[A method of phase-contrast, fluorescence and scanning electron microscopy of one and the same cultured cells undergoing cryogenic action].
Cells cultured on glass substrates have been investigated by phase contrast method. After freeze-thawing the same cells were stained for identification of damage by fluorescent dyes and studied by the phase contrast method, fluorescence and scanning electron microscopy. The method has revealed correlations between the damage of cell surface and the cell damage manifestation at morphological level.


Biochemical variables and survival of patients with type 1 diabetes on renal replacement therapy.
End-stage renal disease (ESRD) is one of the most serious complications of type 1 diabetes, but scarcely studied. Our aim was to estimate the association between biochemical variables and survival among these patients. This was an incident cohort study of patients with type 1 diabetes entering chronic renal replacement therapy (RRT) in Finland 2000-2011 (n = 834). Biochemical variables were measured before the initiation of RRT. Adjusted relative risk of death according to biochemical variables was estimated by Cox regression. When adjusted for age, sex, comorbidities, and initial treatment modality of RRT, the most important predictors of death were low creatinine and albumin and high C-reactive protein. Among type 1 diabetes patients entering chronic RRT, biochemical variables independently associated with survival are creatinine, albumin and C-reactive protein. They reflect the nutritional status, proteinuria, liver function, and ongoing inflammatory process. Treatment of these might improve survival.


[Thyroid cytology].
The fine needle aspiration cytology of the thyroid represents a valuable aid for clinical decisions besides scintigraphy and sonography if representative cellular material is available. False diagnoses of malignancy may be totally avoided whereas a relatively high percentage of malignant tumours escapes the cytological diagnosis mostly as a consequence of insufficient puncture. For the intraoperative decision concerning the extent of resection, imprint cytology shows better results than frozen sections at least for follicular tumours.


Immunomodulatory drugs act as inhibitors of DNA methyltransferases and induce PU.1 up-regulation in myeloma cells.
Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide are efficacious in the treatment of multiple myeloma and significantly prolong their survival. However, the mechanisms of such effects of IMiDs have not been fully elucidated. Recently, cereblon has been identified as a target binding protein of thalidomide. Lenalidomide-resistant myeloma cell lines often lose the expression of cereblon, suggesting that IMiDs act as an anti-myeloma agent through interacting with cereblon. Cereblon binds to damaged DNA-binding protein and functions as a ubiquitin ligase, inducing degradation of IKZF1 and IKZF3 that are essential transcription factors for B and T cell development. Degradation of both IKZF1 and IKZF3 reportedly suppresses myeloma cell growth. Here, we found that IMiDs act as inhibitors of DNA methyltransferases (DMNTs). We previously reported that PU.1, which is an ETS family transcription factor and essential for myeloid and lymphoid development, functions as a tumor suppressor in myeloma cells. PU.1 induces growth arrest and apoptosis of myeloma cell lines. In this study, we found that low-dose lenalidomide and pomalidomide up-regulate PU.1 expression through inducing demethylation of the PU.1 promoter. In addition, IMiDs inhibited DNMT1, DNMT3a, and DNMT3b activities in vitro. Furthermore, lenalidomide and pomalidomide decreased the methylation status of the whole genome in myeloma cells. Collectively, IMiDs exert demethylation activity through inhibiting DNMT1, 3a, and 3b, and up-regulating PU.1 expression, which may be one of the mechanisms of the anti-myeloma activity of IMiDs.


Genetic modifiers of Huntington's disease.
Huntington's disease (HD) is a devastating neurodegenerative disorder that directly affects more than 1 in 10,000 persons in Western societies but, as a family disorder with a long, costly, debilitating course, it has an indirect impact on a far greater proportion of the population. Although some palliative treatments are used, no effective treatment exists for preventing clinical onset of the disorder or for delaying its inevitable progression toward premature death, approximately 15 years after diagnosis. Huntington's disease involves a movement disorder characterized by chorea, as well as a variety of psychiatric disturbances and intellectual decline, with a gradual loss of independence. A dire need exists for effective HD therapies to alleviate the suffering and costs to the individual, family, and health care system. In past decades, genetics, the study of DNA sequence variation and its consequences, provided the tools to map the HD gene to chromosome 4 and ultimately to identify its mutation as an expanded CAG trinucleotide repeat in the coding sequence of a large protein, dubbed huntingtin. Now, advances in genetic technology offer an unbiased route to the identification of genetic factors that are disease-modifying agents in human patients. Such genetic modifiers are expected to highlight processes capable of altering the course of HD and therefore to provide new, human-validated targets for traditional drug development, with the goal of developing rational treatments to delay or prevent onset of HD clinical signs.


Craniotomy for the resection of metastatic brain tumors in the U.S., 1988-2000: decreasing mortality and the effect of provider caseload.
To assist in selecting treatment for patients with brain metastases, the current study assessed the risk of adverse outcomes after contemporary resection of metastatic brain tumors in relation to patient, surgeon, and hospital characteristics, with particular attention to the volume of care and trends in outcomes. A retrospective cohort study of 13,685 admissions from the Nationwide Inpatient Sample between 1988-2000 was performed. Multivariate logistic, ordinal, and loglinear regression were used with endpoints of mortality, discharge disposition, length of stay, and total hospital charges. The overall in-hospital mortality rate was 3.1% and an additional 16.7% of patients were not discharged directly home. In multivariate analyses, larger-volume centers were found to have lower mortality rates for intracranial metastasis resection (odds ratio [OR], 0.79; 95% confidence interval [95% CI], 0.59-1.03 [P = 0.09]). An adverse discharge disposition also was less likely at higher-volume hospitals (OR, 0.75; 95% CI, 0.65-0.86 [P < 0.001]). For surgeon caseload, mortality was lower with higher-caseload providers (OR, 0.49; 95% CI, 0.30-0.80 [P = 0.004]) and an adverse discharge disposition occurred significantly less frequently (OR, 0.51; 95% CI, 0.40-0.64 [P < 0.001]). The annual number of resections increased by 79% during the study period, from 3900 (1988) to 7000 (2000). In-hospital mortality rates decreased from 4.6% (1988-1990) to 2.3% (1997-2000), a 49% relative decrease. Length of stay was reported to be significantly shorter with higher-volume providers. Hospital charges were not found to be associated significantly with hospital caseload and were found to be significantly lower after surgery that was performed by higher-caseload surgeons. The results of the current study found that higher-volume hospitals and surgeons provided superior short-term outcomes after resection of intracranial metastasis was performed, with shorter lengths of stay and a trend toward lower charges.


Juvenile neuroaxonal dystrophy in a Rottweiler: accumulation of synaptic proteins in dystrophic axons.
Dystrophic axons in a 2-year-old male Rottweiler with neuroaxonal dystrophy have shown synaptophysin, synapsin-I, synaptosomal-associated protein of 25 kDa (SNAP-25), Rab 3a, and alpha-synuclein immunoreactivity. Similar findings have been observed in isolated dystrophic axons in the nuclei gracillis and cunneatus in five dogs aged between 14 and 18 years. Abnormal expression of integral synaptic vesicle, synaptic vesicle-associated presynaptic plasma membrane and cytosolic proteins, which participate in the trafficking, docking and fusion of the synaptic vesicle to the plasma membrane, suggest severe disruption of axonal transport in dystrophic axons in canine neuroaxonal dystrophy.


Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis.
Chorioamnionitis and funisitis are associated with preterm labor and postnatal morbidity. Activation of endothelium resulting in up-regulation of adhesion molecules seems to be a key mechanism in development of organ damage. We investigated whether chorioamnionitis with or without funisitis in preterm infants induced expression and shedding of adhesion molecules in the umbilical cord and resulted in increased concentrations of E-selectin, intercellular adhesion molecule (ICAM)-1, IL-1beta, IL-6, and IL-8 in the cord blood. Data were obtained by using immunohistochemistry and ELISA. Thirty-two preterm infants were divided into three groups according to histology: chorioamnionitis with funisitis, chorioamnionitis without funisitis, and controls without signs of inflammation. ICAM-1 expression on arterial endothelium was higher with funisitis compared with chorioamnionitis alone or with the control group. Similar results for ICAM-1 expression were found in venous endothelium, vascular walls, Wharton's jelly, and amnion epithelium. Endothelial E-selectin and vascular cell adhesion molecule (VCAM)-1 expression was only induced significantly with funisitis. Serum-concentrations of soluble ICAM-1 were higher with funisitis compared with chorioamnionitis alone or control group. Similarly, concentrations of soluble E-selectin, IL-1beta, IL-6, and IL-8 were increased exclusively with funisitis. In conclusion, only chorioamnionitis with funisitis was associated with systemic inflammation and endothelial activation with up-regulation and shedding of umbilical cord adhesion molecules. We speculate that this activation of endothelium may not be limited to the umbilical cord but may also involve other organs resulting in neonatal morbidity. This underlines the importance of funisitis as a risk factor for adverse outcome.


Clonotypic comparison of IgG anti-DNA antibodies of healthy subjects and systemic lupus erythematosus patients: studies on heterogeneity and avidity.
Qualitative characteristics of IgG anti-ssDNA antibodies were studied and compared by isoelectric focusing (IEF) and enzyme-linked immunosorbent assay (ELISA) between normal human sera (NHS) and systemic lupus erythematosus (SLE) sera. In NHS, IgG anti-ssDNA spectrotypes were observed in a high alkaline pH range (7.5 to 8.5) at physiological NaCl concentrations (0.15 M). In SLE sera the spectrotypes were found to a more intensified extent in the alkaline pH range as compared to those in NHS. With regard to avidity, analyzed by salt-dependent changes of anti-ssDNA activities, NHS showed strong ssDNA-binding bands in a wide range of pH 7.0-8.5 comparable to those in SLE sera. However, these bands became extremely weak and/or faint in pH 7.5-8.5 as the NaCl concentration was raised to 0.15 M and 0.20 M. On the other hand, SLE sera still exhibited thick binding bands at higher NaCl concentrations. This salt-dependency of these antibodies was-also demonstrated by ELISA of serum samples adjusted to contain comparable antibody levels. These findings suggest that clonotypes of IgG anti-ssDNA antibodies both in NHS and in SLE sera are essentially oligoclonal and highly cationic, and that the distinctive characteristics of these antibodies in NHS may be of low avidity, in contrast to SLE sera which exhibit high avidity.


Supernumerary nipples in a Bartsocas-Papas patient in a consanguineous Iranian family.
We report a patient with Bartsocas-Papas syndrome surviving at 3 months. Our patient has supernumerary nipples in addition to the anomalies described previously in this syndrome.


Development of a Response Inconsistency Scale for the Personality Inventory for DSM-5.
The advent of a dimensional model of personality disorder included in DSM-5 has necessitated the development of a new measurement scheme, specifically a self-report questionnaire termed the Personality Inventory for DSM-5 (PID-5; Krueger, Derringer, Markon, Watson, & Skodol, 2012 ). However, there are many threats to the validity of a self-report measure, including response inconsistency. This study outlines the development of an inconsistency scale for the PID-5. Across both college student and clinical samples, the inconsistency scale was able to reliably differentiate real from random responding. Random responses led to increased scores on the PID-5 facets, indicating the importance of detecting inconsistent responding prior to test interpretation. Thus, this inconsistency scale could be of use to researchers and clinicians in detecting inconsistent responses to this new personality disorder measure.


Development and clinical assay of the BCM ventricular assist device.
The development of a ventricular assist device is depicted. The seven subprograms that make up the project are described briefly. Results obtained during the clinical assay showed that the new design of the input cannula working as a false auricle provides better efficiency, as well as a certain level of autoregulation for the device.


Direct-write fabrication of colloidal photonic crystal microarrays by ink-jet printing.
An array of the colloidal photonic crystals was directly fabricated using an ink-jet printing. The colloidal ink droplets containing the monodispersed polystyrene latex particles were selectively deposited on a hydrophobic surface. Solvent evaporation from each ink droplet leads to a formation of microdome-shaped colloidal assembles of close-packed structures. Microspectroscopic analysis has confirmed that the individual assembly serves as a photonic crystal and its optical properties can be correlated with the microstructural features. Unlike other techniques of patterned growth of colloidal photonic crystal, the substrate does not need to be patterned first and no template is needed in the direct writing by the ink-jet printing. Using our strategy, we have rapidly produced the colloidal photonic crystal microarrays composed of different-sized spheres addressably patterned on the same substrate.


Effects of sex on the incidence and prognosis of spinal meningiomas: a Surveillance, Epidemiology, and End Results study.
Most spinal meningiomas are intradural lesions in the thoracic spine that present with both local pain and myelopathy. By using the large prospective Surveillance, Epidemiology, and End Results (SEER) database, the authors studied the incidence of spinal meningiomas and examined demographic and treatment factors predictive of death. Using SEER*Stat software, the authors queried the SEER database for cases of spinal meningioma between 2000 and 2010. From the results, tumor incidence and demographic statistics were computed; incidence was analyzed as a function of tumor location, pathology, age, sex, and malignancy code. Survival was analyzed by using a Cox proportional hazards ratio in SPSS for age, sex, marital status, primary site, size quartile, treatment modality, and malignancy code. In this analysis, significance was set at a p value of 0.05. The 1709 spinal meningiomas reported in the SEER database represented 30.7% of all primary intradural spinal tumors and 7.9% of all meningiomas. These meningiomas occurred at an age-adjusted incidence of 0.193 (95% CI 0.183-0.202) per 100,000 population and were closely related to sex (337 [19.7%] male patients and 1372 [80.3%] female patients). The Cox hazard function for mortality in males was higher (2.4 [95% CI1.7-3.5]) and statistically significant, despite the lower lesion incidence in males. All-cause survival was lowest in patients older than 80 years. Primary site and treatment modality were not significant predictors of mortality. Spinal meningiomas represent a significant fraction of all primary intradural spinal tumors and of all meningiomas. The results of this study establish the association of lesion incidence and survival with sex, with a less frequent incidence in but greater mortality among males.


