Small-diameter titanium grade IV and titanium-zirconium implants in edentulous mandibles: Ten-year results from a double-blind, randomised controlled split-mouth core-trial.
The goal of this extension study was to compare the 10-year outcome of 3.3 mm diameter titanium-zirconium (TiZr) or grade IV titanium (Ti) implants in mandibular implant-overdentures. This study is the 10-year follow-up from a randomised, controlled, double-blind, split-mouth multicentre clinical trial. Patients with edentulous mandibles had received two implants in the interforaminal region (bone-level, diameter 3.3 mm, microrough surface), one of TiZr (test) and one of Ti (control). Implant survival and success, plaque and sulcus bleeding indices, probing pocket depth, gingival margin, clinical attachment level and radiographic crestal bone levels were evaluated. Fifty of 91 patients with implants were available for the 10-year examination and 36 patients were valid for the intent-to-treat (ITT) analysis. The implant success rate was calculated as 94.6% and 91.9% for the TiZr implants and the Ti implants respectively. Four implants were lost (TiZr = 1; Ti = 3) in the entire study period. Kaplan-Meier survival analyses estimated 10- year implant survival rate for TiZr to 98.9% and Ti 95.8%.The mean of total and functional crestal bone loss was 1.49 mm (±1.37 mm) and 0.82 mm (±1.09 mm) in the TiZr group and 1.56 mm (±1.34 mm) and 0.85 mm (±1.16 mm) in the Ti group. This split-mouth design RCT on mandibular implant-overdentures evidenced, bearing in mind its follow-up time-related reduced cohort size, high 10-year implant success- and survival rates. These results confirm TiZr as well-suited implant material for realising small-diameter implants. Registered on www. gov: NCT01878331.


[Current epidemiology of zoonotic cutaneous leishmaniasis in the Republic of Uzbekistan].
It has been established that the Republic of Uzbekistan is divided into two strata by the epidemic risk for zoonotic cutaneous leishmaniasis (ZCL). The distribution of ZCL endemicity in Urbekistan coincides with that of great gerbils (Rhombomys opimus), the main natural reservoir of leishmaniasis pathogens. In the past 34 years, there have been 8 epidemiological rises in the incidence of ZCL, which are associated with a large number of great gerbils and Ph. papatasis mosquitoes providing the epidemiological process.


Alternative Oxidase: A Potential Target for Controlling Aflatoxin Contamination and Propagation of Aspergillus flavus.
Aflatoxins are among the most hazardous natural cereal contaminants. These mycotoxins are produced by Aspergillus spp. as polyketide secondary metabolites. Aflatoxigenic fungi including A. flavus express the alternative oxidase (AOX), which introduces a branch in the cytochrome-based electron transfer chain by coupling ubiquinol oxidation directly with the reduction of O2 to H2O. AOX is closely associated with fungal pathogenesis, morphogenesis, stress signaling, and drug resistance and, as recently reported, affects the production of mycotoxins such as sterigmatocystin, the penultimate intermediate in aflatoxin B1 biosynthesis. Thus, AOX might be considered a target for controlling the propagation of and aflatoxin contamination by A. flavus. Hence, this review summarizes the current understanding of fungal AOX and the alternative respiration pathway and the development and potential applications of AOX inhibitors. This review indicates that AOX inhibitors, either alone or in combination with current antifungal agents, are potentially applicable for developing novel, effective antifungal strategies. However, considering the conservation of AOX in fungal and plant cells, a deeper understanding of fungal alternative respiration and fungal AOX structure is needed, along with effective fungal-specific AOX inhibitors.


Analysis of the Human Adult Urinary Metabolome Variations with Age, Body Mass Index, and Gender by Implementing a Comprehensive Workflow for Univariate and OPLS Statistical Analyses.
Urine metabolomics is widely used for biomarker research in the fields of medicine and toxicology. As a consequence, characterization of the variations of the urine metabolome under basal conditions becomes critical in order to avoid confounding effects in cohort studies. Such physiological information is however very scarce in the literature and in metabolomics databases so far. Here we studied the influence of age, body mass index (BMI), and gender on metabolite concentrations in a large cohort of 183 adults by using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). We implemented a comprehensive statistical workflow for univariate hypothesis testing and modeling by orthogonal partial least-squares (OPLS), which we made available to the metabolomics community within the online Workflow4Metabolomics.org resource. We found 108 urine metabolites displaying concentration variations with either age, BMI, or gender, by integrating the results from univariate p-values and multivariate variable importance in projection (VIP). Several metabolite clusters were further evidenced by correlation analysis, and they allowed stratification of the cohort. In conclusion, our study highlights the impact of gender and age on the urinary metabolome, and thus it indicates that these factors should be taken into account for the design of metabolomics studies.


Quality evaluation of Salvia miltiorrhiza Bge. by ultra high performance liquid chromatography with photodiode array detection and chemical fingerprinting coupled with chemometric analysis.
An ultra high performance liquid chromatography with photodiode array detection method is developed for the simultaneous quantitative determination of five water-soluble compounds including danshensu, protocatechualdehyde, rosmarinic acid, salvianolic acid B, and salvianolic acid A in Salvia miltiorrhiza Bge. Through method optimization, the five compounds all expressed good linearity (R(2) > 0.9990) in a wide concentration range together with satisfactory accuracy, precision, and stability. Moreover, through qualitative analysis of the chemical fingerprint combined with similarity analysis, hierarchical cluster analysis, principle component analysis, and partial least-squares discriminate analysis, we determined that the 13 batches of Salvia miltiorrhiza Bge. were similar in internal quality and the differences resulted from various cultivation environments, recovery elements, and others. Seen from the results of hierarchical cluster analysis and principle component analysis, the classification of 13 batches was in accordance, and partial least-squares discriminate analysis technique was more suitable than the principle component analysis model to provide a distinct classification of test samples on the basis of their different components. Moreover, a permutation test verified the rationality of partial least-squares discriminate analysis and variable importance plot showed that peaks 37 and 38 were the most significant variables in distinguishing the Salvia miltiorrhiza Bge. The idea of the quantitative and qualitative analysis of Salvia miltiorrhiza Bge. was convenient, sensitive, and comprehensive, which could be applied to evaluate the quality of more traditional Chinese medicines.


Activin Decoy Receptor ActRIIB:Fc Lowers FSH and Therapeutically Restores Oocyte Yield, Prevents Oocyte Chromosome Misalignments and Spindle Aberrations, and Increases Fertility in Midlife Female SAMP8 Mice.
Women of advanced maternal age (AMA) (age ≥ 35) have increased rates of infertility, miscarriages, and trisomic pregnancies. Collectively these conditions are called "egg infertility." A root cause of egg infertility is increased rates of oocyte aneuploidy with age. AMA women often have elevated endogenous FSH. Female senescence-accelerated mouse-prone-8 (SAMP8) has increased rates of oocyte spindle aberrations, diminished fertility, and rising endogenous FSH with age. We hypothesize that elevated FSH during the oocyte's FSH-responsive growth period is a cause of abnormalities in the meiotic spindle. We report that eggs from SAMP8 mice treated with equine chorionic gonadotropin (eCG) for the period of oocyte growth have increased chromosome and spindle misalignments. Activin is a molecule that raises FSH, and ActRIIB:Fc is an activin decoy receptor that binds and sequesters activin. We report that ActRIIB:Fc treatment of midlife SAMP8 mice for the duration of oocyte growth lowers FSH, prevents egg chromosome and spindle misalignments, and increases litter sizes. AMA patients can also have poor responsiveness to FSH stimulation. We report that although eCG lowers yields of viable oocytes, ActRIIB:Fc increases yields of viable oocytes. ActRIIB:Fc and eCG cotreatment markedly reduces yields of viable oocytes. These data are consistent with the hypothesis that elevated FSH contributes to egg aneuploidy, declining fertility, and poor ovarian response and that ActRIIB:Fc can prevent egg aneuploidy, increase fertility, and improve ovarian response. Future studies will continue to examine whether ActRIIB:Fc works via FSH and/or other pathways and whether ActRIIB:Fc can prevent aneuploidy, increase fertility, and improve stimulation responsiveness in AMA women.


A pilot study on transcriptome data analysis of folliculogenesis in pigs.
Three different stages of pig antral follicles have been studied in a granulosa-cell transcriptome analysis on nylon microarrays (1152 clones). The data have been generated from seven RNA follicle pools and several technical replicates were made. The objective of this paper was to state the feasibility of a transcriptomic protocol for the study of folliculogenesis in the pig. A statistical analysis was chosen, relying on the linear mixed model (LMM) paradigm. Low variability within technical replicates was hence checked with a LMM. Relevant genes that might be involved in the studied process were then selected. For the most significant genes, statistical methods such as principal component analysis and unsupervised hierarchical clustering were applied to assess their relevance, and a random forest analysis proved their predictive value. The selection of genes was consistent with previous studies and also allowed the identification of new genes whose role in pig folliculogenesis will be further investigated.


Effect of the growth environment on cell-envelope components of Escherichia coli in relation to sensitivity to human serum.
Three smooth strains of urinary Escherichia coli were grown in a chemostat under carbon-limited (C-lim) and magnesium-limited (Mg-lim) conditions over a range of dilution rates (D). Strain LP1674 was resistant to human serum under C-lim but became sensitive when grown under Mg-lim, the degree of sensitivity increasing as D increased. The transition to serum sensitivity was accompanied by loss of ability to produce extractable K1 antigen and a reduction in the amount of a 46k envelope polypeptide. C-lim cells of strain LP729 exhibited a delayed sensitive response to serum, the degree of lag in serum killing becoming less pronounced with increasing values of D; Mg-lim cells were more sensitive with little or no lag in serum killing. The degree of lag appeared to be directly related to the amount of the O side-chain sugar mannose associated with the lipopolysaccharide. C-lim and Mg-lim cultures of E. coli strain LP1395 were resistant to serum except when growing at near maximal rates. Although C-lim cultures contained more acidic polysaccharide than Mg-lim cells, transition to serum sensitivity did not appear to be related to exopolysaccharide production. Rapidly growing cells of strain LP1395 did, however, have lower lipopolysaccharide 0 side-chain sugar:core-sugar ratios than more slowly growing cells. With all three strains, changes in dilution rate and in the nature of the limiting nutrient were accompanied by changes in envelope protein composition. This study demonstrates that many cell-surface changes occur in response to alterations in the growth environment and some of these may be correlated with changes in sensitivity to serum.


