Reorganization of the adult auditory system: perceptual and physiological evidence from monaural fitting of hearing AIDS.
Changes in the sensory environment modify our sensory experience and may result in experience-related or learning-induced reorganization within the central nervous system. Hearing aids change the sensory environment by stimulating a deprived auditory system; therefore, they may be capable of inducing changes within the central auditory system. Examples of studies that have shown hearing aid induced perceptual and/or physiological changes in the adult human auditory system are discussed. Evidence in the perceptual domain is provided by studies that have investigated (a) speech perception, (b) intensity discrimination, and (c) loudness perception. Evidence in the physiological domain is provided by studies that have investigated acoustic reflex thresholds and event-related potentials. Despite the controversy in the literature concerning the rate, extent, and clinical significance of the acclimatization effect, there is irrefutable evidence that the deprived auditory system of some listeners can be modified with hearing aid experience.


Development of time-resolved immunofluorometric assay of vascular permeability factor.
We describe a two-site time-resolved immunofluorometric assay for guinea pig vascular permeability factor (VPF) for quantifying VPF in different biological fluids. Antibody against the carboxy terminus (C-IgG) is immobilized on microtiter wells, and antibody against the amino terminus (N-IgG) is labeled with Eu(3+)-chelate. Line 10 tumor culture medium, known to be rich in VPF, is assayed in a two-step incubation. Bound Eu3+ is then quantified by dissociation into a fluorescent enhancement solution, with measurement of the time-resolved fluorescence. The analytical sensitivity is 0.35 VPF unit, and the intra-assay CV is about 20%. The assay is specific for VPF, because pre-treatment with the appropriate C- or N-peptide, or pre-extraction of VPF, greatly decreases fluorescence. The VPF immunoassay is highly correlated (r2 = 0.94) with the Miles permeability assay, the classical bioassay of VPF. In addition, the immunofluorometric assay is about 30-fold more sensitive than the Miles assay.


Comparative study and identification of potent eukaryotic transcriptional repressors in gene switch systems.
In mammalian cells, proper gene regulation is achieved by the complex interplay of transcription factors that activate or repress gene expression by binding to the regulatory regions of target promoters. While transcriptional activators have been extensively characterised and classified into functional groups, relatively little is known about the comparative strength and cell type-specificity of transcriptional repressors. Here, we have compared the ability of a series of eukaryotic repression domains to silence basal and activated transcription. A series of the most potent repression domains was further tested in the context of a gene therapy gene-switch system in various cell types. The results indicate that the analysed repression domains exert varying silencing activities in different promoter contexts. Furthermore, their potential for gene silencing varies also depending on the cellular context. When multimerised within one chimeric repressor protein, particular combinations of repressor domains were found to display synergistic repressing effects and efficient repression in a panel of cell lines. This approach thus allowed the identification of transcriptional repressors that are both potent and versatile in terms of cellular specificity as a basis for gene switch systems.


URI in athletes: are mucosal immunity and cytokine responses key risk factors?
Infection incidence among athletes is highest during periods of intensified training and competition and after strenuous long-distance events. Which aspects of depressed immune function are responsible for this increased infection risk are not known, but our hypothesis is that lower salivary immunoglobulin A (IgA) secretion and a higher antiinflammatory cytokine response to antigen exposure are key determinants of infection risk.


Regulation of osteoclastogenesis through Tim-3: possible involvement of the Tim-3/galectin-9 system in the modulation of inflammatory bone destruction.
Galectins are a unique family of lectins bearing one or two carbohydrate recognition domains (CRDs) that have the ability to bind molecules with β-galactoside-containing carbohydrates. It has been shown that galectins regulate not only cell growth and differentiation but also immune responses, as well as inflammation. Galectin-9, a tandem repeat type of galectin, was originally identified as a chemotactic factor for eosinophils, and is also involved in the regulatory process of inflammation. Here, we examined the involvement of galectin-9 and its receptor, T-cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3), in the control of osteoclastogenesis and inflammatory bone destruction. Expression of Tim-3 was detected in osteoclasts and its mononuclear precursors in vivo and in vitro. Galectin-9 markedly inhibited osteoclastogenesis as evaluated in osteoclast precursor cell line RAW-D cells and primary bone marrow cells of mice and rats. The inhibitory effects of galectin-9 on osteoclastogenesis was negated by the addition of β-lactose, an antagonist for galectin binding, suggesting that the inhibitory effect of galectin-9 was mediated through CRD. When galectin-9 was injected into rats with adjuvant-induced arthritis, marked suppression of bone destruction was observed. Inflammatory bone destruction could be efficiently ameliorated by controlling the Tim-3/galectin-9 system in rheumatoid arthritis.


Association between previous health care use and initiation of inhaled corticosteroid and long-acting beta2-adrenergic agonist combination therapy among US patients with asthma.
Combination inhaled corticosteroid and long-acting beta(2)-adrenergic agonist (ICS/LABA) therapy is recommended for patients whose asthma is not adequately controlled by other maintenance therapies and for those with moderate to severe asthma. This study examined the appropriateness of initiation of ICS/LABA combination therapy based on health care use criteria and the proportions of US patients filling prescriptions for either of 2 available therapies. This retrospective cohort study analyzed data from commercially insured asthma patients aged 12 to 64 years who initiated combination therapy with fluticasone propionate/salmeterol (FSC) or budesonide/ formoterol fumarate dihydrate (BFC) from July 1, 2007, to June 30, 2008. Continuously enrolled patients who had not received ICS/LABA therapy during a 12-month preindex period were assigned to the BFC or FSC cohort based on their initial ICS/LABA prescription (index date). Appropriate initiation of ICS/LABA combination therapy was determined based on the risks for asthma exacerbation, high impairment, and previous controller medication use. Specifically, initiation of ICS/LABA therapy was considered appropriate if patients had claims during the preindex period for an ICS or leukotriene receptor antagonist, an asthma-related emergency department visit or hospitalization, >or=2 courses of oral corticosteroid, or >or=6 canisters of a rescue short-acting beta(2)-adrenergic agonist (SABA). Factors associated with appropriate initiation of ICS/LABA therapy were assessed by multivariate logistic regression. Of 16,205 patients initiated on ICS/LABA therapy, 39.2% met >or=1 criterion for appropriate use-788 of 1417 patients (55.6%) in the BFC group and 5572 of 14,788 patients (37.7%) in the FSC group (P < 0.001). Significantly greater proportions of BFC than FSC users met the individual criteria for previous controller medication use (45.7% vs 26.1%, respectively) and high SABA use (9.7% vs 6.1%). BFC users had a significantly higher likelihood of meeting >or=1 appropriateness criterion compared with FSC users (odds ratio = 1.79; 95% CI, 1.60-2.00; P < 0.001). Also significantly associated with appropriate use were receipt of the initial ICS/LABA prescription from a pulmonologist or allergist rather than from a physician in family medicine/general practice (P < 0.001), residence in the West relative to the Northeast (P < 0.005), and presence of specific comorbidities (allergic rhinitis, sinusitis, gastroesophageal reflux disease, and acute respiratory infection; all, P < 0.001). Just under 40% of patients met the criteria for appropriate initiation of ICS/LABA therapy, with significantly greater proportions of BFC than FSC users meeting the overall and individual criteria for appropriate use. Patients with appropriate initiation of ICS/LABA therapy were significantly more likely to be treated by pulmonologists and allergists than by family medicine/general practitioners.


Mental Tasks Modulate Motor-Units Above 10 Hz and are a Potential Control Signal for Movement Augmentation: a Preliminary Study.
Spinal motor neurons receive a wide range of input frequencies. However, only frequencies below ca. 10 Hz are directly translated into motor output. Frequency components above 10 Hz are filtered out by neural pathways and muscle dynamics. These higher frequency components may have an indirect effect on motor output, or may simply represent movement-independent oscillations that leak down from supraspinal areas such as the motor cortex. If movement-independent oscillations leak down from supraspinal areas, they could provide a potential control signal in movement augmentation applications. We analysed high-density electromyography (HD-EMG) signals from the tibialis anterior muscle while human subjects performed various mental tasks. The subjects performed an isometric dorsiflexion of the right foot at a low level of force while simultaneously (1) imagining a movement of the right foot, (2) imagining a movement of both hands, (3) performing a mathematical task, or (4) performing no additional task. We classified the channel-averaged HD-EMG signals and the cumulative spike train (CST) of motor-units using a filter bank and a linear classifier. We found that in some subjects, the mental task can be classified from the channel-averaged HD-EMG signals and the CST in oscillations above 10 Hz. Furthermore, we found that these oscillation modulations are incompatible with a systematic and task-dependent change in force level. Our preliminary findings from a limited number of subjects suggest that some mental task-induced oscillations from supraspinal areas leak down to spinal motor neurons and are discriminable via EMG or CST signals at the innervated muscle.


Cervical cancer in Africa.
Cervical cancer is a relatively rare disease in countries that have instituted and maintained national screening programs, with call and recall of women at various intervals and built-in quality control with appropriate monitoring and evaluation. Unfortunately, this process has failed in most areas of the world where more than 80% of new cases of cervical cancer are diagnosed. Cervical cancer affects women in the prime of their lives causing premature and needless suffering and death in a critically important segment of the world's population, despite being one of the few cancers that can be prevented with simple testing. In the past 15 years innovative approaches to both primary and secondary prevention of cervical cancer have been subjected to a number of large scale, scientifically valid and applicable studies that have opened the way for new approaches. Treatment of cervical cancer in Africa is hampered by the lack of diagnostic and treatment facilities, lack of healthcare infrastructure and poor pathology services. Further, there is a significant brain drain of trained healthcare workers in Africa that exacerbates the problem. Cancer is becoming an increasingly important public health problem as more people live longer. It is time to develop programs for the prevention, early detection, treatment, and palliation of cancer sufferers in Africa.