Rates of release of GABA and catecholamines in the mediobasal hypothalamus of ovariectomized and ovariectomized estrogen-treated rats: correlation with blood prolactin levels.
Push-pull cannulae were implanted into the mediobasal hypothalamus of ovariectomized (ovx) rats. After recovery animals were treated with estradiolbenzoate (E2B) or oil and they were perfused 3 days later. Only the E2B-treated animals which exhibited prolactin surges in the afternoon without concomitant LH surges were used in this study. In ovx animals hypothalamic GABA release, measured in 5-min intervals, was pulsatile, with pulses occurring every 37 min. This pattern was profoundly affected by E2B treatment: the pulse frequency was significantly reduced to 1 pulse every 117 min in steroid-treated rats. No differences in overall mean GABA release rates and pulse amplitudes were observed in ovx vs. E2B-treated rats. Our earlier demonstration of the existence of a large number of estrogen-receptive, GABAergic neurons in the MBH of rats is suggestive that these neurons change their secretory pattern in response to estrogen treatment. Estrogen-induced prolactin surges were accompanied by increased hypothalamic NE release. Concomitant changes in DA or E release rates were not demonstrable since catecholamine concentrations were too low to be reliable. However, the daily overall release rates of these two catecholamines were lower in E2B-treated rats compared to ovx animals. It is concluded that the positive feedback action of estradiol on prolactin release involves a stimulatory noradrenergic mechanism and may also involve estrogen-receptive, GABAergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)


Nonoperative Management of Appendicitis.
We evaluated the outcomes for nonoperative management (NOM) of all children with suspected nonperforated appendicitis, including those patients with an appendicolith. Parents of all children with suspected nonperforated appendicitis were offered NOM versus laparoscopic appendectomy. NOM included administration of intravenous antibiotics and hospital admission. If no improvement within 24 hours, laparoscopic appendectomy was performed. Primary outcomes were initial success rate and recurrence rate. Fifty patients selected NOM. The initial failure rate for NOM was 20%. Of the 10 who failed, 7 had complicated appendicitis. The recurrence rate was 13%. Overall, 34 (68%) patients avoided appendectomy. Patients with an appendicolith had a higher initial failure rate (37%) compared to patients without an appendicolith (10%; P < .05). NOM is feasible and effective in pediatric nonperforated appendicitis. The presence of an appendicolith was associated with a higher failure rate but is not an absolute contraindication for NOM.


Analysis of meaningful conditioned pain modulation effect in a pain-free adult population.
Conditioned pain modulation (CPM) encompasses the effects of inhibitory and facilitatory pain modulatory systems and is inefficient in some chronic pain states. A proportion of healthy subjects also exhibit little or no CPM, perhaps suggesting that inherent factors such as gender or genetics may be influential. However, there is no consensus on how best to determine a meaningful CPM effect. This study aimed to determine the proportion of pain-free subjects exhibiting a meaningful CPM effect. Analyses of associations between 5HTTLPR (serotonin transporter-linked polymorphic region) polymorphisms on the serotonin transporter gene (SLC6A4), gender, and CPM effect were also carried out. A total of 125 healthy subjects (47 male; 78 female) underwent pressure pain threshold testing before, during, and after a cold pressor conditioning stimulus. A buccal cell sample was collected for analysis of 5HTTLPR genotype. Meaningful CPM effect was determined as an increase in pressure pain threshold values from baseline greater than the inherent error of measurement, calculated as 5.3%. During the conditioning stimulus, 116 subjects (92.8%) exhibited a CPM effect whereas 9 did not. CPM effect did not differ significantly between genders or between 5HTTLPR genotypes. This provides a clear basis on which to determine the proportion of patients with a chronic pain disorder that exhibit a meaningful CPM effect. This study proposes a method for calculating meaningful CPM effect and reports the proportion and magnitude of effect elicited in a large sample. Associations between CPM, gender, and genotype were also analyzed. Clarification of normal CPM response may help to elucidate the mechanisms driving CPM inefficiency in chronic pain.


The role of the auxiliary atomic ion beam in C60(+)-Ar+ co-sputtering.
Cluster ion sputtering has been proven to be an effective technique for depth profiling of organic materials. In particular, C(60)(+) ion beams are widely used to profile soft matter. The limitation of carbon deposition associated with C(60)(+) sputtering can be alleviated by concurrently using a low-energy Ar(+) beam. In this work, the role of this auxiliary atomic ion beam was examined by using an apparatus that could analyze the sputtered materials and the remaining target simultaneously using secondary ion mass spectrometry (SIMS) and X-ray photoelectron spectrometry (XPS), respectively. It was found that the auxiliary 0.2 kV Ar(+) stream was capable of slowly removing the carbon deposition and suppresses the carbon from implantation. As a result, a more steady sputtering condition was achieved more quickly with co-sputtering than by using C(60)(+) alone. Additionally, the Ar(+) beam was found to interfere with the C(60)(+) beam and may lower the overall sputtering rate and secondary ion intensity in some cases. Therefore, the current of this auxiliary ion beam needs to be carefully optimized for successful depth profiling.


Understanding physical health of older adults with schizophrenia: building and eroding trust.
Adults with schizophrenia are living longer, and data suggest they face health care disparities contributing to poor physical health. This article presents findings from a study that explored the understanding of physical health among older adults with schizophrenia. One goal was to understand factors that influence experienced health care disparities. This grounded theory study used semi-structured interviews and participant observation and was conducted among 28 older adults with schizophrenia living in a variety of settings. Trust evolved as a dynamic process that was built with factors of respect, caring, advocacy, and consistency and eroded through factors of disrespect, not being heard, lack of time and provider inaction, and stigmatization. When trust is given and received between providers, the health care system, and the older adult with schizophrenia, the adult's physical health outcomes may improve and health care disparities may decline. These findings provide insights to promote optimal physical health outcomes.


Cost analysis of intra-arterial versus intra-venous delivery of bevacizumab for the treatment of recurrent glioblastoma multiforme.
Intra-arterial bevacizumab (IA BV) has been recently identified to be safe in the treatment of recurrent GBM. In this study, we sought to perform a cost analysis of IA BV versus IV BV especially also taking account of patient progression free survival (PFS) and overall survival (OS). We show that IA BV is significantly more cost effective than conventional IV therapy.


Implementing Lecane quadridentata acute toxicity tests to assess the toxic effects of selected metals (Al, Fe and Zn).
An environmental study revealed that three metals (Al, Fe and Zn) are common in the San Pedro River (SPR) (Aguascalientes, Mexico). Regrettably, in many samples the concentrations of these metals exceeded the maximum allowed toxicant concentrations levels as defined in by Mexican legislation. The highest concentrations of the three metals were found during the 2005 dry season, with elevated Al concentrations present along the entire river. Not surprisingly, the highest concentrations for all three metals came from locations adjacent to industrial areas. Estimates of the contribution of these metals to total toxicity revealed that these three metals are important contaminants of the river and responsible for most of the lethal toxicity found in environmental samples. To assess the importance of these reports, we conducted acute toxicity tests to determine LC50 for Al, Fe and Zn on the freshwater rotifer Lecane quadridentata. This permitted us to estimate the contribution of these metals to total toxicity during 2005-2006. Based on LC50 values, all three metals should be considered very toxic, with the zinc LC50 value (0.12 mg L(-1)) making it the most toxic metal for L. quadridentata. This approach can be applied to other sites with similar concentrations of these metals.


