon cancer cells in vitro in association with increased protein citrullination. Expression of a catalytically inactive mutant (C647A) of PADI2 or of PADI2 isoform 2 did not induce such effects, indicating that the protein citrullination activity of PADI2 is required for inhibition of cell growth. The growth defect induced by PADI2 was not attributable to increased apoptosis but rather was accompanied by arrest of cell cycle progression in G1 phase. Finally, we detected citrullinated proteins in normal colon tissue by immunoblot analysis. Our data thus suggest that PADI2 suppresses the proliferation of colonic epithelial cells through catalysis of protein citrullination, and that downregulation of PADI2 expression might therefore contribute to colon carcinogenesis.


[The role of oncogenic human papillomaviruses in tonsillar squamous cell carcinomas with functional inactivation of the retinoblastoma protein].
In order to identify squamous cell carcinomas of the head and neck (HNSCC) with common biological and clinical features, we investigated the incidence and properties of carcinomas lacking retinoblastoma protein (pR6) cell cycle control. Of 208 HNSCC investigated, 23 (11%) showed a lack of pRb expression. The majority of these tumors (65%) were tonsillar carcinomas. The pRb-negative tonsillar tumors were all stage IV, had metastasized to lymph nodes at the time of diagnosis and were in general poorly differentiated or undifferentiated. Very significantly, the pRb-negative phenotype was strongly associated with the presence of oncogenic human papilloma viruses, implying a viral etiology and functional inactivation of pRb by the viral E7 oncoprotein. Despite the very adverse histopathological factors, patients with pRb-negative tonsillar carcinomas had a better clinical outcome, which was consistent with a uniform favorable responsiveness of these tumors to postoperative radiation therapy.


The effect of glutamine and synbiotics on the healing of colonic anastomosis.
Intestinal wound healing is an essential process for surgical reconstruction of the digestive tract. The purpose of this study is to evaluate the effect of perioperative administration of glutamine and synbiotics on the biological behavior of intestinal mucosal barrier and the healing of colonic anastomosis in rats. 80 Wistar rats were divided in five groups. A: Control. B: Mechanical bowel preparation and antibiotics.C: Glutamine. D: Synbiotics. E: Glutamine and synbiotics. The animals were sacrificed on 3rd and 7th postoperative day. Zero mortality and no septic complications were noted. On 3rd postoperative days, a significant weight loss was observed in all groups in comparison with the preoperative weights, but on the 7th day in groups C and E, in contrast with the other groups, weight loss was not significant. On the 3rd postoperative day, neoangiogenesis, inflammatory infiltration and fibroblast activity were significantly enhanced in group E compared to control. On the 7th postoperative day in group E fibroblast activity was significantly enhanced and inflammatory infiltration was significantly limited compared to control. The bursting pressures as well as the hydroxyproline tissue content were significantly higher in the group E on 3rd and 7th postoperative days. The percentage of positive mesenteric lymph node cultures were significantly limited in group E compared to control. The administration of synbiotics in conjunction with glutamine resulted in increasing the mechanical strength of the anastomosis, thus increasing the bursting pressure and decreasing or effacing of anastomotic dehiscence and limiting bacterial translocation.


Association between FAMACHA scores and fecal egg counts in Katahdin lambs.
The FAMACHA system was introduced to the U.S. just over 10 yr ago to allow selective deworming of lambs with anemia associated with and retard the development of anthelmintic resistance. The FAMACHA system was initially developed as a predictor of packed cell volume (PCV), but correlations between FAMACHA and fecal egg counts (FEC) have also been reported. It is important to understand factors that influence FAMACHA scores among farms to improve management of gastrointestinal nematodes. The objectives of this study were therefore to quantify associations between FAMACHA scores, FEC, BW, and age in Katahdin lambs at 2 different measurement times in 8 flocks in the eastern U.S., and to assess consistency of relationships between FAMACHA and FEC among flocks. Data came from 1,644 Katahdin lambs from 7 flocks sampled at approximately 90 d of age, and 1,295 lambs from 6 flocks sampled at approximately 120 d of age over a 5 yr period. Residual correlations among log-transformed FEC (LFEC), FAMACHA scores, BW, and lamb ages at each measurement time were determined. Repeatability of each variable was also determined as residual correlations among repeated measures. At both 90 and 120 d of age, correlations of FAMACHA scores with LFEC and BW were significant ( < 0.001), but numerically modest (0.25 and -0.16, respectively at 90 d; 0.31 and -0.16, respectively at 120 d), demonstrating that higher FAMACHA scores were associated with higher FEC and more likely to be observed in lighter lambs. A small negative correlation was observed between FAMACHA score and lamb age ( = -0.05, = 0.05, 90 d; = -0.11, < 0.001, 120 d) indicating that younger lambs were more likely to have elevated FAMACHA scores. Thus, younger and lighter lambs will likely be more susceptible to parasitism and may need to be managed more diligently than older or heavier lambs. In addition, FAMACHA scores have potential to improve breeding value estimates in programs designed to genetically improve parasite resistance.