Evaluation of drug release, monomer conversion and surface properties of resin composites containing chlorhexidine-loaded mesoporous and nonporous hydroxyapatite nanocarriers.
The aim of this study was to evaluate drug release, degree of conversion (DC), and surface properties of resin composites containing chlorhexidine (CHX)-loaded mesoporous (mHAP) and nonporous hydroxyapatite (HAP) nanocarrier. CHX loaded mHAP and HAP, or CHX without nanocarrier was added into the resin composite in 1% and 5% concentrations. After characterization of experimental materials with XRD, EDX, FT-IR, and SEM, the CHX release on the 1st, 7th, 30th, and 120th days were evaluated by UV-vis spectroscopy. DC, surface roughness, and surface hardness of the samples were also evaluated. The data was statistically analyzed. While mHAP groups released significantly higher CHX on the 30th day (p < .05), there was no statistically significant difference between the HAP and mHAP groups on the 120th day (p > .05). DCs of all groups were similar (p > .05). While mHAP and HAP groups containing 5% CHX showed significantly higher roughness than the other groups (p < .05), no statistically significant difference was observed between the other groups (p > .05). The 1% and 5% CHX groups without nanocarrier showed significantly lower surface hardness (p < .05). However, no statistically significant difference was observed between the other groups in terms of surface hardness (p > .05). A controlled CHX release was achieved by mHAP and HAP nanocarriers for 120 days. The nanocarrier addition up to 5% did not negatively affect the DC and the surface hardness which is one of the surface properties of the resin composites. Although the addition of 5% nanocarrier to the resin composite increased the surface roughness, while adding 1% of these nanocarriers did not change.


Key roles of microRNA-22 family in complex organisms inferred from its evolution.
Previous studies suggested that microRNAs (miRNAs) participate in almost all cellular processes and the continuous development of miRNA-mediated posttranscriptional regulation might have facilitated the development of complex organisms. Especially, the microRNA-22 (miR-22) family has been recently extensively reported. Here, we accessed the evolution of miR-22 structure, regulation, and targets, and this indicated that miR-22 plays key roles in more complex organisms. We demonstrated that the miR-22 family arose approximate 600 million years ago from the latest common ancestor of bilaterians. Moreover, a survey of genomic contexts and the secondary structure of the miR-22 family revealed that it originated de novo from a relatively conserved intron region, and the mature sequence of the miR-22 family evolved by seed pairing with highly conserved 3' "U" and 5' "G" boundaries. Furthermore, a complete picture of the evolution of the regulatory networks associated with miR-22 was obtained from the analysis of experimentally identified, as well as computationally predicted, functional targets of miR-22.


STC2 overexpression mediated by HMGA2 is a biomarker for aggressiveness of high-grade serous ovarian cancer.
High-grade serous cancer (HGSC) is a lethal form of ovarian cancer due to invasion and early metastasis. Gain of epithelial-mesenchymal transition (EMT) contributes to the aggressiveness of HGSC. High-mobility gene group A2 (HMGA2), an architectural transcription factor, plays a major role in HGSC through the regulation of EMT gene expression. Based on the gene profiling analysis, we found that the potent EMT gene, stanniocalcin 2 (STC2), was highly correlated with HMGA2 expression. In the present study, we demonstrated that STC2 was directly regulated by HMGA2 at the transcriptional level. Overexpressing STC2 in vitro directly enhanced cell migration and invasion. To investigate the correlation of STC2 and HMGA2 expression and the potential biomarker for ovarian cancer, three independent large cohorts of ovarian cancer (cohort 1=278, cohort 2=150 and cohort 3=95 cases) were examined in the present study. The results showed that the expression of HMGA2 and STC2 was positively correlated. Furthermore, STC2 expression was significantly associated with tumor grade and histotype. HGSC had significantly higher levels of STC2 expression and was inversely correlated with patient survival. These findings suggested that STC2 is an important new biomarker that can be used for HGSC.


Kinetics of selected plasma cytokines during innate-adaptive immune response transition in adult cattle infected with the bovine ephemeral fever virus.
While virus neutralizing antibodies are known to be variably protective against bovine ephemeral fever (BEF) virus (BEFV) infections, the cytokine events that mediate the nascent adaptive immune response have not been defined in cattle. This study determined the plasma kinetics of IL-2, IFN-γ, IL-6, and IL-10 during the period of innate-immune response transition and evaluated the relationship between the virus neutralizing antibody response and viraemia in BEFV-infected cattle. Plasma from four virus-infected and uninfected negative control animals was tested by cytokine-specific immunoenzymatic assays, viraemia monitored by qRT-PCR, and virus neutralizing antibody titres determined using a standard protocol. Unlike the negative controls, plasma IL-6 and IL-10 were increased in all the virus-infected animals starting several days prior to initiation of viraemia. In one animal, plasma IL-2 and IFN-γ were consistently higher than in the other three virus-infected animals and the negative control mean. The animal with the strongest IL-2 and IFN-γ responses had the shortest viraemia while the heifer with the lowest IL-2/IFN-γ indices demonstrated the longest viraemia. Evidently, increase in plasma IL-6 and IL-10 precedes seroconversion during BEFV infections in cattle suggesting the two cytokines may influence immunological events that pave way to B-cell activation and seroconversion. While there is remarkable variability in IL-2 and IFN-γ expression amongst BEFV-infected animals, increased plasma levels of the two cytokines appear to be associated with a shorter viraemia. Ongoing studies will help define the precise role of T cells in anti-BEFV adaptive immune responses.


Learning Curve for Single-Incision Laparoscopic Anterior Resection for Sigmoid Colon Cancer.
Compared with conventional laparoscopic surgery, single-incision laparoscopic surgery produces better cosmetic benefits. The aim of this study was to investigate the learning curve for single-incision laparoscopic anterior resection (SILAR) for sigmoid colon cancer using multidimensional methods. From September 2009 through May 2014, one hundred and thirteen patients underwent SILAR for sigmoid colon cancer by a single surgeon at Severance Hospital. The learning curve was analyzed using moving average, cumulative sum control chart (CUSUM), and risk-adjusted CUSUM methods. For risk-adjusted CUSUM, surgical failure was defined as conversion to open surgery or conventional laparoscopic surgery, morbidity within 30 days after surgery, <12 harvested lymph nodes, or local recurrence. Using the moving average method, the peak point for operation time occurred at the 65(th) case (173 minutes). The CUSUM method also showed the operation time peak point at the 65(th) case. However, the risk-adjusted CUSUM curve did not ascend after the 61st case. The operation time and hospital stay for the 60 phase 1 patients (cases 1 to 60) were longer than for 53 phase 2 patients (cases 61 to 113) (166.6 vs 140 minutes; p < 0.001 and 7.1 vs 5.5 days; p = 0.009). Phase 2 patients had a significantly larger tumor diameter and more harvested lymph nodes. The learning curve for SILAR for sigmoid colon cancer was 61 to 65 cases according to multidimensional statistical analyses. Single-incision laparoscopic anterior resection is feasible for surgeons experienced in laparoscopic surgery. However, SILAR required more cases for proficiency than the number previously reported for conventional laparoscopic surgery, likely because of its technical challenges.


Regions of Salmonella typhimurium flagellin essential for its polymerization and excretion.
Immunological methods were used to examine the flagellin production of Salmonella typhimurium strains that carried a mutation in one of the two possible genes for flagellin (H1 or H2) and also were incapable of expressing the other gene. Some mutants produced flagellin that was excreted into the culture medium; others accumulated flagellin intracellularly. These two phenotypes were detected in both H1 and H2 mutants. The mutation sites were mapped on the corresponding deletion map (consisting of 21 segments in the case of H1 and 31 segments in the case of H2). H1 and H2 mutations causing excretion of flagellin were clustered mainly in segment 12 and segment 6 from the proximal end, respectively, suggesting that the corresponding segments of the flagellins play a role in polymerization. Mutations causing accumulation in the cytoplasm were clustered in segments 19 to 21 of the H1 map and in segments 25 to 29 of the H2 map, suggesting that an essential region for flagellin transport exists toward the C terminus of flagellin.


Chronic exposure to the opioid antagonist naltrexone during pregnancy: maternal and offspring effects.
The role of endogenous opioids in pregnancy and parturition, and the influence exerted on prenatal and postnatal features of the offspring, were studied in rats. Females received daily injections of 50 mg/kg naltrexone (NTX), a dosage found to block opioids from interacting with opioid receptors for 24 h, throughout pregnancy. No effects on the length of gestation, course of pregnancy, litter size, or the viability of the mother or offspring were noted. The body weights, crown-rump lengths, and wet and dry weights of the brain, heart, kidney, liver, and skeletal muscle (triceps surae) in neonates delivered by NTX-treated rats were substantially elevated compared to newborn animals of saline-injected mothers. Offspring exposed to NTX during prenatal life were larger in body weight and length, and organ wet and dry weights on postnatal days 10 and 21. By weaning (day 21 ), body weights of NTX-exposed rats were 36% greater than controls, and increases were observed in the wet weights of brain (18%), heart (42%), kidney (38%), lungs (22%), liver (44%), and triceps surae (246%). These data lead us to hypothesize that native opioids are important growth-inhibiting, tonically active regulators of prenatal ontogeny, and that events occurring in prenatal life are determinants to postnatal outcome insofar as somatic development.


An examination of high school students' attitudes toward physical education with regard to sex and sport participation.
This study assessed attitudes of high school students toward physical education with regard to sex and sport participation. A total of 440 sport participants (175 girls and 265 boys) and of 427 nonsport participants (227 girls and 200 boys), all of whom were 15 yr. old, voluntarily participated. The Attitudes Toward Physical Education Scale was administered to assess participants' attitudes toward physical education. The results of 2 x 2 (Sex x Sports Participation) analysis of variance indicated a significant difference in attitudes toward physical education between sport participants and nonsport participants, with the former scoring higher, and a difference between boys and girls, with boys scoring higher. However, there was no significant interaction between sex and sports participation on attitudes toward physical education. In general, sport participants had more favorable Attitudes Toward Physical Education scores than nonsport participants, and high school boys scored significantly higher than girls. There was a significant difference in Attitudes Toward Physical Education scores between female and male high school students, with boys having more favorable attitude scores.