Electron wedges for radiation therapy.
Brain tumors can be advantageously treated with electron over photon radiation, by exploiting the rapid fall-off in dose with depth. This advantage could be further enhanced by utilizing multiple electron beams. However, in some beam configurations, wedged dose profiles would be necessary for the dose uniformity. Unlike photons, shaped pieces of material placed in electron beam severely degrade the energy, give additional scattering and, therefore, are suboptimal. The purpose of this study was to create wedged electron fields, using intensity modulation. The combination of electron wedges enables a more uniform coverage of brain tumors with a reduced dose to normal tissue. Intensity modulation was performed for 10 to 50 MeV electrons using a narrow scanning elementary beam of a racetrack Microtron accelerator, delivering radiation pulses with coordinates and intensities prescribed by a custom scan matrix. Dispensing more pulses (or longer pulses) within the field to increase the local dose, one can sharpen the penumbra at depth and generate wedged dose distributions of arbitrary angle as well as many other desired profiles. We modulated the electron beams, measured dose distributions using film in an anthropomorphic phantom, and compared the results with conventional techniques. Intensity modulation of electron beams decreases the 50-90% penumbra at depth by 40% and increases the flatness by 80%. Wedged profiles at depth can be created for any angle up to about 70 degrees, depending on the beam energy. Multiple modulated electron beams give smaller 20-70% but larger 70-100% isodose regions than photon beams. Electron beams can improve dose distributions in brain compared to the same number of photon beams, reducing the 20-70% isodoses region in normal tissue by 30%. Intensity modulation significantly improves the dose distribution from combined electron beams providing a sharper penumbra, better conformity, and reduced margin.


Do hemodynamic responses to the valsalva maneuver reflect myocardial dysfunction?
In 14 consecutive patients with varying myocardial function, evaluation of the Valsalva maneuver was performed using aortic pulse pressure decay to investigate a possible quantitative relationship between the pattern of response and the degree of myocardial dysfunction. The aortic pulse pressure response during strain correlated with resting left ventricular end-diastolic pressure and pulmonary wedge pressure but not with resting cardiac output, cardiac index and ejection fraction. Similar results were obtained when several indices characterizing the aortic pulse pressure decay during Valsalva were used together to predict resting hemodynamic data by multiple regression analysis. In conclusion, quantitative aortic pulse pressure decay during the strain phase of the Valsalva maneuver correlated only moderately with hemodynamic indices used to identify myocardial dysfunction. These results raise doubts about the use of the Valsalva maneuver for the evaluation of myocardial dysfunction.


Perceiving affective content in ambiguous visual stimuli: a component of emotional intelligence.
Emotional intelligence involves the accurate appraisal and expression of emotions in oneself and others and the regulation of emotion in a way that enhances living. One aspect of emotional intelligence is the ability to recognize the consensually agreed upon emotional qualities of objects in the environment. One hundred thirty-nine adults viewed 18 reproductions of faces, color swatches, and abstract designs and rated the emotional content of these visual stimuli. Three scores were extracted, including consensual accuracy, amount, and range of emotion perceived. These scores were compared with other aspects of emotional intelligence such as empathy and related to constructs such as alexithymia and neuroticism. A general ability to perceive consensual emotional content in visual stimuli was found, and it was most strongly associated with the ability to respond empathically to others.


Combined effects of aerobiological pollutants, chemical pollutants and meteorological conditions on asthma admissions and A & E attendances in Derbyshire UK, 1993-96.
The effect of outdoor aeroallergen exposure in asthma may be enhanced by air pollutants, including ozone, nitrogen dioxide and particulates, and by certain weather conditions. It is not yet established whether these interactions are important in determining asthma morbidity at the population level. We have investigated the joint effects of aeroallergens, rainfall, thunderstorms and outdoor air pollutants on daily asthma admissions and Accident and Emergency (A & E) attendance using routinely collected data between 1993 and 1996 from Derby in central England. Daily counts during the aeroallergen season of grass and birch pollen, basidiospores, Didymella, Alternaria and Cladosporium, maximum 1 hour ozone and nitrogen dioxide and daily average black smoke measurements, all made in the vicinity of the city centre, were categorized in tertiles. Rainfall was classified as dry, light (</= 2 mm) or heavy (> 2 mm). The modifying effect of outdoor pollutant levels, and rainfall or the occurrence of a thunderstorm, upon the effects of individual aeroallergens on asthma admissions and A & E attendance were investigated by fitting appropriate interactions in log linear autoregression models with adjustment for potential confounders. We found a significant interaction between the effects of grass pollen and weather conditions upon A & E attendance, such that the increase with grass pollen count was most marked on days of light rainfall (adjusted rate ratio for >/= 50 vs < 10 grains/m3 at lag 2 days = 2.1, 95% CI 1.4, 3.3). Asthma admissions increased with Cladosporium count. We found no statistically significant interactions between effects of any individual aeroallergen and outdoor air pollutant upon either measure of asthma morbidity. Rainfall and thunderstorms are important effect modifiers in the relation between grass pollen and measures of acute asthma morbidity. Interactions between ambient levels of aeroallergens and chemical pollutants in the Derby area do not play a major role in determining asthma admissions and A & E attendance.


Involvement of mu-, delta- and kappa-opioid receptor subtypes in the discriminative-stimulus effects of delta-9-tetrahydrocannabinol (THC) in rats.
Many behavioral effects of delta-9-tetrahydrocannabinol (THC), including its discriminative-stimulus effects, are modulated by endogenous opioid systems. To investigate opioid receptor subtypes involved in the discriminative effects of THC. Rats trained to discriminate 3 mg/kg i.p. of THC from vehicle using a two-lever operant drug-discrimination procedure, were tested with compounds that bind preferentially or selectively to either mu-, delta- or kappa-opioid receptors. The preferential mu-opioid receptor agonist heroin (0.3-1.0 mg/kg, i.p.), the selective delta-opioid receptor agonist SNC-80 (1-10 mg/kg, i.p.) and the selective kappa-opioid receptor agonist U50488 (1-10 mg/kg, i.p.) did not produce generalization to the discriminative effects of THC when given alone. However, heroin, but not SNC-80 or U50488, significantly shifted the dose-response curve for THC discrimination to the left. Also, the preferential mu-opioid receptor antagonist naltrexone (0.1-1 mg/kg, i.p.), the selective delta-opioid receptor antagonist, naltrindole (1-10 mg/kg, i.p.) and the kappa-opioid receptor antagonist nor-binaltorphimine (n-BNI, 5 mg/kg, s.c.), did not significantly reduce the discriminative effects of the training dose of THC. However, naltrexone, but not naltrindole or n-BNI, significantly shifted the dose-response curve for THC discrimination to the right. Finally, naltrexone, but not naltrindole or n-BNI, blocked the leftward shift in the dose-response curve for THC discrimination produced by heroin. mu- but not delta- or kappa-opioid receptors are involved in the discriminative effects of THC. Given the role that mu-opioid receptors play in THC's rewarding effects, the present findings suggest that discriminative-stimulus effects and rewarding effects of THC involve similar neural mechanisms.


