A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility.
Aromatase activity has commonly been associated with male infertility characterized by testicular dysfunction with low serum testosterone and/or testosterone to estradiol ratio. In this subset of patients, and particularly in those with hypogonadism, elevated levels of circulating estradiol may establish a negative feedback on the hypothalamic-pituitary-testicular axis by suppressing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production and impaired spermatogenesis. Hormonal manipulation via different agents such as selective estrogen modulators or aromatase inhibitors to increase endogenous testosterone production and improve spermatogenesis in the setting of infertility is an off-label option for treatment. We carried out a systematic review and meta-analysis of the literature of the past 30 years in order to evaluate the benefits of the use of aromatase inhibitors in the medical management of infertile/hypoandrogenic males. Overall, eight original articles were included and critically evaluated. Either steroidal (Testolactone) or nonsteroidal (Anastrozole and Letrozole) aromatase inhibitors were found to statistically improve all the evaluated hormonal and seminal outcomes with a safe tolerability profile. While the evidence is promising, future prospective randomized placebo-controlled multicenter trials are necessary to better define the efficacy of these medications.


Uterine perforation by intrauterine devices: a 16-year review.
One of the major concerns with the insertion of intrauterine devices is uterine perforation. Though uncommon, it can be debilitating and result in failure of the device. In this article we review uterine perforation with intrauterine contraception (IUC) in a community clinic in the UK over a 16-year period. We prospectively collected data on uterine perforations for the years 2000-2015, reviewed associated factors and calculated the annual rate of perforation, estimating if this lay within the expected range of normal variation using statistical process control (SPC) analysis. We analysed the rates of perforation in relation to the time from delivery and to breastfeeding. We identified 30 uterine perforations in 22 795 IUC insertions over the 16 years of observation, with an annual rate ranging from 0 to 4.3 per 1000 insertions, and a mean annual rate of 1.3 per 1000 insertions (95% CI 0.9 to 1.9), which remain within the SPC limits. Twenty-eight of the perforations were in parous women, 87% of whom were within 18 weeks of delivery, peaking at 13 weeks postpartum. Twenty of these were in breastfeeding women. In 3/28 cases for which we have outcome data the device was adherent to or had perforated either the bladder or bowel. Our perforation rate is consistent with other studies. Most of our perforations were within 18 weeks of childbirth, earlier than in a recent major study. We cannot tell from our data if there is a true peak in perforations 3 months postpartum as that may be a time when a high proportion of insertions are done.


Evolution of the large secreted gel-forming mucins.
Mucins, the major component of mucus, contain tandemly repeated sequences that differ from one mucin to another. Considerable advances have been made in recent years in our knowledge of mucin genes. The availability of the complete genomic and cDNA sequences of MUC5B, one of the four human mucin genes clustered on chromosome 11, provides an exemplary model for studying the molecular evolution of large mucins. The emerging picture is one of expansion of mucin genes by gene duplications, followed by internal repeat expansion that strictly preserves frameshift. Computational and phylogenetic analyses have permitted the proposal of an evolutionary history of the four human mucin genes located on chromosome 11 from an ancestor gene common to the human von Willebrand factor gene and the suggestion of a model for the evolution of the repeat coding portion of the MUC5B gene from a hypothetical ancestral minigene. The characterization of MUC5B, a member of the large secreted gel-forming mucin family, offers a new model for the comparative study of the structure-function relationship within this important family.


Hippocampal Complex Spike Cells do not Change Their Place Fields if the Goal is Moved Within a Cue Controlled Environment.
It has been shown that most hippocampal complex-spike cells fire at specific locations in relation to a set of controlled spatial cues and that they continue to fire in the appropriate places when the cues are removed (O'Keefe and Conway, 1978; O'Keefe and Speakman, 1987). However, the goal remained in a constant position relative to the controlled cues throughout these experiments. It is therefore possible that the unit firing was related to the goal location and not to the controlled cues as was suggested. For example, firing in a particular location might signal the rat's intention to make a particular turn towards the goal from that location and not the location itself. There are many reasons for believing that this is an unlikely class of explanations; nevertheless a test of this hypothesis was undertaken in the present experiment. Nineteen place units were recorded from three rats as they performed the task of finding the goal location. After obtaining an accurate picture of the place fields in relation to the controlled cues and the goal, the location of the goal relative to the cues was moved and the animal retrained to the new goal. After the new goal was being consistently chosen, a second picture of the place fields of the same units was obtained. If the fields were related to the environment created by the cues then they would remain the same during the two stages of the experiment. If they were related to the goal, or to the intended movements towards the goal, then they would rotate relative to the cues. As expected, the majority of place fields remained in the same place in relation to the cues during the two stages of the experiment and were not influenced by the goal relocation. In only two cases was there any suggestion that the place fields changed their location after the goal was moved. It was concluded that the activity of place cells is related to an animal's location in an environment and that the results accord with cognitive map theory of hippocampal function (O'Keefe and Nadel, 1978).


Clinical trials in menopause.
Clinical trials in menopause have undergone much scrutiny over the years. This has led to significant shifts in the treatment of symptomatic menopause and a substantial impact on women. We aim to delineate the key studies contributing to this controversy and highlight new directions specifically related to menopausal hormone therapy (HT) and vascular disease risk. We performed a search of sentinel studies delineating the risks and benefits of HT in otherwise healthy postmenopausal women. Using PubMed we input the following search terms: hormone replacement therapy, cardiovascular disease, coronary artery disease, coronary atherosclerosis, myocardial infarction, angina, coronary heart calcification, carotid intimal thickness, lipids, and/or lipoproteins. We included studies of menopausal women (surgical or natural) using combined estrogen/progestogen therapy or estrogen-only therapy that looked at cardiovascular disease risk factors or outcomes. Studies were evaluated for inclusion by the authors; however, this is not intended to be a systematic or an exhaustive analysis. In women close to the time of menopause, there is a decreased risk of subclinical and clinical coronary heart disease with menopausal HT. Additionally, HT confers a significant benefit to vasomotor symptoms of menopause, bone health, and colorectal cancer. There is an increased risk of venous thromboembolism with oral formulations that appears mitigated with transdermal estradiol. Mixed data regarding breast cancer risk are available, with some studies suggesting an increased risk of invasive breast cancer with estrogen/progestogen therapy and a null effect with estrogen-only therapy. Other more long-term epidemiologic studies identify a decreased risk. The available literature suggests that HT is a viable option for the primary prevention of cardiovascular disease in postmenopausal women. Newer trials will likely verify this assessment. If this is enough to change clinical practice, however, remains to be seen given the general fear of HT by many with prescriptive authority, and also the women in our care.


Nine Degree-of-Freedom Kinematic Modeling of the Upper-Limb Complex for Constrained Workspace Evaluation.
The design of rehabilitation devices for patients experiencing musculoskeletal disorders (MSDs) requires a great deal of attention. This article aims to develop a comprehensive model of the upper-limb complex to guide the design of robotic rehabilitation devices that prioritize patient safety, while targeting effective rehabilitative treatment. A 9 degree-of-freedom kinematic model of the upper-limb complex is derived to assess the workspace of a constrained arm as an evaluation method of such devices. Through a novel differential inverse kinematic method accounting for constraints on all joints1820, the model determines the workspaces in which a patient is able to perform rehabilitative tasks and those regions where the patient needs assistance due to joint range limitations resulting from an MSD. Constraints are imposed on each joint by mapping the joint angles to saturation functions, whose joint-space derivative near the physical limitation angles approaches zero. The model Jacobian is reevaluated based on the nonlinearly mapped joint angles, providing a means of compensating for redundancy while guaranteeing feasible inverse kinematic solutions. The method is validated in three scenarios with different constraints on the elbow and palm orientations. By measuring the lengths of arm segments and the range of motion for each joint, the total workspace of a patient experiencing an upper-limb MSD can be compared to a preinjured state. This method determines the locations in which a rehabilitation device must provide assistance to facilitate movement within reachable space that is limited by any joint restrictions resulting from MSDs.


Associations between biovar and virulence factor genes in Pasteurella multocida isolates from pigs in Spain.
Two hundred and five isolates of Pasteurella multocida from pigs were phenotypically and genetically characterised by determining their biovar, capsular type, virulence-associated genes and pulsed-field gel electrophoresis (PFGE) profiles. All isolates were identified as P multocida subspecies multocida and most were assigned to biovar 3 (58 per cent) and biovar 2 (39.5 per cent). Biovar 1 represented 2.4 per cent of the isolates. According to the capsular type, the great majority of the isolates (79.0 per cent) belonged to capsular type A, 18.5 per cent belonged to capsular type D and 2.4 per cent were of capsular type F. All isolates harboured ompH, psl, oma87, ptfA, nanB, nanH, tonB, hgbA, sodA and sodC genes, while none of them possessed the transferrin-binding protein gene tbpA. The prevalence of toxA, pfhaA and hgbB genes was variable (7.8, 40.5 and 60.5 per cent of the isolates, respectively). After PFGE typing, isolates of biovar 2 and 3 were grouped in two different clusters (A and B) at a level of 45 per cent similarity. In addition, isolates of biovar 2 and 3 exhibited statistically significant differences (P<0.05) in the virulence-associated hgbB and pfhA genes (biovar 3 was hgbB(+) pfhA(-), while biovar 2 was hgbB- pfhA(+)).


Micromolar affinity benzodiazepine receptors: identification and characterization in central nervous system.
Receptors that selectively bind micromolar concentrations of benzodiazepines are present in rat brain membrane. These micromolar receptors exhibit saturable, stereospecific binding, and the potency of benzodiazepine binding to these receptors is correlated with the ability of the benzodiazepines to inhibit maximum electric shock-induced convulsions. Benzodiazepine receptors with nanomolar affinity differ from the micromolar receptors in their binding, kinetic, and pharmacologic characteristics. The micromolar receptors also bind phenytoin, a non-benzodiazepine anticonvulsant. These results provide evidence for a distinct class of clinically relevant benzodiazepine receptors that may regulate neuronal excitability and anticonvulsant activity.


