Role of the Ca2+-Calcineurin-Nuclear Factor of Activated T cell Pathway in Mitofusin-2-Mediated Immune Function of Jurkat Cells.
Mitofusin-2 (MFN2), a well-known mitochondrial fusion protein, has been shown to participate in innate immunity, but its role in mediating adaptive immunity remains poorly characterized. In this study, we explored the potential role of MFN2 in mediating the immune function of T lymphocytes. We manipulated MFN2 gene expression in Jurkat cells via lentiviral transduction of MFN2 small interfering RNA (siRNA) or full-length MFN2. After transduction, the immune response and its underlying mechanism were determined in Jurkat cells. One-way analysis of variance and Student's t-test were performed to determine the statistical significance between the groups. Overexpression of MFN2 enhanced the immune response of T lymphocytes by upregulating Ca2+ (359.280 ± 10.130 vs. 266.940 ± 10.170, P = 0.000), calcineurin (0.513 ± 0.014 vs. 0.403 ± 0.020 nmol/L, P = 0.024), and nuclear factor of activated T cells (NFATs) activation (1.040 ± 0.086 vs. 0.700 ± 0.115, P = 0.005), whereas depletion of MFN2 impaired the immune function of T lymphocytes by downregulating Ca2+ (141.140 ± 14.670 vs. 267.060 ± 9.230, P = 0.000), calcineurin (0.054 ± 0.030 nmol/L vs. 0.404 ± 0.063 nmol/L, P = 0.000), and NFAT activation (0.500 ± 0.025 vs. 0.720 ± 0.061, P = 0.012). Furthermore, upregulated calcineurin partially reversed the negative effects of MFN2 siRNA on T cell-mediated immunity evidenced by elevations in T cell proliferation (1.120 ± 0.048 vs. 0.580 ± 0.078, P = 0.040), interleukin-2 (IL-2) production (473.300 ± 24.100 vs. 175.330 ± 12.900 pg/ml, P = 0.000), and the interferon-γ/IL-4 ratio (3.080 ± 0.156 vs. 0.953 ± 0.093, P = 0.000). Meanwhile, calcineurin activity inhibitor depleted the positive effects of overexpressed MFN2 on T cells function. Our findings suggest that MFN2 may regulate T cell immune functions primarily through the Ca2+-calcineurin-NFAT pathway. MFN2 may represent a potential therapeutic target for T cell immune dysfunction-related diseases.


The Effects of a Normal Rate versus a Slow Intervalled Rate of Oral Nutrient Intake and Intravenous Low Rate Macronutrient Application on Psychophysical Function - Two Pilot Studies.
Stomach distension and energy per time are factors influencing satiety. Moreover, different rates of nutrient intake induce different stomach distension. The goal of our studies was to elucidate the influence of different oral rates of nutrient intake (normal rate versus slow intervalled rate; study I) and intravenous low rate macronutrient application (protein, carbohydrate, fat) or placebo (study II) on psychophysical function. The pilot studies investigated the effects of 1) study I: a mixed nutrient solution (1/3 protein, 1/3 fat, 1/3 carbohydrates) 2) study II: intravenous macronutrient infusions (protein, carbohydrate, fat) or placebo on psychophysical function (mood, hunger, food craving, alertness, smell intensity ratings and hedonic ratings) in human subjects. In study I 10 male subjects (age range: 21-30 years) completed the study protocol participating in both test conditions and in study II 20 male subjects (age range: 19-41 years) completed the study protocol participating in all test conditions. Additionally, metabolic function was analyzed and cognitive and olfactory tests were conducted twice starting 100 min before the beginning of the intervention and 240 min after. Psychophysical (mood, hunger, fat-, protein-, carbohydrate-, sweets- and vegetable-craving), alertness and metabolic function tests were performed seven times on each examination day. Greater effects on hunger and food cravings were observed for normal rate of intake compared to slow intervalled rate of intake and intravenous low rate macronutrient application. Our findings potentially confirm that volume of the food ingested and a higher rate of energy per time contribute to satiety during normal rate of food intake, while slow intervalled rate of food intake and intravenous low rate macronutrient application showed no effects on satiation. Our results motivate the view that a certain amount of volume of the food ingested and a certain energy per time ratio are necessary to reduce hunger and food craving.


The evaluation of bioelectrical activity of pelvic floor muscles depending on probe location: a pilot study.
The main objective was to determine how the depth of probe placement affects functional and resting bioelectrical activity of the PFM and whether the recorded signal might be dependent on the direction in which the probe is rotated. The study comprised of healthy, nulliparous women between the ages of 21 and 25. Bioelectric activity of the PFM was recorded from four locations of the vagina by surface EMG and vaginal probe. There were no statistically significant differences between the results during functional sEMG activity. During resting sEMG activity, the highest bioelectrical activity of the PFM was observed in the L1 and the lowest in the L4 and a statistically significant difference between the highest and the lowest results of resting sEMG activity was observed (P = 0.0043). Different electrodes placement during functional contraction of PFM does not affect the obtained results in sEMG evaluation. In order to diagnose the highest resting activity of PFM the recording plates should be placed toward the anterior vaginal wall and distally from the introitus. However, all of the PFM have similar bioelectrical activity and it seems that these muscles could be treated as a single muscle.


Satisfaction and value: a meta-analysis in the healthcare context.
Understanding healthcare performance from the patient's perspective has attracted more attention from the scholars and practitioners as consumers are becoming the driving force to the innovation of healthcare delivery in the knowledge economy (Morath 2003; Scott 2003). However, most of the studies have been constrained in the methods by which the clinical professionals assess what they perceived as the patient's value. This research attempts to examine the constructs for the conceptualization of patient value and its relationship with patient satisfaction. The results indicate that the providers' skills and knowledge and their respectful communication with the patients are the most important. These attributes followed by the providers' level of empathy and attention and the physical environment factors.


Childhood leukemia: epidemiological investigation and effectiveness in treatment in Nagasaki over the past 12 years.
An epidemiological investigation of childhood leukemia was performed in Nagasaki Prefecture. The objective of this investigation was to analyze the disease as a whole by studying (i) the incidence classified by year, sex, area and disease type, (ii) age of onset, (iii) effectiveness of treatment, (iv) prognosis, and (v) possible association with the atomic bombing in 1945. The annual incidence was 3.0 per 100,000 children under 15 years of age, lower than the national average. There was no significant change in the annual incidence for 12 years. No increase in incidence was observed in Nagasaki City and its surrounding areas. There was no obvious difference in age of onset and incidence by sex from those previously reported. Acute lymphocytic leukemia accounted for a large part of childhood leukemia. There was no increase in the incidence of acute non-lymphocytic leukemia, but its familial occurrence and accumulation were observed. The rate of first complete remission and the number of long-term survivors increased with the improvement of treatment for acute leukemia. The influence of the atomic bomb was not clear when the incidence of disease types was compared between areas. The comparison of the disease type ratio in patients of the second and third generations of atomic bomb victims with that of patients without a family history of atomic bomb exposure also did not show an obvious influence of the bomb.


Analysis of selected designer benzodiazepines by ultra high performance liquid chromatography with high-resolution time-of-flight mass spectrometry and the estimation of their partition coefficients by micellar electrokinetic chromatography.
A new ultra high performance liquid chromatography with electrospray ionization time of flight mass spectrometry method for the selective and sensitive separation, identification, and determination of selected designer benzodiazepines (namely, pyrazolam, phenazepam, etizolam, flubromazepam, diclazepam, deschloroetizolam, bentazepam, nimetazepam, and flubromazolam) in human serum was developed. The separation of the studied designer benzodiazepines was achieved on C18 chromatographic column using gradient elution within 6 min without any significant matrix interferences. Liquid-liquid extraction with butyl acetate was applied for serum samples cleanup and preconcentration of studied designer benzodiazepines. The method was validated in terms of linearity, limit of detection, limit of quantification, matrix effects, specificity, precision, accuracy, recovery, and sample stability. The limit of detection values were 0.10-0.15 ng/mL. The method was applied to a spiked serum sample to demonstrate its applicability for systematic toxicology analysis. Furthermore, a capillary chromatographic method with micellar electrokinetic chromatography was used for the estimation of partition coefficients of studied designer benzodiazepines as important parameters to evaluate their pharmacological and toxicological properties.


Assembling neurospheres: dynamics of neural progenitor/stem cell aggregation probed using an optical trap.
Optical trapping (tweezing) has been used in conjunction with fluid flow technology to dissect the mechanics and spatio-temporal dynamics of how neural progenitor/stem cells (NSCs) adhere and aggregate. Hitherto unavailable information has been obtained on the most probable minimum time (∼5 s) and most probable minimum distance of approach (4-6 µm) required for irreversible adhesion of proximate cells to occur. Our experiments also allow us to study and quantify the spatial characteristics of filopodial- and membrane-mediated adhesion, and to probe the functional dynamics of NSCs to quantify a lower limit of the adhesive force by which NSCs aggregate (∼18 pN). Our findings, which we also validate by computational modeling, have important implications for the neurosphere assay: once aggregated, neurospheres cannot disassemble merely by being subjected to shaking or by thermal effects. Our findings provide quantitative affirmation to the notion that the neurosphere assay may not be a valid measure of clonality and "stemness". Post-adhesion dynamics were also studied and oscillatory motion in filopodia-mediated adhesion was observed. Furthermore, we have also explored the effect of the removal of calcium ions: both filopodia-mediated as well as membrane-membrane adhesion were inhibited. On the other hand, F-actin disrupted the dynamics of such adhesion events such that filopodia-mediated adhesion was inhibited but not membrane-membrane adhesion.


Interactions between adenovirus, a tumor promoter, and chemical carcinogens in transformation of rat embryo cell cultures.
The tumor-promoting agent 12-O-tetradecanoyl-phorbol-13-acetate (TPA) caused a 2- to 3-fold enhancement of transformation of secondary rat embryo cells that had been injected with a temperature-sensitive mutant of adenovirus type 5(H5ts 125). In addition, transformed foci appeared earlier and were larger in cultures grown in the presence of TPA. The addition of TPA could be delayed until up to 7 days after viral injection and still enhancement was observed. Exposure of the cells to 7,12-dimethylbenz[a]pyrene prior to H5ts125 infection also resulted in a 2- to 4-fold enhancement of transformation, and this enhancement was further augmented 2- to 3-fold when cells were grown in TPA after virus infection. Whereas TPA did not enhance the cloning efficiency of normal rat embryo cells, it did enhance the cloning efficiency of isolated colonies of adenovirus-transformed cells when these were grown alone or cocultured with a 100-fold excess of normal rat embryo cells. The enhancement of adenovirus transformation by TPA appears to be due to its ability to facilitate expression of the transformed state rather than an effect on virus uptake or integration.