Risk of breast cancer in women after a salivary gland carcinoma or pleomorphic adenoma in the Netherlands.
Salivary and mammary gland tumors show morphological similarities and share various characteristics, including frequent overexpression of hormone receptors and female preponderance. Although this may suggest a common etiology, it remains unclear whether patients with a salivary gland tumor carry an increased risk of breast cancer (BC). Our purpose was to determine the risk of BC in women diagnosed with salivary gland carcinoma (SGC) or pleomorphic adenoma (SGPA). BC incidence (invasive and in situ) was assessed in two nationwide cohorts: one comprising 1567 women diagnosed with SGC and one with 2083 women with SGPA. BC incidence was compared with general population rates using standardized incidence ratio (SIR). BC risk was assessed according to age at SGC/SGPA diagnosis, follow-up time and (for SGC patients) histological subtype. The mean follow-up was 7.0 years after SGC and 9.9 after SGPA diagnosis. During follow-up, 52 patients with SGC and 74 patients with SGPA developed BC. The median time to BC was 6 years after SGC and 7 after SGPA. The cumulative risk at 10 years of follow-up was 3.1% after SGC and 3.5% after SGPA (95% Confidence Interval (95%CI) 2.1%-4.7% and 2.6%-4.6%, respectively). BC incidence was 1.59 times (95%CI 1.19-2.09) higher in the SGC-cohort than expected based on incidence rates in the general population. SGPA-patients showed a 1.48 times (95%CI 1.16-1.86) higher incidence. Women with SGC or SGPA have a slightly increased risk of BC. The magnitude of risk justifies raising awareness, but is no reason for BC screening.


Effect of aldosterone on sodium and potassium concentrations in human mononuclear leukocytes.
The in vitro effect of aldosterone on intracellular sodium and potassium concentration was investigated in human mononuclear leukocytes (HML). HML were separated from blood by a Percoll gradient and intracellular Na+ and K+ were determined before and after incubation for 1 h at 37 degrees C. The intracellular (ic) Na+ and K+ concentrations after separation of HML were 17 +/- 5 and 59 +/- 18 mmol/kg wet cells (mean +/- SD, n = 6), respectively. In the absence of aldosterone the ic Na+ concentration decreased to 12 +/- 4, whereas the ic Na+ concentration remained constant at 18 +/- 8 mmol/kg wet cells when aldosterone (1.4 nM) was added to the incubation medium. In parallel, the ic K+ concentration decreased without added aldosterone but remained constant with aldosterone. The effect of aldosterone on the ic Na+ and K+ concentrations of HML was blocked by the aldosterone antagonist canrenone (140 nM). Cortisol at a physiological concentration (40 nM) did not alter ic Na and K concentrations in these cells. The results suggest that aldosterone binding to specific receptors in human mononuclear leukocytes significantly contributes to the regulation of monovalent cation levels in these cells. Thus, this easily accessible model of HML allows study of the effects of mineralocorticoids in relation to their receptors in intact cells in normal and pathological states.