Further examination of the factor structure of the Male Role Norms Inventory-Short Form (MRNI-SF): Measurement considerations for women, men of color, and gay men.
Using multigroup structural equation modeling in a large sample of online-survey respondents (N = 6,744), the present study examined the reliability and dimensionality of the Male Role Norms Inventory-Short Form (MRNI-SF), a popular measurement of traditional masculinity ideology (TMI), and also tested measurement invariance between individuals that do and do not fit the White heterosexual male TMI reference group. Results indicated that (a) it is appropriate to model the MRNI-SF using either a bifactor or unidimensional model but not a second-order model, (b) the raw MRNI-SF total score is a suitable measure of the general TMI construct, (c) the raw self-reliance through mechanical skills and negativity toward sexual minorities subscale scores may be appropriate measures of their respective specific factors (akin to subscale factors), and (d) SEM or ipsatizing procedures should be used to model the 5 other specific factors, given the insufficient model-based reliability of their raw subscale scores. When comparing men to women, White men to Black and Asian men, and gay men to heterosexual men, the MRNI-SF demonstrated configural invariance and at least partial metric invariance (i.e., measured similar constructs). However, scalar and residuals invariance were only supported for Asian men compared to White men. Taken together, these findings suggest that a general TMI factor of the MRNI-SF is best represented by a bifactor model, even in individuals that do not fit the White heterosexual male TMI reference group, but the instrument may be tapping somewhat different constructs in women, Black men, and gay men. (PsycINFO Database Record


A glimpsing model of speech perception in noise.
Do listeners process noisy speech by taking advantage of "glimpses"-spectrotemporal regions in which the target signal is least affected by the background? This study used an automatic speech recognition system, adapted for use with partially specified inputs, to identify consonants in noise. Twelve masking conditions were chosen to create a range of glimpse sizes. Several different glimpsing models were employed, differing in the local signal-to-noise ratio (SNR) used for detection, the minimum glimpse size, and the use of information in the masked regions. Recognition results were compared with behavioral data. A quantitative analysis demonstrated that the proportion of the time-frequency plane glimpsed is a good predictor of intelligibility. Recognition scores in each noise condition confirmed that sufficient information exists in glimpses to support consonant identification. Close fits to listeners' performance were obtained at two local SNR thresholds: one at around 8 dB and another in the range -5 to -2 dB. A transmitted information analysis revealed that cues to voicing are degraded more in the model than in human auditory processing.


Using structural information to create physiologically based pharmacokinetic models for all polychlorinated biphenyls.
Physiologically based pharmacokinetic (PBPK) models are useful in describing the distribution, metabolism, and fate of xenobiotics across multiple species. The eventual goal of the present research is to create PBPK models for all 209 polychlorinated biphenyls (PCBs). Key parameters in any PBPK model are the tissue-to-blood partition coefficients. Tissue:blood partition coefficients relate the compound's concentration in a target tissue to its concentration in blood under equilibrium conditions. Data on the adipose:plasma partition coefficients of 24 PCBs were used in a regression analysis to find an expression for the adipose:plasma partition coefficient as a function of molecular structure. Using stepwise regression, it was found that three simple structural descriptors were sufficient to predict adipose:plasma partition coefficients for all 209 PCB congeners. Data on the distribution of PCBs among blood components were used to derive the adipose:blood partition coefficient from the adipose:plasma partition coefficient. The lipid contents of liver, muscle, and skin were used to derive the tissue:blood partition coefficient for those tissues from the adipose:blood partition coefficient. These results allow for the calculation of tissue:blood partition coefficients for liver, skin, muscles, and fat for all 209 PCB congeners.


An improved congenital heart assessment tool: a quality improvement outcome.
CHD was the most prevalent congenital anomaly (60.9 per 10,000, 95% CI 59.0-62.8) in England in 2018, with 1767 babies born with severe cardiac defects. The 30-day survival rates for complex procedures continue to improve; however despite care advances, the early post-operative period and first year of life remain a critical time for these infants. The Congenital Heart Assessment Tool was developed to support parental decision-making, standardise care provision, improve communication, and the safety and quality of care. To further evaluate the Congenital Heart Assessment Tool. A four centre collaborative mixed-methods quality improvement project funded by The Health Foundation, involving eight phases conducted during 2016-2018. Phases six to eight (clinical simulation exercise, parent workshop, and updated tool) are reported in this paper. Four themes emerged from the clinical simulation exercise (phase six) including: improving documentation; preparation of parents; preparation of health care professionals; and communication. One main theme emerged from the parent workshop (phase seven): "what parents know versus what professionals know [about CHD]". These phases further validated the effectiveness of the CHATm in terms of triggering amber and red indicators and demonstrated parents' ability to identify deterioration in their infant's clinical condition. Recommendations arising from the quality improvement project enabled the project team to create an updated version of the Congenital Heart Assessment Tool, CHAT2.


On the interaction between [Ru(NH3)6]3+ and the G-quadruplex forming thrombin binding aptamer sequence.
The interaction between the thrombin binding aptamer (TBA), a G-quadruplex forming DNA sequence, and the electroactive hexaammineruthenium(III) cation has been studied by electrochemical methods and circular dichroism spectroscopy. When TBA is immobilised on a gold surface in a typical aptasensor configuration, the [Ru(NH3)6](3+) cation can be bound to the electrode surface through its interaction with the TBA sequence. This interaction is strong enough to enable the ruthenium complex to remain at the surface when the electrode is immersed in an electrolyte free of [Ru(NH3)6](3+), meaning that the complex does not diffuse back into the solution. A stoichiometry of 2 [Ru(NH3)6](3+) per TBA strand has been determined, indicating that the interaction differs from the conventional, non-specific electrostatic charge compensation, for which a 5 to 1 ratio would be expected between the triply charged cation and the 15 bases sequence. It is shown that this interaction takes place not only at the surface, but also when both TBA and hexaammineruthenium(III) are dissolved in solution. Under such conditions, a similar stoichiometry of 2 [Ru(NH3)6](3+) per TBA strand has been evidenced by two independent methods, namely circular dichroism spectroscopy and differential pulse voltammetry.


Characteristics and behaviour of liposomes when incubated with natural bile salt extract: implications for their use as oral drug delivery systems.
The use of liposomes for oral administration of drugs and for food applications is based on their ability to preserve entrapped substances and to increase their bioavailability. Bile salts are one of the agents that affect the liposome structure during intestinal digestion and the main reported studies on liposome/bile salt systems used only one bile salt. The aim of this work is to characterise the interaction of liposomes with a natural bile salt extract (BSE) at physiological pH and temperature. Three types of liposomes (fluid, gel-state and liquid-ordered bilayers) were studied. Phase diagrams were obtained and a very different behaviour was found. Fluid bilayers were completely permeable to an entrapped dye with partial or complete disruption of vesicles (final size 10 nm). Gel-state bilayers released their content but BSE led to the formation of large mixed structures (2000 nm). Liquid-ordered bilayers formed mixed vesicles (1000 nm) and, surprisingly, retained a high percentage of their aqueous content (about 50%). As a consequence, each type of liposome offers singular features to be used in oral applications due to their specific interaction with bile salts.


Ultrasound confirmation of guidewire position may eliminate accidental arterial dilatation during central venous cannulation.
Ultrasound guidance during central line insertion has significantly reduced complications associated with this procedure and has led to it being incorporated as standard of care in many institutions. However, inadvertent arterial penetration and dilation remains a problem despite ultrasound guidance and can result in significant morbidity and even mortality. Dynamic ultrasound confirmation of guidewire position within the vein prior to dilation may help to prevent and even eliminate this feared complication. A prospectively collected database of central line insertions for one author utilizing this novel technique was retrospectively reviewed for all incidents of arterial dilation over a period from September 2008 to January 2010. During the study period 53 central lines were inserted with no incidents of arterial dilation. Ultrasound confirmation of guidewire position has the potential to reduce or eliminate the morbidity and mortality of arterial dilation during central line placement.


Identification of a novel human mitochondrial endo-/exonuclease Ddk1/c20orf72 necessary for maintenance of proper 7S DNA levels.
Although the human mitochondrial genome has been investigated for several decades, the proteins responsible for its replication and expression, especially nucleolytic enzymes, are poorly described. Here, we characterized a novel putative PD-(D/E)XK nuclease encoded by the human C20orf72 gene named Ddk1 for its predicted catalytic residues. We show that Ddk1 is a mitochondrially localized metal-dependent DNase lacking detectable ribonuclease activity. Ddk1 degrades DNA mainly in a 3'-5' direction with a strong preference for single-stranded DNA. Interestingly, Ddk1 requires free ends for its activity and does not degrade circular substrates. In addition, when a chimeric RNA-DNA substrate is provided, Ddk1 can slide over the RNA fragment and digest DNA endonucleolytically. Although the levels of the mitochondrial DNA are unchanged on RNAi-mediated depletion of Ddk1, the mitochondrial single-stranded DNA molecule (7S DNA) accumulates. On the other hand, overexperssion of Ddk1 decreases the levels of 7S DNA, suggesting an important role of the protein in 7S DNA regulation. We propose a structural model of Ddk1 and discuss its similarity to other PD-(D/E)XK superfamily members.


Minireview: Challenges and opportunities in development of PPAR agonists.
The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity.


[Influence of mental and emotional stress on the levels of electrolytes in the saliva of senior schoolchildren].
Salivary Na+,K+-excretory function was studied in senior schoolchildren-entrants during an academic year and entrance examinations. The time course of changes in the salivary levels of Na+ and K+ in entrants during an academic year was undulating. In late October that is coincident with the beginning of lessons given by tutors, the salivary content of Na+ reduced while that of K+ increased. The second peak of decreased excretion rates for Na+ and increased excretion rates for K+ and that of less Na+/K+ ratios was observed in May on the eve of entrance examinations. On the eve of the examinations, 70% were observed to have tachycardia, elevated levels of integral parameters of cardiac rhythm regulation, a considerable reduction in the concentration of Na+, and an increase in the level of K+ with less Na+/K+ ratios. The pattern of the observed changes also retained in the postexamination period. On the eve of the examinations, 30% were found to have lowered levels of integral parameters of cardiac rhythm regulation and elevated levels of Na+. After an examination, there was a reduction in Na+ excretion which did not yet achieve the initial level. The mechanisms responsible for ionic shifts in the composition of saliva during psychoemotional stress are discussed.