Healthcare-associated influenza in Canadian hospitals from 2006 to 2012.
To determine trends, patient characteristics, and outcome of patients with healthcare-associated influenza in Canadian hospitals. Prospective surveillance of laboratory-confirmed influenza among hospitalized adults was conducted from 2006 to 2012. Adults with positive test results at or after admission to the hospital were assessed. Influenza was considered to be healthcare associated if symptom onset was equal to or more than 96 hours after admission to a facility or if a patient was readmitted less than 96 hours after discharge or admitted less than 96 hours after transfer from another facility. Baseline characteristics of influenza patients were collected. Patients were reassessed at 30 days to determine the outcome. Acute care hospitals participating in the Canadian Nosocomial Infection Surveillance Program. A total of 570 (17.3%) of 3,299 influenza cases were healthcare associated; 345 (60.5%) were acquired in a long-term care facility (LTCF), and 225 (39.5%) were acquired in an acute care facility (ACF). There was year-to-year variability in the rate and proportion of cases that were healthcare associated and variability in the proportion that were acquired in a LTCF versus an ACF. Patients with LTCF-associated cases were older, had a higher proportion of chronic heart disease, and were less likely to be immunocompromised compared with patients with ACF-associated cases; there was no significant difference in 30-day all-cause and influenza-specific mortality. Healthcare-associated influenza is a major component of the burden of disease from influenza in hospitals, but the proportion of cases that are healthcare associated varies markedly from year to year, as does the proportion of healthcare-associated infections that are acquired in an ACF versus an LTCF.


[Changes in the mucosa of the duodenum and stomach as a result of experimental duodenal ulcers and vagotomy].
By means of the transmissive and scanning electron microscopy methods and radioautography, structure of mucous membrane of the stomach and duodenum has been studied under experimentally induced duodenal ulcers before and after vagotomy during various time. The vagotomy results in accelerated healing of the ulcer defect. This is connected with an increased proliferative activity in the crypta cells, however, this is accompanied with deceleration of their differentiation. Under the duodenal ulcers the amount of chief and parietal cells increases in the gastric mucous membrane, this depends on gastrostasis produced by stenosis of the pylorus. At vagotomy the amount of the chief and parietal cells in the fundal glands of the mucous membrane decreases; this is accompanied with a lowered secretory activity.


Efficacy of custom foot orthotics in improving pain and functional status in children with juvenile idiopathic arthritis: a randomized trial.
. To compare the clinical efficacy of custom foot orthotics, prefabricated "off-the-shelf" shoe inserts, and supportive athletic shoes worn alone, on reducing pain and improving function for children with juvenile idiopathic arthritis (JIA). Children with JIA and foot pain (n = 40) were randomized to one of 3 groups receiving: (1) custom-made semirigid foot orthotics with shock absorbing posts (n = 15), (2) off-the-shelf flat neoprene shoe inserts (n = 12), or (3) supportive athletic shoes with a medial longitudinal arch support and shock absorbing soles worn alone (n = 13). Foot pain and functional limitations were measured using the Pediatric Pain Questionnaire-visual analog scale (VAS), Timed Walking, Foot Function Index (FFI), and the Physical Functioning Subscale of the Pediatric Quality of Life Inventory (PedsQL). Measures were administered by personnel blinded to group status at baseline (before wearing the assigned intervention) and at 3 months' followup. Children in the orthotics group showed significantly greater improvements in overall pain (p = 0.009), speed of ambulation (p = 0.013), activity limitations (p = 0.002), foot pain (p = 0.019), and level of disability (p = 0.024) when compared with the other 2 groups. Both children and parents in the orthotics group reported clinically meaningful improvement in child health-related quality of life, although the group by time interaction did not show statistical significance. Except for a reduction in pain for supportive athletic shoes (paired t test, p = 0.011), neither the off-the-shelf shoe inserts nor the supportive athletic shoes worn alone showed significant effect on any of the evaluation measures. In children with JIA, custom-made semirigid foot orthotics with shock-absorbing posts significantly improve pain, speed of ambulation, and self-rated activity and functional ability levels compared with prefabricated off-the-shelf shoe inserts or supportive athletic shoes worn alone.


The fat-mass and obesity-associated (FTO) gene, physical activity, and risk of incident cardiovascular events in white women.
Variation in the Fat-Mass and Obesity-Associated (FTO) gene has been associated with obesity, diabetes, and hypertension. However, its association with cardiovascular disease (CVD) in healthy populations and any interaction with physical activity remain unclear. The FTO rs8050136 allele was determined in a prospective cohort study of 21,674 apparently healthy White US women in the Women's Genome Health Study. During a mean follow-up of 12.7±2.0 years, 664 incident CVD events occurred. The risk allele (A) was associated with higher prevalence of hypertension, diabetes, and metabolic syndrome (all P<.05). In a multivariate model, there was significant association of the risk allele with CVD (hazard ratio [HR] per allele copy 1.14, 95% CI 1.01-1.28) that was no longer significant after additional adjustment for body mass index (BMI) (HR 1.10, 95% CI 0.97-1.23). There was statistical evidence of an interaction between FTO and physical activity (P=.048). We found a significant association of FTO with CVD only among less-active (≤8.8 metabolic equivalent-h/wk) women (HR 1.19, 95% CI 1.02-1.38) in multivariate analyses that included BMI. More-active women did not have this increased risk (HR 0.96, 95% CI 0.79-1.16]). In a model that adjusted for BMI, less-active/high-risk (A/A) women were at 54% increased risk of developing CVD (HR 1.54, 95% CI 1.13-2.11), compared to more-active/low-risk (C/C) women. Carriers of the FTO risk allele have an increased risk of CVD mediated by BMI. There appears to be an interaction with physical activity, such that this risk increase is only in less-active women.


Substrate characterization of ventricular tachycardia in a porcine model of tetralogy of Fallot using noncontact mapping.
Ventricular tachycardia (VT) in patients following tetralogy of Fallot (TOF) repair is challenging to map because of the presence of scar, patch material, and hemodynamic residua of surgery. This study investigates whether noncontact mapping can identify the arrhythmia substrate in a porcine model that involves a right ventricular outflow tract (RVOT) patch and either chronic volume or pressure load on the right ventricle. Nine infant pigs (3-5 kg) underwent surgery involving an RVOT patch and creation of pulmonary insufficiency (PI, n = 4) or pulmonary stenosis (PS, n = 5). After a mean of 4.2 months, pigs underwent invasive electrophysiology studies (EPS) with noncontact mapping (Ensite, St. Jude Medical, St. Paul, MN USA) of the right ventricle. Automated, unipolar voltage maps (VM) were constructed during sinus rhythm. Threshold for substrate was set at -0.5 mV and incrementally adjusted to higher values until a contiguous region of low voltage was delineated. Programmed stimulation was performed to induce VT. VT activation was correlated to location of VM defined substrate. Three control pigs underwent EPS and VM. Free-wall RVOT substrate was identified in each of the model animals, correlating to location of the patch. The mean voltage threshold was -1.1 mV. VT was induced in 6/9 animals. Diastolic activation approximated the inferior or lateral border of the substrate in all animals. No RVOT substrate was identified in the control pigs. Automated voltage mapping of sinus beats identifies substrate for VT in a porcine model of TOF. Consistent diastolic activation of the substrate border was found during VT. Targeting this area may be useful in the ablation of VT after repair of TOF.


Influence of nocturnal and daytime sleep on initial orthostatic hypotension.
The incidence of vasovagal syncope is more common in the morning. Previous researchers have reported negligible diurnal variation in the physiological responses associated with initial orthostatic hypotension (IOH). Nevertheless, physical activity and sleep prior to morning and afternoon test times have not been controlled and may influence the findings. We designed a semi-constant routine protocol to examine diurnal variation in cardiorespiratory and cerebrovascular responses to active standing. At 06:00 and 16:00 hours, nine males (27 ± 9 years) completed an upright-stand protocol. Altimetry-measured sleep durations were 3.3 ± 0.4 and 3.2 ± 0.6 h immediately prior to the morning and afternoon test times. Continuous beat-to-beat measurements of middle cerebral artery velocity (MCAv), mean arterial blood pressure (MAP), heart rate (HR), and end-tidal carbon dioxide were obtained. Intestinal body temperature and salivary melatonin concentrations were also measured. Compared with the afternoon, resting HR and body temperature were 4 ± 2 beats min(-1) and 0.45 ± 0.2 °C lower, respectively, whereas melatonin concentration was 28.7 ± 3.2 pg ml(-1) higher in the morning (P ≤ 0.02). Although all individuals experienced IOH at both times of the day, the initial decline in MAP during standing was 13 ± 4 mmHg greater in the afternoon (P = 0.01). Nevertheless, the decline in MCAv was comparable at both times of day (mean difference: 2 ± 3 cm s(-1); P = 0.5). These findings indicate that a bout of sleep in the afternoon in healthy young individuals results in greater IOH that is compensated for by effective cerebral blood flow regulation.


Memory effects, arches and polar defect ordering at the cross-over from wet to dry active nematics.
We use analytic arguments and numerical solutions of the continuum, active nematohydrodynamic equations to study how friction alters the behaviour of active nematics. Concentrating on the case where there is nematic ordering in the passive limit, we show that, as the friction is increased, memory effects become more prominent and +1/2 topological defects leave increasingly persistent trails in the director field as they pass. The trails are preferential sites for defect formation and they tend to impose polar order on any new +1/2 defects. In the absence of noise and for high friction, it becomes very difficult to create defects, but trails formed by any defects present at the beginning of the simulations persist and organise into parallel arch-like patterns in the director field. We show aligned arches of equal width are approximate steady state solutions of the equations of motion which co-exist with the nematic state. We compare our results to other models in the literature, in particular dry systems with no hydrodynamics, where trails, arches and polar defect ordering have also been observed.


The I1 dynein-associated tether and tether head complex is a conserved regulator of ciliary motility.
Motile cilia are essential for propelling cells and moving fluids across tissues. The activity of axonemal dynein motors must be precisely coordinated to generate ciliary motility, but their regulatory mechanisms are not well understood. The tether and tether head (T/TH) complex was hypothesized to provide mechanical feedback during ciliary beating because it links the motor domains of the regulatory I1 dynein to the ciliary doublet microtubule. Combining genetic and biochemical approaches with cryoelectron tomography, we identified FAP44 and FAP43 (plus the algae-specific, FAP43-redundant FAP244) as T/TH components. WT-mutant comparisons revealed that the heterodimeric T/TH complex is required for the positional stability of the I1 dynein motor domains, stable anchoring of CK1 kinase, and proper phosphorylation of the regulatory IC138-subunit. T/TH also interacts with inner dynein arm d and radial spoke 3, another important motility regulator. The T/TH complex is a conserved regulator of I1 dynein and plays an important role in the signaling pathway that is critical for normal ciliary motility.