Aneurysms of the hepatic artery.
Aneurysms of the hepatic artery are rare and, when symptomatic, they may present a triad of upper abdominal pain, gastrointestinal bleeding, and obstructive jaundice. Asymptomatic and unsuspected aneurysms are demonstrated occasionally by abdominal arteriography or are encountered infrequently during abdominal operation for an unrelated disease. Hepatic artery aneurysms have great potential for rupture with bleeding into the peritioneal cavity, the common bile duct, or an adjacent hollow viscus. Morbidity and mortality with a ruptured aneurysm are high, and aggressive and imaginative operative therapy is required. Patients with an asymptomatic aneurysm should have operation to prevent subsequent rupture and hemorrhage.


Morphological and immunohistochemical evidence suggesting human papillomavirus (HPV) involvement in oral squamous cell carcinogenesis.
Human papillomavirus (HPV) is an agent responsible for squamous cell tumors (verrucae, condylomata and papillomas) at various sites of the body, the oral cavity included. Due to the recently pointed-out association between these HPV lesions and the squamous cell dysplasias and malignancies in the uterine cervix, in the bronchus and in the larynx, the present work was carried out to assess, whether morphological signs (cytopathic effects of HPV) or HPV antigens could be found in lesions of oral squamous cell carcinomas. Biopsies from 40 cases of oral squamous cell carcinomas were surveyed by light microscopy with special emphasis on the presence of the histopathological features suggesting an HPV lesion, i.e. whether flat, inverted or papillomatous condylomas are present concomitantly with the malignancy. All specimens were also subjected to immunoperoxidase staining with anti-HPV serum to disclose the possible HPV antigens in the lesions. Morphological signs of the flat-type HPV lesion were found in 4 cases (10%), those of an inverted type in 3 cases (7.5%), and those of a papillomatous type in 9 cases (22.5%). Epithelial cells (mostly koilocytes) showing HPV-positive nuclei were disclosed in 5 papillomatous lesions, in 2 inverted lesions and in 1 flat lesion. The results suggest that HPV might be the agent involved in the development of at least certain special types of oral squamous cell carcinomas; albeit further confirmatory evidence with other techniques (DNA hybridization) is still needed.


Food labeling: health claims; dietary noncariogenic carbohydrate sweeteners and dental caries. Final rule.
The Food and Drug Administration (FDA) is adopting as a final rule, without change, the provisions of the interim final rule that amended the regulation authorizing a health claim on noncariogenic carbohydrate sweeteners and dental caries, i.e., tooth decay, to include isomaltulose as a substance eligible for the health claim. FDA is taking this action to complete the rulemaking initiated with the interim final rule.


Postoperative infection rates in patients with a negative baseline urine culture undergoing ureteroscopic stone removal: a matched case-control analysis on antibiotic prophylaxis from the CROES URS global study.
To examine the effects of antibiotic prophylaxis on postoperative infection rate in patients with negative urine cultures undergoing ureteroscopy (URS). Using the Clinical Research Office of the Endourological Society (CROES) URS Global Study database, patients with a negative baseline urine culture undergoing URS for ureteral stones (n=1141) or kidney stones (n=184) not receiving antibiotic prophylaxis were matched with those who were predefined by risk factors, including gender, American Society of Anesthesiologists (ASA) score, and ureteral stent placement. Patient characteristics, operative data, and postoperative outcomes, including the development of urinary tract infection (UTI) and fever, in the two groups were compared. Antibiotic prophylaxis use differed widely across participating countries (13%-100%). Differences were found between patients who did or did not receive antibiotic prophylaxis regarding the frequency of anticoagulation medication, previous treatment with URS, stone burden, previous presence of kidney stones, duration of current URS, and complications post-URS. The prevalence of fever and UTI was low (≤2.2%) and similar in both groups. Factors predictive of postoperative UTI or fever were female gender, Crohn's and cardiovascular disease, a high stone burden, and an ASA score of II or higher. In patients with a negative baseline urine culture undergoing URS for ureteral or renal stones, rates of postoperative UTI and fever were not reduced by preoperative antibiotic prophylaxis. Female gender and a high ASA score were specific risk factors for postoperative infection in this patient group.