Geometric criteria of hydrogen bonds in proteins and identification of "bifurcated" hydrogen bonds.
Empirical criteria for identification of hydrogen bonds were analyzed to produce a set of geometrically consistent criteria. For a data set of 30 structures, application of a set of purely geometrical criteria, along with exclusion of abnormal backbone conformations, also excluded a common interaction of Ser/Thr side chains with Asp/Glu side chains ([ST]/[DE] pairs). These interactions were termed "bifurcated hydrogen bonds", which implies delocalization of a positively charged hydrogen of hydroxyl between the two acceptor atoms of the carboxylic group. These "bifurcated" interactions are among the most common packing patterns for [ST]/[DE] pairs of side chains. Therefore, the identification of hydrogen bonds cannot be based on geometrical criteria only and requires introduction of some physico-chemical criteria.


Is combined androgen blockade with bicalutamide cost-effective compared with combined androgen blockade with flutamide?
To determine the cost-effectiveness of combined androgen blockade (CAB) with bicalutamide versus CAB with flutamide in men with Stage D2 prostate cancer. Both bicalutamide and flutamide are commonly used in CAB for prostate cancer. Although the cost of bicalutamide is more than that of flutamide, it is important that the efficacy, quality of life, and side effects are also considered when determining whether CAB with bicalutamide is a cost-effective option. A decision model was created to compare treatment strategies. Survival and side-effect information was based on a randomized trial that directly compared bicalutamide and flutamide. The costs and quality-of-life effects related to therapy were determined from published sources. The incremental cost per quality-adjusted life year gained for bicalutamide versus flutamide was 22,000 dollars and 16,000 dollars at 5 and 10 years, respectively. If a quality adjustment was not included, the incremental cost-effectiveness ratio for CAB with bicalutamide compared with CAB with flutamide was even more favorable (20,000 dollars/life year gained at 5 years). One-way sensitivity analysis demonstrated that the cost-effectiveness estimates were most sensitive to drug costs and survival (baseline survival was not significantly different between therapies). Multi-way uncertainty analysis revealed that the median value of the incremental cost-effectiveness ratio at 5 years was 13,637 dollars/quality-adjusted life year when all the parameters were varied over a clinically reasonable range. Bicalutamide is cost-effective compared with flutamide when used for androgen blockade as part of CAB for men with advanced prostate cancer.


Overcorrection of a Medial Orbital Wall Fracture Using the Endonasal Approach.
Although the endonasal approach is frequently used, and the inadvertent displacement of a bone fragment into the orbital cavity is possible, no reports have yet described the overcorrection of medial orbital wall fractures using the endonasal approach. The authors report 2 patients of the overcorrection of a medial orbital wall fracture using an endonasal approach.In the first patient, a 26-year-old Chinese-Korean woman experienced a fracture of the right medial orbital wall without entrapment of the medial rectus muscle. Eleven days after the trauma, endonasal reduction was performed. Postoperative computed tomography revealed overcorrection of the medial orbital wall and lateral displacement of the medial rectus muscle. On postoperative day 19, exophthalmos of the operated side was still observed (o.d. 20 mm/o.s. 17 mm). In the second patient, a 25-year-old Korean man experienced a fracture of the left medial orbital wall without entrapment of the medial rectus muscle. Postoperative computed tomography showed overcorrection of the medial orbital wall and a laterally displaced medial rectus muscle. On postoperative day 4, exophthalmos of the operated side was observed (o.d. 23 mm/o.s. 26 mm).For fractures of the medial wall, surgery should be performed according to the recommended indications. When the endonasal approach is used to treat medial orbital wall fractures, great care is required in reducing the herniated orbital tissue and inserting the sheet to avoid overcorrection.


Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma.
We aimed to characterize the stomach adenocarcinoma (STAD) microbiota and its clinical value using an integrated analysis of the microbiome and transcriptome. Microbiome and transcriptome data were downloaded from the Cancer Microbiome Atlas and the Cancer Genome Atlas databases. We identified nine differentially abundant microbial genera, including Helicobacter, Mycobacterium, and Streptococcus, which clustered patients into three subtypes with different survival rates. In total, 74 prognostic genes were screened from 925 feature genes of the subtypes, among which five genes were identified for prognostic model construction, including NTN5, MPV17L, MPLKIP, SIGLEC5, and SPAG16. The prognostic model could stratify patients into different risk groups. The high-risk group was associated with poor overall survival. A nomogram established using the prognostic risk score could accurately predict the 1, 3, and 5 year overall survival probabilities. The high-risk group had a higher proportion of histological grade 3 and recurrence samples. Immune infiltration analysis showed that samples in the high-risk group had a higher abundance of infiltrating neutrophils. The Notch signaling pathway activity showed a significant difference between the high- and low-risk groups. In conclusion, a prognostic model based on five feature genes of microbial subtypes could predict the overall survival for patients with STAD.


Eurycoma Longifolia as a potential adoptogen of male sexual health: a systematic review on clinical studies.
Eurycoma longifolia (EL) has been well recognized as a booster of male sexual health. Over the past few decades, numerous in vivo animal studies and human clinical trials have been conducted across the globe to explore the promising role of EL in managing various male sexual disorders, which include erectile dysfunction, male infertility, low libido, and downregulated testosterone levels. The aim of the present review is to analyze and summarize the literature on human clinical trials which revealed the clinical significance and therapeutic feasibility of EL in improving male sexual health. This systematic review is focused on the following databases: Medline, Wiley Online Library, BioMed Central, Hindawi, Web of Knowledge, PubMed Central and Google Scholar, using search terms such as "Eurycoma longifolia", "EL", "Tongkat Ali", "male sexual health", "sexual infertility", "erectile dysfunction", "male libido", and "testosterone levels". Notably, only human clinical studies published between 2000 and 2014 were selected and thoroughly reviewed for relevant citations. Out of 150 articles, 11 met the inclusion criteria. The majority of articles included were randomized placebo-controlled trials, multiple cohort studies, or pilot trials. All these studies demonstrated considerable effects of EL on male sexual health disorders. Among them, 7 studies revealed remarkable association between the use of EL and the efficacy in the treatment of male sexual disorders, and remaining 4 studies failed to demonstrate sufficient effects on male sexual health. In summary, there is convincing evidence for the prominence of EL in improving the male sexual health. The review also substantiates the use of current methodology in the development of novel and more rationale natural herbal medicines for the management of male sexual disorders.


Associations between transition to retirement and changes in dietary intakes in French adults (NutriNet-Santé cohort study).
Few studies have focused on the influence of retirement on dietary behaviors. Our study aimed at assessing the associations between transition to retirement and changes in dietary intake in French adults, particularly according to spousal retirement and baseline income. This prospective study included 577 French participants from the NutriNet-Santé cohort who retired over a 5-year follow-up (2009-2014 or 2010-2015). At baseline and every year, dietary intakes were assessed using 24 h records. Repeated measures of dietary intake were analysed using mixed models adjusted for energy with random effects of time and period (before and after retirement) to assess changes following retirement for each gender. After retirement, intakes of saturated fatty acids and sodium increased in both genders. Women showed specific changes after retirement: decrease in the score of adherence to recommendations and in intakes of fruits, proteins, vitamins; increase in intakes of fatty sweet products. In men with the lowest income at baseline, specific changes in intake were associated with retirement such as decrease in intake of dairy products and increase in intake of lipids. Transition to retirement was associated with unhealthier dietary intakes. These results may help defining interventions during this vulnerable life-period. This study was conducted according to guidelines laid down in the Declaration of Helsinki and all procedures were approved by the Institutional Review Board of the French Institute for Health and Medical Research (IRB Inserm No. 0000388FWA00005831) and the French Data Protection Authority (Commission Nationale Informatique et Libertés No. 908450 and No. 909216). Electronic informed consents were obtained from all participants.


New metallic implant used for permanent contraception in women: evaluation of MR safety.
This ex vivo investigation evaluated the safety of using MR imaging with a new metallic implant designed to provide permanent birth control. The findings indicated that it should be safe for patients with this metallic contraceptive implant to undergo MR imaging with systems using static magnetic fields of 1.5 T or less.


Inverse association of general joint hypermobility with hand and knee osteoarthritis and serum cartilage oligomeric matrix protein levels.
Extensive joint hypermobility, lower serum cartilage oligomeric matrix protein (COMP) levels, and early-onset osteoarthritis (OA) are phenotypes of inherited pseudoachondroplasia and multiple epiphyseal dysplasia. However, few studies have evaluated the association between articular hypermobility and primary OA. We undertook the present study to evaluate this association and to test the hypothesis that COMP levels are associated with hypermobility in patients with OA and individuals without OA. Two separate cohorts were available for analysis, the CARRIAGE (CARolinas Region Interaction of Aging Genes and Environment) extended family and a subset of the GOGO (Genetics of Generalized Osteoarthritis) sibpair cohort. In the CARRIAGE family, we performed hand and knee examinations and hypermobility evaluations (Beighton criteria) and obtained sera for measurement of COMP and hyaluronan (HA). Data on COMP and HA levels and extensive joint radiographic and hypermobility data were also available for the GOGO cohort. The prevalence of hypermobility was 13% in the CARRIAGE family and 5% in the GOGO cohort. In the CARRIAGE family, hypermobility was associated with a significantly reduced prevalence of hand (especially proximal interphalangeal joint) and knee OA and lower mean serum COMP levels, both in the total cohort and in non-hand-OA subgroups. These results were further validated in the GOGO subsets without radiographic OA, in which hypermobility was also associated with a significantly reduced mean serum COMP level (P < 0.0001 adjusted for age). Serum HA levels did not differ in relation to hypermobility in either cohort. The present results indicate that there is an inverse relationship between hypermobility and hand and knee OA, and that hypermobility is associated with lower serum COMP levels. Genetic variations of the COMP gene may account for some subgroups of benign joint hypermobility.