Vocal parameters that indicate threat level correlate with FOS immunolabeling in social and vocal control brain regions.
Transmitting information via communicative signals is integral to interacting with conspecifics, and some species achieve this task by varying vocalizations to reflect context. Although signal variation is critical to social interactions, the underlying neural control has not been studied. In response to a predator, black-capped chickadees (Poecile atricapilla) produce mobbing calls (chick-a-dee calls) with various parameters, some of which convey information about the threat stimulus. We predicted that vocal parameters indicative of threat would be associated with distinct patterns of neuronal activity within brain areas involved in social behavior and those involved in the sensorimotor control of vocal production. To test this prediction, we measured the syntax and structural aspects of chick-a-dee call production in response to a hawk model and assessed the protein product of the immediate early gene FOS in brain regions implicated in context-specific vocal and social behavior. These regions include the medial preoptic area (POM) and lateral septum (LS), as well as regions involved in vocal motor control, including the dorsomedial nucleus of the intercollicular complex and the HVC. We found correlations linking call rate (previously demonstrated to reflect threat) to labeling in the POM and LS. Labeling in the HVC correlated with the number of D notes per call, which may also signal threat level. Labeling in the call control region dorsomedial nucleus was associated with the structure of D notes and the overall number of notes, but not call rate or type of notes produced. These results suggest that the POM and LS may influence attributes of vocalizations produced in response to predators and that the brain region implicated in song control, the HVC, also influences call production. Because variation in chick-a-dee call rate indicates predator threat, we speculate that these areas could integrate with motor control regions to imbue mobbing signals with additional information about threat level.


Sister-chromatid exchange induction by indirect mutagens/carcinogens, aryl hydrocarbon hydroxylase activity and benzo[alpha]pyrene metabolism in cultured human hepatoma cells.
2 human hepatoma cell lines (C-HC-4 and C-HC-20), in which aryl hydrocarbon hydroxylase activity was induced with benz[alpha]anthracene in vitro to about 140- and 64-fold of the respective basal levels, yielded an increased frequency of sister-chromatid exchanges (SCEs) when exposed to benzo[alpha]pyrene (BP), 7,12-dimethylbenz[alpha]anthracene and 3-methylcholanthrene in vitro. Analysis of the metabolism of BP by these cells by high-pressure liquid chromatography revealed that both cell lines produced various BP metabolites including the proximate form BP-7,8-dihydrodiol which has been reported to be the most potent inducer of SCEs among the metabolites of BP. In addition, aflatoxin B1 and cyclophosphamide also induced SCEs in these cell lines. The above findings suggest that these cells may be capable of metabolizing a range of indirect mutagens/carcinogens into DNA-active forms. These cells may therefore serve as a useful test system in vitro for the detection of genotoxic agents, without the use of an exogenous activating system.


Reductive evolution and the loss of PDC/PAS domains from the genus Staphylococcus.
The Per-Arnt-Sim (PAS) domain represents a ubiquitous structural fold that is involved in bacterial sensing and adaptation systems, including several virulence related functions. Although PAS domains and the subclass of PhoQ-DcuS-CitA (PDC) domains have a common structure, there is limited amino acid sequence similarity. To gain greater insight into the evolution of PDC/PAS domains present in the bacterial kingdom and staphylococci in specific, the PDC/PAS domains from the genomic sequences of 48 bacteria, representing 5 phyla, were identified using the sensitive search method based on HMM-to-HMM comparisons (HHblits). A total of 1,007 PAS domains and 686 PDC domains distributed over 1,174 proteins were identified. For 28 Gram-positive bacteria, the distribution, organization, and molecular evolution of PDC/PAS domains were analyzed in greater detail, with a special emphasis on the genus Staphylococcus. Compared to other bacteria the staphylococci have relatively fewer proteins (6-9) containing PDC/PAS domains. As a general rule, the staphylococcal genomes examined in this study contain a core group of seven PDC/PAS domain-containing proteins consisting of WalK, SrrB, PhoR, ArlS, HssS, NreB, and GdpP. The exceptions to this rule are: 1) S. saprophyticus lacks the core NreB protein; 2) S. carnosus has two additional PAS domain containing proteins; 3) S. epidermidis, S. aureus, and S. pseudintermedius have an additional protein with two PDC domains that is predicted to code for a sensor histidine kinase; 4) S. lugdunensis has an additional PDC containing protein predicted to be a sensor histidine kinase. This comprehensive analysis demonstrates that variation in PDC/PAS domains among bacteria has limited correlations to the genome size or pathogenicity; however, our analysis established that bacteria having a motile phase in their life cycle have significantly more PDC/PAS-containing proteins. In addition, our analysis revealed a tremendous amount of variation in the number of PDC/PAS-containing proteins within genera. This variation extended to the Staphylococcus genus, which had between 6 and 9 PDC/PAS proteins and some of these appear to be previously undescribed signaling proteins. This latter point is important because most staphylococcal proteins that contain PDC/PAS domains regulate virulence factor synthesis or antibiotic resistance.


Quartz tube extensometer for observation of Earth tides and local tectonic deformations at the Sopronbánfalva Geodynamic Observatory, Hungary.
In May 1990, a quartz tube extensometer was installed in the Sopronbánfalva Geodynamic Observatory of the Geodetic and Geophysical Research Institute (GGRI) of the Hungarian Academy of Sciences for recording Earth tides and recent tectonic movements. The paper describes the construction of the extensometer and a portable calibrator used for the in situ calibration of the instrument. The extensometer is very sensitive. Its scale factor is 2.093+/-0.032 nm/mV according to the highly precise calibration method developed at the GGRI. Since the stability of extensometers is strongly influenced by the geological structure and properties of the rocks in the vicinity of the recording site, the observatory instrument system was tested by coherence analysis between theoretical (as the input signal) and measured tidal data series (as the output signal). In the semidiurnal tidal frequency band the coherence is better than 0.95, while in the diurnal band it is about 0.8. Probably this is due to the fact that the noise is higher in the diurnal band (0.4-0.5 nstr) than in the semidiurnal band (0.19-0.22 nstr). Coherence analysis between theoretical and measured data corrected for barometric changes yielded a small improvement of coherence in both frequency bands, while using temperature data correction, no observable improvement was obtained. Results of the tidal analysis also show that the observatory instrument system is suitable for recording very small tectonic movements. The 18 years of continuous data series measured by the extensometer prove the high quality of the extensometer. On the basis of investigations, it was pointed out that further efforts should be done to improve the barometric correction method and that correction for ocean load, as well as considering topographic and cavity effects are necessary to increase the accuracy of determining tidal parameters.


Comparison of information processing technologies.
To examine the type of information obtainable from scientific papers, using three different methods for the extraction, organization, and preparation of literature reviews. A set of three review papers was identified, and the ideas represented by the authors of those papers were extracted. The 161 articles referenced in those three reviews were then analyzed using 1) a formalized data extraction approach, which uses a protocol-driven manual process to extract the variables, values, and statistical significance of the stated relationships; and 2) a computerized approach known as "Idea Analysis," which uses the abstracts of the original articles and processes them through a computer software program that reads the abstracts and organizes the ideas presented by the authors. The results were then compared. The literature focused on the human papillomavirus and its relationship to cervical cancer. Idea Analysis was able to identify 68.9 percent of the ideas considered by the authors of the three review papers to be of importance in describing the association between human papillomavirus and cervical cancer. The formalized data extraction identified 27 percent of the authors' ideas. The combination of the two approaches identified 74.3 percent of the ideas considered important in the relationship between human papillomavirus and cervical cancer, as reported by the authors of the three review articles. This research demonstrated that both a technically derived and a computer derived collection, categorization, and summarization of original articles and abstracts could provide a reliable, valid, and reproducible source of ideas duplicating, to a major degree, the ideas presented by subject specialists in review articles. As such, these tools may be useful to experts preparing literature reviews by eliminating many of the clerical-mechanical features associated with present-day scientific text processing.


A Monte Carlo study of the impact of missing data and differential item functioning on theta estimates from two polytomous Rasch family models.
This paper examines the impact of differential item functioning (DIF), missing item values, and different methods for handling missing item values on theta estimates with data simulated from the partial credit model and Andrich's rating scale model. Both Rasch family models are commonly used when obtaining an estimate of a respondent's attitude. The degree of missing data, DIF magnitude, and the percentage of DIF items were varied in MCAR data conditions in which the focal group was 10% of the total population. Four methods for handling missing data were compared: complete-case analysis, mean substitution, hot-decking, and multiple imputation. Bias, RMSE, means, and standard errors of the theta estimates for the focal group were adversely affected by the amount and magnitude of DIF items. RMSE and fidelity coefficients for both the reference and focal group were adversely impacted by the amount of missing data. While all methods of handling missing data performed fairly similarly, multiple imputation and hot-decking showed slightly better performance.


Postnatal depression is a public health nursing issue: perspectives from norway and ireland.
The framework provided by the Millennium Development Goals includes maternal health as an area of priority. Postnatal depression (PND) is a serious public health issue because it occurs at a crucial time in a mothers' life, can persist for long periods, and can have adverse effects on partners and the emotional, behavioural, and cognitive development of infants and children. Internationally, public health nurses (PHNs) are key professionals in the delivery of health care to mothers in the postpartum period, and international research collaborations are encouraged. Two researchers from the European Academy of Nursing Science (EANS) identified a need to collaborate and strengthen research capacity and discussion on postnatal depression, a public health nursing issue in both countries. Within the context of public health and public health nursing in Ireland and Norway, the aim of this paper is to present a discussion on the concept of PND, prevalence, and outcomes; screening issues for PHNs; and the research evidence of the benefits of social support in facilitating recovery for new mothers.


Synthesis and nitric oxide releasing properties of novel fluoro S-nitrosothiols.
A series of new fluoro S-nitrosothiols is reported as potential nitric oxide (NO) donors. A three-step synthesis and the NO releasing kinetic profiles of these species are presented. The stoichiometric release of NO, with the clean formation of corresponding disulfides, confirms that these new species can facilitate their application as NO donors for various applications including creating novel antimicrobial and thromboresistant fluoropolymer-based medical devices.