[Effect of ammonia treatment of peanut meal cake contaminated with A. flavus on nutritional value for the duckling].
Duckling are feeding peanut and meal detoxified or not by ammonia at the level of 25 p. 100. Control group are eating soybean meal at the same level. The raw protein content of diet is the same in each group. Experiment is carried out during four weeks, then duckling are killed. There is no significative difference between peanut meal detoxified and soybean meal relating to growth and food efficiency. Thus body weight is 775 and 764 g on duckling eating soybean meal; 764 and 827 g on duckling with peanut meal detoxified but only 472 and 452 g on birds with diet containing peanut meal not detoxified by NH3. Liver's weight is increased on these subjects. The ratio of liver weight to body weight X 100 is 5,49-4,79 and, respectively, 2,70-3,60 and 3,86-3,56 on duckling with detoxified peanut meal or controls eating soybean meal. Characteristic lesions of aflatoxicosis are developed on duckling consuming peanut meal not detoxified dosing about 285 mug/kg of Aflatoxin B1. Lesions are very slight, but present, on liver and kidney in detoxified peanut meal fed duckling. For kidney's lesions there are no differences between detoxified or not group, duckling eating detoxified peanut meal have absorbed 0,4 mug of Aflatoxin B1 during the eight first days of experiment and 8 to 10 mug during four weeks. These considerations explain light lesions observed and underlines duckling's sensitivity regarding aflatoxicosis.


Attenuative role of mangiferin in oxidative stress-mediated liver dysfunction in arsenic-intoxicated murines.
Mangiferin (MAG), a natural xanthone mainly derived from mangoes, possesses great antioxidative potentials. The present study has been carried out to investigate the hepato-protective role of MAG, against arsenic (As)-induced oxidative damages in the murine liver. As, a well-known toxic metalloid, is ubiquitously found in nature and has been reported to affect nearly all the organs of the human body via oxidative impairment. Administration of As in the form of sodium arsenite (NaAsO2 ) at a dose of 10 mg/kg body weight for 3 months abruptly increased reactive oxygen species (ROS) level, led to oxidative stress and significantly depleted the first line of antioxidant defense system in the body. Moreover, As caused apoptosis in hepatocytes. Treatment with MAG at a dose of 40 mg/kg for body weight for 30 days simultaneously and separately after NaAsO2 administration decreased the ROS production and attenuated the alterations in the activities of all antioxidant indices. MAG also protected liver against the NaAsO2 -induced apoptosis and disintegrated hepatocytes, thus counteracting with As-induced toxicity. It could significantly inhibit the expression of different proapoptotic caspases and upregulate the expression of survival molecules such as Akt and Nrf2. On inhibiting Akt (by PI3K inhibitor, LY294002) and ERK1/2 (by ERK1/2 inhibitor, PD98059) specifically, caspase 3 got activated abolishing mangiferin's protective role on As-induced hepatotoxicity. So here, we have briefly elucidated the signaling cascades involved in As-induced apoptotic cell death in the liver and also the detailed cellular mechanism by which MAG provides protection to this organ. © 2016 BioFactors, 42(5):515-532, 2016.


Manganese dioxide nanosheets induce mitochondrial toxicity in fish gill epithelial cells.
The development and production of engineered 2D nanomaterials are expanding exponentially, increasing the risk of their release into the aquatic environment. A recent study showed 2D MnO2 nanosheets, under development for energy and biomedical applications, dissolve upon interaction with biological reducing agents, resulting in depletion of intracellular glutathione levels within fish gill cells. However, little is known concerning their toxicity and interactions with subcellular organelles. To address this gap, we examined cellular uptake, cytotoxicity and mitochondrial effects of 2D MnO2 nanosheets using an in vitro fish gill cell line to represent a target tissue of rainbow trout, a freshwater indicator species. The data demonstrate cellular uptake of MnO2 nanosheets into lysosomes and potential mechanisms of dissolution within the lysosomal compartment. MnO2 nanosheets induced severe mitochondrial dysfunction at sub-cytotoxic doses. Quantitative, single cell fluorescent imaging revealed mitochondrial fission and impaired mitochondrial membrane potential following MnO2 nanosheet exposure. Seahorse analyses for cellular respiration revealed that MnO2 nanosheets inhibited basal respiration, maximal respiration and the spare respiratory capacity of gill cells, indicating mitochondrial dysfunction and reduced cellular respiratory activity. MnO2 nanosheet exposure also inhibited ATP production, further supporting the suppression of mitochondrial function and cellular respiration. Together, these observations indicate that 2D MnO2 nanosheets impair the ability of gill cells to respond to energy demands or prolonged stress. Finally, our data demonstrate significant differences in the toxicity of the 2D MnO2 nanosheets and their microparticle counterparts. This exemplifies the importance of considering the unique physical characteristics of 2D nanomaterials when conducting safety assessments.


Dual multivariate auto-regressive modeling in state space for temporal signal separation.
Many existing independent component analysis (ICA) approaches result in deteriorated performance in temporal source separation because they have not taken into consideration of the underlying temporal structure of sources. In this paper, we model temporal sources as a general multivariate auto-regressive (AR) process whereby an underlying multivariate AR process in observation space is obtained. In this dual AR modeling, the mixing process from temporal sources to observations is the same as the mixture from the nontemporal residuals of the source AR (SAR) process to that of the observation AR (OAR) process. We can therefore avoid the source temporal effects in performing ICA by learning the demixing system on the independently distributed OAR residuals rather than the time-correlated observations. Particularly, we implement this approach by modeling each source signal as a finite mixture of generalized autoregressive conditional heteroskedastic (GARCH) process. The adaptive algorithms are proposed to extract the OAR residuals appropriately online, together with learning the demixing system via a nontemporal ICA algorithm. The experiments have shown its superior performance on temporal source separation.


Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia.
Modern intensive chemotherapy regimens have improved the prognosis for patients with adult acute lymphocytic leukemia (ALL). With these regimens, the complete response rates are now reported to be > 80%, and the long-term survival rates range from 30% to 45%. The current analysis updated the long-term results with the original hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) program, with a median follow-up time of 63 months. Between 1992 and 2000, 288 patients were treated with Hyper-CVAD. The median age of the patients was 40 years, and 59 patients (20%) were > or = age 60 years. The incidence of Philadelphia chromosome (Ph)-positive ALL was 17%, and the incidence of of T-cell ALL was 13%. A complete response (CR) was achieved in 92% of patients. The induction mortality rate was 5% (2% if the patient's age was < 60 years, and 15% if the patient's age was > or = 60 years). With a median follow-up time of 63 months, the 5-year survival rate was 38% and the 5-year CR duration rate was 38%. Multivariate analysis of prognostic factors for CR duration identified the following adverse factors: age > or = 45 years, leukocytosis > or = 50 x 10(9)/L, poor performance status (an Eastern Cooperative Oncology Group score of 3-4), Ph-positive disease, French-American-British L2 morphology, > 1 course to achieve CR, and Day 14 bone marrow blasts > 5%. Patients were divided into low-risk (risk score 0-1; 37%), intermediate risk (risk score 2-3; 36%), and poor-risk groups (risk score > or = 4; 27%) with 5-year CR duration rates of 52%, 37%, and 10%, respectively. Compared with the previous VAD regimens, Hyper-CVAD was associated with significantly better CR rates, CR duration, and survival. The long-term follow-up results of Hyper-CVAD were favorable. Comparison of Hyper-CVAD with other established adult ALL regimens is warranted.


Phenotype variability and different genotype of four patients with thyroid hormone resistance syndrome due to variants in the THRB gene.
Resistance to thyroid hormone (RTH) is a rare dominantly inherited disorder mainly due to variants in the THRB gene leading to decreased end-organ responsiveness to thyroid hormones. Clinical and molecular characteristics of four patients with RTH are described. Four patients with various phenotypes were studied; two prepubertal boys and two adults (one male and one female). Sequencing analysis of the THRB was performed. All individuals had persistently elevated free thyroxine and/or free triiodothyronine associated with non-suppressed thyroid-stimulating hormone (TSH), and all had non-autoimmune goiters of various sizes. In both adults, antithyroid drugs were previously administered without successful suppression of the thyroid hormones. The 27-year-old female had resting tachycardia as the only symptom. The 35-year-old male had a degree of cognitive impairment and was initially diagnosed with atrial fibrillation. The eight-year-old boy was diagnosed with attention deficit disorder and had resting tachycardia. The oldest boy (age nine years) underwent thyroid function tests as a part of the investigation for obesity and learning difficulties. Direct sequencing analysis of the THRB gene showed three previously reported variants: p.His435Leu (c.1304A>T) in the 35-year-old male, p.Pro453Thr (c.1357C>A) in the oldest boy, and p.Arg438Cys (c.1312C>T) variant in the other two patients. Various phenotypes characterize common variants in the THRB gene, asymptomatic, thyroid hormone deprivation symptoms, or thyroid hormone excess symptoms. RTH should be suspected in both adults and children with elevated thyroid hormones and not suppressed TSH. A prompt molecular diagnosis and genetic counseling could prevent unnecessary tests and inappropriate treatments. HIPPOKRATIA 2019, 23(3): 135-139.