Therapeutic alternatives in dilated cardiomyopathy--a review of current options.
In addition to the underlying pathophysiological processes that cause myocarditis and dilated cardiomyopathy, structural, biochemical, neurohormonal and haemodynamic influences and interrelations promote progression of the heart failure syndrome. Independent of their symptomatic benefits, diuretics, digitalis, ACE inhibitors, PDE inhibitors and dopamine agonists exert specific influences on factors that retard or accelerate progression of congestive heart failure (CHF). Important factors that indicate or promote progression of CHF are discussed here, with special emphasis on therapeutic options. Interference with baroreceptor function (digitalis, ACE inhibitors), the RAA system (ACE inhibitors), the sympathetic nerve system (dopamine agonists, ACE inhibitors, digitalis) can potentially retard progression of CHF, while other therapeutic options, such as PDE inhibitors and diuretics, might accelerate progression of left ventricular dysfunction and CHF.


[Studies on Kochiae Fructus. I. Antipruritogenic effect of 70% ethanol extract from kochiae fructus and its active component].
The antipruritogenic effect of the 70% ethanol extract obtained from Kochiae Fructus (fruits of Kochia scoparia) and its active components were investigated on a compound 48/80-induced pruritogenic model in male ddY strain mice. The extract (200, 500 mg/kg, p.o.) inhibited the scratching behavior as a pruritogenic indicator. Oleanolic acid oligoglycoside, momordin Ic, isolated from the extract also exhibited the inhibition. These results suggest that Kochiae Fructus could be used as an antipruritogenic agent and its inhibitory effect may be partially attributed to momordin Ic.


[Psychotic symptoms in patients with mild intellectual disability: follow an integrative approach].
In The Netherlands, approximately 1 in 8 citizens (2.2 million) have an IQ between 70 and 85. Together the combination of a low IQ (< 70) and low adaptive functioning is referred to as mild intellectual disability (ID). People with ID are vulnerable to stress and psychological problems. The diagnosis and treatment of psychotic symptoms in patients with mild ID can prove to be a challenge. In this clinical lesson we present two different cases. We encourage physicians to adhere to a holistic approach. Furthermore the AAIDD model may guide structuring the analysis of psychotic symptoms. This enables finding the right treatment which may include medical treatment or emphasis on context improvement or a combination of both. Upon treatment initiation with antipsychotics, it's important to start low and go slow regarding the dosage. And if the context is the main problem, it is important to taper off the use of antipsychotics.


Integration of Multiple Redox Centers into Porous Coordination Networks for Ratiometric Sensing of Dissolved Oxygen.
The application of porphyrin metal-organic frameworks (MOFs) as a ratiometric electrochemical sensing platform is still unexplored. In this paper, we report a ratiometric electrochemical sensor by the integration of multiple redox centers into porphyrin MOFs for the detection of dissolved oxygen (DO). Specifically, the ferrocene (Fc) group was integrated into the nanosized PCN-222(Fe) (PCN = porous coordination networks) via acid-base reaction to synthesize the Fc@PCN-222(Fe) composite with two redox centers of the Fc group and Fe-porphyrin. The Fc group that is insensitive to DO serves as an internal reference, and the Fe-porphyrin in PCN-222(Fe) is a DO indicator. The ratios of the cathodic currents for the two redox centers exhibit a linear relationship with DO concentrations from 2.8 to 28.9 mg mL-1 and a limit of detection of 0.3 mg mL-1. In addition, the ratiometric electrochemical sensor has high selectivity and stability for DO sensing results from the Fc@PCN-222(Fe) composite. Because there are numerous redox centers, such as methylene blue and thionine, which can be integrated into MOFs, many MOF-based ratiometric electrochemical sensors can be simply developed for high-performance biosensing.


Enhancement of phase-locking in rodents. I. An axonal recording study in gerbil.
The trapezoid body (TB) contains axons of neurons in the anteroventral cochlear nucleus projecting to monaural and binaural nuclei in the superior olivary complex (SOC). Characterization of these monaural inputs is important for the interpretation of response properties of SOC neurons. In particular, understanding of the sensitivity to interaural time differences (ITDs) in neurons of the medial and lateral superior olive requires knowledge of the temporal firing properties of the monaural excitatory and inhibitory inputs to these neurons. In recent years, studies of ITD sensitivity of SOC neurons have made increasing use of small animal models with good low-frequency hearing, particularly the gerbil. We presented stimuli as used in binaural studies to monaural neurons in the TB and studied their temporal coding. We found that general trends as have been described in the cat are present in gerbil, but with some important differences. Phase-locking to pure tones tends to be higher in TB axons and in neurons of the medial nucleus of the TB (MNTB) than in the auditory nerve for neurons with characteristic frequencies (CFs) below 1 kHz, but this enhancement is quantitatively more modest than in cat. Stronger enhancement is common when TB neurons are stimulated at low frequencies below CF. It is rare for TB neurons in gerbil to entrain to low-frequency stimuli, i.e., to discharge a well-timed spike on every stimulus cycle. Also, complex phase-locking behavior, with multiple modes of increased firing probability per stimulus cycle, is common in response to low frequencies below CF.NEW & NOTEWORTHY Phase-locking is an important property of neurons in the early auditory pathway: it is critical for the sensitivity to time differences between the two ears enabling spatial hearing. Studies in cat have shown an improvement in phase-locking from the peripheral to the central auditory nervous system. We recorded from axons in an output tract of the cochlear nucleus and show that a similar but more limited form of temporal enhancement is present in gerbil.


Serum sirtuin 1 levels in patients with polycystic ovary syndrome.
Objective of the study is to determine the human nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 level in women with polycystic ovary syndrome (PCOS). This cross-sectional study included 24 patients aged 20-38 years, who were diagnosed to have PCOS (patient group). The control group included 16 age- and body mass index-matched healthy female volunteers. The patients and controls were compared in terms of pre-prandial blood glucose, the homoeostatic model assessment for insulin resistance (HOMA-IR) index, and cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), C-reactive protein (CRP) and sirtuin 1 levels. The mean sirtuin 1 level in the patient group (6.67 ± 2.29 ng mL(-1)) was significantly higher than that in the control group (4.69 ± 1.85 ng mL(-1)) (P = 0.007). Correlation analysis showed that there were no significant differences between the groups in fasting blood glucose, HOMA-IR index or cholesterol, triglyceride, HD, LDL and CRP levels. The sirtuin 1 level, which is associated with inflammation, the immune system and insulin metabolism, was higher in the PCOS patients than in the healthy controls.


Getting by with less - the "frugal tie".
The ability to tie surgical knots efficiently and effectively is an essential surgical skill for medical procedures, especially pacemaker implantation. Device generators and their leads need to be safely anchored with sutures during implantation to prevent dislodgement and inadequate packaging in the pacemaker pocket. With most knot tying techniques, a generous amount of suture slack is required. We introduce a new technique that is a variation of the 2-handed surgical square knot and the 1-handed surgeon's knot that allows one to finish or tie a knot when left with little slack.


Corneal interface contamination during laser in situ keratomileusis.
To measure the rate of corneal interface contamination during laser in situ keratomileusis (LASIK), determine probable sources of the contamination, and evaluate how the cornea reacts to the contamination. Department of Ophthalmology, Baqyatallah Hospital, Baqyatallah University, Tehran, Iran. In this case series, 200 eyes were evaluated for the corneal interface contamination at the end of LASIK. Cultures were taken from the upper and lower eyelid margins and the inferior fornices before surgery and from the corneal interface and the instrument at the end of surgery. Media were cultured at 37 degrees C for 14 days under aerobic and anaerobic conditions. Bacteria from positive cultures were isolated and identified by biochemical procedures to determine the species of the organisms. The rate of contamination was 24.5%. The most common retrieved organism was Staphylococcus epidermidis (43 cases, 87.7%). None of the contaminated or noncontaminated cases developed corneal ulcers; however, 2 eyes developed diffuse lamellar keratitis. The corneal stroma has the ability to clear introduced microorganisms during LASIK.


Sinonasal inverted papilloma in eastern part of Nepal.
To evaluate the clinicopathological profile of sinonasal inverted papilloma in a tertiary referral center in eastern part of Nepal. A prospective study consisting of total 28 histologically proven cases of sinonasal inverted papilloma was conducted in the ENT department of the center. The study period was from April 2002 to November 2005. Out of 28 cases studied, 21 were males and 7 were females with male to female ratio of 3:1. The highest incidence was seen in the 5th and 6th decades of life. The duration of symptoms varied from 5 months to 20 years with mean duration of 3.9 years. The lateral nasal wall and nasal cavity involvement was seen in all 28 cases. Maxillary sinus was involved in 27(96.4%) subjects followed by ethmoid (20), sphenoid (10) and the frontal sinus (7). The principle presenting symptom was nasal obstruction seen in 96.4% of the patients. Twenty two cases were treated by lateral rhinotomy with medial maxillectomy while, orbital exenteration was done in two cases. Associated carcinoma was noticed in 10.15% of all the subjects studied. Sinonasal papilloma mostly presented in fifth to six decades of life mainly affecting the male patients. Majority of the patients were treated by lateral Rhinotomy with medial maxillectomy surgery. Early presentation would have given chances for endoscopic surgery.


Atorvastatin donor pretreatment prevents ischemia/reperfusion injury in renal transplantation in rats: possible role for aldose-reductase inhibition.
The aim of the present study was to evaluate the effect of donor pretreatment with atorvastatin on ischemia/reperfusion (I/R) injury in renal transplantation in rats. Donor rats were pretreated orally with atorvastatin or vehicle 2 days prior to explantation. Kidneys were stored for 24 hr at 4 degrees C in University of Wisconsin solution and transplanted into isogeneic or allogeneic recipients. Donor treatment with atorvastatin improved initial graft function, reduced renal inflammation, and the number of TUNEL-positive cells in renal tissue after prolonged cold storage and isogeneic transplantation. In the allogeneic transplantation model, donor treatment with atorvastatin reduced renal inflammation in grafts harvested after 5 days, but no improvement of long-term graft survival (24 weeks) could be observed. A genome wide gene expression profile of donor kidneys from atorvastatin treated or vehicle treated rats revealed a fivefold downregulation of aldose reductase in all atorvastatin treated animals (P<0.01). Donor treatment with an aldose-reductase inhibitor improved kidney function and reduced renal inflammation after prolonged cold storage and isogeneic transplantation. Our data suggest that downregulation of aldose reductase in renal tissue might underlie the protective effect of donor atorvastatin treatment. Donor pretreatment with a statin or an aldose reductase inhibitor could offer a new treatment strategy to prevent transplantation associated tissue injury.