Trends in the incidence and survival of intracerebral hemorrhage by its location in a Japanese community.
No previous population-based studies have examined secular trends in the incidence of intracerebral hemorrhage (ICH) by its location. We established 3 cohorts consisting of residents of Hisayama, Japan, aged ≥40 years without a history of stroke or myocardial infarction in 1961 (the first cohort, n=1,618), in 1974 (the second cohort, n=2,038), and in 1988 (the third cohort, n=2,637). Each cohort was followed for 13 years. The age- and sex-adjusted incidence of ICH significantly declined from the first to the second cohort and showed no further change in the third cohort. With regard to the ICH location, the incidence of putaminal hemorrhage decreased steadily, mainly in subjects aged 60-69 years, whereas the incidence of thalamic hemorrhage increased, especially in those aged ≥70 years. Both hypertension and alcohol intake were strong risk factors for ICH in the first cohort, but their influence declined with time. Blood pressure levels in hypertensive subjects decreased significantly, and the proportion of current drinkers decreased slightly over the study period. Our findings suggest that the ICH incidence steeply declined from the 1960s to the 1970s in Japan as a result of the reduced influence of hypertension and alcohol intake, but that this decline has leveled off since then, probably because of the increased incidence of thalamic hemorrhage in the elderly in recent years.


Stem cell research: a target article collection: Part III--determining moral status.
In this chapter, I review some of the background thinking concerning matters of moral status that I had developed in previous years and that I would now bring to the work of the Human Embryo Research Panel. Two ideas were at the forefront of my thinking. First, that biology usually offers not decisive "events" but only continuous processes of development. Second, in making status determinations we do not so much "identify" a point on a developmental continuum where moral respect should be accorded as "choose" that point. These choices are "balancing decisions" in which the community of moral agents weighs its interests in protecting an entity against the burdens of doing so. After illustrating these two contentions, I consider some of the reasons why thinkers on the "right" and "left" of our bioethics debates have resisted or missed this basic insight.


Psychiatric treatment outcome following traumatic brain injury.
The relationship between self-reported history of traumatic brain injury (TBI) and psychiatric treatment outcome was investigated. TBI was hypothesized to be frequent, associated with cognitive deficits on neuropsychological testing, and less amenable to standard psychiatric treatment. Subjects were 42 psychiatric patients with a self-reported history of TBI and 25 psychiatric patients with no TBI history. Subjects received approximately 2 weeks of inpatient psychiatric treatment. Subjects received neuropsychological testing and completed the Brief Symptom Inventory weekly. TBI was frequent (66% of subjects); multiple injuries were common. Neuropsychological performance was generally average in both groups with few group differences. Subjects, on average, reported significantly decreased psychiatric symptoms on discharge. However, the TBI group appeared to improve less than the control group; group status was a significant predictor of treatment outcome. Implications of results for assessment and treatment of psychiatric disorders in patients with a history of TBI are discussed.


[Effect of enterally administrated oxygenated water on electrical activity of the small intestine in early postoperative period in rats].
The effect of oxygen, structurally-binded with water (oxygen water), on electrical activity of rat jejunum in early postoperative period. It was shown, that in contrast to effect of 0.9% NaCl, there is normalization of electrical activity parameters (frequency and slow wave amplitude) of jejunum in early postoperative period under the influence of oxygen water.


[Risk of thromboembolism and oral contraceptives].
Four studies recently showed an increased risk of venous thromboembolic events (VTE) in current users of oral contraceptives (OCs). This risk was higher in users of Ocs containing third generation progestagens than in users of Ocs containing levonorgestrel. The excess of VTE attributable to the third generation pills should be about 10 per 100 000 woman-years. Conversely, the risk of death due to cardiovascular disease was not significantly increased in users of third generation pills. In addition, the risk of myocardial infarction associated with these latter types of pill was two-fold lower than the risk associated with the pills containing levonorgestrel, and this decrease was of borderline significance (p = 0.10). The results of these different studies are described and discussed in this paper.