HIV testing experiences and their implications for patient engagement with HIV care and treatment on the eve of 'test and treat': findings from a multicountry qualitative study.
In view of expanding 'test and treat' initiatives, we sought to elicit how the experience of HIV testing influenced subsequent engagement in HIV care among people diagnosed with HIV. As part of a multisite qualitative study, we conducted in-depth interviews in Uganda, South Africa, Tanzania, Kenya, Malawi and Zimbabwe with 5-10 health workers and 28-59 people living with HIV, per country. Topic guides covered patient and provider experiences of HIV testing and treatment services. Themes were derived through deductive and inductive coding. Various practices and techniques were employed by health workers to increase HIV testing uptake in line with national policies, some of which affected patients' subsequent engagement with HIV services. Provider-initiated testing was generally appreciated, but rarely considered voluntary, with instances of coercion and testing without consent, which could lead to disengagement from care.Conflicting rationalities for HIV testing between health workers and their clients caused tensions that undermined engagement in HIV care among people living with HIV. Although many health workers helped clients to accept their diagnosis and engage in care, some delivered static, morally charged messages regarding sexual behaviours and expectations of clinic use which discouraged future care seeking. Repeat testing was commonly reported, reflecting patients' doubts over the accuracy of prior results and beliefs that antiretroviral therapy may cure HIV. Repeat testing provided an opportunity to develop familiarity with clinical procedures, address concerns about HIV services and build trust with health workers. The principles of consent and confidentiality that should underlie HIV testing and counselling practices may be modified or omitted by health workers to achieve perceived public health benefits and policy expectations. While such actions can increase HIV testing rates, they may also jeopardise efforts to connect people diagnosed with HIV to long-term care, and undermine the potential of test and treat interventions.


Bilinguals' Plausibility Judgments for Phrases with a Literal vs. Non-literal Meaning: The Influence of Language Brokering Experience.
Previous work has shown that prior experience in language brokering (informal translation) may facilitate the processing of meaning within and across language boundaries. The present investigation examined the influence of brokering on bilinguals' processing of two word collocations with either a literal or a figurative meaning in each language. Proficient Spanish-English bilinguals classified as brokers or non-brokers were asked to judge if adjective+noun phrases presented in each language made sense or not. Phrases with a literal meaning (e.g., stinging insect) were interspersed with phrases with a figurative meaning (e.g., stinging insult) and non-sensical phrases (e.g., stinging picnic). It was hypothesized that plausibility judgments would be facilitated for literal relative to figurative meanings in each language but that experience in language brokering would be associated with a more equivalent pattern of responding across languages. These predictions were confirmed. The findings add to the body of empirical work on individual differences in language processing in bilinguals associated with prior language brokering experience.


Randomized controlled trial: roxatidine vs omeprazole for non-erosive reflux disease.
Proton pump inhibitor (PPI) therapy is considered as the first choice for treatment of non-erosive reflux disease (NERD). However, NERD is less sensitive to PPIs than erosive gastroesophageal reflux disease (GERD) and the differences between PPIs and H2 receptor antagonists are less evident in NERD than in erosive GERD. Since gastric acid secretion is lower in the Japanese population than in Western populations, we aimed to investigate whether PPI therapy is really necessary for NERD patients in Japan. Thirty-three symptomatic endoscopically diagnosed NERD patients were randomly assigned to receive roxatidine acetate 75 mg twice daily (n = 16) or omeprazole 20 mg once daily (n = 17). Gastrointestinal symptoms were assessed using the Gastrointestinal Symptom Rating Scale at baseline and after 4 and 8 weeks of treatment. Both roxatidine and omeprazole significantly improved the heartburn score at 4 and 8 weeks. The clinical response rates did not differ between roxatidine and omeprazole. Both roxatidine and omeprazole significantly relieved not only reflux but also abdominal pain and indigestion. The degrees of improvement did not differ between the two groups. Roxatidine relieved the symptoms of NERD patients with similar effectiveness to omeprazole. Therefore, roxatidine may be a good choice for NERD treatment.


Channel-forming activity of immunoaffinity-purified connexin32 in single phospholipid membranes.
Connexin32, a member of the family of proteins that forms gap junction channels between cells, was immunoaffinity-purified from rat liver using a monoclonal antibody, under nondenaturing conditions and reconstituted into unilamellar phospholipid liposomes and bilayers. Gel-filtration studies indicate that the connexin32 is purified predominantly in structures of a size consistent with that of single hemichannels and too small to be junctional channels (dimers of hemichannels). Purified connexin formed channels permeable to sucrose and to Lucifer Yellow. The permeability was reversibly reduced by acidic pH and unaffected by several agents that modulate coupling between cells. Modeling of the distribution of the permeability in the liposomes indicates that it is mediated by connexin structures that distribute among the liposomes as single hemichannels. Bilayer recordings of the purified connexin show high conductance channels with asymmetric voltage sensitivity. The results show that immunopurified connexin32 can form channels, in single phospholipid membranes, that have permeability similar to that of gap junction channels and thus can be utilized in studies of permeability and its regulation to investigate its role in normal physiological function, development, and disease.


Improved detection of small cavernous hemangiomas of the liver with high-resolution three-headed SPECT.
The purpose of this study was to review our experience with 99mTc-red blood cell scintigraphy for diagnosis of cavernous hemangiomas of the liver using a new three-headed, high-resolution dedicated SPECT system. Of 19 patients referred with a total of 38 lesions seen on CT, US, or MRI, 14 patients had 24 lesions that were hemangioma-positive with SPECT (all true-positives). Six of these 14 patients also had 9 hemangioma-negative lesions; all were less than or equal to 1.3 cm in size and false-negative. The remaining five patients had hemangioma-negative lesions only (1 false-negative, 4 true-negatives). Two hemangiomas were seen by SPECT that were not detected by CT, US, or MR. The sensitivity for hemangiomas greater than or equal to 1.4 cm. was 100% (20/20). The sensitivity was 33% for lesions 0.9-1.3 cm, and 20% for lesions less than or equal to 0.8 cm. The smallest hemangioma detected was 0.5 cm. These results show a definite improvement in sensitivity with high-resolution triple-headed SPECT over previously reported results using single-headed SPECT. High-resolution SPECT has improved our ability to detect small cavernous hemangiomas of the liver.


No evidence of subgroups found in amphetamine consumers in Iran.
Amphetamine type substances are the second most commonly consumed illicit drug type and their use is an important contributor to the global burden of disease. This investigation set out to determine whether, similar to alcohol or nicotine addiction, subgroups of consumers can also be found in amphetamine addicts. 204 consumers of methamphetamine only (n = 50) or both methamphetamine and heroin (n = 154) have been investigated in Mashhad, Iran by means of "Lesch Alcoholism Typology". No significant differences in consumption pattern or age of onset have been found between the different types. Many subjects, however, reported symptoms of anxiety (n=78) or depression (n = 129) prior to drug use. These findings highlight the need for high quality epidemiological studies further addressing this issue.


Changes in the lumbosacral angle, sacral inclination and the curvature of the lumbar spine during aging.
Measurements of the curvature of the lumbar spine are useful in the investigations of low back pain. It is unclear whether the degree of lumbar lordosis, sacral inclination and lumbosacral angulation are the same for all normal adults. Radiographic studies were carried out on the lumbar spines of subjects aged 9-61 years. Mean and 95% tolerance ranges of the values of lumbar lordosis, lumbosacral angle and sacral inclination for adult age groups up to the sixth decade are given. The results showed that all three parameters varied steadily with age. The pattern of changes differed in males and females. Females had greater angles than males. Sacral inclination appeared to be a more important determinant of the degree of lumbar lordosis. All three parameters showed a tendency to decrease after the sixth decade. The significance of the findings is discussed.


The role of mental rotations in primate-inspired robot navigation.
The use of a primate's spatial ability of mental rotation to serve as a basis for robotic navigation has been almost entirely overlooked by the robotics community to date. In this paper, the role of this cognitive capacity is presented as an adjunct to existing robotic control systems, with the underlying approach being derived from studies of primate spatial cognition. Specifically, optical flow is used as a basis for transitory representations (snapshots) that are compared to an a priori visual goal to provide corrective course action for a robot when moving through the world. The underlying architecture and procedures are described.


Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
The role of orthotopic liver transplantation in the treatment of patients with cirrhosis and hepatocellular carcinoma is controversial, and determining which patients are likely to have a good outcome after liver transplantation is difficult. We studied 48 patients with cirrhosis who had small, unresectable hepatocellular carcinomas and who underwent liver transplantation. In 94 percent of the patients, the cirrhosis was related to infection with hepatitis B virus, hepatitis C virus, or both. The presence of tumor was confirmed by biopsy or serum alpha-fetoprotein assay. The criteria for eligibility for transplantation were the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter, in patients with multiple tumors. Thirty-three patients with sufficient hepatic function underwent treatment for the tumor, mainly chemoembolization, before transplantation. After liver transplantation, the patients were followed prospectively for a median of 26 months (range, 9 to 54). No anticancer treatment was given after transplantation. The overall mortality rate was 17 percent. After four years, the actuarial survival rate was 75 percent and the rate of recurrence-free survival was 83 percent. Hepatocellular carcinoma recurred in four patients (8 percent). The overall and recurrence-free survival rates at four years among the 35 patients (73 percent of the total) who met the predetermined criteria for the selection of small hepatocellular carcinomas at pathological review of small hepatocellular carcinomas at pathological review of the explanted liver wer 85 percent and 92 percent, respectively, whereas the rates in the 13 patients (27 percent) whose tumors exceeded these limits were 50 percent and 59 percent, respectively (P=0.01 for overall survival; P=0.002 for recurrence-free survival). In this group of 48 patients with early-stage tumors, tumor-node-metastasis status, the number of tumors, the serum alphafetoprotein concentration, treatment received before transplantation, and 10 other variables were not significantly correlated with survival. Liver transplantation is an effective treatment for small, unresectable hepatocellular carcinomas in patients with cirrhosis.