[Influence of diabetes mellitus on corneal thickness].
Ultrastructural changes in corneas of patients with diabetes mellitus have been previously described. The aim of this study was to compare central corneal thickness (CDR) values in diabetic patients without retinopa- thy at the stage of diabetic nonproliferative and proliferative retinopathy and CDR in a control group of healthy subjects. The study included 121 diabetic patients and 125 healthy subjects matched according to gender and age. Each patient underwent ophthalmological examination involving a dilated fundus examination and CDR measurement using the ultrasound pachymeter. The eyes of diabetic patients were classified according to Early Treatment Diabetic Retinopathy Study into three groups: without diabetic retinopathy (NDR), with nonproliferative diabetic retinopathy (NPDR) and a group with proliferative diabetic retinopathy (PDR). Only one eye of each subject was chosen for the study. The mean CDR value was significantly higher in the diabetic group (570.52 ± 31.81 μm) compared with the control group (541.42 ± 27.82 μm). The difference between the two groups was statistically significant (p<0.0001). The highest mean CDR value was recorded in the PDR group (585.97 ± 28.58 μm), followed by the NPDR group (570.84 ± 30.27 μm), whereas the lowest mean CDR value was recorded in the NDR group (559.80 ± 31.55 μm). There was a statistically significant difference in CDR between the NDR and PDR groups, as well as between the NPDR and PDR groups (p < 0.001, p < 0.05 respectively). No significant difference was recorded between the NDR and NPDR groups (p>0.05). CDR of diabetic patients was higher compared to healthy subjects. The highest mean value of CDR was registered in the PDR group, followed by the NPDR and the NDR groups.


The painful shoulder.
Although a common symptom, shoulder pain is not always due to intrinsic disorders of the joint; it can be referred from lesions of the cervical spine or from visceral disease.


Modulated fibronectin anchorage at polymer substrates controls angiogenesis.
A set of maleic anhydride copolymer thin films exhibiting well-defined differences in hydrophobicity and reactivity was compared with respect to the capability of supporting angiogenesis of human endothelial cells grown in contact. The physicochemical surface characteristics of the polymer substrates were found to modulate the anchorage of immobilized fibronectin. This was demonstrated to determine whether endothelial cells grow as a monolayer or form capillary networks. Enhanced reorganization of predeposited fibronectin into cell-matrix adhesions and slightly elevated levels of membrane-type matrix metalloproteinase 14 (MMP-14) occurred with weakly bound fibronectin layers where angiogenesis was most obvious. The key role of fibronectin-substrate binding for angiogenesis-under otherwise constant conditions-was further confirmed by the absence of variations in the expression of angiogenesis-related integrins (alpha(v)beta(3)) and in the secretion of the metalloproteinase MMP-2. Altogether, the results of this study point at the relevance of physicochemical surface characteristics of polymer materials for the stimulation of angiogenesis.


Follicle measurements using sonography-based automated volume count accurately predict the yield of mature oocytes in in vitro fertilization/intracytoplasmic sperm injection cycles.
We define criteria to predict the number of mature oocytes using automated three-dimensional (3D) ultrasound follicle measurements. Fifty in vitro fertilization/intracytoplasmic sperm injection patients underwent automated 3D echographic monitoring by a single researcher following the stimulation procedure. Classic criteria for triggering oocyte maturation as defined in the literature were utilized. 3D parameters, including the follicular volume and follicle diameter calculated from the volume measurement, were related to the oocyte count, mature oocyte count and the number of observed fertilized oocytes. We found that when oocyte maturation was induced, 55% of the total follicles with a diameter of at least 10 mm had a volume of at least 1.5 cm³. The number of mature eggs that were retrieved was correlated with the number of follicles observed with a volume of at least 1 cm³ or a calculated follicle diameter of at least 12 mm. Sonography-based automated volume count measurements of follicle volume and reconstructed follicle diameter can be used to reliably predict the number of mature oocytes.


Biotransformation of organic micropollutants by anaerobic sludge enzymes.
Biotransformation of organic micropollutants (OMPs) in wastewater treatment plants ultimately depends on the enzymatic activities developed in each biological process. However, few research efforts have been made to clarify and identify the role of enzymes on the removal of OMPs, which is an essential knowledge to determine the biotransformation potential of treatment technologies. Therefore, the purpose of the present study was to investigate the enzymatic transformation of 35 OMPs under anaerobic conditions, which have been even less studied than aerobic systems. Initially, 13 OMPs were identified to be significantly biotransformed (>20%) by anaerobic sludge obtained from a full-scale anaerobic digester, predestining them as potential targets of anaerobic enzymes. Native enzymes were extracted from this anaerobic sludge to perform transformation assays with the OMPs. In addition, the effect of detergents to recover membrane enzymes, as well as the effects of cofactors and inhibitors to promote and suppress specific enzymatic activities were evaluated. In total, it was possible to recover enzymatic activities towards 10 out of these 13 target OMPs (acetyl-sulfamethoxazole and its transformation product sulfamethoxazole, acetaminophen, atenolol, clarithromycin, citalopram, climbazole, erythromycin, and terbutryn, venlafaxine) as well as towards 8 non-target OMPs (diclofenac, iopamidol, acyclovir, acesulfame, and 4 different hydroxylated metabolites of carbamazepine). Some enzymatic activities likely involved in the anaerobic biotransformation of these OMPs were identified. Thereby, this study is a starting point to unravel the still enigmatic biotransformation of OMPs in wastewater treatment systems.


Alcoholic beverage preference and diet in a representative Dutch population: the Dutch national food consumption survey 2007-2010.
The habitual consumption of a specific type of alcoholic beverage may be related to the overall dietary pattern. The objective of this cross-sectional study was to investigate associations between alcoholic beverage preference and dietary intake in The Netherlands. A total of 2100 men and women from the Dutch National Food Consumption Survey 2007-2010 were studied. A general questionnaire assessed alcoholic beverage preference and two non-consecutive 24-h dietary recalls assessed overall diet. Mean nutrient and food group intakes, and adherence to the 2006 Dutch dietary guidelines across categories of alcoholic beverage preference were compared and adjusted for age, sex, body mass index (BMI), education, smoking, physical activity, energy intake and frequency and absolute alcohol consumption. Largest differences in dietary habits were detected between persons who preferred wine and those who preferred beer. Persons with a beer preference had a higher absolute intake of meat, soft drinks, margarine and snacks. In contrast, persons with a wine preference had a higher absolute consumption of healthy foods. However, after multiple adjustments, wine consumers still consumed less energy and more vegetables and fruit juices compared with beer consumers. Adherence to the Dutch dietary guidelines did not differ between preference categories after multiple adjustments. In this cross-sectional analysis in a representative sample of the Dutch population, a beer preference was associated with less healthy dietary behaviour, especially compared with wine preference. However, these differences were largely explained by other socio-demographic and lifestyle factors. These results suggest that alcoholic beverage preference may not be independently related to diet.


Doloplus-2 pain assessment: an effective tool in patients over 85 years with advanced dementia and persistent pain.
Persistent pain in the elderly with dementia is neglected and effective pain diagnostic tools still lack. The aim of the study was to re-assess pain after 1 year in a group of elderly with dementia, resident in a Nursing Home. Doloplus-2 scale was adopted to detect pain and to evaluate its adequacy to address analgesia. Thirty-six out of 90 residents were affected by moderate-severe dementia and 23 patients with persistent pain were enrolled in the study. The results showed a significant reduction of Doloplus-2 score in the observational period (p <0.001) and of its mean score below the pain threshold (p <0.0001). This case analysis confirmed the clinical utility of Doloplus-2 to detect pain in patients with very advanced age and with severe dementia. The tool also confirmed its handiness and clinical applicability by nurses in order to support a systematic pain assessment in long term care.


Effects of chronic beta-blocker treatment on admission haemodynamics in STEMI patients treated with primary angioplasty.
The association between chronic beta-blocker treatment and haemodynamics at admission in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention is not well studied. We investigated the impact of chronic beta-blocker treatment on the risk of cardiogenic shock and pre-shock at admission in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention. A total of 4907 patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention were included in the study. A total of 1148 patients (23.3%) were on chronic beta-blocker treatment. Cardiogenic shock was observed in 264 patients (5.3%). Pre-shock was defined as a shock index (the ratio of heart rate and systolic blood pressure) of 0.7 or greater, and was observed in 1022 patients (20.8%). The risk of cardiogenic shock in patients with chronic beta-blocker treatment was not increased (adjusted hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.65-1.46, P=0.90). Chronic beta-blocker treatment was also not associated with an increased risk of pre-shock (adjusted HR 0.86, 95% CI 0.68-1.07, P=0.19). Also after propensity score matched analysis, there was no increased risk of cardiogenic shock or pre-shock in patients with chronic beta-blocker treatment (respectively HR 0.97, 95% CI 0.61-1.51, P=0.88 and HR 0.82, 95% CI 0.65-1.06, P=0.12). In ST-segment elevation myocardial infarction, chronic beta-blocker treatment is not associated with an increased risk of cardiogenic shock or pre-shock.


High Spatial Inhomogeneity in the Intima-Media Thickness of the Common Carotid Artery is Associated with a Larger Degree of Stenosis in the Internal Carotid Artery: The PARISK Study.
Purpose Inhomogeneity of arterial wall thickness may be indicative of distal plaques. This study investigates the intra-subject association between relative spatial intima-media thickness (IMT) inhomogeneity of the common carotid artery (CCA) and the degree of stenosis of plaques in the internal carotid artery (ICA). Materials and Methods We included 240 patients with a recent ischemic stroke or transient ischemic attack and mild-to-moderate stenosis in the ipsilateral ICA. IMT inhomogeneity was extracted from B-mode ultrasound recordings. The degree of ICA stenosis was assessed on CT angiography according to the European Carotid Surgery Trial method. Patients were divided into groups with a low (≤ 2 %) and a high (> 2 %) IMT inhomogeneity scaled with respect to the local end-diastolic diameter. Results 182 patients had suitable CT and ultrasound measurements. Relative CCA-IMT inhomogeneity was similar for the symptomatic and asymptomatic side (difference: 0.02 %, p = 0.85). High relative IMT inhomogeneity was associated with a larger IMT (difference: 235 µm, p < 0.001) and larger degree of ICA stenosis (difference: 5 %, p = 0.023) which remained significant (p = 0.016) after adjustment for common risk factors. Conclusion Regardless of common risk factors, high relative CCA-IMT inhomogeneity is associated with a greater degree of ICA stenosis and is therefore indicative of atherosclerotic disease. The predictive value of CCA-IMT inhomogeneity for plaque progression and recurrence of cerebrovascular symptoms will be determined in the follow-up phase of PARISK.