Direct analysis of donor-acceptor distance and relationship to isotope effects and the force constant for barrier compression in enzymatic H-tunneling reactions.
The role of dynamical effects in enzyme catalysis is both complex and widely debated. Understanding how dynamics can influence the barrier to an enzyme catalyzed reaction requires the development of new methodologies and tools. In particular compressive dynamics-the focus of this study-may decrease both the height and width of a reaction barrier. By making targeted mutations in the active site of morphinone reductase we are able to alter the equilibrium of conformational states for the reactive complex in turn altering the donor-acceptor (D-A) distance for H-transfer. The sub-A changes which we induce are monitored using novel spectroscopic and kinetic "rulers". This new way of detecting variation in D-A distance allows us to analyze trends between D-A distance and the force constant of a compressive dynamical mode. We find that as the D-A distance decreases, the force constant for a compressive mode increases. Further, we demonstrate that-contrary to current dogma-compression may not always cause the magnitude of the primary kinetic isotope effect to decrease.


Anti-tumor necrosis factor therapy: 6 year experience of a single center in northern Israel and possible impact of health policy on results.
Infliximab and etanercept have been included in the Israeli national list of health services since 2002 for rheumatoid arthritis and juvenile idiopathic arthritis, and since 2005 for psoriatic arthritis and ankylosing spondylitis. The regulator (Ministry of Health and health funds) mandates using fixed doses of infliximab as the first drug of choice and prohibits increased dosage. For other indications (e.g., vasculitis), anti-tumor necrosis factor therapy is given on a "compassionate" basis in severe refractory disease. To describe our experience with anti-TNF therapy in a single tertiary referral center in northern Israel and to analyze the impact of the national health policy on the results. We reviewed the medical records of patients who received anti-TNF therapy in our institution, and analyzed demographic data, diagnosis, clinical and laboratory features, previous and current therapies, and anti-TNF treatment duration and side effects. Between 2001 and 2006, 200 patients received anti-TNF therapy for rheumatoid arthritis (n = 108), juvenile idiopathic arthritis (n = 11), psoriatic arthritis (n = 37), ankylosing spondylitis (n = 29), adult Still's disease (n = 4), overlap disease (RA and scleroderma or polymyositis, n = 6), temporal arteritis (n = 1), polyarteritis nodosa (n = 1), dermatomyositis (n = 1), amyloidosis secondary to RA (n = 1) and Wegener's granulomatosis (n = 1). Forty percent of RA patients discontinued the first anti-TNF agent due to side effects or insufficient response. Higher sedimentation rate and lower or negative rheumatoid factor predicted better response to therapy among RA patients. AS and PS patients had a better safety and efficacy profile. Severe infections occurred in 2% of patients. All eight patients who presented lung involvement as part of their primary rheumatic disease remained stable or improved. A significant improvement was achieved in all six patients with overlap disease. Our daily practice data are generally in agreement with worldwide experience. The 'deviations' might be explained by the local health policy at that time. The impact of health policy and economic and administrative constraints should be taken into account when analyzing cohort daily practice data.


MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo.
Myocardial infarction causes a rapid and largely irreversible loss of cardiac myocytes that can lead to sudden death, ventricular dilation, and heart failure. Members of the mitogen-activated protein kinase (MAPK) signaling cascade have been implicated as important effectors of cardiac myocyte cell death in response to diverse stimuli, including ischemia-reperfusion injury. Specifically, activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) has been associated with cardioprotection, likely through antagonism of apoptotic regulatory pathways. To establish a causal relationship between ERK1/2 signaling and cardioprotection, we analyzed Erk1 nullizygous gene-targeted mice, Erk2 heterozygous gene-targeted mice, and transgenic mice with activated MEK1-ERK1/2 signaling in the heart. Although MEK1 transgenic mice were largely resistant to ischemia-reperfusion injury, Erk2+/- gene-targeted mice showed enhanced infarction areas, DNA laddering, and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick-end labeling (TUNEL) compared with littermate controls. In contrast, enhanced MEK1-ERK1/2 signaling protected hearts from DNA laddering, TUNEL, and preserved hemodynamic function assessed by pressure-volume loop recordings after ischemia-reperfusion injury. These data are the first to demonstrate that ERK2 signaling is required to protect the myocardium from ischemia-reperfusion injury in vivo.