Detection of herpes simplex virus type-2 antigen(s) in biopsies from carcinoma of the uterine cervix.
Indirect immunofluorescence technique was employed to detect herpes simplex virus type-2 (HSV-2) antigens in tumor biopsies from 215 patients with carcinoma of the uterine cervix. A total of 169 samples (79%) revealed brilliant nuclear fluorescence. Inflammatory cells infiltrating the tumor mass were positive to 60 of the 215 patients (28%). Samples showed no significant variation in the degree of fluorescence or proportion of cells binding HSV antibody with advancement in the clinical stage of the disease. Fluorescence was totally abolished when incubated with HSV-2 antiserum absorbed with a specific homologous virus. Among controls, there was fluorescence in 27% of cervical scrapings from normal women and 34% (42/124) among patients with gynecological disorders other than cervical malignancy. In cervical dysplasia 23 out of 40 patients (58%) expressed herpes virus-associated antigens. There was membrane fluorescence in live malignant cell preparations in 3 of 28 patients (11%). Normal cervix tissue from hysterectomy specimens and breast cancer cells were negative for herpes simplex virus-related antigens. Pre-immune serum and PBS showed nonspecific fluorescence in 25% and 23% of sera, respectively.


Turn that frown upside down: implementation of a visual cue improves communication during emergency department to inpatient hand-offs.
When a patient is admitted to the hospital from the emergency department (ED), the ED clinician passes on relevant clinical information to the admitting team to transition care, a process known as patient hand-off and commonly referred to as 'calling report'. This information exchange between clinical teams is not only important for care continuity but also signifies a transition of care.However, there are unique challenges in this hand-off process given the unpredictability of the busy ED environment, ED boarding and discontinuity in physician, nursing and transportation workflows. These challenges create the potential for gaps in communication and can create patient safety concerns, particularly if a patient is transported to an inpatient bed before hand-off takes place.We set out to determine whether introducing a visual cue on the electronic health record (EHR) ED trackboard to communicate that report had been given would improve hand-off compliance. We sought to improve the utility of the visual cue and compliance of calling report prior to patient transport through a series of several Plan Do Study Act (PDSA) cycles.Baseline compliance using the 'Report Called' button prior to implementation of our visual intervention was 9.8%. With staff education alone, compliance rose to 41.3%. However, with an easily recognisable visual cue highlighted on the trackboard and an improved workflow compliance immediately rose to >97% and has been sustained for 84 months. Additionally, we have had zero reported incidents of patients being transported to a hospital bed before physician report was called since implementation.Our study demonstrates that simple visual cues and incorporation of a user-friendly process in the workflow can improve compliance with ensuring report is called prior to patient transfer from the ED. This may have a positive impact on physician communication and patient safety during the admission process.


Borrelia burgdorferi complement regulator-acquiring surface protein 2 does not contribute to complement resistance or host infectivity.
Borrelia burgdorferi, the pathogen of Lyme disease, cycles in nature through Ixodes ticks and mammalian hosts. At least five Complement Regulator-Acquiring Surface Proteins (BbCRASPs) are produced by B. burgdorferi, which are thought to assist spirochetes in host immune evasion. Recent studies established that BbCRASP-2 is preferentially expressed in mammals, and elicits robust antibody response in infected hosts, including humans. We show that BbCRASP-2 is ubiquitously expressed in diverse murine tissues, but not in ticks, reinforcing a role of BbCRASP-2 in conferring B. burgdorferi defense against persistent host immune threats, such as complement. BbCRASP-2 immunization, however, fails to protect mice from B. burgdorferi infection and does not modify disease, as reflected by the development of arthritis. An infectious BbCRASP-2 mutant was generated, therefore, to examine the precise role of the gene product in spirochete infectivity. Similar to wild type B. burgdorferi, BbCRASP-2 mutants remain insensitive to complement-mediated killing in vitro, retain full murine infectivity and induce arthritis. Quantitative RT-PCR assessment indicates that survivability of BbCRASP-2-deficient B. burgdorferi is not due to altered expression of other BbCRASPs. Together, these results suggest that the function of a selectively expressed B. burgdorferi gene, BbCRASP-2, is not essential for complement resistance or infectivity in the murine host.


Statistics: a brief overview.
The Accreditation Council for Graduate Medical Education sets forth a number of required educational topics that must be addressed in residency and fellowship programs. We sought to provide a primer on some of the important basic statistical concepts to consider when examining the medical literature. It is not essential to understand the exact workings and methodology of every statistical test encountered, but it is necessary to understand selected concepts such as parametric and nonparametric tests, correlation, and numerical versus categorical data. This working knowledge will allow you to spot obvious irregularities in statistical analyses that you encounter.


Top-down control in a patchy environment: revisiting the stabilizing role of food-dependent predator dispersal.
In this paper, we revisit the stabilizing role that predator dispersal and aggregation have in the top-down regulation of predator-prey systems in a heterogeneous environment. We consider an environment consisting of sites interconnected by dispersal, and propose a novel mechanism of stabilization for the case with a non-sigmoid functional response of predators. We assume that the carrying capacity of the prey is infinitely large in each site, and show that successful top-down regulation of this otherwise globally unstable system is made possible through an interplay between the unevenness of prey fitness across the sites and the rapid food-dependent migration of predators. We argue that this mechanism of stabilization is different from those previously reported in the literature: in particular, it requires a high degree of synchronicity in local oscillations of species densities across the sites. Prey outbreaks take place synchronously, but the unevenness of prey growth rates across the sites results in a pronounced difference in the species densities, and so the predator quickly disperses to the sites with the highest prey abundances. For this reason, the consumption of prey mostly takes place in the sites with high densities of prey, which assures an efficient suppression of outbreaks. Furthermore, when the total size of prey population is low, the distribution of both species among the sites becomes more even, and this prevents overconsumption of the prey by the predator. Finally, we put forward the hypothesis that this mechanism, when considered in a tri-trophic plankton community in the water column, can explain the stability of the nutrient-rich low-chlorophyll open ocean regions.


Streptomyces durmitorensis sp. nov., a producer of an FK506-like immunosuppressant.
Screening of soil samples from the Durmitor National Park, Serbia and Montenegro, for strains producing immunosuppressants with a similar mechanism of action to FK506 resulted in the isolation of the actinomycete strain MS405(T). Isolate MS405(T) was found to have morphological and phenotypic properties that were consistent with its classification as a Streptomyces strain. The DNA G+C content of strain MS405(T) was 72 mol%. 16S rRNA gene sequence data confirmed the taxonomic position of the strain, following the generation of phylogenetic trees by using various treeing algorithms. On the basis of 16S rRNA gene sequence similarity, strain MS405(T) was shown to belong to the Streptomyces albidoflavus 'supercluster', being related to Streptomyces aureus DSM 41785(T) (99.59 % similarity) and Streptomyces kanamyceticus DSM 40500(T) (99.32 %). The 16S-23S rRNA internally transcribed spacer (ITS) region exhibited variations in length and sequence composition, showing limited usefulness in phylogenetic analyses. However, DNA relatedness values support the classification of this isolate within a novel species. A number of physiological and biochemical tests distinguished strain MS405(T) from its closest phylogenetic neighbours. Therefore, strain MS405(T) represents a novel species, for which the name Streptomyces durmitorensis sp. nov. is proposed, with the type strain MS405(T) (=DSM 41863(T) =CIP 108995(T)).


NAA and 6-BA promote accumulation of oleanolic acid by JA regulation in Achyranthes bidentata Bl.
Application of plant growth regulators has become one of the most important means of improving yield and quality of medicinal plants. To understand the molecular basis of phytohormone-regulated oleanolic acid metabolism, RNA-seq was used to analyze global gene expression in Achyranthes bidentata treated with 2.0 mg/L 1-naphthaleneacetic acid (NAA) and 1.0 mg/L 6-benzyladenine (6-BA). Compared with untreated controls, the expression levels of 20,896 genes were significantly altered with phytohormone treatment. We found that 13071 (62.5%) unigenes were up-regulated, and a lot of differentially expressed genes involved in hormone or terpenoid biosynthesis, or transcription factors were significantly up-regulated. These results suggest that oleanolic acid biosynthesis induced by NAA and 6-BA occurs due to the expression of key genes involved in jasmonic acid signal transduction. This study is the first to analyze the production and hormonal regulation of medicinal A. bidentata metabolites at the molecular level. The results herein contribute to a better understanding of the regulation of oleanane-type triterpenoid saponins accumulation and define strategies to improve the yield of these useful metabolites.


Perception or real illness? How chronic conditions contribute to gender inequalities in self-rated health.
In Spain, as in many countries, women report poorer general health and more daily activity limitations due to health reasons when compared with men. This study aims to examine whether these poorer indicators are due to a greater prevalence of health problems and to identify the types of problems that contribute most to gender inequalities. Cross-sectional study on the population aged >15 years and residing in Spain, with data from the 2006 National Health Survey (n = 29139). The sex prevalence ratios (PR) of poor self-rated health and chronic limitation of activity are sequentially adjusted by age and the presence of 27 chronic conditions by means of robust Poisson regression. At equal number of disorders, women reported equal or even better health than men. The excess of poor health in women (age-adjusted PR and 95% CI: self-rated health = 1.36, 1.29-1.41; chronic limitation = 1.25, 1.18-1.32) disappeared when adjusting for the number of chronic diseases (self-rated health = 1.00, 0.96-1.04; chronic limitation = 0.90, 0.85-0.96). Musculoskeletal, mental and other pain disorders accounted for most of the association. The results were consistent in different strata of age, social class, and type of country of birth. These results suggest that the poorer self-rated health of women is a reflection of the higher burden of disease they suffer. A health system responsive to gender inequalities should increase its efforts in addressing and resolving musculoskeletal, mental and other pain disorders, usually less considered in favour of disorders with greater impact on mortality.


[Limb edema and lymphoscintigraphy].
Lymphoscintigraphic investigations represent techniques of nuclear medicine very contributive for the management and treatment of the limb edemas, either primary or secundary. Their principle is presented and methodologies proposed in the literature are reviewed. Their diagnostic contributions are detailed. The sensitivities and specificities of several protocols of investigation are reported. Some limitations of these examinations are analyzed and discussed. Clinical indications for their use are proposed and their interest with regard to the various treatments that can be applied to these limb edemas is discussed.