A permanent tendon-to-bone suture technique in the distal phalanx.
This technique is used to place a permanent tendon-to-bone suture in the distal phalanx without increasing the amount of dissection beyond that needed for a Bunnell button repair. This technique has the advantage of greater strength without the problems of a percutaneous device that must be removed before full wound healing strength has developed.


Azithromycin and Doxycycline Resistance Profiles of U.S. Mycoplasma genitalium Strains and Their Association with Treatment Outcomes.
Mycoplasma genitalium is a sexually transmitted bacterium associated with nongonococcal urethritis (NGU) in men and cervicitis, endometritis, and pelvic inflammatory disease in women. Effective treatment is challenging due to the inherent, and increasingly acquired, antibiotic resistance in this pathogen. In our treatment trial conducted from 2007 to 2011 in Seattle, WA, we demonstrated poor efficacy of azithromycin (AZM) and doxycycline (DOX) against M. genitalium among men with NGU. In the present study, we cultured M. genitalium from 74 of 80 (92.5%) PCR-positive men at enrollment (V-1) and defined the MICs of AZM (N = 56 isolates) of DOX (N = 62 isolates). Susceptibility to AZM was bimodal; MICs were >8 μg/ml (44.6%) and <0.004 μg/ml (55.4%) for these isolates. The association of MIC with treatment efficacy was determined for men initially treated with either AZM (N = 30) or DOX (N = 24). Men treated with AZM were more likely to experience microbiologic treatment failure (P < 0.001) if infected with isolates that had AZM MICs of >8 μg/ml (18/18 men) than those with isolates that had AZM MICs of <0.004 μg/ml (1/12 men). Clinical treatment failure also was more likely to occur (P = 0.002) with AZM MICs of >8 μg/ml (12/18 men) than with AZM MICs of <0.004 μg/ml (1/12 men). In contrast, DOX MICs ranged from <0.125 to 2 μg/ml and were not correlated with microbiologic (P = 0.71) or clinical treatment (P = 0.41) failure, demonstrating no relationship between DOX MICs and treatment efficacy. Given the rapid spread of AZM resistance and the emergence of quinolone resistance, the current second-line therapy, monitoring MICs and evaluating other potential treatments for M. genitalium will be critical.


Congenital absence of the right common carotid artery, internal carotid artery and external carotid artery associated with anterior communicating artery aneurysm: a rare case.
Congenital absence of the common carotid artery (CCA), internal carotid artery (ICA) and external carotid artery (ECA) is very rare. We present such a rare case in a 53-year-old woman, associated with a saccular aneurysm of anterior communicating artery (ACA) presenting with subarachnoid haemorrhage (SAH). An embryological hypothesis for the anomalies of the aortic arch is proposed. The correlation between the abnormal haemodynamic stress of the circle of Willis caused by the absence of the right ICA and the development of intracranial aneurysm is discussed.


National trends in bowel and upper abdominal procedures in ovarian cancer surgery.
In the United States, trends in the initial treatment approach for ovarian cancer reflect a shift in paradigm toward the increased use of neoadjuvant chemotherapy and interval cytoreductive surgery. The aim of this study was to evaluate the trends in surgical cytoreductive procedures in ovarian cancer patients who underwent either primary or interval cytoreductive surgery. This retrospective, population-based study examined patients with stage III/IV ovarian cancer diagnosed between January 2000 and December 2013 identified using SEER-Medicare. Small or large bowel resection, ostomy creation, and upper abdominal procedures were identified using relevant billing codes and compared over time. A 1:1 primary and interval cytoreductive propensity matched cohort was created using demographic and clinical variables. 30-day complications and the use of acute care services were compared. A total of 5417 women were identified. 34% underwent bowel resections, 16% ostomy creation, and 8% upper abdominal procedures. There was an increase in bowel resections and upper abdominal procedures from 2000 to 2013 in patients who underwent primary cytoreductive surgery. Compared with patients who received primary cytoreduction, patients who underwent interval cytoreductive surgery were less likely to undergo bowel resection (OR=0.50; 95% CI [0.41, 0.61]) or ostomy creation (OR=0.48; 95% CI [0.42, 0.56]). Upper abdominal procedures did not differ between groups. For patients who underwent primary cytoreductive surgery, these procedures were associated with intensive care unit stay (4.6% vs <2%, P<0.01). In both primary and interval cytoreductive surgery patients, the receipt of bowel and upper abdominal procedures was associated with multiple 30-day postoperative complications and higher rates of readmission and emergency room visits. The performance of upper abdominal procedures in ovarian cancer patients increased from 2000 to 2013. Interval cytoreductive surgery was associated with decreased likelihood of bowel surgery. In matched primary and interval cytoreductive surgery cohorts, the receipt of these procedures were associated with the increased likelihood of postoperative complications and use of acute care services.


Preptin in women with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) patients, frequently develop metabolic complications, such as insulin resistance (IR), impaired carbohydrate metabolism, dyslipidemia, obesity. Among the new markers responsible for metabolic disorders, preptin seems to be of great significance. One hundred and thirty-four women aged 17-45 were enrolled. PCOS was diagnosed in 73 women on the basis of ESHRE-ASRM criteria. Non-PCOS group consisted of 61 women with regular menstruation matched for nutritional status. All women underwent anamnesis, physical examination, anthropometric measurements, the abdominal ultrasound examination, and dual energy X-ray absorptiometry (DXA). Serum adropin levels were determined by ELISA. Biochemical and hormonal (testosterone, androstenedione, LH, FSH, estradiol) measurements were also performed. Insulin resistance indices (HOMA, QUICKI, Matsuda) and free androgen index (FAI) were calculated with the test results according to the standard formula. For all comparisons, statistical significance was defined by p ≤ .05. Serum preptin levels were significantly higher in the PCOS group. No significant correlations between preptin level and metabolic and hormonal markers were observed. The logistic regression analysis demonstrated that serum preptin level was an independent factor differentiating the two groups. Serum preptin levels were significantly higher in women with PCOS compared with controls. This peptide might be an independent predictor of PCOS in the future.


Metabolic syndrome, autoimmunity and rheumatic diseases.
Metabolic syndrome (MetS) is a cluster of metabolic and cardiovascular (CV) risk factors including obesity and visceral adiposity, insulin resistance, dyslipidemia and hypertension contributing to CV mortality. The interface between the metabolic and immune systems has been of great interest recently. These interactions are regulated through genetics, nutritional status, and the intestinal microbiome. Alterations in the immune-metabolic cross-talk contribute to the development of autoimmune diseases. Adipokines exert a variety of metabolic activities contributing to the ethiopathogenesis of MetS and are involved in the regulation of both inflammatory processes and autoimmunity occurring in rheumatic diseases. Patients with autoinflammatory disease such as gout and those with autoimmune rheumatic diseases (ARD), such as systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, ankylosing spondylitis and vasculitis among others, have increased prevalence of MetS. Despite recent advances in treatment of ARD, incidence of CVD remains high. MetS and altered secretion patterns of proinflammatory adipokines could be the link between CVDs and ARD. In addition, in ARD the activation of proinflammatory signalling pathways results in the induction of several biological markers of chronic inflammation contributing to CVD. In the present paper, we review recent evidences of the interactions between MetS and ARD, as well as novel therapeutic targets.


Diversification and senescence of Foxp3+ regulatory T cells during experimental autoimmune encephalomyelitis.
The fate of Foxp3(+) regulatory T (Treg) cells responding during autoimmunity is not well defined. We observed a marked elevation in KLRG1(+) (where KLRG1 stands for killer cell lectin-like receptor G1) CNS-infiltrating Treg cells in experimental autoimmune encephalomyelitis (EAE), and assessed their origin and properties. KLRG1(+) Treg cells showed increased activation marker expression, Foxp3 and CD25 levels, and more rapid cell cycling than KLRG1(-) cells. KLRG1(-) Treg cells converted into KLRG1(+) cells and this was increased in autoimmune inflammation. Conversion was unidirectional; KLRG1(+) Treg cells did not revert to a KLRG1(-) state. KLRG1(+) but notKLRG1(-) Treg cells survived poorly, indicative of terminal differentiation. This was associated with diminished BCL2 and increased apoptosis of isolated cells. KLRG1 was also upregulated on iTreg cells after transfer and EAE induction or on iTreg cells developing spontaneously during EAE. KLRG1(+) Treg cells produced more IL-10 and had altered effector cytokine production compared with their KLRG1(-) counterparts. Despite their differences, KLRG1(+) and KLRG1(-) Treg cells proved similarly potent in suppressing EAE. KLRG1(+) and KLRG1(-) populations were phenotypically heterogeneous, with the extent and pattern of activation marker expression dependent both on cellular location and inflammation. Our results support an extensive diversification of Treg cells during EAE, and associate KLRG1 with altered Treg-cell function and senescence.


Experimental validation in a neutron exposure frame of the MINAS TIRITH for cell damage simulation.
In the domains of medicine and space exploration, refining risk assessment models for protecting healthy tissue from ionizing radiation is crucial. Understanding radiation-induced effects requires biological experimentations at the cellular population level and the cellular scale modeling using Monte Carlo track structure codes. We present MINAS TIRITH, a tool using Geant4-DNA Monte Carlo-generated databases to study DNA damage distribution at the cell population scale. It introduces a DNA damage location module and proposes a method to convert double-strand breaks (DSB) into DNA Damage Response foci. We evaluate damage location precision and DSB-foci conversion parameters. MINAS TIRITH's accuracy is validated againstγ-H2AX foci distribution from cell population exposed to monoenergetic neutron beams (2.5 or 15.1 MeV) under different configurations, yielding mixed radiation fields. Strong agreement between simulation and experimental results was found demonstrating MINAS TIRITH's predictive precision in radiation-induced DNA damage topology. Additionally, modeling intercellular damage variability within a population subjected to a specific macroscopic dose identifies subpopulations, enhancing realistic fate models. This approach advances our understanding of radiation-induced effects on cellular systems for risk assessment improvement.