Physiological roles and properties of potassium channels in corporal smooth muscle.
Decreased penile vascular resistance induced by corporal smooth muscle relaxation is the most important step in penile erection. The heightened tone of the corporal smooth muscles is considered a major cause in impotence. Modulation of corporal smooth muscle tone is a complex process requiring the integration of a host of intracellular events and extracellular signals. In intracellular events of corporal smooth muscle cell, the potassium channels and calcium channels play a major role. Functionally, potassium channels are important regulators of smooth muscle membrane potential in response to depolarizing stimuli and they counteract calcium channels. Potassium channels have been shown to play a fundamental role in both the physiologic and pathophysiologic regulation of smooth muscle tone in diverse tissues. Among the several subtypes of potassium channels, the calcium-sensitive (K(Ca)) or maxi-K potassium channel subtypes are thought to be the most physiologically relevant in human corporal smooth muscle. Because of the physiological role of maxi-K channels in human corporal smooth muscles, we investigated the maxi-K channels for the genetic therapy of erectile dysfunction. These data indicate that naked hSlo DNA of maxi-K channels is quite easily incorporated into corporal smooth muscle and expression of the maxi-K hSlo cDNA appeared to be sustained for 1-4 months postinjection. These results show the possibility of a similar genetic strategy of potassium channels in humans.


Effects of corticosteroids on synaptic transmission in rat dorsolateral septal nucleus.
The effects of corticosteroids on synaptic transmission in the rat dorsolateral septal nucleus (DLSN) were examined, in vitro, by using intracellular and voltage-clamp recording methods. Prednisolone (100 microM) increased the amplitude of excitatory postsynaptic potential (EPSP) and depressed both fast and slow inhibitory postsynaptic potentials (IPSP). Under voltage-clamp conditions, prednisolone (100 microM) increased the amplitude of excitatory postsynaptic current (EPSC) and depressed the fast and slow inhibitory postsynaptic currents (IPSCs). Corticosterone (100 microM) mimicked the effects of prednisolone on the postsynaptic currents (PSCs). To examine the direct effects of prednisolone on the EPSC and slow IPSC, the fast IPSC was blocked by bicuculline (20 microM). Under these experimental conditions, prednisolone (100 microM) did not alter the isolated EPSC but depressed slow IPSC by 22 +/- 3% (n = 10). The fast IPSC was isolated by pretreatment with kynurenic acid and CGP55845A, where the EPSC and slow IPSC were blocked. Prednisolone (100 microM) depressed the isolated fast IPSC in DLSN neurons. Prednisolone (100 microM) did not change either the inward current produced by glutamate or the outward current produced by gamma-aminobutyric acid (GABA). The results suggest that corticosteroids facilitate excitatory synaptic transmission in the DLSN by reducing the release of GABA from the presynaptic nerve terminals of interneurons.


Pharmacokinetics of imiquimod 3.75% cream applied daily for 3 weeks to actinic keratoses on the face and/or balding scalp.
Imiquimod 3.75% cream is a topical formulation of imiquimod intended for daily application to treat actinic keratoses of the entire face or balding scalp. The objective of the study was to characterize serum imiquimod and metabolite pharmacokinetics. Nineteen subjects with actinic keratoses applied two packets of imiquimod 3.75% cream (18.75 mg imiquimod total) once daily for 21 days to a treatment area approximately 200 cm(2) in size on the face and/or balding scalp. Blood samples were obtained prior to application of doses 1, 7, 14 and 21, and at selected timepoints after application of doses 1 and 21. After multiple dosing (day 21) serum imiquimod mean C (max) was 0.323 (standard deviation 0.159) ng/mL, mean AUC(0-24) 5.974 (3.088) ng h/mL, and mean T(1/2) 29.3 (17.0) h. Steady-state was achieved by day 14; multiple dose accumulation ratios were 2.8 based on imiquimod C (max) and 3.9 based on AUC. Serum concentrations of imiquimod metabolites were only sporadically quantifiable in three subjects. One subject discontinued from study for adverse events of body aches and fatigue that were attributed to study drug. Treatment-related adverse events occurred in 42.1% (8/19) of the subjects. Systemic imiquimod exposure, as reflected by serum drug concentration, was low after daily application of two packets of imiquimod 3.75% cream for 21 days. Steady state was achieved by day 14, and the observed half-life of approximately 29 h supports daily dosing of the product.


Comparison of the effects of Bay K 8644 and aortic constriction on regional myocardial blood flow and function in canine nonischemic and ischemic myocardium.
The effects of Bay K 8644, aortic constriction, and a placebo on regional myocardial blood flows (RMBFs) and contractile function (RCF) were compared in three groups of open-chest anesthetized dogs during coronary stenosis. Bay K 8644 was investigated in two doses: 0.1 micrograms/kg, which exhibited no systemic hemodynamic effect, and 1 microgram/kg, which significantly increased arterial pressure. Aortic constriction was performed to raise afterload to the same extent as Bay K 8644 1 microgram/kg. As compared with placebo, Bay K 8644 0.1 microgram/kg, significantly increased coronary resistance, decreased RMBFs without changing RCF in nonischemic myocardial zones, and affected neither RMBFs nor RCF in ischemic zones. In nonischemic myocardium, Bay K 8644 1 microgram/kg increased RMBFs without affecting RCF, whereas aortic constriction did not modify RMBFs but decreased RCF. In ischemic myocardium, both Bay K 8644 1 microgram/kg and aortic constriction increased RMBFs but did not affect RCF. Thus, the low dose of Bay K 8644 exerts a direct and selective coronary vasoconstrictor effect that has no deleterious consequences on nonischemic RCF. Despite this intrinsic coronary vasoconstrictor effect, the high dose of Bay K 8644 increases RMBFs and maintains RCF in both ischemic and nonischemic zones in relation with the drug-induced increases in coronary perfusion pressure (both zones) and in contractility (nonischemic zones).