In the presence of the other: How glyphosate and peptide molecules alter the dynamics of sorption on goethite.
The interactions with soil mineral surfaces are among the factors that determine the mobility and bioavailability of organic contaminants and of nutrients present in dissolved organic matter (DOM) in soil and aquatic environments. While most studies focus on high molar mass organic matter fractions (e.g., humic and fulvic acids), very few studies investigate the impact of DOM constituents in competitive sorption. Here we assess the sorption behavior of a heavily used herbicide (i.e., glyphosate) and a component of DOM (i.e., a peptide) at the water/goethite interface, inclusive of potential glyphosate-peptide interactions. We used in-situ ATR-FTIR (attenuated total reflectance Fourier-transform infrared) spectroscopy to study sorption kinetics and mechanisms of interaction as well as conformational changes to the secondary structure of the peptide. NMR (nuclear magnetic resonance) spectroscopy was used to assess the level of interaction between glyphosate and the peptide and changes to the peptide' secondary structure in solution. For the first time, we illustrate competition for sorption sites results in co-sorption of glyphosate and peptide molecules that affects the extent, kinetics, and mechanism of interaction of each with the surface. In the presence of the peptide, the formation of outer-sphere glyphosate-goethite complexes is favored albeit inner-sphere glyphosate-goethite bonds (i.e., POFe) are still formed. The presence of glyphosate induces secondary structural shifts of the sorbed peptide that maximizes the formation of H-bonds with the goethite surface. However, glyphosate and the peptide do not seem to interact with one another in solution nor at the goethite surface upon sorption. The results of this work highlight potential consequences of competition for sorption sites, for example the transport of organic contaminants and nutrient-rich (i.e., nitrogen) DOM components in relevant environmental systems. Predicting the rate and extent with which organic pollutants are removed from solution by a given solid is also one of the most critical factors for the design of effective sorption systems in engineering applications.


Molecular insight into the effect of lipid bilayer environments on thrombospondin-1 and calreticulin interactions.
Thrombospondin-1 (TSP1) binding to cell surface calreticulin (CRT) stimulates the association of CRT with low-density lipoprotein (LDL) receptor-related protein (LRP1) to signal focal adhesion disassembly and engagement of cellular activities. A recent study demonstrated that membrane rafts are necessary for TSP1-mediated focal adhesion disassembly, but the molecular role of membrane rafts in mediating TSP1-CRT-LRP1 signaling is unknown. In this study, we investigated the effect of lipid bilayer environments on TSP1 and CRT interactions via atomically detailed molecular dynamics simulations. Results showed that the microscopic structural properties of lipid molecules and mesoscopic mechanical properties and electrostatic potential of the bilayer were significantly different between a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer and a raftlike lipid bilayer [a POPC/cholesterol (CHOL) raftlike lipid bilayer or a POPC/CHOL/sphingomyelin (SM) raftlike lipid bilayer], and the difference was enhanced by SM lipids in a raftlike lipid bilayer. These bilayer property differences affect the interactions of CRT with the bilayer, further influencing CRT conformation and TSP1-CRT interactions. A raftlike lipid bilayer stabilized CRT conformation as compared to a POPC bilayer environment. TSP1 binding to CRT resulted in a conformation for the CRT N-domain more "open" than that of the CRT P-domain in a raftlike lipid bilayer environment, which could facilitate binding of CRT to LRP1 to engage downstream signaling. The open conformational changes of CRT by binding to TSP1 in a raftlike lipid bilayer were enhanced by SM lipids in a lipid bilayer. The direct interactions of both the N- and P-domains of CRT with the bilayer contribute to the more open conformation of CRT in the TSP1-CRT complex on a raftlike lipid bilayer as compared to that on a POPC bilayer. The interactions of CRT or the TSP1-CRT complex with the lipid bilayer also caused CHOL molecules and/or lipids to be more coordinated and to aggregate into patchlike regions in the raftlike lipid bilayers. The lipid and CHOL molecule coordination and aggregation could in turn affect the interactions of CRT with the membrane raft, thereby altering TSP1-CRT interactions and CRT conformational changes that potentially regulate its interactions with LRP1. This study provides molecular insights into the role of lipid bilayer environments in TSP1-CRT interactions and in the CRT conformational changes that are predicted to facilitate binding of CRT to LRP1 to engage downstream signaling events.


Outstanding Synergy of Sensitivity and Linear Range Enabled by Multigradient Architectures.
Flexible pressure sensors are devices that mimic the sensory capabilities of natural human skin and enable robots to perceive external stimuli. One of the main challenges is maintaining high sensitivity over a broad linear pressure range due to poor structural compressibility. Here, we report a flexible pressure sensor with an ultrahigh sensitivity of 153.3 kPa-1 and linear response over an unprecedentedly broad pressure range from 0.0005 to 1300 kPa based on interdigital-shaped, multigradient architectures, featuring modulus, conductivity, and microstructure gradients. Such multigradient architectures and interdigital-shaped configurations enable effective stress transfer and conductivity regulation, evading the pressure sensitivity-linear range trade-off dilemma. Together with high pressure resolution, high frequency response, and good reproducibility over the ultrabroad linear range, proof-of-concept applications such as acoustic wave detection, high-resolution pressure measurement, and healthcare monitoring in diverse scenarios are demonstrated.


Refining the Rib-sparing Approach in Microsurgical Breast Reconstruction: Keys to Success.
Free tissue transfer using microsurgical techniques is a popular option for breast reconstruction, and the internal mammary vessels remain the most popular recipient vessels for the anastomosis. Traditionally, ribs were resected for better access to these vessels in the intercostal space. However, rib resection has the potential for complications and adds a surgical step. Here, the authors evaluate and compare both techniques in a retrospective study as well as offer technical pearls. The 400 most recent consecutive patients who underwent microsurgical breast reconstruction by a single surgeon were retrospectively reviewed. 54 patients underwent the traditional rib-resecting approach. 346 patients underwent the rib-sparing approach, which was the preferred approach of the senior author, when possible. Patients requiring the rib-resecting approach were distributed evenly throughout the series. Primary outcomes were any immediate post-operative complications. Between the two clinical groups, there was no difference between demographic or clinical details, the flap type, history of previous radiation, or timing of reconstruction. Complications of any kind as well as the subset of complications were significantly more frequent in the rib resection than in the rib-sparing group. Specifically, the rate of reanastomosis was higher in the rib resection group [10.6 vs 2.7%, p < 0.001] as was the frequency of return to the OR in the immediate post-operative setting [3.0 vs 0.3%, p < 0.001]. There is a 4.50 odds ratio of having a complication in a rib resection case versus rib sparing [CI: 1.97-10.30, p < 0.001]. All cases were initiated with the intent to perform a rib-sparing approach if possible, and they were converted to a rib-resection approach as needed. In the largest reported series to date, the rib-sparing approach is demonstrated to be both safe and efficacious in microsurgical breast reconstruction.


Contributions of chemical and diffusive exchange to T1ρ dispersion.
Variations in local magnetic susceptibility may induce magnetic field gradients that affect the signals acquired for MR imaging. Under appropriate diffusion conditions, such fields produce effects similar to slow chemical exchange. These effects may also be found in combination with other chemical exchange processes at multiple time scales. We investigate these effects with simulations and measurements to determine their contributions to rotating frame (R1ρ ) relaxation in model systems. Simulations of diffusive and chemical exchange effects on R1ρ dispersion were performed using the Bloch equations. Additionally, R1ρ dispersion was measured in suspensions of Sephadex and latex beads with varying spin locking fields at 9.4 T. A novel analysis method was used to iteratively fit for apparent chemical and diffusive exchange rates with a model by Chopra et al. Single- and double-inflection points in R1ρ dispersion profiles were observed, respectively, in simulations of slow diffusive exchange alone and when combined with rapid chemical exchange. These simulations were consistent with measurements of R1ρ in latex bead suspensions and small-diameter Sephadex beads that showed single- and double-inflection points, respectively. These observations, along with measurements following changes in temperature and pH, are consistent with the combined effects of slow diffusion and rapid -OH exchange processes.


Viral pathogen detection using multiplex gastrointestinal molecular panels: The pros and cons of viral target inclusion.
Diagnosis of gastrointestinal infections has been revolutionized by the development of in vitro diagnostic (IVD) multiplex molecular panels for the detection of viral nucleic acids. In addition to a high degree of accuracy, these panels are commercially available and relatively simple to perform in the clinical laboratory. However, use of these panels must be carefully considered owing to the laboratory costs of the test, limited reimbursement, and potential for overuse. In this review from the Pan American Society for Clinical Virology, we focus on the viral components of GI multiplex panels (GIPs), presenting a brief overview of pathogens included on most panels and a discussion of advantages and challenges of the inclusion of viral targets on GIPs that should be considered before implementation in the clinical laboratory.


Rational design of a novel fluorescent biosensor for beta-lactam antibiotics from a class A beta-lactamase.
A rational design strategy was used to construct a sensitive "turn-on" biosensor for beta-lactam antibiotics and beta-lactamase inhibitors from a class A beta-lactamase mutant with suppressed hydrolytic activity. A fluorescein molecule was attached to the 166 position on the Omega-loop of the E166C mutant close to the active site of the beta-lactamase. Upon binding with antibiotics or inhibitors, the flexibility of the Omega-loop allows the fluorescein molecule to move out from the active site and be more exposed to solvent. This process is accompanied by an increase in the fluorescence of the labeled enzyme. The fluorescence intensity of the biosensor increases with the concentration of antibiotics or inhibitors, which can detect penicillin G at concentrations as low as 50 nM in water. This approach opens a possibility for converting highly active and nonallosteric enzymes into substrate-binding proteins for biosensing purposes.