[Treatment of donor wounds after cutting of full-thickness skin transplants with a dermatome].
An analysis of the results of the treatment of 180 donor wounds following cutting off thick or full-thickness grafts by means of a dermatome in 123 patients with post-burn deformities and contractures is presented. The healing period variants, depending on the thickness of the grafts and on the treatment method, have been found. The authors recommend to cover the donor wounds with thin grafts or with sieve grafts.


The impact of inpatient suicide on psychiatric nurses and their need for support.
The nurses working in psychiatric hospitals and wards are prone to encounter completed suicides. The research was conducted to examine post-suicide stress in nurses and the availability of suicide-related mental health care services and education. Experiences with inpatient suicide were investigated using an anonymous, self-reported questionnaire, which was, along with the Impact of Event Scale-Revised, administered to 531 psychiatric nurses. The rate of nurses who had encountered patient suicide was 55.0%. The mean Impact of Event Scale-Revised (IES-R) score was 11.4. The proportion of respondents at a high risk (≥ 25 on the 88-point IES-R score) for post-traumatic stress disorder (PTSD) was 13.7%. However, only 15.8% of respondents indicated that they had access to post-suicide mental health care programmes. The survey also revealed a low rate of nurses who reported attending in-hospital seminars on suicide prevention or mental health care for nurses (26.4% and 12.8%, respectively). These results indicated that nurses exposed to inpatient suicide suffer significant mental distress. However, the low availability of systematic post-suicide mental health care programmes for such nurses and the lack of suicide-related education initiatives and mental health care for nurses are problematic. The situation is likely related to the fact that there are no formal systems in place for identifying and evaluating the psychological effects of patient suicide in nurses and to the pressures stemming from the public perception of nurses as suppliers rather than recipients of health care.


Transferrin Receptor Functionally Marks Thermogenic Adipocytes.
Thermogenic adipocytes, including beige and brown adipocytes, are critical for thermogenesis and energy homeostasis. Identification of functional cell surface markers of thermogenic adipocytes is of significance for potential application in biological and clinical practices. With a combination of RNA-sequencing of in vivo and in vitro models, we identified transferrin receptor (Tfr1), a receptor specialized for cellular iron uptake, as a previously unappreciated cell surface molecule for thermogenic adipocytes compared to white adipocytes. The alternation of Tfr1 levels under physiological and pathological stimuli was assessed, and the mitochondria functionality, browning capacity, and iron metabolism of mature adipocytes were examined with Tfr1 knockdown. Tfr1 was expressed predominantly in thermogenic adipocytes versus white adipocyte, and its expression levels were tightly correlated with the activation or inhibition status of thermogenic adipocytes under external stimuli. Besides, Tfr1 gene deficiency in thermogenic adipocytes led to reduced thermogenic gene programs and mitochondrial integrity. Tfr1 functionally marks thermogenic adipocytes and could serve as a potential thermogenic adipocyte surface marker.


Prevention of tumor seeding during needle biopsy by chemotherapeutic-releasing gelatin sticks.
Needle biopsy is an indispensable diagnostic tool in obtaining tumor tissue for diagnostic examination. Tumor cell seeding in the needle track during percutaneous needle biopsies has been reported for various types of cancers. The mechanical force of the biopsy both directly displaces the malignant cells and causes bleeding and fluid movement that can further disseminate cells. To prevent the risk of tumor cell seeding during biopsy, we developed a gelatin stick loaded with chemotherapeutics such as doxorubicin (DXR) that was inserted into the biopsy canal. The gelatin-doxorubicin sticks (GDSs) were created by passively loading precut gelatin foam strips (Gelfoam) with doxorubicin solution. The dried GDSs were inserted into the needle track through the sheath during the needle biopsy and eventually self-absorbed. We showed that this procedure prevented iatrogenic tumor seeding during needle biopsies in two subcutaneous tumor models. In an alternative application, using GDSs in intracranial brain tumor implantation avoided the outgrowth of tumor from the rodent brain, which could otherwise potentially fuse the tumor with the meninges and distort the results in therapeutic studies in rodent brain tumor models.


Evaluation of arrhythmia scoring systems and exercise-induced cardioprotection.
Exercise is protective against ventricular arrhythmias induced by ischemia (I), the condition of inadequate blood flow, and reperfusion (R), the reestablishment of blood flow. This protection is observed clinically and scientifically by decreased incidence in ECG abnormalities. Numerous scoring systems exist for the quantification of ventricular arrhythmia severity. On the basis of preventricular contractions, ventricular tachycardia, and ventricular fibrillation frequency, these scoring systems are intended to provide more robust ECG outcome indicators than individual arrhythmia variables. Scoring systems vary primarily on continuous versus discontinuous treatment of the data, which should be considered when matching these arrhythmia metrics to scientific applications. The aim of this investigation was to evaluate seven ECG scoring systems in the assessment of ventricular arrhythmia severity after IR in male Sprague-Dawley rats. Animals remained sedentary or exercised (3 d of treadmill exercise for 60 min) before surgically induced IR. A subset of sedentary animals served as sham, undergoing surgical procedure without IR. ECGs were evaluated under blinded conditions by three trained individuals. Single arrhythmia data and the parametric score were analyzed by one-way ANOVA, whereas the Kruskal-Wallis was used to compare group means for all nonparametric scoring systems between groups. IR produced a significant arrhythmic response in exercised and sedentary rats as determined by all arrhythmia scoring systems. Four arrhythmia metrics resulted in significant differences between exercised and sedentary treatments (P < 0.001), whereas three metrics did not. Continuous versus discontinuous treatment of the data may account for variation in scoring system outcomes. These data confirm that exercise protects against IR-induced arrhythmias, and care must be taken when selecting an arrhythmia scoring system for ECG evaluation.


Endoscopically facilitated reduction laryngochondroplasty.
Endoscopic verification of the level of excision of the thyroid cartilage in reduction laryngochondroplasty maximizes the aesthetic result of the operation and prevents possible injury to the vocal cords. A prominent thyroid cartilage is identified with male sex. Reduction of the thyroid cartilage prominence (Adam's apple), also known as laryngochondroplasty, is often requested by patients undergoing male-to-female transsexual surgery. Some women, and even occasional slender men, with a markedly pronounced thyroid cartilage prominence also request this treatment to refine their neck contour. Topographic studies place the true vocal cords at a level corresponding to halfway up the thyroid cartilage. Because of the proximity of the thyroid cartilage prominence to the attachment of the true vocal cords, any anatomic variation may lead to injury to the phonatory apparatus during the cartilage excision. Attempts to avoid this occurrence may result in overconservative reduction of the thyroid prominence and less-than-optimal aesthetic results. Herein we describe a combined endoscopic and external surgical approach to reduction laryngochondroplasty.


One-step purification of recombinant human amelogenin and use of amelogenin as a fusion partner.
Amelogenin is an extracellular protein first identified as a matrix component important for formation of dental enamel during tooth development. Lately, amelogenin has also been found to have positive effects on clinical important areas, such as treatment of periodontal defects, wound healing, and bone regeneration. Here we present a simple method for purification of recombinant human amelogenin expressed in Escherichia coli, based on the solubility properties of amelogenin. The method combines cell lysis with recovery/purification of the protein and generates a >95% pure amelogenin in one step using intact harvested cells as starting material. By using amelogenin as a fusion partner we could further demonstrate that the same method also be can explored to purify other target proteins/peptides in an effective manner. For instance, a fusion between the clinically used protein PTH (parathyroid hormone) and amelogenin was successfully expressed and purified, and the amelogenin part could be removed from PTH by using a site-specific protease.


Role of prenatal characteristics and early growth on pubertal attainment of British girls.
The objective of this study was to explore the influence of maternal prenatal characteristics and behaviors and of weight and BMI gain during early childhood on the timing of various puberty outcomes in girls who were enrolled in the Avon Longitudinal Study of Parents and Children. Repeated self-assessments of pubertal development were obtained from approximately 4000 girls between the ages of 8 and 14. Data on prenatal characteristics and weight at birth and 2, 9, and 20 months of age were obtained from questionnaires, birth records, and clinic visits. Infants' weights were converted to weight-for-age and BMI SD scores (SDSs; z scores), and change values were obtained for the 0- to 20-month and other intervals within that age range. We used parametric survival models to estimate associations with age of entry into Tanner stages of breast and pubic hair and menarche. Maternal initiation of menarche at age<12, smoking during pregnancy, and primiparity were associated with earlier puberty. A 1-unit increase in the weight SDS change values for the 0- to 20-month age interval was associated with earlier ages of entry into pubertal outcomes (0.19-0.31 years). Increases in the BMI SDS change values were also associated with earlier entry into pubertal outcomes (0.07-0.11 years). Many of the maternal prenatal characteristics and weight and BMI gain during infancy seemed to have similar influences across different puberty outcomes. Either such early factors have comparable influences on each of the hormonal processes involved in puberty, or processes are linked and awakening of 1 aspect triggers the others.


Prospective association of low total testosterone concentrations with an adverse lipid profile and increased incident dyslipidemia.
Earlier studies have suggested that total testosterone concentrations influence the lipid metabolism. Whether these concentrations are prospectively associated with an adverse lipid profile and an increased risk of incident dyslipidemia has not yet been investigated. Our study population consisted of 1468 men, aged 20–79 years, who were repeatedly examined as part of the population-based Study of Health in Pomerania. Serum total testosterone concentrations measured by the chemiluminescent enzyme immunoassays were categorized into age-specific quartiles. We used generalized estimating equations models to assess the prospective association between total testosterone concentrations and lipid profile components including total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride (TG) concentrations, as well as incident dyslipidemia after 5 years of follow-up. Multivariate models revealed that total testosterone concentrations in the lowest quartile were associated with higher TC and TG concentrations in both cross-sectional [TC: 0.23 mmol/l (95% confidence interval, CI, 0.02–0.42); TG: 0.73 mmol/l (95% CI, 0.53–0.94)] and longitudinal analyses [TC: 0.20 mmol/l (95% CI, 0.03–0.27); TG: 0.62 mmol/l (95% CI, 0.43–0.80)], but not with high-density lipoprotein cholesterol or low-density lipoprotein cholesterol concentrations. Baseline prevalence of dyslipidemia was 57.1% with a crude incidence rate of 46.6 per 1000 person-years. Total testosterone concentrations in the lowest quartile predicted dyslipidemia; age-adjusted relative risks (RR) for men in quartiles 1, 2, and 3 as compared to quartile 4 (highest, reference) were 1.28 (95% CI, 1.06–1.54), 1.10 (95% CI, 0.91–1.33), and 1.05 (95% CI, 0.86–1.29), respectively. This effect was particularly strong among men aged 20–39 years (relative risk, 1.51; 95% CI, 1.08–2.10). Low total testosterone concentrations are prospectively associated with an adverse lipid profile and increased risk of incident dyslipidemia. These findings are particularly interesting and may contribute to an explanation for the higher cardiovascular disease risk in men with lower total testosterone concentrations.