Endothelial dysfunction in heart failure identifies responders to cardiac resynchronization therapy.
The presence of endothelial dysfunction is associated with increased heart failure mortality. Cardiac resynchronization therapy (CRT) improves heart failure outcomes; however, current guidelines do not adequately identify responders to CRT. The purpose of this study was to determine whether endothelial dysfunction can predict response to CRT. Brachial artery flow-mediated dilation, a measure of endothelial function, was measured at baseline preimplant and 90 days postimplant in 33 patients undergoing CRT (age 64.2 +/- 16.8 years, left ventricular ejection fraction [LVEF] 25% +/- 9%, QRS duration 158 +/- 25 ms, New York Heart Association class III-IV). Of the 33 patients, 19 (58%) were responders to CRT. Baseline flow-mediated dilation was 4.6% +/- 4.5% in responders and 8.6% +/- 4.2% in nonresponders (P <.01). After 90 days of CRT, responders had significant improvement in LVEF (23% +/- 8% to 30% +/- 9%, P = .03), 6-minute walk distance (756 +/- 213 feet to 1,089 +/- 242 feet, P = .04), and quality of life (52 +/- 22 to 31 +/- 28, P <.005), whereas nonresponders did not show improvement in these measures. The presence of baseline endothelial dysfunction correlated with impaired baseline functional capacity (r = 0.39, P = .03), and improvement in flow-mediated dilation correlated with improvement in 6-minute walk distance (r = 0.34, P = .05). Logistic regression analysis showed that every 1% reduction in baseline flow-mediated dilation correlated with an approximately 5% increased likelihood of response to CRT. The predictive value of baseline endothelial dysfunction was independent of QRS duration, LVEF, or dyssynchrony and provided additive prognostic value. The presence of endothelial dysfunction independently identifies CRT responders and provides additive prognostic value for predicting response over current criteria. Addition of endothelial function assessment to current selection criteria may improve the ability to identify CRT responders.


fMRI as a Preimplant Objective Tool to Predict Postimplant Oral Language Outcomes in Children with Cochlear Implants.
Despite the positive effects of cochlear implantation, postimplant variability in speech perception and oral language outcomes is still difficult to predict. The aim of this study was to identify neuroimaging biomarkers of postimplant speech perception and oral language performance in children with hearing loss who receive a cochlear implant. The authors hypothesized positive correlations between blood oxygen level-dependent functional magnetic resonance imaging (fMRI) activation in brain regions related to auditory language processing and attention and scores on the Clinical Evaluation of Language Fundamentals-Preschool, Second Edition (CELF-P2) and the Early Speech Perception Test for Profoundly Hearing-Impaired Children (ESP), in children with congenital hearing loss. Eleven children with congenital hearing loss were recruited for the present study based on referral for clinical MRI and other inclusion criteria. All participants were <24 months at fMRI scanning and <36 months at first implantation. A silent background fMRI acquisition method was performed to acquire fMRI during auditory stimulation. A voxel-based analysis technique was utilized to generate z maps showing significant contrast in brain activation between auditory stimulation conditions (spoken narratives and narrow band noise). CELF-P2 and ESP were administered 2 years after implantation. Because most participants reached a ceiling on ESP, a voxel-wise regression analysis was performed between preimplant fMRI activation and postimplant CELF-P2 scores alone. Age at implantation and preimplant hearing thresholds were controlled in this regression analysis. Four brain regions were found to be significantly correlated with CELF-P2 scores. These clusters of positive correlation encompassed the temporo-parieto-occipital junction, areas in the prefrontal cortex and the cingulate gyrus. For the story versus silence contrast, CELF-P2 core language score demonstrated significant positive correlation with activation in the right angular gyrus (r = 0.95), left medial frontal gyrus (r = 0.94), and left cingulate gyrus (r = 0.96). For the narrow band noise versus silence contrast, the CELF-P2 core language score exhibited significant positive correlation with activation in the left angular gyrus (r = 0.89; for all clusters, corrected p < 0.05). Four brain regions related to language function and attention were identified that correlated with CELF-P2. Children with better oral language performance postimplant displayed greater activation in these regions preimplant. The results suggest that despite auditory deprivation, these regions are more receptive to gains in oral language development performance of children with hearing loss who receive early intervention via cochlear implantation. The present study suggests that oral language outcome following cochlear implant may be predicted by preimplant fMRI with auditory stimulation using natural speech.


Cholinergic transmission in the dorsal hippocampus modulates trace but not delay fear conditioning.
Although cholinergic mechanisms have been widely implicated in learning and memory processes, few studies have investigated the specific contribution of hippocampal cholinergic transmission during trace fear conditioning, a form of associative learning involving a temporal gap between two stimuli. Microinfusions of scopolamine, a muscarinic receptor antagonist, into the dorsal hippocampus (DH) produced dose-dependent impairment in the acquisition and expression of a conditioned response (CR) following trace fear conditioning with a tone conditioned stimulus (CS) and a footshock unconditioned stimulus (US) in rats. The same infusions, however, had no effect on delay conditioning, general activity, pain sensitivity or attentional modulation. Moreover, scopolamine infusions attenuated phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala, indicating that cholinergic signals in the DH are important for trace fear conditioning. Taken together, the current study provides evidence that cholinergic neurotransmission in the DH is essential for the cellular processing of CS-US association in the amygdala when the two stimuli are temporally disconnected.


[Intravenous clomipramine for depressive disorders].
51 patients with depressive episode (40--recurrent depressive disorder, 11--bipolar affective disorder) were treated by the clomipramine intravenous infusions. The number of infusions varied from 5 to 21 (mostly 10-16). The median of maximal dose was 150 mg. There were significant clinical improvement measured by CGI. The therapy was well tolerated.


Epicardial activation-to-repolarization coupling differs in the local areas and on the entire ventricular surface.
Local and global activation-to-repolarization coupling differ from each other. Experiments were done in 12 dogs and 7 frogs. Activation times (ATs), end of repolarization times (RTs), and activation-recovery intervals (ARIs) were measured in 24 or 64 leads on the entire ventricular surface and on the epicardial patch 5 × 5 mm. The ARI and RT dispersions were greater than AT dispersion on the entire ventricular epicardium but not in the local patch. Both ATs and ARIs were inversely related to each other in the patch but not necessarily on the entire epicardium. The RT sequence depended on the AT sequence within the local patch but not on the entire surface. The contributions of the AT sequence and ARI distribution to the RT sequence was determined by the AT/ARI dispersion ratio. Thus, the AT sequence strongly influenced the RT sequence of the local epicardial fragment but not of the entire ventricular surface.


Martius advancement flap for low rectovaginal fistula: short- and long-term results.
Many surgical approaches have been described for the treatment of low rectovaginal fistulae (LRVF); however, all are associated with a high recurrence rate and a poor function. The Martius flap technique was first described in 1928 and has since been modified for the treatment of LRVF. The aims of this study were to evaluate the short- and long-term results of the Martius flap procedure. Twenty patients who underwent the Martius flap procedure between 2000 and 2010 were retrospectively included. Operative results and morbidity were evaluated. Quality of life (SF-12 score), quality of sexual life [Female Sexual Function Index (FSFI) score] and anal continence (Wexner score) were determined. Crohn's disease was the predominant aetiology (n = 8, 40%). The Martius flap was mostly harvested from the left side (n = 14, 66.7%). The morbidity rate was 15% (n = 3), and the mean hospital stay was 7.7 ± 3.7 days. At a mean follow up of 35 months, the success rate was 65%. Seven patients still had an LRVF: in patients with Crohn's disease the success rate was 50% (4/8). Fifteen patients (75%) answered the three questionnaires. Quality of life score was in the normal range: physical component summary score (PCS: 46.7 ± 9) and mental component summary score (MCS: 44.7 ± 11.3). The median (range) FSFI score was 5 (2-31.7). Eight patients (53%) deemed cured suffered no incontinence. The Wexner score was significantly higher in the presence of a persisting LRVF (2.6 ± 5.5 vs 13.4 ± 3.78) (P = 0.0018). Use of a right-sided flap was associated with a higher success rate (P = 0.0442). The Martius flap procedure for LRVF, had a success rate of about 60% and a low morbidity.