Exposure to high concentrations of nitrosamines and cancer mortality among a cohort of rubber workers.
To examine if the occurrence of different cancers was increased among rubber workers, as the highest known exposures of humans to nitrosamines have occurred in the rubber industry. A cohort of 8933 rubber workers (hired after 1 January 1950, still active or retired on 1 January 1981 and employed for at least 1 year in one of five study factories) was followed up for mortality from 1 January 1981 to 31 December 1991. Work histories were reconstructed with routinely documented cost centre codes, which allowed identification by employment in specific work areas. For each cost centre code time and factory specific, semi-quantitative exposures to nitrosamines (three levels: low, medium, high) and other compounds were estimated by industrial hygienists. Rate ratios for medium (RRm) and high (RRh) exposures and 95% confidence intervals (95% CIs) were calculated with Cox's proportional hazards models with the low exposure as reference. Exposure to nitrosamines was significantly associated with an increased mortality from cancers of the oesophagus (13 deaths: RRm 1.7, 95% CI 0.3 to 10.3; RRh 7.3, 95% CI 1.9 to 27.8) and of the oral cavity and pharynx (17 deaths: RRm 0.8, 95% CI 0.2 to 4.1; RRh 3.9, 95% CI 1.4 to 11.1). A non-significant trend of increasing mortality with exposure to higher concentrations of nitrosamines was found for mortality from cancer of the prostate (26 deaths: RRm 1.4, 95% CI 0.5 to 3.8; RRh 2.2, 95% CI 0.9 to 5.6), and the brain (six deaths: RRm 3.9, 95% CI 0.3 to 42.6; RRh 6.0, 95% CI 0.6 to 57.6). No association was found between exposure to nitrosamines and cancer of the stomach (RRm 0.8, 95% CI 0.4 to 1.8; RRh 1.2, 95% CI 0.5 to 2.5) or lung (RRm 1.0, 95% CI 0.6 to 1.5; RRh 1.0, 95% CI 0.7 to 1.6). Exposure to high concentrations of nitrosamines is associated with increased mortality from cancers of the oesophagus, oral cavity, and pharynx, but not with increased mortality from cancers of the stomach or lung.


Growth in atopic eczema: a controlled study by questionnaire.
The parents of 128 children with atopic eczema and 117 healthy control children responded to a questionnaire that included measurement of their own and their children's heights at home after standardised instructions. When cases and controls were compared there was no significant difference in parental height but the children with eczema were significantly shorter than the healthy control group. This difference remained significant when children with associated asthma were excluded from the analysis.


Diagnosing cognitive disorders in older adults with epilepsy.
To characterize the nature and prevalence of cognitive disorders in older adults with temporal lobe epilepsy (TLE) and compare their cognitive profiles to patients with amnestic mild cognitive impairment (ie, aMCI). Seventy-one older patients with TLE, 77 aMCI, and 69 normal aging controls (NACs), all 55-80 years of age, completed neuropsychological measures of memory, language, executive function, and processing speed. An actuarial neuropsychological method designed to diagnose MCI was applied to individual patients to identify older adults with TLE who met diagnostic criteria for MCI (TLE-MCI). A linear classifier was performed to evaluate how well the diagnostic criteria differentiated patients with TLE-MCI from aMCI. In TLE, the contribution of epilepsy-related and vascular risk factors to cognitive impairment was evaluated using multiple regression. Forty-three TLE patients (60%) met criteria for TLE-MCI, demonstrating marked deficits in both memory and language. When patients were analyzed according to age at seizure onset, 63% of those with an early onset (<50 years) versus 56% of those with late onset (≥ 50 years) met criteria for TLE-MCI. A classification model between TLE-MCI and aMCI correctly classified 81.1% (90.6% specificity, 61.3% sensitivity) of the cohort based on neuropsychological scores. Whereas TLE-MCI showed greater deficits in language relative to aMCI, patients with aMCI showed greater rapid forgetting on memory measures. Both epilepsy-related risk factors and the presence of leukoaraiosis on MRI contributed to impairment profiles in TLE-MCI. Cognitive impairment is a common comorbidity in epilepsy and it presents in a substantial number of older adults with TLE. Although the underlying etiologies are unknown in many patients, the TLE-MCI phenotype may be secondary to an accumulation of epilepsy and vascular risk factors, signal the onset of a neurodegenerative disease, or represent a combination of factors.


Intracoronal bleaching of discolored non-vital teeth.
This clinical study compared the effectiveness of bleaching non-vital teeth with an open pulp chamber during bleaching using 10% carbamide peroxide compared to the modified walking bleach technique and extracoronal bleaching. Sixty discolored, non-vital teeth were treated. They were divided into three groups. Each group was treated with one of the bleaching materials and methods: extracoronally using 10% carbamide peroxide for two weeks as negative control (Group A), intracoronally using sodium perborate mixed with 3% hydrogen peroxide (modified walking bleach technique) (Rotstein, Mor & Friedman, 1993) for four weeks (Group B) and intracoronally and extracoronally using 10% carbamide peroxide for two weeks (Group C) (Liebenberg, 1997). Tooth color was measured at baseline, (BL), immediately post-bleaching (IP) and six months post-bleaching (SP) with a colorimeter (Castor, Sigma, Germany) using a tooth-positioning jig. The color was determined according to the CIELAB system, which records lightness as L* and chromaticity coordinates as a* and b*. The difference in L* and b* among the three groups was significant between BL and IP examination. The post-bleaching, whitening effect in Group C was significantly better, but after six months, in Group C, it was as effective as in Group B.


Small bowel perforation caused by Epstein-Barr virus-associated B cell lymphoma in a patient with angioimmunoblastic T-cell lymphoma.
On rare occasions, secondary Epstein-Barr virus (EBV)-associated B cell lymphoma can develop in a patient with angioimmunoblastic T-cell lymphoma (AITL). We report a case of a 66-year-old Japanese woman who developed diffuse large B-cell lymphoma (DLBCL) in her small intestine after chemotherapy for AITL. She was found to have panperitonitis due to perforation of the small intestine. Partial ileectomy specimen showed DLBCL cells infiltrating into the intestinal wall. In situ hybridization for EBV-encoded RNA revealed positivity in the lymphoma cells. The lymph nodes diagnosed as AITL were negative for EBV infection and there was no coexistence of B cell neoplasms in them. We thought small bowel perforation in this case was caused by EBV-associated B cell lymphoma secondary to AITL. Our case showed a remarkable deficiency of cellular immunity after chemotherapy, which we postulate was related to the cause of occurrence of B-cell lymphoma.


The localization of plasminogen activator inhibitor-1 in glomerular subepithelial deposits in membranous nephropathy.
In this study, the localization of plasminogen activator inhibitor-1 (PAI-1) and its association with glomerular subepithelial deposits of vitronectin (VN) in membranous nephropathy (MN) was evaluated. Renal biopsy tissue from 30 patients with MN along with specimens of normal kidney removed from six patients with renal tumors were examined for glomerular deposits of urokinase-type plasminogen activator, tissue-type plasminogen activator (t-PA), PAI-1, VN, and fibrinogen by using immunofluorescence and immunoelectron microscopic techniques. Deposits were characterized by pretreating the frozen sections with arginine, glycine, and t-PA to dissociate the VN-PAI-1 complexes, thus providing evidence of PAI-1 binding to VN. Glomeruli isolated from normal frozen kidney and from frozen kidney tissue with MN were subjected to immunoblot analysis. VN was found in the mesangial area and t-PA was observed along the capillary wall of normal glomeruli. Coarse granular deposits of VN, PAI-1, and t-PA were observed along the glomerular basement membrane in MN. Immunoelectron microscopy showed the presence of VN, PAI-1, and t-PA in the subepithelial immune deposits. Pretreating the samples with arginine decreased or abolished immunofluorescence staining for PAI-1 and t-PA, but not for VN. Pretreatment with t-PA decreased the immunofluorescence staining for PAI-1, but not for VN. Pretreatment with glycine decreased or abolished the staining for all three proteins. Immunoblot analysis revealed the presence of VN, PAI-1, t-PA, and t-PA-PAI-1 complex in glomeruli with MN as well as the presence of VN, but not of PAI-1, t-PA, or complex in the normal glomeruli. The findings from this study strongly suggest that PAI-1 was deposited in the glomeruli in MN as a result of binding to VN. Thus, VN-associated PAI-1 may injure the integrity of the fibrinolytic system in glomeruli affected by MN.


Development of a biodegradable, temperature-sensitive dextran-based polymer as a cell-detaching substrate.
A biodegradable, temperature-sensitive dextran-allyl isocyanate-ethylamine (TSDAIE) as a nonenzymatic cell detachment polymeric substrate for human endothelial progenitor cells (EPCs) is developed and examined. The lower critical solution temperature of TSDAIE is determined; its phase transition occurrs at 18 to 22 °C. For EPC culture, cell culture flasks are coated with TSDAIE and type I collagen. The TSDAIE coating enables EPC detachment when the culture is cooled to 4 °C. The concentration of TSDAIE affects EPC attachment, which is thereby used to optimize the concentration of TSDAIE for coating. At the determined optimal concentration, TSDAIE is found to be compatible for use in EPC culture as revealed by cell attachment, spreading, proliferation, and phenotype. Overall, biodegradable TSDAIE shows promise for applications that culture and expand EPCs including vascular regenerative medicine and tissue engineering.


Direct-bandgap emission from hexagonal Ge and SiGe alloys.
Silicon crystallized in the usual cubic (diamond) lattice structure has dominated the electronics industry for more than half a century. However, cubic silicon (Si), germanium (Ge) and SiGe alloys are all indirect-bandgap semiconductors that cannot emit light efficiently. The goal1 of achieving efficient light emission from group-IV materials in silicon technology has been elusive for decades2-6. Here we demonstrate efficient light emission from direct-bandgap hexagonal Ge and SiGe alloys. We measure a sub-nanosecond, temperature-insensitive radiative recombination lifetime and observe an emission yield similar to that of direct-bandgap group-III-V semiconductors. Moreover, we demonstrate that, by controlling the composition of the hexagonal SiGe alloy, the emission wavelength can be continuously tuned over a broad range, while preserving the direct bandgap. Our experimental findings are in excellent quantitative agreement with ab initio theory. Hexagonal SiGe embodies an ideal material system in which to combine electronic and optoelectronic functionalities on a single chip, opening the way towards integrated device concepts and information-processing technologies.


PACAP is a stimulator of neurogenic contraction in guinea pig ileum.
The myotropic effect of pituitary adenylate cyclase-activating polypeptide (PACAP), a novel brain-gut peptide with high sequence homology to vasoactive intestinal polypeptide (VIP), was studied in the isolated guinea pig ileum in vitro. PACAP contracts the guinea pig ileum significantly more potently and efficiently compared with VIP. PACAP-induced contraction was abolished by tetrodotoxin, dynorphin, and somatostatin, partially reduced by atropine, and not affected by ganglionic and adrenergic blockade. The atropine-resistant component was sensitive to spantide, to the induction of tachyphylaxis with substance P, and to omega-conotoxin. Ileal strips desensitized to PACAP did not respond to VIP, although they maintained their sensitivity to PACAP after desensitization to VIP. COOH-terminal-truncated derivatives of PACAP exhibited full biological activity, although some of them showed substantially reduced potency. Deletion of NH2-terminal amino acids abolished biological activity. PACAP produced a concentration-dependent increase in the release of [3H]acetylcholine from longitudinal muscle-myenteric plexus preparations preloaded with [3H]choline. This effect was Ca2+ dependent, tetrodotoxin sensitive, and resistant to hexamethonium and scopolamine. In contrast, PACAP inhibited release of acetylcholine evoked by field stimulation. In summary, PACAP-induced contraction of the guinea pig ileum is mediated via release of acetylcholine and substance P through interaction with PACAP-1 and VIP/PACAP-2 receptors. PACAP has to be added to the list of myotropic neuropeptides of the gastrointestinal tract.