The (dis)appearance of the dying patient in generalist hospital and care home nurses' talk about the patient.
This article explores interview data from a study of 50 Norwegian generalist nurses' focus group accounts of caring for dying patients in the hospital and care home. An eclectic discourse analytic approach was applied to nurses' accounts of the patient and three discursive contexts of reference to the patient were identified: the 'taken as read' patient, the patient paired with particular characteristics and the patient as psychologically present. Talk about the patient falls mainly into the first two contexts, which position the patient in relation to three closely related discursive processes: individualization, anonymization and objectification. The third context presents the patient as a person with a particular identity. The analysis is discussed in a broader philosophical and sociological context in which we return to some of the theoretical work on death and dying of the 1990s and the topic of sequestration. We suggest that nurses' talk about the patient can be heard to participate in a continuing sequestration of the dying patient in healthcare institutions focused on 'result-oriented' care.


Ethnic and socioeconomic trends in breast cancer incidence in New Zealand.
Breast cancer incidence varies between social groups, but differences have not been thoroughly examined in New Zealand. The objectives of this study are to determine whether trends in breast cancer incidence varied by ethnicity and socioeconomic position between 1981 and 2004 in New Zealand, and to assess possible risk factor explanations. Five cohorts of the entire New Zealand population for 1981-86, 1986-1991, 1991-1996, 1996-2001, and 2001-2004 were created, and probabilistically linked to cancer registry records, allowing direct determination of ethnic and socioeconomic trends in breast cancer incidence. Breast cancer rates increased across all ethnic and socioeconomic groups between 1981 and 2004. Māori women consistently had the highest age standardised rates, and the difference between Māori and European/Other women increased from 7% in 1981-6 to 24% in 2001-4. Pacific and Asian women had consistently lower rates of breast cancer than European/Other women over the time period studied (12% and 28% lower respectively when pooled over time), although young Pacific women had slightly higher incidence rates than young European/other women. A gradient between high and low income women was evident, with high income women having breast cancer rates approximately 10% higher and this difference did not change significantly over time. Differences in breast cancer incidence between European and Pacific women and between socioeconomic groups are explicable in terms of known risk factors. However no straightforward explanation for the relatively high incidence amongst Māori is apparent. Further research to explore high Māori breast cancer rates may contribute to reducing the burden of breast cancer amongst Māori women, as well as improving our understanding of the aetiology of breast cancer.


Deficiency in methionine, tryptophan, isoleucine, or choline induces apoptosis in cultured cells.
Cells in culture die by apoptosis when deprived of the essential nutrient choline. We now report that cells (both proliferating PC12 cells and postmitotic neurons isolated from fetal rat brains) undergo apoptosis when deprived of other individual essential nutrients (methionine, tryptophan or isoleucine). In PC12 cells, deficiencies of each nutrient independently led to ceramide accumulation and to caspase activation, both recognized signals of several apoptotic pathways. A similar profile of caspases was activated in PC12 cells deprived of choline, methionine, tryptophan or isoleucine. More than one caspase was involved and these caspases appeared to transmit parallel signals for apoptosis induction because only broad-spectrum caspase inhibitors, but not inhibitors for specific individual caspases inhibited apoptosis in choline- or methionine-deprived cells. The induction of these caspase-dependent apoptosis pathways likely did not involve the same upstream signals. Choline deficiency perturbed choline metabolism but did not affect protein synthesis, whereas amino acid deficiencies inhibited protein synthesis but did not perturb choline metabolism. In addition, a subclone of PC12 cells that was resistant to choline deficiency-induced apoptosis was not resistant to tryptophan deficiency-induced apoptosis. These observations suggest that deficiency of each studied nutrient activates different pathways for signaling apoptosis that ultimately converge on a common execution pathway.


Glutathione synthesis and turnover in the human erythrocyte: alignment of a model based on detailed enzyme kinetics with experimental data.
The erythrocyte is exposed to reactive oxygen species in the circulation and also to those produced by autoxidation of hemoglobin. Consequently, erythrocytes depend on protection by the antioxidant glutathione. Mathematical models based on realistic kinetic data have provided valuable insights into the regulation of biochemical pathways within the erythrocyte but none have satisfactorily accounted for glutathione metabolism. In the current model, rate equations were derived for the enzyme-catalyzed reactions, and for each equation the nonlinear algebraic relationship between the steady-state kinetic parameters and the unitary rate constants was derived. The model also includes the transport processes that supply the amino acid constituents of glutathione and the export of oxidized glutathione. Values of the kinetic parameters for the individual reactions were measured predominately using isolated enzymes under conditions that differed from the intracellular environment. By comparing the experimental and simulated results, the values of the enzyme-kinetic parameters of the model were refined to yield conformity between model simulations and experimental data. Model output accurately represented the steady-state concentrations of metabolites in erythrocytes suspended in plasma and the changing glutathione concentrations in whole and hemolyzed erythrocytes under specific experimental conditions. Analysis indicated that feedback inhibition of gamma-glutamate-cysteine ligase by glutathione had a limited effect on steady-state glutathione concentrations and was not sufficiently potent to return glutathione concentrations to normal levels in erythrocytes exposed to sustained increases in oxidative load.


Balamuthia mandrillaris: Morphology, biology, and virulence.
Balamuthia mandrillaris is a protist pathogen that can cause encephalitis with a fatality rate of >95%. This is due to our incomplete understanding of the pathogenesis and pathophysiology of B. mandrillaris encephalitis. B. mandrillaris has two stages in its life cycle, an active trophozoite stage during which it divides mitotically. However, under unfavorable conditions, the trophozoite transforms into a dormant cyst stage. A major concern during the course of therapy is that B. mandrillaris can transform into cysts. Cysts are highly resistant to physical and chemical conditions and present a problem in successful antimicrobial chemotherapy. Several lines of evidence suggest that B. mandrillaris encephalitis develops as a result of hematogenous spread, but it is unclear how circulating amoebae enter the central nervous system and cause inflammation, blood-brain barrier disruption, and neuronal injury. Recent studies have identified several parasite-host determinants for B. mandrillaris translocation of the blood-brain barrier, and host inflammatory markers that may be associated with neuronal injury. These determinants may provide important targets for the prevention and treatment of this devastating infection. Here, we present a brief overview of the current understanding of the morphology, biology, pathogenesis, and pathophysiology of B. mandrillaris encephalitis.


Role of MPK4 in pathogen-associated molecular pattern-triggered alternative splicing in Arabidopsis.
Alternative splicing (AS) of pre-mRNAs in plants is an important mechanism of gene regulation in environmental stress tolerance but plant signals involved are essentially unknown. Pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) is mediated by mitogen-activated protein kinases and the majority of PTI defense genes are regulated by MPK3, MPK4 and MPK6. These responses have been mainly analyzed at the transcriptional level, however many splicing factors are direct targets of MAPKs. Here, we studied alternative splicing induced by the PAMP flagellin in Arabidopsis. We identified 506 PAMP-induced differentially alternatively spliced (DAS) genes. Importantly, of the 506 PAMP-induced DAS genes, only 89 overlap with the set of 1950 PAMP-induced differentially expressed genes (DEG), indicating that transcriptome analysis does not identify most DAS events. Global DAS analysis of mpk3, mpk4, and mpk6 mutants in the absence of PAMP treatment showed no major splicing changes. However, in contrast to MPK3 and MPK6, MPK4 was found to be a key regulator of PAMP-induced DAS events as the AS of a number of splicing factors and immunity-related protein kinases is affected, such as the calcium-dependent protein kinase CPK28, the cysteine-rich receptor like kinases CRK13 and CRK29 or the FLS2 co-receptor SERK4/BKK1. Although MPK4 is guarded by SUMM2 and consequently, the mpk4 dwarf and DEG phenotypes are suppressed in mpk4 summ2 mutants, MPK4-dependent DAS is not suppressed by SUMM2, supporting the notion that PAMP-triggered MPK4 activation mediates regulation of alternative splicing.


The PTPase YopH inhibits uptake of Yersinia, tyrosine phosphorylation of p130Cas and FAK, and the associated accumulation of these proteins in peripheral focal adhesions.
Pathogenic Yersinia resist uptake by eukaryotic cells by a mechanism involving the virulence protein YopH, a protein tyrosine phosphatase. We show that p130Cas and FAK are phosphorylated and recruited to peripheral focal complexes during bacterial uptake in HeLa cells. The inactive form of YopH interacts with the tyrosine phosphorylated forms of FAK and p130Cas and co-localizes with these proteins in focal adhesions. On the other hand, the presence of active YopH results in inhibition of uptake, dephosphorylation of p130Cas and FAK, and disruption of peripheral focal complexes. We suggest that p130Cas and FAK are substrates for YopH and that the dephosphorylation of these proteins impairs the uptake of Yersinia pseudotuberculosis into HeLa cells.


The re-infection rate of high-risk HPV and the recurrence rate of vulvar intraepithelial neoplasia (VIN) usual type after surgical treatment.
VIN usual type appears to be related to the HPV's oncogenic types. The aim of this prospective multicenter study was to evaluate the re-infection rate of high-risk HPV and the recurrence rate of VIN usual type after surgical treatment. The study enrolled 103 women affected by VIN usual type. They underwent wide local excision by CO2 laser. The patients were investigated by clinical evaluation and HPV DNA test 6 months after surgical treatment, and then were followed-up at 12, 18, 24, and 36 months. The recurrences were treated with re-excision. The rate of HPV infection after surgical treatment was 34% at 6 months, 36.9% at 12 months, 40% at 18 months, 41.7% at 24 months and 44.7% at 36 months. The mean time from HPV infection to the development of VIN was 18.8 months. HPV testing in the follow-up of VIN usual type patients might be useful for identifying those patients with a higher risk of recurrence after surgical treatment, although more studies are needed. These preliminary data suggest that the test, in addition to clinical examination, can improve the efficacy of the follow-up.