Leaf palatability, life expectancy and herbivore damage.
Observations on leaves from plants with a wide range of life-forms, ruderals to trees, indicate that palatability to insect herbivores is strongly correlated with the life-expectancy of the leaves. The amount of damage suffered in the field is however inversely correlated with palatability; although the rate of damage is less on unpalatable leaves, their longer life means that they accumulate damage over a longer period. It is only with extremely well-defended evergreen leaves, that the total damage is less than that experienced by less palatable (but short-lived) leaves. These observations are related to the current theories on relative palatability (the apparency theory and the resource availability theory), within the framework of the habitat templet.


Temperature-dependent thermal properties of supported MoS2 monolayers.
Thermal properties can substantially affect the operation of various electronics and optoelectronics devices based on two-dimensional materials. In this work, we describe our investigation of temperature-dependent thermal conductivity and interfacial thermal conductance of molybdenum disulfide monolayers supported on SiO2/Si substrates, using Raman spectroscopy. We observed that the calculated thermal conductivity (κ) and interfacial thermal conductance (g) decreased with increasing temperature from 62.2 W m(-1) K(-1) and 1.94 MW m(-2) K(-1) at 300 K to 7.45 W m(-1) K(-1) and 1.25 MW m(-2) K(-1) at 450 K, respectively.


Influence of polymer adjuvants on the ultrasound-mediated transfection of cells in culture.
The purpose of this study was to further understand the mechanisms involved in ultrasound-mediated delivery of DNA (sonoporation); in particular, to understand how a plasmid should be formulated with an ultrasound contrast agent (UCA). Different polymer adjuvant-UCA combinations were formulated, and their impact on in vitro DNA transfection, was determined, under various experimental conditions. When present in the medium surrounding a cell suspension, and in the presence of a plasmid encoding for the green fluorescent protein (GFP), expression following sonoporation was increased by more than 1.5-fold compared to that achieved in control experiments (without the adjuvants). The effects of the adjuvants were not influenced by the nature of the UCA, nor by that of the transfected cells; in contrast, the adjuvant concentrations, their physico-chemical properties, and the manner in which they were used, did have an impact on transfection. Close association of the adjuvants to the UCA inhibited their action, suggesting that these substances must have access to the cell membrane to be effective. Indeed, Pluronic F127 appeared to improve the efficacy of transfection (percentage of GFP-positive cells and cell viability), via fluidization of the cell membrane, perhaps facilitating thereby the formation of transient pores and their re-sealing. The mechanism of action of polyethylene glycols, on the other hand, remains unclear.


Understanding practitioner ethnography.
Thomas David Barton provides an overview of practitioner ethnography, a research approach that provides practitioners with a way of exploring the culture of their workplace. He compares practitioner and traditional ethnography and looks at the pros and cons of the method.


Heart rate variability changes and its association with the development of severe retinopathy of prematurity.
To evaluate differences in autonomic nervous system (ANS) activity associated with the development of retinopathy of prematurity. Heart rate variability (HRV) as an indicator of ANS activity was calculated in two groups of premature infants: (1) a treatment group of infants who developed type 1 ROP and underwent treatment and (2) a control group of infants who did not develop ROP more severe than stage 1 and who were matched to the treatment group in terms of age, weight, and similar risk factors, including similar frequency of intraventricular hemorrhage, bronchopulmonary dysplasia, and sepsis. HRV was analyzed during the first 5 days of life, within 5 days of initial ROP examination, and within 5 days of ROP treatment for the treatment group or, for controls, on the day of last electrocardiogram data prior to discharge. Calculations were performed for the high frequency, low frequency, and low frequency-high frequency values of the HRV components for all infants. Between the initial ophthalmologic evaluation and the final evaluation, there was a tendency for reduction in both the low- and high-frequency components of the HRV indices in the treatment group, whereas there was a tendency for an increase in both components of the HRV indices in the control group. The difference in the rate of change of the high frequency between groups was statistically significant (P = 0.021). Disruption in ANS activity may play an important role in the development and severity of ROP.


Rapid concentration of bacteria using submicron magnetic anion exchangers for improving PCR-based multiplex pathogen detection.
Rapid concentration of bacterial targets from dilute solutions to improve subsequent PCR detection is investigated in this study. Submicron (average size 500nm) superparamagnetic anion-exchangers (SiMAG-DEAE) were used successfully to concentrate target bacteria from very dilute solutions. A mass-balance model predicted that for Escherichia coli, the extent of cell concentrating increases almost linearly with increasing sample/SiMAG volume ratio up to about 2000, accompanied by only a slight decrease in the capture efficiency (<10%). Our experimental data generally support this analysis in that the SiMAG beads concentrated bacterial targets by two to three orders of magnitude using a sample/bead volume ratio of about 1000, and lowered the PCR detection limit to a level of 10(2)CFU/mL, from 10(4) to 10(5)CFU/mL without concentrating. Several target bacteria can be concentrated concurrently and detected via multiplex PCR, as illustrated using E. coli and Agrobacterium tumefaciens as model bacteria. Finally, concentration and detection of bacteria in fresh produce samples were demonstrated. The integration of submicron magnetic ion exchangers and PCR detection provides an appealing alternative to immunomagnetic separation/PCR in improving pathogen detection.


[Element concentrations in Rheum palmatum and R. likiangense plants and soil in Tibet plateau].
The characteristics of element concentrations in Rheum palmatum and R. likiangense plants and soil were studied using ICP method. The results showed that the P concentrations in soil was significantly lower than that in leaves and rhizomes; Fe concentration was 50-100 times higher in soil than in rhizomes, and leaves, and without significant difference between rhizomes and leaves; Na, Mn and Cu concentrations appeared soil > leaves > rhizomes; and Ca concentration showed soil < leaves < rhizomes for R. palmatum, and soil > leaves > rhizomes for R. likiangense. Although K, Mg, Ca, Mn and Zn concentrations were obviously different between soils of the 2 species, K and Mg concentrations were consistent in their leaves or rhizomes, and the difference of Ca, Mn and Zn concentrations between their rhizomes was insignificant.


Reconstruction of the forehead acoustic properties in an Indo-Pacific humpback dolphin (Sousa chinensis), with investigation on the responses of soft tissue sound velocity to temperature.
Computed tomography (CT) imaging and ultrasound experimental measurements were combined to reconstruct the acoustic properties (density, velocity, and impedance) of the head from a deceased Indo-Pacific humpback dolphin (Sousa chinensis). The authors extracted 42 soft forehead tissue samples to estimate the sound velocity and density properties at room temperature, 25.0 °C. Hounsfield Units (HUs) of the samples were read from CT scans. Linear relationships between the tissues' HUs and velocity, and HUs and density were revealed through regression analyses. The distributions of the head acoustic properties at axial, coronal, and sagittal cross sections were reconstructed, suggesting that the forehead soft tissues were characterized by low-velocity in the melon, high-velocity in the muscle and connective tissues. Further, the sound velocities of melon, muscle, and connective tissue pieces were measured under different temperatures to investigate tissues' velocity response to temperature. The results demonstrated nonlinear relationships between tissues' sound velocity and temperature. This study represents a first attempt to provide general information on acoustic properties of this species. The results could provide meaningful information for understanding the species' bioacoustic characteristics and for further investigation on sound beam formation of the dolphin.