Fiber density index correlates with reduced fractional anisotropy in white matter of patients with glioblastoma.
A quantitative description of white matter fiber attenuation, the fiber density index (FDi) is described. This measure is derived from quantitative analysis of diffusion tensor imaging and reveals an index of the number of fiber paths traversing a region of interest. In this report, FDi is computed in 10 patients with glioblastoma multiforme, in white matter that is peritumoral and contralateral. FDi is shown to correlate significantly with fractional anisotropy.


TiArA: a virtual appliance for the analysis of Tiling Array data.
Genomic tiling arrays have been described in the scientific literature since 2003, yet there is a shortage of user-friendly applications available for their analysis. Tiling Array Analyzer (TiArA) is a software program that provides a user-friendly graphical interface for the background subtraction, normalization, and summarization of data acquired through the Affymetrix tiling array platform. The background signal is empirically measured using a group of nonspecific probes with varying levels of GC content and normalization is performed to enforce a common dynamic range. TiArA is implemented as a standalone program for Linux systems and is available as a cross-platform virtual machine that will run under most modern operating systems using virtualization software such as Sun VirtualBox or VMware. The software is available as a Debian package or a virtual appliance at http://purl.org/NET/tiara.


MDM2 SNP309 rs2279744 polymorphism and gastric cancer risk: a meta-analysis.
MDM2 is a major negative regulator of p53, and a single nucleotide polymorphism (SNP) in the MDM2 promoter region SNP309 has been demonstrated to be associated with an increased MDM2 expression and a significantly earlier age of onset of several tumors, including gastric cancer. Several studies were published to evaluate the association between SNP309 and gastric cancer risk. However, the results remain conflicting rather than conclusive. The aim of this study was to assess the association between the MDM2 SNP309 polymorphism and gastric risk. We performed a meta-analysis to investigate this relationship. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. Five published case-control studies, including 1,621 gastric cancer cases and 2,639 controls were identified. We found that the MDM2 SNP309 polymorphism was associated with a significantly increased risk of gastric cancer risk when all studies were pooled into the meta-analysis (GG versus TT, OR = 1.54; 95%CI = 1.04-2.29, and GG versus GT/TT, OR = 1.49, 95%CI = 1.30-1.72). Furthermore, Egger's test did not show any evidence of publication bias (P = 0.799 for GG versus TT). Our results suggest that the MDM2 SNP309 polymorphism may be a low-penetrant risk factor for the development of gastric cancer.


Which patients with cancer die at home? A study of six European countries using death certificate data.
This study examines the proportion of cancer deaths occurring at home in six European countries in relation to illness and to demographic and health care factors. Death certificate data of all cancer-related deaths in 2002 in Italy and 2003 in Belgium, the Netherlands, Norway, England, and Wales (N = 238,216) were linked with regional health care and area statistics. Multivariate binomial logistic regressions were performed to examine factors associated with dying at home. The percentage of all cancer deaths occurring at home was 12.8 in Norway, 22.1 in England, 22.7 in Wales, 27.9 in Belgium, 35.8 in Italy, and 45.4 in the Netherlands. Having solid cancers and being married increased the chances of dying at home in all countries. Being older and being a woman decreased the chances of dying at home, except in Italy where the opposite was the case. A higher educational attainment was associated with better chances of dying at home in Belgium, Italy, and Norway (countries where information on educational attainment was available). Better chances of dying at home were also associated with living in less urbanized areas in all countries but England. The number of hospital and care home beds seemed not to be universally strong predictors of dying at home. There are large country differences in the proportion of patients with cancer dying at home, and these seem influenced by country-specific cultural, social, and health care factors. Alongside cross-national differences, country-specific aspects need to be considered in the development of policy strategies facilitating home death.


Penetration of telithromycin (HMR 3647), a new ketolide antimicrobial, into inflammatory blister fluid following oral administration.
The penetration of telithromycin (HMR 3647), a novel ketolide antimicrobial, has been assessed in an open, single-dose study in eight healthy male subjects. Following a single, oral, 600 mg dose the mean ratio of the concentration of telithromycin in blister fluid over plasma was 1.38. Significant blister fluid concentrations were maintained up to 24 h post-dose. These results indicate that telithromycin penetrates well into inflammatory extracellular fluid, achieving high and sustained concentrations in this medium.


The type of competition modulates the ecophysiological response of grassland species to elevated CO2 and drought.
The effects of elevated CO2 and drought on ecophysiological parameters in grassland species have been examined, but few studies have investigated the effect of competition on those parameters under climate change conditions. The objective of this study was to determine the effect of elevated CO2 and drought on the response of plant water relations, gas exchange, chlorophyll a fluorescence and aboveground biomass in four grassland species, as well as to assess whether the type of competition modulates that response. Elevated CO2 in well-watered conditions increased aboveground biomass by augmenting CO2 assimilation. Drought reduced biomass by reducing CO2 assimilation rate via stomatal limitation and, when drought was more severe, also non-stomatal limitation. When plants were grown under the combined conditions of elevated CO2 and drought, drought limitation observed under ambient CO2 was reduced, permitting higher CO2 assimilation and consequently reducing the observed decrease in aboveground biomass. The response to climate change was species-specific and dependent on the type of competition. Thus, the response to elevated CO2 in well-watered grasses was higher in monoculture than in mixture, while it was higher in mixture compared to monoculture for forbs. On the other hand, forbs were more affected than grasses by drought in monoculture, while in mixture the negative effect of drought was higher in grasses than in forbs, due to a lower capacity to acquire water and mineral nutrients. These differences in species-level growth responses to CO2 and drought may lead to changes in the composition and biodiversity of the grassland plant community in future climate conditions.


Generation of specific antisera directed against D-amino acids: focus on the neuroanatomical distribution of D-glutamate and other D-amino acids.
This review updates the findings about the anatomical distribution (using immunohistochemical techniques) and possible functions of D-glutamate in the central nervous system of mammals, as well as compares the distribution of D-glutamate with the distribution of the most studied D-amino acids: D-serine and D-aspartate. The protocol used to obtain highly specific antisera directed against D-amino acids is also reported. Immunoreactivity for D-glutamate was found in dendrites and cell bodies, but not in nerve fibers. Perikarya containing D-glutamate were found in the mesencephalon and thalamus. The highest density of cell bodies was found in the dorsal raphe nucleus, the mesencephalic central grey matter, the superior colliculus, and in the subparafascicular thalamic nucleus. In comparison with the distribution of immunoreactive cell bodies containing D-serine or D-aspartate, the distribution of D-glutamate-immunoreactive perikarya is less widespread. Currently, the physiological actions mediated by D-glutamate in the brain are unknown but the restricted neuroanatomical distribution of this D-amino acid suggests that D-glutamate could be involved in very specific physiological mechanisms. In this sense, the possible functional roles of D-glutamate are discussed.


[So-called "dense-vascularised" peritoneal adhesions: clinical and aetiopathogenetic considerations].
In the daily clinical practice of surgeons operating electively or, more frequently, in the emergency setting, within the abdominal cavity and pelvis, the detection of an intestinal adhesive disorder is frequent and is capable of causing numerous complications and subsequent reintervention. We report three cases of female patients referred to our observation for bowel subocclusion due to adhesive syndrome. After laparotomy, which revealed the presence of singular tenacious fibrovascular adhesions, the patients were subjected to immunohistochemical and receptor analysis yielding a diagnosis of leiomyomatosis peritonealis disseminata. The simultaneous combination of high levels of exogenous female hormones (hormone replacement therapy or prolonged exposure to oral contraceptives) or endogenous hormones (as happens during pregnancy), a genetic predisposition (including genetic malformations) and previous surgery (peritoneal trauma), as evidenced in our patients, all seem to play a key role in the pathogenesis of so-called "dense-vascularised", particularly tenacious adhesions responsible for the activation of multipotent mesenchymal submesothelial peritoneal cells. This striking macroscopic picture, when related to the anatomico-pathological description, is the basis of the pathological entity known as leiomyomatosis peritonealis disseminata.


Audit in orthodontic practice: how well do we communicate with our referring practitioners?
A questionnaire survey of 102 dental practitioners who refer patients to our specialist practice was undertaken to determine how satisfied they were with our current communication methods. Eighty-five replies were received (83 per cent). Seventy-two per cent felt that they were kept sufficiently informed about treatment decisions and progress. Almost all the practitioners were satisfied with our current extraction letter arrangements and with our practice of referring patients requiring oral surgery procedures directly to a local oral surgeon. Forty-six per cent of respondents noted a lapse in attendance by some patients undergoing active orthodontic treatment and 40 per cent requested more information regarding our waiting list. In general, 34 per cent of our referring practitioners felt that our communication methods could be improved to some degree, and a number of suggested improvements were made. Additional information was also obtained on referral patterns and the practitioners' own involvement with providing orthodontic treatment.


Molecular Dynamics Study on the Reverse Osmosis Using Multilayer Porous Graphene Membranes.
In this study, the reverse osmosis (RO) of a salt solution was investigated using a molecular dynamics method to explore the performance of a multilayer porous graphene membrane. The effects of the salt solution concentration, pressure, layer separation and pore offset on the RO performance of the membrane were investigated and the influences of the number of layers and the gradient structure were determined. The results show that as the salt solution concentration increases, the energy barrier of the water molecules passing through the bilayer porous graphene membranes changes slightly, indicating that the effect of the water flux on the membrane can be ignored. The salt rejection performance of the membrane improves with an increase in the concentration of the salt solution. When the pressure is increased, the energy barrier decreases, the water flux increases and the salt rejection decreases. When the layer separation of the bilayer porous graphene membrane is the same as the equilibrium spacing of the graphene membrane, the energy barrier is the lowest and the membrane water flux is the largest. The energy barrier of the bilayer porous graphene membrane increases with increasing layer separation, resulting in a decrease in the water flux of the membrane. The salt rejection increases with increasing layer separation. The water flux of the membrane decreases as the energy barrier increases with increasing pore offset and the salt rejection increases. The energy barrier effect is more pronounced for a larger number of graphene layers and the water flux of the membrane decreases because it is more difficult for the water molecules to pass through the porous graphene membrane. However, the salt rejection performance improves with the increase in the number of layers. The gradient pore structure enhances the energy barrier effect of the water molecules permeating through the membrane and the water flux of the membrane decreases. The salt rejection performance is improved by the gradient pore structure. The research results provide theoretical guidance for research on the RO performance of porous graphene membranes and the design of porous graphene membranes.