Biochemical and immunological studies of nucleocapsid proteins of severe acute respiratory syndrome and 229E human coronaviruses.
Severe acute respiratory syndrome (SARS) is a serious health threat and its early diagnosis is important for infection control and potential treatment of the disease. Diagnostic tools require rapid and accurate methods, of which a capture ELISA method may be useful. Toward this goal, we have prepared and characterized soluble full-length nucleocapsid proteins (N protein) from SARS and 229E human coronaviruses. N proteins form oligomers, mostly as dimers at low concentration. These two N proteins degrade rapidly upon storage and the major degraded N protein is the C-terminal fragment of amino acid (aa) 169-422. Taken together with other data, we suggest that N protein is a two-domain protein, with the N-terminal aa 50-150 as the RNA-binding domain and the C-terminal aa 169-422 as the dimerization domain. Polyclonal antibodies against the SARS N protein have been produced and the strong binding sites of the anti-nucleocapsid protein (NP) antibodies produced were mapped to aa 1-20, aa 150-170 and aa 390-410. These sites are generally consistent with those mapped by sera obtained from SARS patients. The SARS anti-NP antibody was able to clearly detect SARS virus grown in Vero E6 cells and did not cross-react with the NP from the human coronavirus 229E. We have predicted several antigenic sites (15-20 amino acids) of S, M and N proteins and produced antibodies against those peptides, some of which could be recognized by sera obtained from SARS patients. Antibodies against the NP peptides could detect the cognate N protein clearly. Further refinement of these antibodies, particularly large-scale production of monoclonal antibodies, could lead to the development of useful diagnostic kits for diseases associated with SARS and other human coronaviruses.


Clinical evaluation of guidelines and two-test approach for lyme disease.
The diagnosis of Lyme disease should be based on objective clinical signs and symptoms. In a clinical study, we have evaluated whether the recommended two-step approach for serodiagnosis of Lyme disease is useful in daily clinical practice and can influence clinical decision making. The signs and symptoms of patients with ongoing musculoskeletal complaints, assumed by their referring physician or themselves to be attributable to active or chronic Lyme disease, and of patients diagnosed as having Lyme disease, were evaluated. On the basis of clinical evaluation only, patients were classified into three groups: previous Lyme disease, active Lyme disease and no Lyme disease. Antibodies to Borrelia burgdorferi were determined by means of an enzyme-linked immunosorbent assay (ELISA), followed, when positive, by immunoblotting. One hundred and three patients (41 males and 62 females, mean age 48.7 yr) participated in the study. Of the 49 patients classified as previous Lyme disease, 25 (51%) had antibodies to B. burgdorferi. All 10 patients with active Lyme disease had positive antibodies and 12 of the 44 patients (27%) classified as no Lyme disease had positive antibodies. No statistically significant differences were found between the percentage of positive immunoblots from patients with previous Lyme disease (72%) and patients with active Lyme disease (100%). In the group of no Lyme disease, five out of 12 patients had a negative immunoblot. Concerning serological testing, immunoblotting could have added additional information. However, immunoblotting did not influence clinical decision making in this group of patients. Immunoblotting did not influence clinical decision making for the 47 patients with antibodies to B. burgdorferi in this study.


Removal and excretion of immunoreactive rat growth hormone by the isolated kidney.
The renal uptake of immunoreactive rat growth hormone (rGH), molecular weight 21,500 daltons, was examined in the isolated perfused rat kidney to determine whether peritubular removal of a protein greater than 12,000 daltons occurs and to assess the functional characteristics of renal GH uptake. Organ clearance of rGH (OCGH) in control kidneys was 1,039 +/- 99 microliters/min and was unaffected by an excess of insulin but markedly depressed by col (10 degrees C( and KCN. Although glomerular filtration rate (GFR) did not differ significantly from OCGH in the control rats, we suspected that filtration could not account for all the rGH removed because of glomerular protein sieving. However, GFR was significantly less than OCGH with cold and KCN treatment, indicating the occurrence of peritubular removal. In nonfiltering kidneys, rGH removal exceeded that of [14C]inulin (P less than 0.05), demonstrating peritubular rGH removal. Tubular absorption of rGH was unaffected by insulin but markedly depressed by cold and KCN. We conclude that rGH is removed from the renal circulation mainly by the glomerular filtration-tubular absorptive pathway, but, in addition, as with smaller proteins, that peritubular removal occurs.


Quantitation by competitive PCR assay of vascular endothelial growth factor in non-small cell lung carcinomas.
The vascular endothelial growth factor (VEGF) is known to be one of the most important angiogenic factors under both physiological and pathological conditions. The VEGF overexpression by a wide spectrum of neoplastic diseases has suggested an important role of this cytokine in tumor-neovascularization. A method is described for quantification by reverse transcription-polymerase chain reaction (RT-PCR) of VEGF mRNA in non-small cell lung cancer tissues (NSCLC). The method entails addition to the sample of competitor DNA molecules that share the same primer recognition sites as the amplified target, but which can be easily distinguished by gel electrophoresis because of their different lengths (competitive PCR). We analyzed the VEGF mRNA expression level in 34 cases of lung tumor tissues compared to the respective adjacent normal tissues. In 4 out of 34 (11.7%) analyzed couples there was no VEGF mRNA expression, in 8 out of 34 (23.5%) only normal parenchymal tissue was positive for VEGF mRNA expression; in the remaining 22 cases (64. 7%) both normal and tumor tissues showed PCR products for VEGF. In 17 out of these 22 couples (77.2%) a higher number of VEGF mRNA molecules were present in tumor specimens than in the normal counterpart. According to these results, the competitive PCR-method seems to provide a useful tool for the quantitate VEGF expression in order to identify its role in the development of lung cancer.


Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systematic review and meta-analysis of randomized trials.
Brachial plexus nerve blocks (BPBs) have analgesic and opioid sparing benefits for upper extremity surgery. Single-injection techniques are limited by the pharmacological duration and therapeutic index of local anaesthetics (LAs). Continuous catheter techniques, while effective can present management challenges. Off-label use of perineural dexamethasone as an LA adjuvant has been utilized to prolong single-injection techniques. The objectives of this systematic review and meta-analysis are to assess the contemporary literature and quantify the effects of dexamethasone on BPB. The authors searched for randomized, placebo-controlled trials that compared BPB performed with LA alone with that performed with LA and perineural dexamethasone. Meta-analysis was performed using a random effects model with subgroup analysis stratified by LA (long vs intermediate). The primary outcome was duration of sensory block or analgesia; the secondary outcomes were motor block duration, opioid consumption, and BPB complications. Nine trials (801 patients) were included with 393 patients receiving dexamethasone (4-10 mg). Dexamethasone prolonged the analgesic duration for long-acting LA from 730 to 1306 min [mean difference 576 min, 95% confidence interval (CI) 522-631] and for intermediate from 168 to 343 min (mean 175, 95% CI 73-277). Motor block was prolonged from 664 to 1102 min (mean 438, 95% CI 89-787). The most recent trial demonstrated equivalent prolongation with perineural or systemic administration of dexamethasone compared with placebo. Perineural administration of dexamethasone with LA prolongs BPB effects with no observed adverse events. The effects of systemic administration of dexamethasone on BPB must be investigated.


HR-HPV E6/E7 mRNA In Situ Hybridization: Validation Against PCR, DNA In Situ Hybridization, and p16 Immunohistochemistry in 102 Samples of Cervical, Vulvar, Anal, and Head and Neck Neoplasia.
Dysregulated expression of oncogenic types of E6 and E7 is necessary for human papillomavirus (HPV)-driven carcinogenesis. An HPV E6/E7 mRNA in situ hybridization (ISH) assay covering 18 common high-risk types ("HR-RISH," aka HR-HPV RNA18 ISH) has not been extensively studied in the anogenital tract or validated on automated technology. We herein compare HR-RISH to DNA polymerase chain reaction (PCR), p16 immunohistochemistry, and a previously available HPV DNA ISH assay in HPV-related anogenital and head and neck (H&N) neoplasia. A total of 102 squamous intraepithelial lesions (16 CIN1, 25 CIN3, 3 AIN1, 12 AIN3, 9 VIN3)/invasive squamous cell carcinomas (17 cervical, 2 anal, 18 H&N) as well as 10 normal and 15 reactive cervix samples were collected. HR-RISH, DNA ISH, and p16 immunohistochemistry were performed on whole formalin-fixed, paraffin-embedded sections. RNA ISH for 6 low-risk HPV types (LR-RISH) was also performed. RNA and DNA ISH assays used automated systems. HR-HPV PCR was performed on morphology-directed formalin-fixed, paraffin-embedded punches. HR-RISH was ≥97% sensitive for PCR+ and p16+ neoplasia, as well as morphologically defined anogenital high grade squamous intraepithelial lesion/invasive squamous cell carcinoma. HR-RISH was also positive in 78% of anogenital low grade squamous intraepithelial lesion, including 81% of CIN1. Furthermore, a subset of PCR-negative/invalid and p16-negative lesions was positive for HR-RISH. Only 1 problematic reactive cervix sample and no normal cervix samples stained. These results demonstrate that HR-RISH is a robust method for the detection of HR-HPV-related neoplasia and provides insight into HPV pathobiology. Performance meets or exceeds that of existing assays in anogenital and H&N lesions and may play a role in resolving diagnostically challenging CIN1 versus reactive cases.


Biomechanical evaluations of various c1-c2 posterior fixation techniques.
A biomechanical in vitro study using human cadaveric spine. To compare the biomechanical stability of pedicle screws versus various established posterior atlantoaxial fixations used to manage atlantoaxial instability. Rigid screw fixation of the atlantoaxial complex provides immediate stability and excellent fusion success though has a high risk of neurovascular complications. Some spine surgeons thus insert shorter C2 pedicle or pars/isthmus screws as alternatives to minimize the latter risks. The biomechanical consequences of short pedicle screw fixation remain unclear, however. Seven human cadaveric cervical spines with the occiput attached (C0-C3) had neutral zone (NZ) and range of motion (ROM) evaluated in three modes of loading. Specimens were tested in the following sequence: initially (1) the intact specimens were tested, after destabilization of C1-C2, then the specimens underwent (2) C1 lateral mass and C2 short pedicle screw fixation (PS-S), (3) C1 lateral mass and C2 long pedicle screw fixation (PS-L), (4) C1 lateral mass and C2 intralaminar screw fixation (ILS), (5) Sonntag's modified Gallie fixation (MG) and (6) C1-C2 transarticular screw fixation with posterior wiring (TAS 1 MG). (7) The destabilized spine was also tested. All instrumented groups were significantly stiffer in NZ and ROM than the intact spines, except in lateral bending, which was statistically significantly increased in the TAS 1 MG group. The MG group's NZ and ROM values were statistically significantly weaker than those of the PS-S, PS-L, and the ROM values of the TAS 1 MG groups. The ILS group's NZ values were higher than those of the TAS 1 MG group and for ROM, than that of the PS-S and PS-L groups. In flexion, the NZ and ROM values of the TAS 1 MG group were significantly less than those of the PS-S, PS-L, ILS, and MG groups. In axial rotation, the NZ and ROM values of the MG group were statistically significantly higher than those of the PS-S, PS-L, ISL and TAS 1 MG groups. The TAS 1 MG procedures provided the highest stability. The MG method alone may not be adequate for atlantoaxial arthrodesis, because it does not provide sufficient stability in lateral bending and rotation modes. The C2 pedicle screw and C2 ILS techniques are biomechanically less stable than the TAS 1 MG. In the C1 lateral mass-C2 pedicle screw fixation, the use of a short pedicle screw may be an alternative when other screw fixation techniques are not feasible.