[Ultrasonic diagnosis of limited forms of appendicular peritonitis in children].
Results of an analysis of echographic diagnostics of appendicular peritonitis in 60 children have shown its high informative value. Under consideration are problems of the rational technique of investigation depending on localization of the pathological focus. Differential diagnostic criteria of various forms of limited peritonitis in children are presented. Possibilities of the method to establish the objective efficiency of the therapeutic treatment and substantiation of tactics of the treatment are shown.


Fasting insulin and endogenous hormones in relation to premenopausal breast density (Canada).
Mammographic breast density (BD) is associated with increased risk of breast cancer. This study asks which circulating metabolic and reproductive biomarkers are associated with BD, particularly dense breast area, in premenopausal women not taking exogenous hormones. In a cross-sectional study, 299 premenopausal women aged 40-49 completed questionnaires, provided a fasting blood sample, had height, weight, percentage body fat, waist and hip measurements taken, and attended a screening mammogram. Multivariate linear regression was used to calculate adjusted means for percentage BD, absolute dense and non-dense area, across categories of covariates, adjusted for day of menstrual cycle, age, parity, body mass index, percentage body fat, and ethnicity. Fasting insulin levels were inversely associated, and insulin-like growth factor-binding protein 1 levels directly associated with percentage BD, but lost statistical significance after multivariate adjustment. Sex hormone-binding globulin levels were directly associated with percentage BD, still significant after multivariate adjustment (p = 0.03). A significant inverse dose-response association was observed between progesterone levels and dense area (p < 0.01). Breast density in premenopausal women seems unrelated or inversely related to insulin resistance, levels of insulin-like growth factor 1 and its binding proteins, and levels of sex steroids; therefore, the mechanism by which radiodensity on a mammogram is related to breast cancer risk remains unclear.


Predicting Autism Spectrum Disorder Using Blood-based Gene Expression Signatures and Machine Learning.
The aim of this study was to identify a transcriptomic signature that could be used to classify subjects with autism spectrum disorder (ASD) compared to controls on the basis of blood gene expression profiles. The gene expression profiles could ultimately be used as diagnostic biomarkers for ASD. We used the published microarray data (GSE26415) from the Gene Expression Omnibus database, which included 21 young adults with ASD and 21 age- and sex-matched unaffected controls. Nineteen differentially expressed probes were identified from a training dataset (n=26, 13 ASD cases and 13 controls) using the limma package in R language (adjusted p value <0.05) and were further analyzed in a test dataset (n=16, 8 ASD cases and 8 controls) using machine learning algorithms. Hierarchical cluster analysis showed that subjects with ASD were relatively well-discriminated from controls. Based on the support vector machine and K-nearest neighbors analysis, validation of 19-DE probes with a test dataset resulted in an overall class prediction accuracy of 93.8% as well as a sensitivity and specificity of 100% and 87.5%, respectively. The results of our exploratory study suggest that the gene expression profiles identified from the peripheral blood samples of young adults with ASD can be used to identify a biological signature for ASD. Further study using a larger cohort and more homogeneous datasets is required to improve the diagnostic accuracy.


Genetic variation associates with susceptibility for cigarette smoke-induced neutrophilia in mice.
Neutrophilic airway inflammation is one of the major hallmarks of chronic obstructive pulmonary disease and is also seen in steroid resistant asthma. Neutrophilic airway inflammation can be induced by different stimuli including cigarette smoke (CS). Short-term exposure to CS induces neutrophilic airway inflammation in both mice and humans. Since not all individuals develop extensive neutrophilic airway inflammation upon smoking, we hypothesized that this CS-induced innate inflammation has a genetic component. This hypothesis was addressed by exposing 30 different inbred mouse strains to CS or control air for 5 consecutive days, followed by analysis of neutrophilic lung inflammation. By genomewide haplotype association mapping, we identified four susceptibility genes with a significant association to lung tissue levels of the neutrophil marker myeloperoxidase under basal conditions and an additional five genes specifically associated with CS-induced tissue MPO levels. Analysis of the expression levels of the susceptibility genes by quantitative RT-PCR revealed that three of the four genes associated with CS-induced tissue MPO levels had CS-induced changes in gene expression levels that correlate with CS-induced airway inflammation. Most notably, CS exposure induces an increased expression of the coiled-coil domain containing gene, Ccdc93, in mouse strains susceptible for CS-induced airway inflammation whereas Ccdc93 expression was decreased upon CS exposure in nonsusceptible mouse strains. In conclusion, this study shows that CS-induced neutrophilic airway inflammation has a genetic component and that several genes contribute to the susceptibility for this response.


L-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes.
L-selectin mediates rolling of lymphocytes in high endothelial venules (HEVs) of peripheral lymph nodes (PLNs). Cross-linking of L-selectin causes proteolytic shedding of its ectodomain, the physiological significance of which is unknown. To determine whether L-selectin shedding regulates lymphocyte migration, a mutant form that resists shedding (LdDeltaP-selectin) was engineered. Transgenic mice expressing either LDeltaP or wild-type (WT) L-selectin on T cells were crossed with L-selectin knockout (KO) mice. The cellularity and subset composition of secondary lymphoid organs did not differ between LDeltaP and WT mice, however, they were different from C57BL/6. Plasma levels of soluble L-selectin in LDeltaP mice were reduced to <5% of WT and C57BL/6 mice. The rolling properties of T lymphocytes from LDeltaP and WT mice on immobilized L-selectin ligands were similar. Furthermore, similar numbers of LDeltaP and WT T lymphocytes were recruited from the bloodstream into PLNs in mice, although LDeltaP T cells transmigrated HEVs more slowly. WT, but not LDeltaP-selectin, underwent rapid, metalloproteinase-dependent shedding after TCR engagement, and LDeltaP T cells retained the capacity to enter PLNs from the bloodstream. These results suggest that the ability to shed L-selectin is not required for T cell recirculation and homing to PLNs. However, L-selectin shedding from antigen-activated T cells prevents reentry into PLNs.


Operative treatment of new onset radiculopathy secondary to combat injury.
We set out to describe combat-related spine trauma over a 10-year period, and thereby determine the frequency of new onset radiculopathy secondary to injuries sustained in support of combat operations. We performed a retrospective analysis of a surgical database at three military institutions. Patients undergoing spine surgery following a combat-related injury in Afghanistan or Iraq between July 2003 and July 2013 were evaluated. We identified 105 patients with combat-related (Operations Enduring and Iraqi Freedom) spine trauma requiring operative intervention. Of these, 15 (14.3%) patients had radiculopathy as their primary complaint after injury. All patients were diagnosed with herniated nucleus pulposus. The average age was 39 years, with 80% injured in Iraq and 20% in Afghanistan. The most common mechanism of injury was mounted improvised explosive device (33%). The cervical spine was most commonly involved (53%), followed by lumbar spine (40%). Average time from injury to surgery was 23.4 months; 53% of patients had continued symptoms following surgery, and two patients had at least one revision surgery. Two patients were medically retired because of their symptoms. This study is the only of its kind evaluating the operative treatment of traumatic radiculopathy following combat-related trauma. We identified a relatively high rate of radiculopathy in these patients.


The vitamin D status among Tibetans.
UVB from the sun and intake from food are the only human sources of vitamin D. Tibet is a unique region for comparisons of these sources: (1) it lies at a low latitude and at a high altitude and has very large annual fluences of UVB; (2) the traditional Tibetan food is poor in vitamin D. Blood samples were taken from 63 persons of different age, with different occupations and staying at different places. UVB doses at these places were measured. The samples were analyzed by a standard radioimmune assay for determination of the serum concentration of 25 hydroxyvitamin D (25(OH)D). The main finding was that among nomads, there seems to be severe vitamin D deficiency (serum levels of 25(OH)D<30 nM). We tentatively propose that the low level of 25(OH)D of nomads is related to their clothing and sun exposure habits. For persons of other occupations (students, teachers and farmers) the levels are higher, although a significant fraction of these persons also have lower levels than 75 nm, by many regarded as a limit for insufficiency related to a number of negative health conditions. The annual dose of vitamin D-generating UVB is about five times larger in Lhasa than in Oslo. Despite this, the average vitamin D status seems to be similar, except in the case of nomads. This phenomenon is certainly related to food habits. In conclusion, the 25(OH)D status among nomads in Tibet appears to be alarmingly low. However, for people of other occupations the status is more normal.


Epidemiology of rotavirus infection in children in Blantyre, Malawi, 1997-2007.
Acute gastroenteritis caused by rotavirus infection is an important cause of morbidity and mortality among infants and young children in Africa. From 1997 through 2007, we enrolled 3740 children <5 years of age with acute gastroenteritis who received hospital care at the Queen Elizabeth Central Hospital in Blantyre, Malawi. Group A rotavirus was detected in fecal specimens by enzyme immunoassay. Rotavirus strains were characterized for VP7 (G) and VP4 (P) types with use of reverse-transcription polymerase chain reaction. Overall, rotavirus was detected in one-third of children. The median age of children with rotavirus gastroenteritis was 7.8 months, compared with 10.9 months for those without rotavirus in stool specimens (P > .001). Rotavirus circulated throughout the year, with the detection proportion greatest during the dry season (from May through October). A total of 15 single rotavirus strain types were detected during the study period, with genotypes P[8]G1, P[6]G8, P[4]G8, P[6]G1, P[8]G3, and P[6]G9 comprising 83% of all strains characterized. Serotype G12 was detected for the first time in Blantyre during the final 2 years of study. Zoonotic transmission and viral reassortment contributed to the rich diversity of strains identified. Current rotavirus vaccines have the potential to greatly reduce the rotavirus disease burden in Malawi, but they will be required to protect against a broad range of rotavirus serotypes in a young population with year-round rotavirus exposure.