Executive functioning and compliance in HIV patients.
25 adult HIV patients were evaluated in a study of appointments, medication, and compliance with restrictions on sexual activity. The Executive Interview (EXIT) was useful in assessing these patients for cognitive difficulties; compliance with medication and countertransference issues were negatively correlated with EXIT scores.


Genetic interactions between ABA signalling and the Arg/N-end rule pathway during Arabidopsis seedling establishment.
The Arg/N-end rule pathway of ubiquitin-mediated proteolysis has multiple functions throughout plant development, notably in the transition from dormant seed to photoautotrophic seedling. PROTEOLYSIS6 (PRT6), an N-recognin E3 ligase of the Arg/N-end rule regulates the degradation of transcription factor substrates belonging to Group VII of the Ethylene Response Factor superfamily (ERFVIIs). It is not known whether ERFVIIs are associated with all known functions of the Arg/N-end rule, and the downstream pathways influenced by ERFVIIs are not fully defined. Here, we examined the relationship between PRT6 function, ERFVIIs and ABA signalling in Arabidopsis seedling establishment. Physiological analysis of seedlings revealed that N-end rule-regulated stabilisation of three of the five ERFVIIs, RAP2.12, RAP2.2 and RAP2.3, controls sugar sensitivity of seedling establishment and oil body breakdown following germination. ABA signalling components ABA INSENSITIVE (ABI)4 as well as ABI3 and ABI5 were found to enhance ABA sensitivity of germination and sugar sensitivity of establishment in a background containing stabilised ERFVIIs. However, N-end rule regulation of oil bodies was not dependent on canonical ABA signalling. We propose that the N-end rule serves to control multiple aspects of the seed to seedling transition by regulation of ERFVII activity, involving both ABA-dependent and independent signalling pathways.


The everyday realities of the multi-dimensional role of the high school community nurse.
The traditional role of the high school based community community health nurse has changed considerably over recent decades. This article describes a qualitative study, in which nine community health nurses from eight different high schools completed a diary of the interventions and events during the course of two working days in order to identify the dimensions of their role. A short demographic questionnaire was also completed by the nurses and included two open-ended questions concerning their main professional issues and concerns. The researchers sought verification of the interpretation of the data through a focus group interview with the high school nurses. Data analysis indicated that the role of the high school community health nurses (CHN) consisted of seven categories. These were provider of clinical care, counsellor/ mediator, advocacy and support, liaison/referral, health promotion/education and resource agent, and professional management and research role. The findings highlight the complex and demanding aspects of the role of the high school nurse and articulate the importance of describing the contribution of such practitioners in to the promotion of health among adolescents.


Confocal corrected attenuation coefficient imaging in phantoms and in vivo using chromatic focal shift calibration.
Optical coherence tomography (OCT) is conventionally used for structural imaging of tissue. Calibrating the intensity values of OCT images can give information on the tissue's inherent optical properties, such as the attenuation coefficient, which can provide an additional parameter to quantify possible pathological changes. To obtain calibrated intensity values, the focus position and Rayleigh length of the incident beam need to be known. We explore the feasibility of extracting the focus position from an OCT scan acquired with a single focus setting using the chromatic aberration of the system. The chromatic focal shift of an OCT system is exploited to achieve different focus positions for sub-spectrum reconstructed OCT images. The ratios of these images are used to estimate the focus position. Reconstruction of a high-resolution B-scan from coherent addition of sub-spectrum confocal function corrected B-scans and subsequent high-resolution OCT attenuation coefficient imaging is demonstrated. Furthermore, we introduce a method to experimentally determine the chromatic focal shifts of an OCT system in phantoms and an in vivo human retina. These shifts are compared to the theoretically expected shifts calculated with ray tracing.


A cassette ligation strategy with thioether replacement of three Gly-Gly peptide bonds: total chemical synthesis of the 101 residue protein early pregnancy factor [psi(CH(2)S)28-29,56-57,76-77].
The 101 residue protein "early pregnancy factor" (EPF), also known as human chaperonin 10, was synthesized from four functionalized, but unprotected, peptide segments by a sequential thioether ligation strategy. The approach exploits the differential reactivity of a peptide-NHCH(2)CH(2)SH thiolate with XCH(2)CO-peptides, where X = Cl or I/Br. Initial model studies with short functionalized (but unprotected) peptides showed a significantly faster reaction of a peptide-NHCH(2)CH(2)SH thiolate with a BrCH(2)CO-peptide than with a ClCH(2)CO-peptide, where thiolate displacement of the halide leads to chemoselective formation of a thioether surrogate for the Gly-Gly peptide bond. This rate difference was used as the basis of a novel sequential ligation approach to the synthesis of large polypeptide chains. Thus, ligation of a model bifunctional N(alpha)-chloroacetyl, C-terminal thiolated peptide with a second N(alpha)-bromoacetyl peptide demonstrated chemoselective bromide displacement by the thiol group. Further investigations showed that the relatively unreactive N(alpha)-chloroacetyl peptides could be "activated" by halide exchange using saturated KI solutions to yield the highly reactive N(alpha)-iodoacetyl peptides. These findings were used to formulate a sequential thioether ligation strategy for the synthesis of EPF, a 101 amino acid protein containing three Gly-Gly sites approximately equidistantly spaced within the peptide chain. Four peptide segments or "cassettes" comprising the EPF protein sequence (BrAc-[EPF 78-101] 12, ClAc-[EPF 58-75]-[NHCH(2)CH(2)SH] 13, ClAc-[EPF 30-55]-[NHCH(2)CH(2)SH] 14, and Ac-[EPF 1-27]-[NHCH(2)CH(2)SH] 15) of EPF were synthesized in high yield and purity using Boc SPPS chemistry. In the stepwise sequential ligation strategy, reaction of peptides 12 and 13 was followed by conversion of the N-terminal chloroacetyl functional group to an iodoacetyl, thus activating the product peptide for further ligation with peptide 14. The process of ligation followed by iodoacetyl activation was repeated to yield an analogue of EPF (EPF psi(CH(2)S)(28)(-)(29,56)(-)(57,76)(-)(77)) 19 in 19% overall yield.


Uremic Leontiasis Ossea in a Patient With Chronic Renal Insufficiency Demonstrated on Bone Scintigraphy.
A 37-year-old woman with chronic renal insufficiency underwent bone scintigraphy to evaluate renal osteodystrophy (ROD). Markedly increased uptakes were shown in the maxilla and the mandible, which suggested extensive maxillary and mandibular hypertrophy. CT image revealed that diffuse bony thickening and ground-glass appearance in the skull, maxilla, and mandible with poor distinction of the corticomedullary junction. Whole-body bone scintigraphy images also demonstrated various skeletal characteristics of ROD. This case emphasizes the utility of bone scintigraphy for the surveillance of the whole body in ROD.


Future developments in ambulatory blood pressure monitoring and self-blood pressure monitoring in clinical practice.
A number of factors interact to promote the increased clinical use of both ambulatory blood pressure monitoring (ABPM) and self-blood pressure monitoring (SBPM). These include the phasing out of mercury, evidence of the unreliability of clinic measurements, technical advances in automated blood pressure measurement, increasing evidence that out-of-office measurements give the best risk assessment, and a gradual recognition by payers of the clinical utility of ABPM and SBPM. Both ABPM and SBPM have been endorsed by the two major guidelines for managing hypertensive patients (World Health Organization-International Society of Hypertension and Joint National Committee VI). The use of SBPM has grown enormously over the past few years, mostly because of direct sales to patients. Although SBPM may give a better estimate of the true blood pressure than clinic readings, there are concerns about the accuracy of the monitors in individual patients. The main clinical indication for ABPM is the diagnosis of white-coat hypertension. This requires the demonstration that the blood pressure is normal outside the clinic, which can be established using SBPM and confirmed by ABPM. Even though ABPM may save drug costs in patients with white-coat hypertension, its use may also lead to increased drug expenditure in others in whom it demonstrates suboptimal blood pressure control. SBPM has the potential to reduce the number of clinic visits and also to improve blood pressure control. The ultimate validation of both procedures will be whether they can prevent cardiovascular morbidity. There have been suggestions that a non-dipping pattern of nocturnal blood pressure may carry a bad prognosis, but this may apply only to certain disease end-points. The greater recognition of the relevance of dipping status should provide an additional stimulus to the growth of both procedures. It is anticipated that, in the future, hypertension will be managed by the 'virtual hypertension clinic', using ABPM for the initial diagnosis, and SBPM with electronic linkage between the patient and the health-care provider for maintenance and follow-up.


Dynamical transitions and sliding friction of the phase-field-crystal model with pinning.
We study the nonlinear driven response and sliding friction behavior of the phase-field-crystal (PFC) model with pinning including both thermal fluctuations and inertial effects. The model provides a continuous description of adsorbed layers on a substrate under the action of an external driving force at finite temperatures, allowing for both elastic and plastic deformations. We derive general stochastic dynamical equations for the particle and momentum densities including both thermal fluctuations and inertial effects. The resulting coupled equations for the PFC model are studied numerically. At sufficiently low temperatures, we find that the velocity response of an initially pinned commensurate layer shows hysteresis with dynamical melting and freezing transitions for increasing and decreasing applied forces at different critical values. The main features of the nonlinear response in the PFC model are similar to the results obtained previously with molecular dynamics simulations of particle models for adsorbed layers.