Evidence that high variation in ovarian reserves of healthy young adults has a negative impact on the corpus luteum and endometrium during estrous cycles in cattle.
Low progesterone concentrations and diminished ovarian reserves (total number of healthy oocytes) during reproductive cycles are linked to infertility in single-ovulating species like cattle. However, the extent and mechanisms whereby the inherently high variation in ovarian reserves may negatively affect progesterone production are unknown. Cattle were chosen to address these questions because the size of their ovarian reserves can be predicted based on an antral follicle count (AFC) during follicular waves. The present study determined if progesterone concentrations, differentiation and function of the corpus luteum (CL), and endometrial thickness differed during reproductive cycles of age-matched healthy young adult cattle with low versus high AFC during follicular waves. The results showed that, despite enhanced LH secretion, progesterone concentrations were lower during estrous cycles for animals with low versus high AFC. Animals with low versus high AFC also had a decreased basal, LH-, and 25-hydroxycholesterol-induced capacity of luteal and granulosal cells to produce progesterone, reduced amounts of STAR and mRNAs for STAR and LH receptor in the CL, and no change in endometrial thickness during estrous cycles. Taken together, these results 1) supported the conclusion that high variation in ovarian reserves of young adults is associated with alterations in differentiation and function of the CL and 2) provided insight into the potential factors that may cause suboptimal luteal function (e.g., heightened LH secretion and desensitization of the LH receptor, diminished LH responsiveness, diminished STAR, inherent deficiency in capacity of granulosal cells to undergo luteinization) and infertility (e.g., low progesterone, poor endometrial growth) in individuals with diminished ovarian reserves.


Blood Biomarkers for the Early Diagnosis of Stroke: The Stroke-Chip Study.
Stroke diagnosis could be challenging in the acute phase. We aimed to develop a blood-based diagnostic tool to differentiate between real strokes and stroke mimics and between ischemic and hemorrhagic strokes in the hyperacute phase. The Stroke-Chip was a prospective, observational, multicenter study, conducted at 6 Stroke Centers in Catalonia. Consecutive patients with suspected stroke were enrolled within the first 6 hours after symptom onset, and blood samples were drawn immediately after admission. A 21-biomarker panel selected among previous results and from the literature was measured by immunoassays. Outcomes were differentiation between real strokes and stroke mimics and between ischemic and hemorrhagic strokes. Predictive models were developed by combining biomarkers and clinical variables in logistic regression models. Accuracy was evaluated with receiver operating characteristic curves. From August 2012 to December 2013, 1308 patients were included (71.9% ischemic, 14.8% stroke mimics, and 13.3% hemorrhagic). For stroke versus stroke mimics comparison, no biomarker resulted included in the logistic regression model, but it was only integrated by clinical variables, with a predictive accuracy of 80.8%. For ischemic versus hemorrhagic strokes comparison, NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) >4.9 (odds ratio, 2.40; 95% confidence interval, 1.55-3.71; P<0.0001) and endostatin >4.7 (odds ratio, 2.02; 95% confidence interval, 1.19-3.45; P=0.010), together with age, sex, blood pressure, stroke severity, atrial fibrillation, and hypertension, were included in the model. Predictive accuracy was 80.6%. The studied biomarkers were not sufficient for an accurate differential diagnosis of stroke in the hyperacute setting. Additional discovery of new biomarkers and improvement on laboratory techniques seem necessary for achieving a molecular diagnosis of stroke.