[Local thrombolytic treatment of peripheral arterial thrombosis and embolism].
Local intra-arterial low-dose thrombolysis has become a therapeutic alternative for acute and subacute occlusion of vascular grafts and native vessels in the lower limbs. The series comprises 31 patients treated with Streptokinase as thrombolytic agent. Complete primary thrombolysis was achieved in 20 patients, whereas in 11 patients the outcome was only partially successful or a failure. Vascular stenoses were considered to precipitate thrombosis in 18 cases, and prompted percutaneous transluminal angioplasty after thrombolysis. Two-year patency was 48% (30-66%) in the total series and 74% (56-92%) among the patients with successful primary thrombolysis. There were no major complications. Five patients sustained local inguinal haemorrhage, of whom three required surgical revision. Local intra-arterial thrombolysis is an elaborate procedure associated with potential hazardous complications. It should be carried out in institutions with radiological and vascular surgical expertise.


[Some developmental features of Escherichia coli Mu phage in Pseudomonas aeruginosa cells].
In order to determine the replication-transposition (RT) efficiency of Escherichia coli phage Mu in Pseudomonas aeruginosa cells, the change of Mu DNA copy number after transfer of P. aeruginosa (RP4::Mu) from 42 (the condition of RP4::Mu plasmid stability and low phage production level in P. aeruginosa) to 30 degrees C (the condition of RP4::Mu plasmid instability and higher phage production level in P. aeruginosa) was analysed. It was shown that the temperature shift causes no increase in Mu DNA copy number, although free phage DNA is revealed after transfer of the cells at 30 degrees C. Considering that the studied cells contained also a linear RP4 DNA and the free Mu DNA hybridized with the RP4 DNA, we proposed that the mature Mu DNA arises as a result of Mu genome packaging from the original plasmid. So, the Mu genome RT is uneffective in P. aeruginosa and all of the phage particles released from P. aeruginosa (RP4::Mu) cells contain Mu DNA apparently originated from the DNA of hybrid plasmid RP4::Mu. Moreover, these results suggest that the Mu DNA packaging is not effective in P. aeruginosa (taking into account that the P. aeruginosa (RP4::Mu) cells release about 10(-2) p.f.u./cell and that originally the copy number of RP4::Mu > or = 1).


Public Perception of Uncertainties Within Climate Change Science.
Climate change is a complex, multifaceted problem involving various interacting systems and actors. Therefore, the intensities, locations, and timeframes of the consequences of climate change are hard to predict and cause uncertainties. Relatively little is known about how the public perceives this scientific uncertainty and how this relates to their concern about climate change. In this article, an online survey among 306 Swiss people is reported that investigated whether people differentiate between different types of uncertainty in climate change research. Also examined was the way in which the perception of uncertainty is related to people's concern about climate change, their trust in science, their knowledge about climate change, and their political attitude. The results of a principal component analysis showed that respondents differentiated between perceived ambiguity in climate research, measurement uncertainty, and uncertainty about the future impact of climate change. Using structural equation modeling, it was found that only perceived ambiguity was directly related to concern about climate change, whereas measurement uncertainty and future uncertainty were not. Trust in climate science was strongly associated with each type of uncertainty perception and was indirectly associated with concern about climate change. Also, more knowledge about climate change was related to less strong perceptions of each type of climate science uncertainty. Hence, it is suggested that to increase public concern about climate change, it may be especially important to consider the perceived ambiguity about climate research. Efforts that foster trust in climate science also appear highly worthwhile.


Gamma interferon and 5-azacytidine cause transcriptional elevation of class I major histocompatibility complex gene expression in K562 leukemia cells in the absence of differentiation.
We studied the effects of gamma interferon (IFN-gamma) on HLA class I gene expression, differentiation, and proliferative capacity of K562 human leukemia cells. In the uninduced state, K562 cells show little or no class I gene expression but actively express the erythroid-specific gamma-globin gene as well as genes associated with cell proliferation, including the transferrin receptor, c-myc, and alpha-actin genes At both the surface protein and mRNA levels, IFN-gamma induces class I and beta 2-microglobulin gene expression, but does not alter the expression of the gamma-globin, transferrin receptor, c-myc, or alpha-actin genes. A 10-fold maximal induction of both class I surface protein and mRNA occurs at 48 h and is reversible upon withdrawal of IFN-gamma from the culture medium. In vitro nuclear run-on transcription assays were performed to directly establish that IFN-gamma exerts an early effect at the level of transcription, with maximal transcription rates occurring within 4 h. The difference between the time course of transcription induction and that of mRNA accumulation suggests that the regulation of class I gene expression in this human leukemic cell line also involves posttranscriptional mechanisms. Measurements of cell proliferation rates and cell cycle distribution, as well as the reversibility of the effects of IFN-gamma, demonstrate that the selective induction of class I genes in these cells occurs in the absence of differentiation.


Robust Stride Detector from Ankle-Mounted Inertial Sensors for Pedestrian Navigation and Activity Recognition with Machine Learning Approaches.
In this paper, a stride detector algorithm combined with a technique inspired by zero velocity update (ZUPT) is proposed to reconstruct the trajectory of a pedestrian from an ankle-mounted inertial device. This innovative approach is based on sensor alignment and machine learning. It is able to detect 100% of both normal walking strides and more than 97% of atypical strides such as small steps, side steps, and backward walking that existing methods can hardly detect. This approach is also more robust in critical situations, when for example the wearer is sitting and moving the ankle or when the wearer is bicycling (less than two false detected strides per hour on average). As a consequence, the algorithm proposed for trajectory reconstruction achieves much better performances than existing methods for daily life contexts, in particular in narrow areas such as in a house. The computed stride trajectory contains essential information for recognizing the activity (atypical stride, walking, running, and stairs). For this task, we adopt a machine learning approach based on descriptors of these trajectories, which is shown to be robust to a large of variety of gaits. We tested our algorithm on recordings of healthy adults and children, achieving more than 99% success. The algorithm also achieved more than 97% success in challenging situations recorded by children suffering from movement disorders. Compared to most algorithms in the literature, this original method does not use a fixed-size sliding window but infers this last in an adaptive way.


Developing a Center for Education Research and Scholarship in a Department of Pediatrics.
This article was migrated. The article was marked as recommended. Background The skills needed to engage in scholarship in medical education are not part of the training that all physicians acquire. To build skills and promote scholarship, we developed a Center for Education Research and Scholarship (CERS) in the Department of Pediatrics at the University of Colorado. In this paper, we offer recommendations for others who seek to establish departmental-level efforts to support education. Approach and Lessons Learned CERS provides an "education home" for those interested in education scholarship, supplementing campus-wide efforts such as an Academy of Medical Educators. Mentorship from two experienced leaders in medical education provided a foundation for other faculty in the department and helped to build scholarship efforts more broadly. Through a weekly meeting and an annual departmental retreat, CERS provides opportunities for community among educators, faculty development in the skills needed to engage in education research, and a forum for generating ideas and planning projects. Essential resources for success include at least one leader with expertise in educational research, an administrative and/or research assistant, and some funding for faculty time and initiation of projects. Mentors with experience in education research and scholarship are also needed, although a group of mentors quickly grows as more individuals engage. Results Benefits to the department include peer-reviewed presentations and publications in medical education, with regional, national, and international recognition. Faculty members can focus on medical education as a key component of their careers, and the quality of education programs is enhanced. Conclusions While it takes time to fully develop a departmental center for education scholarship, it is possible to start small and grow. One or two leaders in education with vision can begin the effort and engage others, and the faculty will begin to experience the satisfaction of collaborative projects in education, successful innovation, and dissemination of scholarship.


Metastatic uveal melanoma. Correlation between survival time and cytomorphometry of primary tumors.
The length of survival time following enucleation was determined for 29 patients with primary malignant melanoma of the choroid and ciliary body who subsequently died of metastatic disease. Histologic sections of the 29 tumors were studied by standard light microscopic techniques and computerized morphometry. The largest diameter of each tumor was measured on the 37% formaldehyde-fixed, paraffin-embedded slides; a cell type was assigned to each tumor on the basis of histologic study, using the modified Callender cell-type classification system; and inverse standard deviation of the nucleolar area (ISDNA) was determined for each tumor by computerized morphometric analysis. The observed death-order of these patients was then compared with the death-order predicted by ranking cases in ascending order of age at treatment, size of tumor, cell type, and ISDNA. Using rank-order correlation coefficient tests, only the correlation between ISDNA rank-order and observed death-order was found to be statistically significant. We believe that the limitations of the modified Callender cell-type classification system in predicting length of survival time following enucleation are related to the relatively few categories (four) in which to classify tumors, whereas the ISDNA represents a continuous spectrum of unlimited categories. As such, ISDNA can be more discriminant in selecting tumors of high malignant potential.


Effect of ursolic acid on MAPK in cyclin D1 signaling and RING-type E3 ligase (SCF E3s) in two endometrial cancer cell lines.
Cyclin D1 regulates G1 progression and is important in the development and proliferation of various human cancers. Cyclin D1 gene expression is activated by the Ras kinase cascade. Nuclear cyclin D1 levels are dependent on cytoplasmic degradation of cyclin D1 via ubiquitin-mediated proteolysis. We sought to determine whether the important MAPK signaling pathway, in the cyclin D1 cascade, including FBXW8, Cullin1, and the ubiquitination pathway mediated these effects. Ursolic acid (UA) treatment of SNG-2 cells, an endometrial cancer cell line, decreased cyclin D1, pERK1/2, FBXW8, and Cullin1 levels in a dose- and time-dependent manner. RING-type E3 ligase consists of CulIin1, Rbx, Skp1, and a member of the F-box protein family. In SNG-2, both dose- and time-dependent inhibition of Rbx 1 were observed following treatment with UA. Moreover, in HEC108 cells, another endometrial cancer cell line, UA treatment decreased cyclin D1, pERK1/2, and Cullin1 levels in a dose- and time-dependent manner and UA markedly inhibited FBXW8. Treatment of HEC108 cells moderately decreased Rbx1 in a dose- and-time-dependent fashion. In contrast, UA treatment increased ubiquitinated proteins in a dose- and time-dependent manner in both cell lines. RING-type E3 ligase accumulated in the cytoplasm following UA treatment of SNG-2cells. That in turn prevented cytoplasmic degradation of cyclin D1 via RING-type E3 (SCF E3s) ligase. In conclusion, our study found inhibition of the MAPK- cyclin D1 pathway and RING type E3 ligase (SCF E3s) in both endometrial cancer cell lines. Furthermore, CD36 was noted as a cell surface receptor for UA.