Metastases to the pancreas and their surgical extirpation.
The pancreas is an unusual but occasionally favored site for metastases, notably from carcinomas of the kidney and lung. The pancreas may be the only identified locus of spread, and therefore may provide an opportunity for significant palliation or even cure using pancreatectomy. To report the treatment and outcome of patients presenting with metastases to the pancreas. Five-year survey. Tertiary referral center. Ten patients with apparently isolated metastases to the pancreas were identified from January 1, 1991, to December 31, 1995. All patients were followed up until death or to September 1997. The patients had been treated previously for carcinoma of the lung (n=4), renal cell carcinoma (n=2), sarcoma (n=2), breast carcinoma (n=1), and endometrial carcinoma (n=1). The interval between primary treatment and presentation of the metastases averaged 70 months (14-24 months for lung cancer, 10 and 22 years for renal cell carcinoma, 4 and 6 years for sarcoma, 8 years for breast cancer, and 36 months for endometrial carcinoma). Metastases were initially misdiagnosed as primary pancreatic cancers in 7 patients. In 4 patients (those with renal cell cancer and sarcomas), the tumor was completely resected using total pancreatectomy (n=3) or Whipple resection (n=1). Survival after diagnosis averaged 22 months. Two of the 4 patients undergoing pancreatic resection remain alive and well 20 and 25 months after pancreatectomy. The pancreas may be the presenting and perhaps sole locus for metastasis, typically years after treatment for certain extrapancreatic malignant neoplasms. Recognition and surgical treatment can provide worthwhile palliation and long-term survival.


Are transversion mutations better? A Mutagenesis Assistant Program analysis on P450 BM-3 heme domain.
Directed evolution represents a versatile tool to tailor enzyme properties to needs in industrial applications and to understand structure-function relationships. Genetic diversity is commonly generated using error-prone PCR. Exploration of sequence space by random mutagenesis strongly favors transitions when enzyme-based mutagenesis methods are employed (Wong, T. S., Zhurina, D., Schwaneberg, U., Comb. Chem. High Throughput Screen. 2006, 9, 271-288). The genetic code has been organized in a manner that limits chemical diversity when a single transition mutation occurs in a codon (Wong, T. S., Roccatano, D., Schwaneberg, U., Biocatal. Biotransformation 2006, in press). Are transitions more beneficial than transversions for adapting biocatalysts to non-natural process conditions? In a statistical analysis performed with the Mutagenesis Assistant Program (MAP), we compared the consequences of transition and transversion bias on amino acid substitution patterns of the P450 BM-3 heme domain. For the analysis, we used a recently introduced benchmarking system consisting of a protein structure indicator, an amino acid diversity indicator with a codon diversity coefficient, and a chemical diversity indicator. A detailed analysis for the P450 BM-3 heme domain showed that an ideal transversion bias generates more diverse amino acid substitution patterns with a significantly different chemical composition than an ideal transition bias. Emphasis is given on the theoretical analysis with a brief discussion on potential implication of transition and transversion bias in directed evolution experiments.


Postoperative Management After Total Pharyngolaryngectomy Using the Free Ileocolon Flap: A 5-Year Surgical Intensive Care Unit Experience.
Management after total pharyngolaryngectomy with free ileocolon flaps can be challenging. Adequate postoperative surgical guidelines are essential to avoid complications. Factors, such as agitation, hypotension, or prolonged mechanical ventilation, might compromise final outcomes. Herein, we describe our experience in the early postoperative care of patients after total pharyngolaryngectomy with immediate reconstruction using the free ileocolon flap. This is a retrospective review of all patients who underwent total pharyngolaryngectomy and immediate reconstruction using the free Ileocolon flap. Demographics, etiology of resection, neoadjuvant therapy, surgical time, method of sedation, postoperative use of vasopressors, length of intensive care unit (ICU) stay, time of discontinuation of mechanical ventilation, and complications were recorded and analyzed. Between 2010 and 2015, a total of 34 patients underwent total pharyngolaryngectomy and immediate reconstruction using the free Ileocolon flap. The most common cause of total pharyngolaryngectomy was cancer. Twenty-eight patients had neoadjuvant therapy (radiation). The average surgical time was 11.5 hours (range, 8-14.5 hours), average length of ICU stay was 3 days (range, 2-15 days) with an average time for mechanical ventilation cessation of 3 days (range, 1-20 days). Midazolam and dexmedetomidine were the most common sedatives used during surgery and in the ICU period. Three patients required vasopressors due to hypotension, 2 had unplanned self-extubation from the tracheostomy site, 2 experienced postoperative bleeding, 1 had pneumonia, 4 required unplanned return to the operating room, 2 had partial flap loss, and 1 had complete flap loss. Overall, a majority of patients recovered well postoperatively with minimal complications and low rate of reoperation. Our research provides a foundation to develop a risk-stratified approach to determine the need for an ICU admission or early transfer to floor care.


Cryo-EM structure of an early precursor of large ribosomal subunit reveals a half-assembled intermediate.
Assembly of eukaryotic ribosome is a complicated and dynamic process that involves a series of intermediates. It is unknown how the highly intertwined structure of 60S large ribosomal subunits is established. Here, we report the structure of an early nucleolar pre-60S ribosome determined by cryo-electron microscopy at 3.7 Å resolution, revealing a half-assembled subunit. Domains I, II and VI of 25S/5.8S rRNA pack tightly into a native-like substructure, but domains III, IV and V are not assembled. The structure contains 12 assembly factors and 19 ribosomal proteins, many of which are required for early processing of large subunit rRNA. The Brx1-Ebp2 complex would interfere with the assembly of domains IV and V. Rpf1, Mak16, Nsa1 and Rrp1 form a cluster that consolidates the joining of domains I and II. Our structure reveals a key intermediate on the path to establishing the global architecture of 60S subunits.


Pituitary response to intravenous hypothalamic releasing peptides in cynomolgus monkeys treated with contraceptive steroids.
The secretory response of the pituitary to an iv bolus dose of hypothalamic releasing peptides (HRP) was evaluated in male and cycling (CYC) or contraceptive-treated female cynomolgus monkeys. Parenteral delivery of levonorgestrel and 17 beta-estradiol by intravaginal ring (CVR) was compared with oral administration (OC) of norgestrel and ethinyl estradiol in the diet. LH secretion was suppressed in the CVR group compared to that in other groups, and the response in males was greater than that in either CYC or OC females (P less than 0.01). Elevated plasma PRL concentrations in the CVR group during the baseline period (P less than 0.05) together with their larger pituitary weights (P less than 0.01) suggested lactotroph hypertrophy or hyperplasia compared to other groups. The plasma GH response was similar in the male, CYC, and CVR groups, but plasma GH levels increased from -15 to 0 min before HRP injection in the OC group (P less than 0.001) and continued to be higher for 15 min after HRP compared to values in the other groups (P less than 0.001), suggesting a treatment effect. Neither plasma TSH nor T4 levels were different among the groups after HRP administration, but T4 was elevated (P less than 0.01) in the OC group due to increased T4-binding globulin. The greater ACTH response 15 min after HRP treatment (P less than 0.05) in the CVR group compared to that in the other groups was associated with greater adrenal weights of the CVR females (P less than 0.05), suggesting chronic tropic stimulation. However the adrenal steroid results did not support this interpretation. We conclude that the differences in pituitary hormone secretion during these studies could be attributed to the nature of the reproductive steroid environment.


Boc-protected amines via a mild and efficient one-pot Curtius rearrangement.
[reaction: see text] The reaction of a carboxylic acid with di-tert-butyl dicarbonate and sodium azide allowed the formation of an acyl azide intermediate, which undergoes a Curtius rearrangement in the presence of tetrabutylammonium bromide and zinc(II) triflate. The trapping of the isocyanate derivative in the reaction mixture led to the desired tert-butyl carbamate in high yields at low temperature. These reaction conditions are compatible with a variety of substrates, including malonate derivatives, which provide access to protected amino acids.


Thoracic manifestations of sickle cell disease.
Sickle cell disease is the most common inherited disease in the African American population. Multiorgan pathologic features with a predilection for thoracic organs predominate. Acute cardiopulmonary diseases include acute chest syndrome, pneumonia, and left ventricular failure. Cardiomegaly, pleural effusions, pulmonary consolidation, pulmonary edema on chest radiographs, and ground-glass opacities on computed tomographs are characteristic. Chronic changes include sickle cell lung disease with lung fibrosis, pulmonary arterial hypertension, hyperkinetic circulation related to severe anemia, and thoracic skeletal abnormalities; the latter are H-shaped vertebrae, rib infarction, and extramedullary hematopoesis.


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The widespread debate about the falling birth rate and contraception in Germany and France culminated before 1914. Physicians took a considerable part in this discussion about mental modernization. They were the first to discover and describe the concrete means of reducing births. the liberal reaction to contraception was a 'laisser-faire' attitude which dominated medical responses until 1900, in France even longer. A minority of doctors became politically active Neo-Malthusians or even defenders of birth control as a means of improving race. The majority of physicians, however, remained hostile to contraception. Both groups used this issue to improve their social standing. Arguing morally, doctors took over the role of the priest; arguing scientifically, they shared the growing prestige of science; arguing nationalistically, they presented themselves as important advisors to the fatherland.


Appearance and characterization of fruit image textures for quality sorting using wavelet transform and genetic algorithms.
Images of four qualities of mangoes and guavas are evaluated for color and textural features to characterize and classify them, and to model the fruit appearance grading. The paper discusses three approaches to identify most discriminating texture features of both the fruits. In the first approach, fruit's color and texture features are selected using Mahalanobis distance. A total of 20 color features and 40 textural features are extracted for analysis. Using Mahalanobis distance and feature intercorrelation analyses, one best color feature (mean of a* [L*a*b* color space]) and two textural features (energy a*, contrast of H*) are selected as features for Guava while two best color features (R std, H std) and one textural features (energy b*) are selected as features for mangoes with the highest discriminate power. The second approach studies some common wavelet families for searching the best classification model for fruit quality grading. The wavelet features extracted from five basic mother wavelets (db, bior, rbior, Coif, Sym) are explored to characterize fruits texture appearance. In third approach, genetic algorithm is used to select only those color and wavelet texture features that are relevant to the separation of the class, from a large universe of features. The study shows that image color and texture features which were identified using a genetic algorithm can distinguish between various qualities classes of fruits. The experimental results showed that support vector machine classifier is elected for Guava grading with an accuracy of 97.61% and artificial neural network is elected from Mango grading with an accuracy of 95.65%. The proposed method is nondestructive fruit quality assessment method. The experimental results has proven that Genetic algorithm along with wavelet textures feature has potential to discriminate fruit quality. Finally, it can be concluded that discussed method is an accurate, reliable, and objective tool to determine fruit quality namely Mango and Guava, and might be applicable to in-line sorting systems.