Biotransformation of the aerosol propellant 1,1,1,2,3,3,3-heptafluoropropane (HFA-227): lack of protein binding of the metabolite hexafluoroacetone.
The biotransformation of the aerosol propellant 1,1,1,2,3,3,3-heptafluoropropane (HFA-227) was investigated in rats in vivo and in rat and human liver microsomes. In the urine of rats exposed to 5000 ppm HFA-227 for 6 hr, very small amounts of hexafluoroacetone trihydrate were identified as an HFA-227 metabolite by 19F-NMR. Fluoride concentrations in the urine samples (0-48 hr after the end of the exposure) from exposed animals were not significantly different from those found in samples from nonexposed rats. In rat and human liver microsomes, fluoride and hexafluoroacetone trihydrate formation from HFA-227 was detected in very low levels only in liver microsomes from pyridine-treated rats and in two of eight human liver microsome samples, which exhibited the highest cytochrome P4502E1 activities. Because some aldehydes may covalently bind to proteins and the formation of fluorinated protein adducts has been implicated in immune-mediated hepatitis induced by halothane, the binding of hexafluoroacetone trihydrate to proteins was also investigated. Hexafluoroacetone trihydrate also gave only a very small resonance in fluorine NMR experiments when binding to human serum albumin was studied in comparison with the acylating agent S-ethyltrifluoroacetate. Moreover, no fluorine-containing products were formed by the reaction of hexafluoroacetone trihydrate with N alpha-acetyl-L-lysine, and hexafluoroacetone trihydrate was not metabolized to fluorine-containing metabolites or inorganic fluoride in rats. Comparative studies in human liver microsomes demonstrated that a halothane metabolite may covalently bind to proteins; in contrast, metabolism and covalent binding of HFA-227 could not be demonstrated. In summary, these data indicate that HFA-227 is biotransformed at very low rates to hexafluoroacetone trihydrate but irreversible binding of hexafluoroacetone trihydrate cannot be demonstrated, even with the application of very sensitive methods, and is considered unlikely, based on the combination of the results obtained.


Best predictors of grayscale ultrasound combined with color Doppler in the diagnosis of retained products of conception.
To determine the best predictors of the presence of retained products of conception (RPOC) on grayscale and color Doppler transvaginal sonographic examination. This was a retrospective study of 91 consecutive patients who underwent transvaginal sonography (TVS) with color Doppler to evaluate for the presence of RPOC. The images of TVS studies were reviewed by two radiologists in consensus blinded to the final outcome. Data on a number of variables including endometrial measurable mass and focal increased color vascularity were collected as predictors of RPOC. The patients' ages ranged from 17 to 48 years (mean, 31.8 ± 6.8) and gestational age from 5 to 24 weeks (mean, 9.2 ± 3.8). Thirty-six were confirmed as RPOC by dilatation and curettage (D&C) and pathology. Fifty-five were considered negative, 9 based on D&C results and 46 on clinical grounds. Sensitivity, specificity, negative- and positive-predictive and accuracy values were 81% (CI: 68%-94%), 71% (CI: 59%-83%), 85% (CI: 74%-95%), 64% (CI: 50%-78%), and 75% (CI: 66%-84%) to detect RPOC when a mass was present. The corresponding numbers for the presence of focal color vascularity were 94% (CI: 87%-100%) (p = 0.07), 67% (CI: 55%-80%) (p > 0.05), 95% (CI: 88%-100%) (p = 0.1), 65% (CI: 52%-78%) (p > 0.05), and 78% (CI: 70%-87%) (p > 0.05). Of the patients with confirmed RPOC on pathology, five had focal increased vascularity and no massand none had a mass without focal increased vascularity. An area of focal increased vascularity with or without a mass is the best predictor of the presence of RPOC.


Carbon storage regulator A contributes to the virulence of Haemophilus ducreyi in humans by multiple mechanisms.
The carbon storage regulator A (CsrA) controls a wide variety of bacterial processes, including metabolism, adherence, stress responses, and virulence. Haemophilus ducreyi, the causative agent of chancroid, harbors a homolog of csrA. Here, we generated an unmarked, in-frame deletion mutant of csrA to assess its contribution to H. ducreyi pathogenesis. In human inoculation experiments, the csrA mutant was partially attenuated for pustule formation compared to its parent. Deletion of csrA resulted in decreased adherence of H. ducreyi to human foreskin fibroblasts (HFF); Flp1 and Flp2, the determinants of H. ducreyi adherence to HFF cells, were downregulated in the csrA mutant. Compared to its parent, the csrA mutant had a significantly reduced ability to tolerate oxidative stress and heat shock. The enhanced sensitivity of the mutant to oxidative stress was more pronounced in bacteria grown to stationary phase compared to that in bacteria grown to mid-log phase. The csrA mutant also had a significant survival defect within human macrophages when the bacteria were grown to stationary phase but not to mid-log phase. Complementation in trans partially or fully restored the mutant phenotypes. These data suggest that CsrA contributes to virulence by multiple mechanisms and that these contributions may be more profound in bacterial cell populations that are not rapidly dividing in the human host.