Shared buccal mucosal graft for simultaneous repair of severe upper and lower eyelid cicatricial entropion.
Cicatricial entropion is typically an acquired condition that can affect the upper and lower eyelids. The purpose of this prospective study is to examine the effect of shared buccal mucosal grafts for simultaneous repair of severe upper and lower eyelid cicatricial entropion on eyelid position. Patients at the University of Texas-Southwestern Medical Center Aston Ophthalmology clinic were identified who were diagnosed with cicatricial entropion. Patients found to have severe upper and lower eyelid cicatricial entropion were included in the study if they had undergone or were scheduled to undergo simultaneous upper and lower eyelid repair through the use of a shared mucosal graft. Pre-operative exams which included pre-operative photos and description of eyelid position were performed. Shared mucosal graft surgery was performed. At post-operative week 1, the patients had splitting of their shared mucosal grafts. Post-operative photos as well as post-operative description of eyelid position were made at 6 weeks, 3 months, and 6 months. At 6 months after surgical repair of severe upper and lower eyelid cicatricial entropion by shared mucosal grafts, patients were found to have resolution of entropic eyelid position as well improvement in ocular surface irritation. No adverse events were found and no graft failures occurred. The use of a shared mucosal graft for the repair of severe upper and lower eyelid entropion, when sufficient tarsal structural support is present, is effective for the correction of eyelid malpositions and ocular surface irritation.


Estimating Protistan Diversity Using High-Throughput Sequencing.
Sequencing hypervariable regions from the 18S rRNA gene is commonly employed to characterize protistan biodiversity, yet there are concerns that short reads do not provide the same taxonomic resolution as full-length sequences. A total of 7,432 full-length sequences were used to perform an in silico analysis of how sequences of various lengths and target regions impact downstream ecological interpretations. Sequences that were longer than 400 nucleotides and included the V4 hypervariable region generated results similar to those derived from full-length 18S rRNA gene sequences. Present high-throughput sequencing capabilities are approaching protistan diversity estimation comparable to whole gene sequences.


Metabolomic Diversity and Identification of Antibacterial Activities of Bacteria Isolated From Marine Sediments in Hawai'i and Puerto Rico.
Antibiotic resistance is a growing concern worldwide and consequently metabolomic tools are being applied increasingly in efforts aimed at identifying new antimicrobial compounds. Marine bacteria-derived compounds have shown great promise in this area. A metabolomics-based study was undertaken to study the diversity of secondary metabolites from marine sediment bacteria isolated from different locations of Hawai'i and Puerto Rico. This effort included characterizing the biodiversity in the sediment samples and searching for antibacterial activity and associated compounds. Bacterial strains were isolated using several different nutrient agars and culture conditions. DNA sequencing (16s rDNA) was used for phylogenetic characterization. Antibacterial activity was assessed against antibiotic-resistant strains of Escherichia coli, Salmonella enterica, Acinetobacter baumannii, Staphylococcus aureus, and Enterococcus faecalis. Ethyl acetate extracted bacterial secondary metabolites were measured by ultra-performance liquid chromatography-mass spectrometry, processed in Progenesis QI and further analyzed by partial least squares-discriminant analysis using MetaboAnalyst 3. Among the strains (n = 143) that were isolated from these two geographical areas and tested for antibiotic activity, 19 exhibited antibacterial activity against at least one antibiotic-resistant human pathogen. One strain from Hawai'i possessed broad-spectrum activity against all five pathogens. Metabolite profiles were diverse and separated the strains into two clusters in PCA analysis that mirrored geographical origin of the isolated strains. A diversity of bacteria and potential antibacterial compounds were observed in this study. Marine environments represent an opportunity to discover a rich diversity of antibacterial compounds for which resistance mechanisms may be uncommon in human pathogens.


Melatonin, a promising role in taxane-related neuropathy.
Melatonin has neuroprotective effects in animal studies and has been suggested to decrease adverse reactions of chemotherapy including neuropathy. This pilot trial aimed at assessing whether melatonin, given during taxane chemotherapy for breast cancer, will decrease the incidence and/or severity of neuropathy. Twenty two consecutive patients beginning chemotherapy for breast cancer with paclitaxel, or docetaxel were enrolled. Patients received melatonin 21 mg daily at bedtime. Incidence and severity of neuropathy were assessed using neurological examinations, toxicity assessment per NCI-CTC 3.0 scale and FACT-Taxane quality of life questionnaire. Neuropathy was seen in 45% (n = 10) of patients, 23% (n = 6) grade 1 and 22% (n = 5) Grade 2 neuropathy. No grade 3 neuropathies were reported. The majority (55%) of all patients reported no neuropathy. Compliance with melatonin (>60% of dose) was seen in most patients (86%) No patient reported daytime sedation. The median FACT-Taxane quality of life end of study score was 137, with only a 0.5 median decline from baseline. Patients receiving melatonin during taxane chemotherapy had a reduced incidence of neuropathy. Melatonin may be useful in the prevention or reduction of taxane-induced neuropathy and in maintaining quality of life. Larger trials are warranted to further explore the role of melatonin in neuropathy treatment and prevention.


STI Health Disparities: A Systematic Review and Meta-Analysis of the Effectiveness of Preventive Interventions in Educational Settings.
The purpose of this systematic review and meta-analysis was to address disparities related to sexual health among students by examining the effectiveness of sexually transmitted infection (STI) preventive interventions in educational settings. PubMed, Medline, Cochrane Library, Public Health Database, and EMBASE databases were used to conduct searches. Information relating to studies, programs, participants, and quantitative outcome variables were extracted. Risk of bias was assessed and meta-analysis was conducted. This systematic review included 16 articles. The outcomes were classified into behavioral and psychosocial categories. The behavioral category included sexual partners, sexual activity, condom use, STI/HIV testing, and alcohol/drug use before sex. The psychosocial category consisted of knowledge, motivational factors, and skills. Interventions had a significantly positive impact on both behavioral (OR, 1.28; 95% CI, 1.17⁻1.39) and psychosocial (OR, 1.92; 95% CI, 1.36⁻2.72) outcomes. Among the psychosocial outcomes, the interventions were most effective at promoting knowledge (OR, 3.17; 95% CI, 2.13⁻4.72), followed by enhancing motivational factors (OR, 1.69; 95% CI, 1.04⁻2.75) and increasing behavioral skills (OR, 1.43; 95% CI, 1.13⁻1.81). The results of this systematic review provide empirical evidence for public health professionals and policy makers regarding planning, implementation, evaluation, and modification of STI preventive intervention programs in educational settings.


Quantifying the contribution of pincer deformity to femoro-acetabular impingement using 3D computerised tomography.
To provide a simple, reliable method for the three-dimensional quantification of pincer-type hip deformity. Computerised tomography scans of 16 normal female hips and 15 female hips with clinical femoro-acetabular impingement (FAI) and radiographic signs of pincer secondary to acetabular protrusio were analysed. After orientating the pelvis in the anterior pelvic plane, the acetabular centre was determined, and the ratios of its coordinates to the corresponding pelvic dimensions were calculated. Acetabular coverage of the femoral head and centre-edge angles were also measured for the two groups. In hips with a pincer, the hip was medialised by 37 % (p = 0.03), more proximal by 5 % (p = 0.05) and more posterior by 9 % (p = 0.03) compared with the normal hips. Coverage of the femoral head in protrusio hips was significantly greater than normal (average 71 % vs 82 %, p = 0.0001). Both the lateral centre-edge angle and the combined anterior-posterior centre-edge angle were greater in protrusio hips than in the normal ones (48° vs 37 °, p < 0.001; and 216° vs 176°, p < 0.0001 respectively). Displacement in acetabular protrusio occurs in all planes. This CT-based method allows for the accurate and standardised quantification of the extent of displacement, as well as 3D measurement of femoral head coverage. In the adult female population, a combined centre-edge angle of over 190° suggests an acetabulum that is too deep and a potential cause of symptoms of femoro-acetabular impingement. Conversely, an acetabulum that has a combined centre-edge angle of less than 190° may be considered to be of normal depth, and therefore not contributing a pincer to FAI should it occur.


Nuclear envelope assembly defects link mitotic errors to chromothripsis.
Defects in the architecture or integrity of the nuclear envelope are associated with a variety of human diseases1. Micronuclei, one common nuclear aberration, are an origin for chromothripsis2, a catastrophic mutational process that is commonly observed in cancer3-5. Chromothripsis occurs after micronuclei spontaneously lose nuclear envelope integrity, which generates chromosome fragmentation6. Disruption of the nuclear envelope exposes DNA to the cytoplasm and initiates innate immune proinflammatory signalling7. Despite its importance, the basis of the fragility of the micronucleus nuclear envelope is not known. Here we show that micronuclei undergo defective nuclear envelope assembly. Only 'core' nuclear envelope proteins8,9 assemble efficiently on lagging chromosomes, whereas 'non-core' nuclear envelope proteins8,9, including nuclear pore complexes (NPCs), do not. Consequently, micronuclei fail to properly import key proteins that are necessary for the integrity of the nuclear envelope and genome. We show that spindle microtubules block assembly of NPCs and other non-core nuclear envelope proteins on lagging chromosomes, causing an irreversible defect in nuclear envelope assembly. Accordingly, experimental manipulations that position missegregated chromosomes away from the spindle correct defective nuclear envelope assembly, prevent spontaneous nuclear envelope disruption, and suppress DNA damage in micronuclei. Thus, during mitotic exit in metazoan cells, chromosome segregation and nuclear envelope assembly are only loosely coordinated by the timing of mitotic spindle disassembly. The absence of precise checkpoint controls may explain why errors during mitotic exit are frequent and often trigger catastrophic genome rearrangements4,5.