Characteristics of effective village treatment assistants: the Kongwa Trachoma Project.
Mass treatment of entire communities with tetracycline eye ointment is one method for treatment of hyperendemic trachoma. Village Treatment Assistants (VTAs) are often recruited to implement mass treatment in their neighborhoods. We determined characteristics of these volunteers that were associated with effective treatment outcomes. Three villages received mass treatment with tetracycline ointment daily for four weeks as part of a clinical trial. Community members selected VTAs to administer the ointment. Trachoma status was assessed by grading photographs of the tarsal conjunctiva in a sample of children randomly selected from households in each village. Change in trachoma status was determined from baseline to one month post treatment. VTA performance outcome was "good" if there was improvement in the majority of the children treated by the VTA, "poor" if the majority worsened, and "neutral" if there was neither improvement nor worsening on average. Trained interviewers administered a questionnaire measuring socioeconomic and demographic variables to 82% of all VTAs. A total of 280 VTAs (229 with questionnaire) were evaluated: 36.8% had good outcomes and 12.5% had poor outcomes. Those VTAs with poor outcomes tended to be unmarried females (OR = 11.73) and those who used a bicycle to carry out treatment activities (OR = 4.16). Formal education or prior experience as a health worker were not predictors of performance. Community selection and effective, non-formal, training are key components for the use of VTAs in mass treatment campaigns. Prior education or health training does not play a major role in effectiveness. The possible effects of gender roles in the community need to be considered in program design.


Seasonal variation in denitrification and dissimilatory nitrate reduction to ammonia process rates and corresponding key functional genes along an estuarine nitrate gradient.
This research investigated spatial-temporal variation in benthic bacterial community structure, rates of denitrification and dissimilatory nitrate reduction to ammonium (DNRA) processes and abundances of corresponding genes and transcripts at three sites-the estuary-head, mid-estuary and the estuary mouth (EM) along the nitrate gradient of the Colne estuary over an annual cycle. Denitrification rates declined down the estuary, while DNRA rates were higher at the estuary head and middle than the EM. In four out of the six 2-monthly time-points, rates of DNRA were greater than denitrification at each site. Abundance of gene markers for nitrate-reduction (nitrate reductase narG and napA), denitrification (nitrite reductase nirS) and DNRA (DNRA nitrite reductase nrfA) declined along the estuary with significant relationships between denitrification and nirS abundance, and DNRA and nrfA abundance. Spatially, rates of denitrification, DNRA and corresponding functional gene abundances decreased along the estuary. However, temporal correlations between rate processes and functional gene and transcript abundances were not observed.


Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling.
Excessive production of reactive oxygen species (ROS) is frequently observed in cancer and is known to strongly influence hematopoietic cell function. Here we report that extracellular ROS production is strongly elevated (mean >10-fold) in >60% of acute myeloid leukemia (AML) patients and that this increase is attributable to constitutive activation of nicotinamide adenine dinucleotide phosphate oxidases (NOX). In contrast, overproduction of mitochondrial ROS was rarely observed. Elevated ROS was found to be associated with lowered glutathione levels and depletion of antioxidant defense proteins. We also show for the first time that the levels of ROS generated were able to strongly promote the proliferation of AML cell lines, primary AML blasts, and, to a lesser extent, normal CD34(+) cells, and that the response to ROS is limited by the activation of the oxidative stress pathway mediated though p38(MAPK). Consistent with this, we observed that p38(MAPK) responses were attenuated in patients expressing high levels of ROS. These data show that overproduction of NOX-derived ROS can promote the proliferation of AML blasts and that they also develop mechanisms to suppress the stress signaling that would normally limit this response. Together these adaptations would be predicted to confer a competitive advantage to the leukemic clone.


Interactions of leucine-enkephalin with alpha-adrenoceptors in the conscious dog.
Leucine-enkephalin (Leu-ENK) administered systemically to the conscious dog increases heart rate and blood pressure, a response prevented by naloxone and hence mediated by opiate receptors. Clonidine attenuates the heart rate increase without affecting the pressor response. Propranolol also reduces the magnitude of the heart rate increase but to a lesser degree than does clonidine. Clonidine appears to inhibit the Leu-ENK-induced heart rate increase by both a centrally mediated increase in vagal tone and a peripheral presynaptic alpha 2-agonist effect. The presence of a pressor response to Leu-ENK after prazosin pretreatment suggests that Leu-ENK may also increase blood pressure independently of the alpha 1-adrenoceptor. Thus, Leu-ENK appears to act via a naloxone-sensitive receptor (perhaps a vagal afferent chemoreceptor), the response involving both sympathetic and parasympathetic mechanisms. The pressor response may also involve a direct effect on peripheral vessels or a non-alpha 1-adrenergic efferent pathway.


Nurture outpaces nature: fostering with an attentive mother alters social dominance in a mouse model of stress sensitivity.
Maternal care is critical for epigenetic programming during postnatal brain development. Stress is recognized as a critical factor that may affect maternal behavior, yet owing to high heterogeneity in stress response, its impact varies among individuals. We aimed here to understand the connection between inborn stress vulnerability, maternal care, and early epigenetic programming using mouse populations that exhibit opposite poles of the behavioral spectrum (social dominance [Dom] and submissiveness [Sub]) and differential response to stress. In contrast to stress-resilient Dom dams, stress-vulnerable Sub dams exhibit significantly lower maternal attachment, serum oxytocin, and colonic Lactobacillus reuteri populations. Sub offspring showed a reduced hippocampal expression of key methylation genes at postnatal day (PND) 7 and a lack of developmentally-dependent increase in 5-methylcytosine (5-mC) at PND 21. In addition, Sub pups exhibit significant hypermethylation of gene promoters connected with glutamatergic synapses and behavioral responses. We were able to reverse the submissive endophenotype through cross-fostering Sub pups with Dom dams (Sub/D). Thus, Sub/D pups exhibited elevated hippocampal expression of DNMT3A at PND 7 and increased 5-mC levels at PND 21. Furthermore, adult Sub/D offspring exhibited increased sociability, social dominance, and hippocampal glutamate and monoamine levels resembling the neurochemical profile of Dom mice. We postulate that maternal inborn stress vulnerability governs epigenetic patterning sculpted by maternal care and intestinal microbiome diversity during early developmental stages and shapes the array of gene expression patterns that may dictate neuronal architecture with a long-lasting impact on stress sensitivity and the social behavior of offspring.


Induction of Plasmodium falciparum transmission-blocking antibodies by recombinant vaccinia virus.
Many candidate antigens of malaria vaccines have limited immunological recognition. One exception is Pfs25, a cysteine-rich, 25-kilodalton sexual stage surface protein of Plasmodium falciparum. Pfs25 is a target of monoclonal antibodies that block transmission of malaria from vertebrate host to mosquito vector. The surface of mammalian cells infected with a recombinant vaccinia virus that expressed Pfs25 specifically bound transmission-blocking monoclonal antibodies. Furthermore, major histocompatibility complex-disparate congenic mouse strains immunized with recombinant Pfs25 elicited transmission-blocking antibodies, demonstrating that the capacity to develop transmission-blocking antibodies is not genetically restricted in mice. Live recombinant viruses may provide an inexpensive, easily administered alternative to subunit vaccines prepared from purified recombinant proteins to block transmission of malaria in developing countries.


N-tropomodulin: a novel isoform of tropomodulin identified as the major binding protein to brain tropomyosin.
We have identified and characterized two proteins in rat brain that bind to the neuron-specific tropomyosin isoform, TMBr3. The two proteins were identified by blot overlay assay, in which the proteins immobilized on the membrane were probed by epitope-tagged TMBr3, followed by detection with anti-epitope antibody. We have purified these proteins using a TMBr3 affinity column. Peptide sequencing as well as immunoblotting showed that one of the two proteins is identical to tropomodulin, a tropomyosin-binding protein originally identified in erythrocytes. The cDNA for the other protein was cloned from an adult rat brain cDNA library using degenerate oligonucleotides that we designed based on the peptide sequences. Sequence analysis of the cDNA clone revealed this protein to be a novel isoform of tropomodulin which is the product of a distinct gene, and is herein referred to as N-tropomodulin. Recombinant N-tropomodulin bound to TMBr3 as well as to other low molecular mass tropomyosins (TM5a or TM5), but not to high molecular mass tropomyosins (TM2 or TMBr1). Northern blotting and RNase protection assays as well as immunoblotting showed that N-tropomodulin is expressed predominantly in brain. Furthermore, RNase protection assays revealed no alternatively spliced regions within the coding sequence. Developmentally, N-tropomodulin was detected in rat brain as early as embryonic day 14 and reaches the adult level before birth. Immunofluorescence of primary frontal cortex cell cultures showed that N-tropomodulin is specifically expressed in neurons. The neuron-specific expression of N-tropomodulin strongly suggests specialized roles of this TM-binding protein in neurons.


Endocrine disruption of sexual selection by an estrogenic herbicide in the mealworm beetle (Tenebrio molitor).
The role that endocrine disruption could play in sexual selection remains relatively untested, and although estrogens occur in insects, little information exists about their biological role in insect reproduction. Atrazine is a commonly applied herbicide that mimics estrogen in vertebrates. Tenebrio molitor were raised from egg to adult under a gradation of environmentally relevant atrazine exposures and a non-treated control. Atrazine was delivered in the drinking water ad libitum. Female T. molitor were provided with a choice between unrelated males raised under three levels of atrazine exposures. Female preference for males demonstrated a non-monotonic inverted U-shaped response to atrazine exposure. There was no significant difference between the control and the high exposure to atrazine. Excluding the control, female preference increased as exposure concentration increased. These results have important repercussions for nonlethal effects of endocrine disruption on populations, their capacity to interfere with sexual selection, and the role of estrogen in pheromone communication among insects.