A new framework for interpreting the outcomes of imperfectly blinded controlled clinical trials.
It is well known that the outcome of an intervention is affected both by the inherent effects of the intervention and the patient's expectations. For this reason in comparative clinical trials an effort is made to conceal the nature of the administered intervention from the participants in the trial i.e. to blind the trial. Yet, in practice perfect blinding is impossible to ensure or even verify post hoc. The current clinical standard is to follow up the trial with an auxiliary questionnaire, which allows trial participants to express in closed form their belief concerning the intervention, i.e. trial group assignment (treatment or control). Auxiliary questionnaire responses are then used to compute the extent of blinding in the trial in the form of a blinding index. If the estimated extent of blinding exceeds a particular threshold the trial is deemed sufficiently blinded; otherwise, the strength of evidence of the trial is brought into question. This may necessitate that the trial is repeated. In this paper we make several contributions. Firstly, we identify a series of problems of the aforesaid clinical practice and discuss them in context of the most commonly used blinding indexes. Secondly, we formulate a novel approach for handling imperfectly blinded trials. We adopt a feedback questionnaire of the same form as that which is currently in use, but interpret the collected data using a novel statistical method, significantly different from that proposed in the previous work. Unlike the previously proposed approaches, our method is void of any ad hoc free parameters and robust to small changes in the participants' feedback responses. Our method also does not discard any data and is not predicated on any strong assumptions used to interpret participants' feedback. The key idea behind the present method is that it is meaningful to compare only the corresponding treatment and control participant sub-groups, that is, sub-groups matched by their auxiliary responses. A series of experiments on simulated trials is used to demonstrate the effectiveness of the proposed approach and its superiority over those currently in use.


Predictions of the properties of water from first principles.
A force field for water has been developed entirely from first principles, without any fitting to experimental data. It contains both pairwise and many-body interactions. This force field predicts the properties of the water dimer and of liquid water in excellent agreement with experiments, a previously elusive objective. Precise knowledge of the intermolecular interactions in water will facilitate a better understanding of this ubiquitous substance.


PAR1, but not PAR4, activates human platelets through a Gi/o/phosphoinositide-3 kinase signaling axis.
Thrombin-mediated activation of platelets is critical for hemostasis, but the signaling pathways responsible for this process are not completely understood. In addition, signaling within this cascade can also lead to thrombosis. In this study, we have defined a new signaling pathway for the thrombin receptor protease activated receptor-1 (PAR1) in human platelets. We show that PAR1 couples to G(i/o) in human platelets and activates phosphoinositide-3 kinase (PI3K). PI3K activation regulates platelet integrin alphaIIbbeta3 activation and platelet aggregation and potentiates the PAR1-mediated increase in intraplatelet calcium concentration. PI3K inhibitors eliminated these effects downstream of PAR1, but they had no effect on PAR4 signaling. This study has identified an important role for the direct activation of G(i/o) by PAR1 in human platelets. Given the efficacy of clopidogrel, which blocks the G(i/o)-coupled P2Y purinoceptor 12, as an antiplatelet/antithrombotic drug, our data suggest that specifically blocking only PAR1-mediated G(i/o) signaling could also be an effective therapeutic approach with the possibility of less unwanted bleeding.


Circulating oxidized low-density lipoprotein and its association with carotid intima-media thickness in asymptomatic members of familial combined hyperlipidemia families.
Oxidized low-density lipoprotein (Ox-LDL)is implicated in the pathogenesis of atherosclerosis. Circulating oxidation-specific epitopes on plasma Ox-LDL has been linked with coronary artery disease, but its determinants and its association with early development of atherosclerosis in familial combined hyperlipidemia (FCHL) has not been very well studied. This study aimed to investigate the determinants of the circulating Ox-LDL and the association between Ox-LDL and carotid intima-media thickness (IMT) in asymptomatic members of FCHL families. Ox-LDL, susceptibility of LDL to oxidation in vitro, plasma 8-isoprostane and antioxidants, lipids and lipoproteins, LDL particle size, and carotid IMT were measured in 150 asymptomatic FCHL family members. Affected FCHL family members had reduced LDL particle size and lag time for LDL oxidation, increased plasma levels of Ox-LDL, increased plasma urate and alpha-tocopherol, and a trend for the increase of 8-isoprostane as compared with nonaffected FCHL. Ox-LDL was independently associated with serum LDL cholesterol, apoB, and 8-isoprostane in multivariate analysis but only univariately correlated with LDL particle size and lag time for LDL oxidation. In addition, Ox-LDL was significantly associated with carotid mean IMT independently of other clinical and biochemical variables in a multivariate model. Serum LDL cholesterol, apoB levels, and 8-isoprostane were the most important determinants of Ox-LDL. Ox-LDL is independently associated with carotid IMT in asymptomatic FCHL family members and can be used as a marker of early atherosclerosis in FCHL.


CT dose reduction and dose management tools: overview of available options.
In the past decade, the tremendous advances in computed tomography (CT) technology and applications have increased the clinical utilization of CT, creating concerns about individual and population doses of ionizing radiation. Scanner manufacturers have subsequently implemented several options to appropriately manage or reduce the radiation dose from CT. Modulation of the x-ray tube current during scanning is one effective method of managing the dose. However, the distinctions between the various tube current modulation products are not clear from the product names or descriptions. Depending on the scanner model, the tube current may be modulated according to patient attenuation or a sinusoidal-type function. The modulation may be fully preprogrammed, implemented in near-real time by using a feedback mechanism, or achieved with both preprogramming and a feedback loop. The dose modulation may occur angularly around the patient, along the long axis of the patient, or both. Finally, the system may allow use of one of several algorithms to automatically adjust the current to achieve the desired image quality. Modulation both angularly around the patient and along the z-axis is optimal, but the tube current must be appropriately adapted to patient size for diagnostic image quality to be achieved.


Sexual selection and population divergence III: Interspecific and intraspecific variation in mating signals.
A major challenge for studying the role of sexual selection in divergence and speciation is understanding the relative influence of different sexually selected signals on those processes in both intra- and interspecific contexts. Different signals may be more or less susceptible to co-option for species identification depending on the balance of sexual and ecological selection acting upon them. To examine this, we tested three predictions to explain geographic variation in long- versus short-range sexual signals across a 3,500 + km transect of two related Australian field cricket species (Teleogryllus spp.): (a) selection for species recognition, (b) environmental adaptation and (c) stochastic divergence. We measured male calling song and male and female cuticular hydrocarbons (CHCs) in offspring derived from wild populations, reared under common garden conditions. Song clearly differentiated the species, and no hybrids were observed suggesting that hybridization is rare or absent. Spatial variation in song was not predicted by geography, genetics or climatic factors in either species. In contrast, CHC divergence was strongly associated with an environmental gradient supporting the idea that the climatic environment selects more directly upon these chemical signals. In light of recently advocated models of diversification via ecological selection on secondary sexual traits, the different environmental associations we found for song and CHCs suggest that the impact of ecological selection on population divergence, and how that influences speciation, might be different for acoustic versus chemical signals.


Physicochemical studies on the interaction of gelatin with cationic surfactants alkyltrimethylammonium Bromides (ATABs) with special focus on the behavior of the hexadecyl homologue.
The interaction of a denatured interfacially active protein, gelatin (G) (at pH 9, above its isoelectric pH 4.84, and ionic strength mu=0.005), with a cationic amphiphile, hexadecyl (or cetyl) trimethylammonium bromide, CTAB, has been elaborately studied using a variety of techniques. Two types of protein-surfactant complexes at a concentration below the normal critical micellar concentration (cmc) were formed in solution. The first, G-CTAB (monomer) combined complex (GS(n)(I)) adsorbed at the air/solution interface, followed by its gradual transformation to the poor interfacially active second G-CTAB (aggregate) complex (GS(m)(B)) at a critical aggregation concentration (cac) of the interacting oppositely charged surfactant. In the higher concentration range, upon completion of GS(m)(B) formation, coacervation (association of GS(m)(B)) led to add turbidity. With increasing addition of CTAB, the coacervates became disintegrated and ultimately remained dissolved in the free micellar solution of CTAB. The above features were studied using the techniques of tensiometry, conductometry, turbidimetry, fluorimetry, and microcalorimetry. The interaction features were prominent at [G] >or= 0.05 g %, and several of these were either marginal or absent at [G]<0.05 g %. The denatured protein was found to form viscous as well as gel-forming consistencies at higher [G] and at lower temperature. A temperature variation study on the interaction of G with CTAB has revealed that enhanced interaction takes place at higher temperature. The effect of [G] on its interaction with cationic surfactants of varying chain length in the alkyltrimethylammonium bromide (ATAB) series has been also studied; a similar interactional profile as that of CTAB has been exhibited by octadecyltrimethylammonium bromide; however, the lower homologues (dodecyl- and tetradecyl-) of ATAB have offered different profiles. It has been found that the ATABs with higher alkyl chain lengths were more interactive with negatively charged G than their lower homologues. Quantification of the results in terms of different transition points, counterion binding of the protein-bound surfactant aggregates and free micelles, the enthalpy of binding interactions and energetics of ATAB micellization, and so forth have been studied. The results have been rationalized in terms of an interaction model.