The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease.
To identify rates of and risk factors for psychiatric diagnosis preceding the diagnosis of neurodegenerative disease. Systematic, retrospective, blinded chart review was performed of 252 patients with a neurodegenerative disease diagnosis seen in our specialty clinic between 1999 and 2008. Neurodegenerative disease diagnoses included behavioral-variant frontotemporal dementia (n = 69), semantic dementia (n = 41), and progressive nonfluent aphasia (n = 17) (all meeting Neary research criteria); Alzheimer's disease (n = 65) (National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association research criteria); corticobasal degeneration (n = 25) (Boxer research criteria); progressive supranuclear palsy (n = 15) (Litvan research criteria); and amyotrophic lateral sclerosis (n = 20) (El Escorial research criteria). Reviewers remained blinded to each patient's final neurodegenerative disease diagnosis while reviewing charts. Extensive caregiver interviews were conducted to ensure accurate and reliable diagnostic histories. For each patient, we recorded history of psychiatric diagnosis, family psychiatric and neurologic history, age at symptom onset, and demographic information. A total of 28.2% of patients with a neurodegenerative disease received a prior psychiatric diagnosis. Depression was the most common psychiatric diagnosis in all groups. Behavioral-variant frontotemporal dementia patients received a prior psychiatric diagnosis significantly more often (50.7%; P < .001) than patients with Alzheimer's disease (23.1%), semantic dementia (24.4%), or progressive nonfluent aphasia (11.8%) and were more likely to receive diagnoses of bipolar disorder or schizophrenia than were patients with other neurodegenerative diseases (P < .001). Younger age (P < .001), higher education (P < .05), and a family history of psychiatric illness (P < .05) increased the rate of prior psychiatric diagnosis in patients with behavioral-variant frontotemporal dementia. Cognitive, behavioral, and emotional characteristics did not distinguish patients who did or did not receive a prior psychiatric diagnosis. Neurodegenerative disease is often misclassified as psychiatric disease, with behavioral-variant frontotemporal dementia patients at highest risk. While this study cannot rule out the possibility that psychiatric disease is an independent risk factor for neurodegenerative disease, when patients with neurodegenerative disease are initially classified with psychiatric disease, the patient may receive delayed, inappropriate treatment and be subject to increased distress. Physicians should consider referring mid- to late-life patients with new-onset neuropsychiatric symptoms for neurodegenerative disease evaluation.


Comparative anatomy of the rotator cuff.
While the evolution of the bony skeleton of the shoulder girdle is well described, there is little information regarding the soft tissues, in particular of the rotator cuff. We dissected the shoulders of 23 different species and compared the anatomical features of the tendons of the rotator cuff. The alignment and orientation of the collagen fibres of some of the tendons were also examined histologically. The behaviour of the relevant species was studied, with particular reference to the extent and frequency of forward-reaching and overhead activity of the forelimb. In quadrupedal species, the tendons of supraspinatus, infraspinatus and teres minor were seen to insert into the greater tuberosity of the humerus separately. They therefore did not form a true rotator cuff with blending of the tendons. This was only found in advanced primates and in one unusual species, the tree kangaroo. These findings support the suggestion that the appearance of the rotator cuff in the evolutionary process parallels anatomical adaptation to regular overhead activity and the increased use of the arm away from the sagittal plane.


Antiviral prophylaxis in patients with solid tumours and haematological malignancies--update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO).
Reactivation of viral infections is common in patients with solid tumour or haematological malignancy. Incidence and severity depend on the extent of cellular immunosuppression. Antiviral prophylaxis may be effective to prevent viral reactivation. In 2006, the Infectious Diseases Working Party of German Society for Hematology and Medical Oncology (DGHO) published guidelines for antiviral prophylaxis in these patient populations. Here, we present an update of these guidelines for patients with solid and haematological malignancies undergoing antineoplastic treatment but not allogeneic stem cell transplantation. Relevant literature for reactivation of different viruses (herpes simplex virus (HSV), varicella zoster virus (VZV), hepatitis B virus (HBV) and respiratory viruses) is discussed to provide evidence-based recommendations for clinicians taking care of this patient population. We recommend a risk-adapted approach with (val)acyclovir against HSV and VZV in patients treated with alemtuzumab, bortezomib or purine analogues. Seasonal vaccination against influenza is recommended for all patients with solid or haematological malignancies regardless of antineoplastic therapy. Hepatitis B screening is recommended in lymphoproliferative disorders, acute leukaemia, and breast cancer, and during treatment with monoclonal anti-B-cell antibodies, anthracyclines, steroids and in autologous stem cell transplantation. In those with a history of hepatitis B prophylactic lamivudine, entecavir or nucleotide analogues as adefovir are recommended to prevent reactivation.


[Entry of cyclic nucleotides into frog muscles in vivo and in vitro].
The radioactive isotopes of cyclic nucleotides were used to study the possibility of their income to the isolated frog muscle from the environment as well as their distribution between blood plasma and muscle after injection to an animal. It is shown that the intracellular levels of nucleotides may be considerably higher after soaking the isolated muscle in 10(-6) M cGMP or 10(-4) cAMP solutions. After the cAMP injection into the lymphatic sac its content in blood and especially in muscles is high for a long time. In this case the label loss in muscles proceeds slower than in blood. A conclusion is drawn that conduction of studies on the artificial increase of the intracellular level of cyclic nucleotides by means of their injection to an animal is appropriate.


Acetaminophen toxicity: suicidal vs. accidental.
Acetaminophen toxicity, which can lead to hepatotoxicity, is a burden on our health care system and contributes significantly to intensive care unit admissions and cost of hospitalization. The aim of our study was to determine the epidemiology of various types of acetaminophen poisoning and analyze their outcome compared with their admission characteristics. We identified 93 consecutive patients, hospitalized for acetaminophen toxicity over a 52-month period from 1996 to 1999 in our urban county hospital. Retrospective case-control analysis was carried out using the data obtained from the medical records. Acetaminophen accounted for 7.5% of all cases of poisoning admitted during this period. Of the 93 patients, 80 were classified as suicidal and 13 had accidentally poisoned themselves in an attempt to relieve pain. The ratio of females to males was found to be 2:1. Of the 93 patients studied, 88 were admitted to the intensive care unit for initial 24-48 hours of monitoring. Peak acetaminophen levels were higher in the suicidal overdose group (mean 121.7 +/- 97.0 mg/l vs. 64.5 +/- 61.8 mg/l, P < 0.05) than in the accidental group. In spite of this, peak aminotransferase levels >1000 IU/l were more often seen in the latter (39% vs. 12%, P < 0.05). Hepatic coma and death were seen more often in the accidental overdose group (15% vs 0%, P < 0.05). Interestingly chronic alcohol abuse was also more frequent in the accidental overdose category (39% vs 18%, P = 0.05). Although the peak acetaminophen level in the suicidal group was significantly higher, cases of therapeutic misadventure had higher rates of morbidity and mortality. Peak acetaminophen levels correlate poorly with hepatic dysfunction, morbidity and mortality. We recommend that the patients with suicidal acetaminophen overdose, without any concomitant poisoning, can safely managed on the medical floors.


Combined treatment with temporary short-term high dose rate iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma.
To evaluate the treatment outcome after radical radiotherapy of localized prostate cancer in 50 patients (38 patients with stage T1-2 and 12 patients with stage T3) after a median follow-up time of 45 months (range 18-92 months). The treatment was given by combination of external beam radiotherapy (50 Gy) and brachytherapy (2 x 10 Gy). The brachytherapy was given using TRUS-guided percutaneously inserted temporary needles with a high dose rate remote afterloading technique with Ir-192 as the radionuclide source. Three target definitions and dose levels inside the prostate gland were used. Local control was evaluated by digital rectal examination, TRUS-guided biopsies and serum PSA evaluations. Clinical and biopsy verified local control was achieved in 48 of the 50 (96%) patients; for stage T1-2 in 37 of 38 (97%) patients and for stage T3 in 11 of 12 (92%) patients. A posttreatment serum PSA level < or =1.0 ng/ml was seen in 42 (84%) patients, values from >1.0 to < or =2.0 ng/ml were seen in four (8%) patients and values exceeding 2.0 were seen in four (8%) patients. The late toxicity was minimal. The local control results and the minimal toxicity after the combined radiotherapy treatment are promising. However, long term results are necessary before general use.


[Detoxification gene polymorphisms and potential role of selection].
Based on published data on the occurrence of GST genes in various groups and populations, the authors have analyzed the potential role of polymorphism in the process of adaptation. The estimated dynamics of the occurrence of normal or deleted alleles makes it possible to assess a selection factor (S) in favor of heterozygotes / homozygotes by normal alleles. Its value can be 0.2-0.3.