Nuclear survivin expression correlates with endoglin-assessed microvascularisation in laryngeal carcinoma.
Survivin-a member of the family of inhibitor of apoptosis proteins that control cell division, apoptosis and metastasis-is overexpressed in virtually all human cancers, including laryngeal squamous cell carcinoma (LSCC). Recent findings also correlate survivin expression with the regulation of angiogenesis. The novel main aim of this study was a preliminary investigation into the potential role of survivin expression in LSCC neoangiogenesis, as determined by endoglin-assessed microvascular density (MVD). Immunohistochemical expression of nuclear survivin and endoglin-assessed MVD were ascertained by image analysis in 75 consecutive LSCCs. Statistical analysis disclosed a strong direct correlation between nuclear survivin expression and MVD. Patients whose nuclear survivin expression was ≥6.0% had a significantly higher LSCC recurrence rate, and a significantly shorter disease-free survival (DFS) than those with a nuclear survivin expression <6.0%. The LSCC recurrence rate was also higher and the DFS shorter in patients with endoglin-assessed MVD ≥6.89%. The OR for recurrence was 2.79 in patients with LSCC with a nuclear survivin expression ≥6.0%, and 12.31 in those with an MVD≥6.89%. Survivin-targeting strategies to enhance tumour cell response to apoptosis and inhibit tumour growth should receive more attention with a view to developing agents for use in multimodality advanced LSCC treatment, or combined with conventional chemotherapy. Given the present preliminary evidence in LSCC, survivin targeting should also be further investigated for anti-angiogenic purposes, to reduce tumour blood flow and induce cancer necrosis.


Human-mouse comparative analysis reveals that branch-site plasticity contributes to splicing regulation.
The formation of base-pairing between the branch-site (BS) sequence and the U2 snRNP is an important step in mRNA splicing. We developed a new algorithm to identify both the BS sequence and the polypyrimidine tract (PPT) and validated its predictions experimentally. To assess BS conservation between human and mouse, we assembled and analyzed 46 812 and 242 constitutively and alternatively spliced orthologs of human-mouse intron pairs, respectively. Combinations of BSs and PPTs can be found in most of the constitutive and alternative introns. The average distance between the BS and the 3' splice site (3'ss) is 33-34 nt. Acceptor-like AG dinucleotides that resided between the predicted BS and the 3'ss were found to appear mostly within 5 nt, but not more than 19 nt, downstream of the BS. However, although 32% of homologous alternatively spliced BS sequences were fully conserved between human and mouse, only a small fraction (3%) of homologous constitutive counterparts was fully conserved. This indicates that the full sequence of the BS is under weak purifying selection in constitutively spliced introns and further strengthens the view that the BS sequence is just one of several factors determining the ability of the splicing machinery to identify the BS location. Mutations in the putative BS revealed a shift from constitutive to alternative splicing, and it also controls the inclusion/skipping ratio in alternative splicing. This suggests a role for BS sequences in regulated splicing.


Geographical boundaries of facial reconstruction.
The principle of considering defined areas of the face as separate entities when planning reconstructive procedures is explained. The resurfacing of these individual areas is discussed, and the priorities in the order of reconstruction are defined.


Coupling of light into nanowire arrays and subsequent absorption.
We present a theoretical study of the absorption of light in periodic arrays of InP nanowires. The absorption in the array depends strongly on the diameter and the length of the nanowires, as well as the period of the array. Nanowires of a length of just 2 microm are able, after an appropriate choice for the other parameters, to absorb more than 90% of the incident energy of TE and TM polarized light, with photon energies almost all the way down to the band gap energy and an incidence angle up to 50 degree. This high total absorption arises from a good coupling of the incident light into the nanowire array at the top interface between air and the array and absorption inside the array before the light reaches the interface between the nanowires and the substrate. We find that for a given photon energy there exists a critical nanowire diameter above which a dramatic increase in the absorption occurs. The critical diameter decreases for increasing photon energies, and is directly related to the dispersion of waveguiding modes in single isolated nanowires. A characterization showed that the absorption characteristics of the nanowire arrays are very promising for photovoltaic applications.


Thyroid FNA: Is cytopathologist review of ultrasound features useful?
Cytopathologist review of thyroid ultrasound (US) has been proposed to be useful in diagnosis and patient triage. This review explores the implications for practicing cytopathologists of integrating US review into the thyroid fine-needle aspiration diagnosis. At present, there is no agreed-upon system for combining cytologic and US features and communicating those results as a single report. If cytologists are performing tasks that require expertise in US interpretation, then they should know and be fully conversant with US interpretation. Whether cytologists performing aspirations require expertise in US interpretation is not clear. Regardless, cytologists should avoid using US results to alter their cytologic interpretations unless they clearly communicate that this is what they are doing. An evidence-based integrated reporting system that would allow cytologists to clearly explain to other physicians exactly how they reached their interpretation might provide value beyond current standard practice.


Cif is negatively regulated by the TetR family repressor CifR.
We previously reported that the novel Pseudomonas aeruginosa toxin Cif is capable of decreasing apical membrane expression of the cystic fibrosis transmembrane conductance regulator (CFTR). We further demonstrated that Cif is capable of degrading the synthetic epoxide hydrolase (EH) substrate S-NEPC [(2S,3S)-trans-3-phenyl-2-oxiranylmethyl 4-nitrophenol carbonate], suggesting that Cif may be reducing apical membrane expression of CFTR via its EH activity. Here we report that Cif is capable of degrading the xenobiotic epoxide epibromohydrin (EBH) to its vicinal diol 3-bromo-1,2-propanediol. We also demonstrate that this epoxide is a potent inducer of cif gene expression. We show that the predicted TetR family transcriptional repressor encoded by the PA2931 gene, which is immediately adjacent to and divergently transcribed from the cif-containing, three-gene operon, negatively regulates cif gene expression by binding to the promoter region immediately upstream of the cif-containing operon. Furthermore, this protein-DNA interaction is disrupted by the epoxide EBH in vitro, suggesting that the binding of EBH by the PA2931 protein product drives the disassociation from its DNA-binding site. Given its role as a repressor of cif gene expression, we have renamed PA2931 as CifR. Finally, we demonstrate that P. aeruginosa strains isolated from cystic fibrosis patient sputum with increased cif gene expression are impaired for the expression of the cifR gene.


Stereospecific binding sites for [3H]nicotinamide adenine dinucleotide in the rat brain.
NAD is a potent inhibitor of electrical activity in the dentate gyrus of the guinea pig hippocampus. NAD is rapidly degraded by an NADase enzyme present on synaptosomal membranes that we have recently found to be inhibited by nicotinamide mononucleotide. In this report we have characterised the binding sites present on brain membranes for [3H]NAD in the presence of this inhibitor. We have demonstrated two binding sites of KdS 49 nM and 4.26 microM that are modulated by GTP. From structure-activity studies we have shown the binding to be stereospecific for the beta-isomer of NAD requiring the whole of the molecule for full receptor affinity. The binding sites are distinct from those reported for adenosine and their presence has significance for the physiological role of NAD in the mammalian brain.


Effects of naturally occurring and synthetic organoselenium compounds on protein profiling in androgen responsive and androgen independent human prostate cancer cells.
Prostate cancer represents a major clinical public health challenge. Both epidemiological and clinical intervention studies support the protective role of selenium against development of prostate cancer. However, the mechanisms responsible for the inhibitory activity by this micronutrient remain elusive. Furthermore, literature reports consistently have shown that the dose and form of selenium are important factors in cancer chemoprevention. Thus, in the present investigation using androgen responsive (AR) lymph node carcinoma of the prostate (LNCaP) and its androgen-independent clone (AI) LNCaP C4-2 human prostate cancer cells, we compared the effects of selenomethionine (SM) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC) on cell growth, DNA synthesis, and on proteomic profiles. p-XSC (5-20 microM) significantly inhibited cell growth in both cell types in a dose-dependent manner; SM was also effective but at much higher doses (50-100 microM). We hypothesize that the inhibition of cell growth is due, in part, to selenium interaction with redox-sensitive proteins. Using 2D gel electrophoresis, both organoselenium compounds altered the expression, to a varied extent, of several unrecognized selenium-responsive proteins. Employing matrix-assisted laser-desorption ionization (MALDI) and time-of-flight (TOF; MALDI-TOF) followed by tandem mass spectrometric analysis, we identified the following proteins: cofilin-2, heterogeneous nuclear ribonucleoprotein, single-stranded mitochondrial DNA binding protein, chaperonin 10, nucleoside diphosphate kinase 6, and chain A Horf 6 human peroxidase enzyme. This is the first report showing that SM and p-XSC are capable of altering these proteins; their roles in prostate cancer prevention warrant further investigations.


Denitrification potential in relation to lithology in five headwater riparian zones.
The influence of riparian zone lithology on nitrate dynamics is poorly understood. We investigated vertical variations in potential denitrification activity in relation to the lithology and stratigraphy of five headwater riparian zones on glacial till and outwash landscapes in southern Ontario, Canada. Conductive coarse sand and gravel layers occurred in four of the five riparian areas. These layers were thin and did not extend to the field-riparian perimeter in some riparian zones, which limited their role as conduits for ground water flow. We found widespread organic-rich layers at depths ranging from 40 to 300 cm that resulted from natural floodplain processes and the burial of surface soils by rapid valley-bottom sedimentation after European settlement. The organic matter content of these layers varied considerably from 2 to 5% (relic channel deposit) to 5 to 21% (buried soils) and 30 to 62% (buried peat). Denitrification potential (DNP) was measured by the acetylene block method in sediment slurries amended with nitrate. The highest DNP rates were usually found in the top 0- to 15-cm surface soil layer in all riparian zones. However, a steep decline in DNP with depth was often absent and high DNP activity occurred in the deep organic-rich layers. Water table variations in 2000-2002 indicated that ground water only interacted frequently with riparian surface soils between late March and May, whereas subsurface organic layers that sustain considerable DNP were below the water table for most of the year. These results suggest that riparian zones with organic deposits at depth may effectively remove nitrate from ground water even when the water table does not interact with organic-rich surface soil horizons.