The human obesity gene map: the 2003 update.
This is the tenth update of the human obesity gene map, incorporating published results up to the end of October 2003 and continuing the previous format. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) from human genome-wide scans and animal crossbreeding experiments, and association and linkage studies with candidate genes and other markers is reviewed. Transgenic and knockout murine models relevant to obesity are also incorporated (N = 55). As of October 2003, 41 Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. QTLs reported from animal models currently number 183. There are 208 human QTLs for obesity phenotypes from genome-wide scans and candidate regions in targeted studies. A total of 35 genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 272 studies reporting positive associations with 90 candidate genes. Fifteen such candidate genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, more than 430 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful sites can be found at http://obesitygene.pbrc.edu.


Prochlorococcus marinus Chisholm et al. 1992 subsp. pastoris subsp. nov. strain PCC 9511, the first axenic chlorophyll a2/b2-containing cyanobacterium (Oxyphotobacteria).
The formal description of Prochlorococcus marinus Chisholm et al. 1992, 299 was based on the non-axenic nomenclatural type, strain CCMP 1375T. The purification and properties of the axenic strain PCC 9511, derived from the same primary culture (SARG) as the type species, are reported here. Prochlorococcus PCC 9511 differs from the latter in possessing horseshoe-shaped thylakoids, exhibiting a low chlorophyll b2 content and lacking phycoerythrin, but shares these phenotypic properties with Prochlorococcus strain CCMP 1378. This relationship was confirmed by 16S rRNA sequence analyses, which clearly demonstrated that the axenic isolate is not co-identic with the nomenclatural type. Strain PCC 9511 has a low mean DNA base composition (32 mol% G+C) and harbours the smallest genome of all known oxyphotobacteria (genome complexity 1.3 GDa = 2 Mbp). Urea and ammonia are the preferred sources of nitrogen for growth, whereas nitrate is not utilized. Several different organic phosphorus compounds efficiently replace phosphate in the culture medium, indicative of ecto-phosphohydrolase activity. In order to distinguish strain PCC 9511 from the nomenclatural type, a new subspecies is proposed, Prochlorococcus marinus Chisholm et al. 1992 subsp. pastoris subsp. nov.


Comparison of the effects of two different trigger strategies - dual (hCG + Leuprolide) versus hCG trigger - in antagonist non-donor IVF: a randomized controlled trial.
Conventionally, hCG is used as a 'faux' LH surge to bring final oocyte maturation due to structural similarity with LH. Although GnRH agonists induce a more physiological gonadotropin surge for follicular maturation, they have been associated with luteal phase deficiency. Our aim was to assess whether adding a gonadotropin-releasing hormone agonist (GnRHa) to hCG trigger improves oocyte maturation and the number of high-grade embryos in GnRH antagonist IVF cycles. This was a single center, open-labelled, randomized controlled trial including 100 patients between 21-38 years (tubal factor, male factor, unexplained infertility, with normal ovarian reserve) undergoing IVF using the GnRH antagonist protocol. Patients were randomized to receive either the dual trigger (Leuprolide acetate 1mg + rhCG 250µg, n=50) or a single hCG trigger (rhCG 250µg, n=50). Analysis was done by ITT. Independent-t and chi-square tests were used in the comparisons of normally distributed quantitative variables and qualitative variables. With similar baseline characteristics, the number of MII oocytes (7.82 vs. 5.92, p=0.003) and day-3 grade-1 embryos (4.24 vs. 1.8, p<0.001) and consequently, number of embryos cryopreserved (2.68 vs. 0.94, p<0.001) were significantly higher in the dual trigger group. However, the fertilization (91.82% vs. 88.51%, p=0.184) and clinical pregnancy rates between the two groups (21% vs. 19.6%, p=0.770) were comparable. Serum LH levels 12 hours post trigger were high in the dual trigger group (46.23mIU/ml vs. 0.93mIU/ml, p<0.0001). This study found that the addition of GnRHa to hCG trigger leads to improved embryological outcomes and the possibility of cryopreserving surplus embryos, thereby increasing cumulative live births.