Multicenter surveillance of species distribution and antifungal susceptibilities of Candida bloodstream isolates in South Korea.
Multicenter data on in vitro susceptibility of Candida bloodstream isolates to echinocandin antifungal agents is still lacking in South Korea. We performed a prospective multicenter study to determine the species distribution of Candida bloodstream isolates and their susceptibility to five antifungal agents, including caspofungin and micafungin. A total of 639 isolates were collected from 20 tertiary hospitals between September 2006 and August 2007. Antifungal susceptibilities were determined through the use of the CLSI broth microdilution method M27-A3. The overall species distribution was as follows; Candida albicans (38%), Candida parapsilosis (26%), Candia tropicalis (20%), Candida glabrata (11%), and miscellaneous Candida species (5%). Although C. parapsilosis and miscellaneous Candida species were less susceptible to both echinocandins, all 639 isolates were susceptible to both caspofungin and micafungin (MIC, <or= 2 microg/ml). Nearly all isolates (99.7%) had a MIC <or= 1 microg/ml to amphotericin B. Resistance to fluconazole and voriconazole was found in 0.8% and 0.3%, respectively, among all Candida isolates, with C. glabrata and C. krusei isolates displaying the greatest level of resistance. This is the largest multicenter candidemia study conducted in South Korea and shows that non-C. albicans Candida species, including C. parapsilosis, constitutes over 60% of all Candida species isolates recovered from the bloodstream. In addition, the rates of resistance to all five antifungals, including two echinocandins, are still low among bloodstream isolates in South Korea.


pH-dependent picosecond structural dynamics in the distal pocket of nitrophorin 4 investigated by 2D IR spectroscopy.
Nitrophorin 4 (NP4) belongs to a family of pH-sensitive, nitric oxide (NO) transporter proteins that undergo a large structural change from a closed to an open conformation at high pH to allow for NO delivery. Measuring the pH-dependent structural dynamics in NP4-NO around the ligand binding site is crucial for developing a mechanistic understanding of NO binding and release. In this study, we use coherent two-dimensional infrared (2D IR) spectroscopy to measure picosecond structural dynamics sampled by the nitrosyl stretch in NP4-NO as a function of pH at room temperature. Our results show that both the closed and open conformers of the protein are present at low (pD 5.1) and high (pD 7.9) pH conditions. The closed and open conformers are characterized by two frequencies of the nitrosyl stretching vibration labeled A0 and A1, respectively. Analysis of the 2D IR line shapes reveals that at pD 5.1, the closed conformer experiences structural fluctuations arising from solvation dynamics on a ∼3 ps time scale. At pD 7.9, both the open and closed conformers exhibit fluctuations on a ∼1 ps time scale. At both pD conditions, the closed conformers maintain a static distribution of structures within the experimental time window of 100 ps. This is in contrast to the open conformer, which is able to interconvert among its substates on a ∼100 ps time scale. Our results directly measure the time scales of solvation dynamics in the distal pocket, the flexibility of the open conformation at high pH, and the rigidity of the closed conformers at both pH conditions. We discuss how the pH-dependent equilibrium structural fluctuations of the nitrosyl ligand measured in this study are related to the uptake and delivery of nitric oxide in NP4.


Reye's syndrome and salicylate use.
During an outbreak of influenza A, seven patients with Reye's syndrome and 16 ill classmate control subjects were evaluated for characteristics of the patients' prodromal illness and the control subjects illness and for medication usage. Patients during the prodrome and control subjects had similar rates of sore throat, coryza, cough, headache, and gastrointestinal complaints except for documented fever which occurred significantly more often in patients than in control subjects (P = .05). While medications which did not contain salicylate were taken as frequently by patients as control subjects, patients took more salicylate-containing medications than did control children (P < .01). All seven patients took salicylate whereas only eight of 16 control subjects did so (P < .05). Patients took larger doses of salicylate than did the entire control group (P < .01). When the eight control subjects who took salicylate were compared with the patients, the patients still tended to take larger doses (P = .08). Patients with fever took salicylate more frequently than control subjects with fever (P < .01). In addition, salicylate consumption was correlated with severity of Reye's syndrome (P < .05). It is postulated that salicylate, operating in a dose-dependent manner, possibly potentiated by fever, represents a primary causative agent of Reye's syndrome.


Trichomonas vaginalis infection in men who submit self-collected penile swabs after internet recruitment.
Submission of self-collected penile samples collected at home could remove barriers that men face in getting tested for sexually transmitted infections (STIs). From December 2006 to July 2012, sexually active men aged ≥14 years were recruited by an educational internet program (http://www.iwantthekit.org) which offered free testing for Trichomonas vaginalis infection. Kits were ordered online and swabs were sent via US mail to the laboratory and tested by nucleic acid amplification tests. Demographics and sexual risk factors were accessed by questionnaires. Men called or were contacted to receive their results. Risk factors for trichomonas infection were determined by multivariate logistic regression Of 4398 men requesting kits, 1699 (38.6%) returned swabs by mail (55.4% returned in 2012). Forty-one percent of men were aged <25 years, 43% were black subjects and 45% were white. The overall prevalence for trichomonas in the 1699 men was 3.7%; the highest prevalence by age group was for men aged 40-49 years (5.2%) and, by year, 216 men screened in 2008 had the highest prevalence (12.5%). Risk factors for 919 men whose risk information was collected by questionnaire (prevalence 6.0%) indicated that 9.6% had a concurrent chlamydia infection. Significantly associated risks factors included: black race (adjusted OR 2.67), residence in Illinois (OR 12.02), age 30-39 years (OR 6.63) and age >40 years (OR 5.31). A fairly high prevalence of trichomonas and sexual risk factors were demonstrated from internet recruitment of men. This method of engaging men to get screened for trichomonas may augment screening in STI clinics.


Effect of oxidative stress and acidosis on diaphragm contractile function.
Acidosis during exercise has long been associated with skeletal muscle fatigue. Recent evidence also has linked reactive oxygen species (ROS) with fatigue in skeletal muscle, including the diaphragm. We hypothesized that acidosis (designed to mimic blood pH during maximal exercise) would worsen ROS-induced depression of diaphragm contractility. The xanthine oxidase (XO) reaction in solution (0.01 U/ml) allows direct assessment of the effects of oxidant stress by ROS. Costal diaphragm fiber bundles from 24 Sprague-Dawley rats (200-250 g) were divided into four treatment groups: 1) pH 7.4, no XO (H); 2) pH 7.4 + XO (HXO); 3) pH 7.0, no XO (L); and 4) pH 7.0 + XO (LXO). Baseline twitch mechanics and force-frequency relationships (Pre) were determined in control Krebs solution (pH 7.4, no XO) before treatment. Treatment solutions were introduced, and the diaphragm underwent 2 min of contractions at 25 Hz (250 ms) at a rate of 1/s. After 10 min of recovery, the control solution was reintroduced into the bath and postcontractile function (Post) was measured. Significant reductions in twitch tension and low-frequency tetanic tension were greater in HXO and LXO compared with H, without an effect on maximal tetanic tension. One-half relaxation time was prolonged only by the combination of acidosis and oxidative stress. Addition of superoxide dismutase (50 U/ml) worsened and catalase (1,800 U/ml) attenuated XO-induced depression of diaphragm contractility. We concluded that XO induced a reduction of low-frequency tension in the fatigued diaphragm, which was mediated directly or indirectly through hydrogen peroxide and was exacerbated to a modest extent with acidosis.


[Paronychia and the formation of granulation tissue during isotretinoin therapy].
This paper reports on the association of two uncommon side effects of isotretinoin therapy for cystic acne: paronychia and excess granulation tissue in the nail sulci. An explanation for these side effects is suggested, but the exact pathogenesis remains obscure.


A comparison of the effects of tixocortol pivalate (JO 1016), hydrocortisone acetate and beclomethasone dipropionate on collagen synthesis and degradation.
The effects of a corticosteroid substitute pregn-4-ene-3,20-dione-11 beta,17 alpha-dihydroxy-21-pivalate (tixocortol, JO 1016, Pivalone), hydrocortisone acetate and beclomethasone dipropionate on collagen metabolism in mouse calvariae were compared by histological and biochemical determination of collagen content, and by radio-assays of collagenase and collagenase inhibitor. Hydroxyproline assay revealed dose-related increases in collagen content/wet wt. tissue. These were greatest in explants treated with beclomethasone dipropionate, tixocortol pivalate being effective only at much higher concentrations than the other 2 drugs. Hydrocortisone acetate and beclomethasone dipropionate stimulated collagenase production at the lowest levels tested whereas tixocortol pivalate was only slightly stimulatory at the highest treatment level. These results suggest that in clinical use tixocortol pivalate would be much less likely than hydrocortisone acetate or beclomethasone dipropionate to cause degenerative changes in connective tissue.


Cloning and adoption: a reply to Levy and Lotz.
In previous articles I discussed the ethics of human reproductive cloning, focusing on a possible future scenario in which reproductive cloning can be accomplished without an elevated risk of anomalies to the children who are created. I argued that in such a scenario it would be ethically permissible for infertile couples to use cloning as a way to have genetically related children and that such use should not be prohibited. In 'Reproductive Cloning and a (Kind of) Genetic Fallacy', Neil Levy and Mianna Lotz raise objections to my conclusions. They disagree with the view, for which I argued, that some couples can have defensible reasons for desiring genetically related children. They also offer several new arguments against reproductive cloning, including an argument that it would diminish the number of adoptions, thereby adversely affecting the welfare of children who need to be adopted. In this paper I point out that Levy and Lotz's criticisms misconstrue my arguments and that there are serious problems with their arguments for prohibiting infertile couples from using cloning, including their argument from adoption.


Neurosurgery in a patient with Creutzfeldt-Jakob disease after pituitary derived growth hormone therapy in childhood.
The case of a young man who had previously received pituitary derived growth hormone for treatment of radiation induced growth hormone deficiency is reported. He underwent neurosurgery for presumed recurrence of a posterior fossa tumour but was subsequently shown to have Creutzfeldt-Jakob disease, confirmed on necropsy. The risk of transmission of Creutzfeldt-Jakob disease by neurosurgical instruments is discussed. Since the occurrence of this case the Department of Health have issued guidelines concerning neurosurgery and ophthalmic surgery in patients who have previously received treatment with pituitary derived growth hormone and may therefore be at risk of developing Creutzfeldt-Jakob disease. Surgical instruments used on such patients should under no circumstances be reused, and should be destroyed after use.


Vulnerabilities to misinformation in online pharmaceutical marketing.
Given the large percentage of Internet users who search for health information online, pharmaceutical companies have invested significantly in online marketing of their products. Although online pharmaceutical marketing can potentially benefit both physicians and patients, it can also harm these groups by misleading them. Indeed, some pharmaceutical companies have been guilty of undue influence, which has threatened public health and trust. We conducted a review of the available literature on online pharmaceutical marketing, undue influence and the psychology of decision-making, in order to identify factors that contribute to Internet users' vulnerability to online pharmaceutical misinformation. We find five converging factors: Internet dependence, excessive trust in the veracity of online information, unawareness of pharmaceutical company influence, social isolation and detail fixation. As the Internet continues to change, it is important that regulators keep in mind not only misinformation that surrounds new web technologies and their contents, but also the factors that make Internet users vulnerable to misinformation in the first place. Psychological components are a critical, although often neglected, risk factor for Internet users becoming misinformed upon exposure to online pharmaceutical marketing. Awareness of these psychological factors may help Internet users attentively and safely navigate an evolving web terrain.