Chronic administration of amitriptyline differentially alters neuropathic pain-related behaviour in the presence and absence of a depressive-like phenotype.
Chronic pain and depression share a complex, reciprocal relationship. Furthermore, in addition to treating depression, antidepressants such as amitriptyline are a first-line treatment for chronic pain conditions, indicating possible common neural substrates underlying both depression and pain. However, there is a paucity of studies examining the effect of antidepressant treatment on nociceptive and neuropathic pain responding in the presence of a depressive phenotype. The current study aimed to examine the effect of chronic amitriptyline administration on neuropathic pain-related behaviour and associated neuroinflammatory processes in the olfactory bulbectomised (OB) rat model of depression. Nociceptive responding to mechanical, innocuous cold or noxious heat stimuli in sham or OB rats was not altered by chronic amitriptyline administration. The induction of neuropathic pain following L5-L6 spinal nerve ligation (SNL) resulted in robust mechanical and cold allodynia and heat hyperalgesia in both sham and OB vehicle-treated animals. Chronic amitriptyline administration attenuated SNL-induced mechanical allodynia in both sham and OB rats at day 7 post-SNL, an effect which was enhanced and prolonged in OB rats. In comparison, chronic amitriptyline administration attenuated SNL-induced cold allodynia and heat hyperalgesia in sham, but not OB, rats. Evaluating the affective/motivational aspect of pain using the place escape avoidance paradigm revealed that OB-SNL rats exhibit reduced noxious avoidance behaviour when compared with sham counterparts, an effect not altered by chronic amitriptyline administration. Chronic amitriptyline administration prevented the increased expression of GFAP, IL-10 and CCL5, and enhanced the expression of TNFα, in the prefrontal cortex of OB-SNL rats. In conclusion, these data demonstrate that chronic amitriptyline differentially alters somatic nociceptive responding following peripheral nerve-injury, depending on stimulus modality and the presence or absence of a depressive-like phenotype, an effect which may involve modulation of neuroinflammatory processes.


Asymptomatic bacteriuria and symptomatic urinary tract infections in pregnancy.
Symptomatic and asymptomatic bacteriuria is common in pregnant women. A history of previous urinary tract infections and low socioeconomic status are risk factors for bacteriuria in pregnancy. Escherichia coli is the most common aetiologic agent in both symptomatic and asymptomatic infection and quantitative culture is the gold standard for diagnosis. Treatment of asymptomatic bacteriuria has been shown to reduce the rate of pyelonephritis in pregnancy and therefore screening for and treatment of asymptomatic bacteriuria has become a standard of obstetrical care. Antibiotic treatment of asymptomatic bacteriuria is associated with a decrease in the incidence of low birth weight, but the methodological quality of the studies limits the strength of the conclusions that can be drawn. Debate exists in the literature as to whether treated pyelonephritis is associated with adverse fetal outcomes. There is no clear consensus in the literature on antibiotic choice or duration of therapy for infection. With increasing antibiotic resistance, consideration of local resistance rates is necessary when choosing therapy.


[Experimento-clinical basis for using papain in purulent surgery].
Experimental injections of a home-made proteolytic enzyme of vegetative origin--papain--in doses 5 to 36 mg/kg have not provoked any toxic effect upon the body and the serous membranes. The clinical use of 0.2-0.5% papain solution for the local treatment of purulent processes has proved its high proteolytic activity and its ability to shorten the first phase of the wound process. The preparation does not cause any local or general complications and can be successfully used in purulent surgery in hospital and in out-patient practice.


Prognostic significance of dysadherin expression in epithelioid sarcoma and its diagnostic utility in distinguishing epithelioid sarcoma from malignant rhabdoid tumor.
Dysadherin is a cancer-associated cell membrane glycoprotein, which downregulates E-cadherin and promotes metastasis. We studied the clinicopathological features in 72 cases of epithelioid sarcoma and in six cases of malignant rhabdoid tumor, and also assessed the immunohistochemical expression of dysadherin, E-cadherin and MIB-1 in epithelioid sarcoma and malignant rhabdoid tumor cases. In addition, we compared dysadherin mRNA expression between epithelioid sarcoma and malignant rhabdoid tumor cell lines, using RT-PCR and real-time quantitative RT-PCR analysis. Immunohistochemical dysadherin expression was more frequently observed in proximal-type epithelioid sarcoma (71%) in comparison with distal-type epithelioid sarcoma (36%) (P = 0.037). Furthermore, seven proximal-type epithelioid sarcoma cases mimicking malignant rhabdoid tumor (histologically classified as the large cell type, accompanied by frequent rhabdoid cells and located in deep soft tissue) were all positive for dysadherin (100%), whereas dysadherin expression was not detected at all in any of the true six malignant rhabdoid tumors (0%). Cell lines established from proximal-type epithelioid sarcoma revealed significantly higher levels of dysadherin mRNA expression, compared with the levels seen in malignant rhabdoid tumor cell lines by real-time quantitative RT-PCR (P = 0.0433). Epithelioid sarcoma patients with dysadherin expression survived for a significantly shorter time than those without dysadherin expression (P = 0.001). In multivariate analysis, dysadherin immunopositivity (P = 0.0004) was one of the two independent adverse prognostic factors. We conclude that dysadherin expression in epithelioid sarcoma is a significant poor prognostic factor and that it is a powerful diagnostic marker for distinguishing epithelioid sarcoma, including the proximal-type epithelioid sarcoma, from malignant rhabdoid tumor. In epithelioid sarcoma, especially in proximal-type epithelioid sarcoma, increased cell disadhesion and motility by dysadherin plays an important role to acquire aggressive biological behavior. However, in malignant rhabdoid tumor, cell growth cycle that is regulated by hSNF5/INI1 gene seems to be critical to lethal biological behavior rather than dysadherin.


Systematic review and meta-analyses of psychosocial interventions for veterans of the military.
The efficacy of psychosocial therapies for common mental health disorders in veterans is unclear and requires further examination. Systematic review and meta-analyses of randomised controlled trials (RCTs). Twenty databases were searched. Studies were included if they reported a psychosocial intervention designed to treat or reduce common mental health symptoms in veterans identified as being symptomatic at the time they entered the study. Studies of substance dependency disorders and psychosis were excluded. Eligible studies were assessed against methodological quality criteria and data were extracted and analysed. Twenty-nine RCTs were identified. There was evidence for the use of trauma-focused therapies for post-traumatic stress disorder (PTSD) and some evidence for psychological interventions in the treatment of borderline personality disorder, depression, insomnia, and panic disorder co-morbid to PTSD. However, methodological quality of many of the studies was less than optimal. Trauma-focused psychological therapies are likely to be effective for combat-related PTSD but there is a need for more research to determine the efficacy of psychological treatments for other mental health disorders in veterans.


Activated integrin alphavbeta3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cells.
Expression of adhesion receptor integrin alphavbeta3 in an activated functional form strongly promotes metastasis in human breast cancer cells. Here, we report that alphavbeta3 cooperates with matrix metalloproteinase type 9 (MMP-9) in breast cancer cell migration. This cooperation is regulated by the activation state of the integrin. Expression of activated alphavbeta3 in metastatic variants of MDA-MB 435 human breast cancer cells and primary metastatic cells from breast cancer patients strongly enhanced migration toward vitronectin and fibrinogen. This enhancement was mediated by a soluble factor produced by breast cancer cells expressing activated alphavbeta3. When transferred, this factor also up-regulated alphavbeta3-dependent migration of breast cancer cells that express the nonactivated integrin. The factor was identified as metalloproteinase MMP-9. Whereas all tested breast cancer cell variants produced latent MMP-9, only those with activated alphavbeta3 produced the mature form of this metalloproteinase. Recombinant mature MMP-9, but not latent MMP-9 or either form of MMP-2, enhanced alphavbeta3-dependent breast cancer cell migration. The migratory response was inhibited by tissue inhibitors of metalloproteinase or when MMP-9 was depleted from the inducing supernatants. The results indicate a causal relationship between the expression of activated integrin alphavbeta3 and production of enzymatically active MMP-9 in metastatic breast cancer cells. These molecules cooperate to enhance breast cancer cell migration toward specific matrix proteins, and this may contribute to the strongly enhanced metastatic capacity of breast cancer cells that express activated alphavbeta3.


Limitations of Water Resources Infrastructure for Reducing Community Vulnerabilities to Extremes and Uncertainty of Flood and Drought.
Debate and deliberation surrounding climate change has shifted from mitigation toward adaptation, with much of the adaptation focus centered on adaptive practices, and infrastructure development. However, there is little research assessing expected impacts, potential benefits, and design challenges that exist for reducing vulnerability to expected climate impacts. The uncertainty of design requirements and associated government policies, and social structures that reflect observed and projected changes in the intensity, duration, and frequency of water-related climate events leaves communities vulnerable to the negative impacts of potential flood and drought. The results of international research into how agricultural infrastructure features in current and planned adaptive capacity of rural communities in Argentina, Canada, and Colombia indicate that extreme hydroclimatic events, as well as climate variability and unpredictability are important for understanding and responding to community vulnerability. The research outcomes clearly identify the need to deliberately plan, coordinate, and implement infrastructures that support community resiliency.


The effects of endocrine and mechanical stimulation on stage I lactogenesis in bovine mammary epithelial cells.
The study objective was to evaluate the effect of endocrine and mechanical (gel release) signaling on bovine mammary epithelial cell ultrastructure and gene expression. Cultures receiving only one stimulus demonstrated partially differentiated ultrastructure, which included abundant polysomes, limited rough endoplasmic reticulum, and absence of secretory products, whereas the 2 stimuli together induced a more complete lactogenic phenotype that included increased rough endoplasmic reticulum, abundant lipid droplets, and secretory vesicles containing casein micelles. The structural data indicated that although synthesis of milk components was initiated, the copious synthesis and secretion associated with stage II lactogenesis was not evident. Microarray analysis revealed that both prolactin and gel release independently regulated several genes linked to a wide array of cellular activities. In combination, they regulated fewer genes targeted to lactogenesis. Genes regulated by the combination treatment included claudin 7, multiple caseins, xanthine oxidoreductase, and several protein synthesis, packaging, and transport genes. Genes related to structural activity including keratin 15 (morphogenesis), alpha-spectrin (cell shape via actin cytoskeleton), and chitinase-like protein 1 (tissue remodeling) were up-regulated by the combination treatment as was the transcription factor Kruppel-like factor 2 (KLF-2). However, Snail 2, which down-regulates and inhibits tight junction components, was repressed in response to the combination treatment. These results suggest coordination between endocrine and physical signals at the genomic level that produces a more specific and targeted transcriptional response associated with stage I lactogenesis. A molecular pathway analysis of the differentially expressed genes revealed that genes regulating cell signaling were linked to those regulating cell structure and adhesion.