Predicting the failure in distal femur fractures.
The incidence of nonunion after fractures of the distal femur is up to 6%. The distal femoral nonunion is a disabling disease that needs complex steps in his treatment. Aim of our study is to find predicting factors of non-unions. We retrospectively analyzed 116 cases of distal femoral fractures and 20 cases of non-unions. In both surgeries we analyzed: accuracy of reduction, stability of fixation, hardware used, residual medial or lateral bone defect, use of autologous or heterologous bone grafts. Malreduction, particularly axial defect, associated with unbalanced fixation, and a medial cortical bone defect of greater or lesser extent were found to be the major risk factors of nonunion. Addressing both the mechanical and the biological environment was associated with successful non union treatment. The main principles for solving a distal femoral nonunion are new better reduction, correction of the medial bone defect and biological support with bone grafting. From the mechanical side the association of a medial strut graft or a medial column plate could be very useful in the treatment of these non-unions.


Interaction of fibre type, potentiation and fatigue in human knee extensor muscles.
To examine the effect of fibre type on potentiation and fatigue. Young men (n = 4 per group) with a predominance of type I [61.4 +/- 6.9% (SD), group I (GI)] or type II [71.8 +/- 9.2%, group II (GII)] fibres in vastus lateralis, performed a fatigue protocol of sixteen 5-s maximal voluntary isometric contractions (MVCs) of the right knee extensors. Maximal twitches and corresponding muscle action potentials (M-waves) were evoked before the first MVC, during the 3-s rest period after each MVC and at intervals during the 5-min recovery period after the last MVC. Group II [49.3 +/- 2.6% (SE)] had a greater decrease in MVC force than GI (22.8 +/- 6.2%) during the fatigue protocol. Group II (126.4 +/- 13.6%) showed greater twitch force potentiation early in the fatigue protocol than GI (38.2 +/- 2.3%), but greater depression at the end (33.7 +/- 13.7% vs.17.4 +/- 3.4%). Twitch time-to-peak torque (TPT) and half relaxation time (HRT) initially decreased but then increased as the fatigue protocol progressed; GII had a greater increase in HRT. During a 5-min recovery period twitch force increased above the prefatigue level and remained so until the end of the recovery period; the pattern was similar in GI and GII. Twitch TPT and HRT remained elevated during recovery. M-wave area increased throughout the fatigue protocol and the first part of recovery before returning to baseline values in GII, whereas there were no significant changes in GI. The interaction between potentiation and fatigue was amplified in GII early in the fatigue protocol with concurrently greater twitch and M-wave potentiation, and greater MVC force decrease and HRT increase. Late in the protocol, GII had a greater decrease in twitch and MVC force combined with greater M-wave potentiation. It is concluded that fibre type distribution influences potentiation and fatigue of the twitch, and potentiation of the M-wave during fatiguing exercise.


Hyaluronan-Inorganic Nanohybrid Materials for Biomedical Applications.
Nanomaterials, including gold, silver, and magnetic nanoparticles, carbon, and mesoporous materials, possess unique physiochemical and biological properties, thus offering promising applications in biomedicine, such as in drug delivery, biosensing, molecular imaging, and therapy. Recent advances in nanotechnology have improved the features and properties of nanomaterials. However, these nanomaterials are potentially cytotoxic and demonstrate a lack of cell-specific function. Thus, they have been functionalized with various polymers, especially polysaccharides, to reduce toxicity and improve biocompatibility and stability under physiological conditions. In particular, nanomaterials have been widely functionalized with hyaluronan (HA) to enhance their distribution in specific cells and tissues. This review highlights the most recent advances on HA-functionalized nanomaterials for biotechnological and biomedical applications, as nanocarriers in drug delivery, contrast agents in molecular imaging, and diagnostic agents in cancer therapy. A critical evaluation of barriers affecting the use of HA-functionalized nanomaterials is also discussed, and insights into the outlook of the field are explored.


RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models.
The BRAF(V600E) mutation is common in several human cancers, especially melanoma. RG7204 (PLX4032) is a small-molecule inhibitor of BRAF(V600E) kinase activity that is in phase II and phase III clinical testing. Here, we report a preclinical characterization of the antitumor activity of RG7204 using established in vitro and in vivo models of malignant melanoma. RG7204 potently inhibited proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing BRAF(V600E) or other mutant BRAF proteins altered at codon 600. In contrast, RG7204 lacked activity in cell lines that express wild-type BRAF or non-V600 mutations. In several tumor xenograft models of BRAF(V600E)-expressing melanoma, we found that RG7204 treatment caused partial or complete tumor regressions and improved animal survival, in a dose-dependent manner. There was no toxicity observed in any dose group in any of the in vivo models tested. Our findings offer evidence of the potent antitumor activity of RG7204 against melanomas harboring the mutant BRAF(V600E) gene.


Modulation of HAT activity by the BRCA2 N372H variation is a novel mechanism of paclitaxel resistance in breast cancer cell lines.
Paclitaxel stabilizes microtubule polymerization, enhances microtubule assembly, and G2/M arrests, leading to cell death. Paclitaxel resistance has been attributed to a variety of mechanisms. In the present study, we define a new resistance mechanism to paclitaxel based on BRCA2 variation. Chemo-sensitivity to paclitaxel based on the variations was compared. Restoration of paclitaxel sensitivity was induced indirectly with combined treatment of paclitaxel and HDAC inhibitor. Variant and wild type of BRCA2 clones were obtained from wild and variant cells, respectively. Chemo-sensitivity, P/CAF and BubR1 expression and acetylation, BRCA2-P/CAF and BRCA2-BubR1 interactions, and HAT activities of the clones with BRCA2 variation were compared. We identified an association between chemo-sensitivity and BRCA2 N372H variation. The IC50 of paclitaxel in heterozygous variation was higher than that of wild type. There were no differences in basic expression levels of BRCA2 among variant types. However, P/CAF expression, of BRCA2-P/CAF interaction, and HAT activity were significantly lower in heterozygous variants than in the wild type. After HDAC inhibitor treatment, HAT activity and paclitaxel sensitivity were restored in variant cells. Cell lines transformed from wild to variant or from variant to wild showed reciprocal changes in P/CAF expression, BRCA2-P/CAF interaction, HAT activity, and paclitaxel sensitivity. Forced expression of the BRCA2 heterozygous variant induced paclitaxel resistance due to altered HAT activity (p<0.001). This was reversed by the TSA combination. Restoration of wild BRCA2 from variant type improved paclitaxel sensitivity (p<0.001). Modulation of HAT activity by BRCA2 N372H variation is a new mechanism of paclitaxel resistance in breast cancer.


[Localization of Mg2+-ATPase in the membranes of the skeletal muscles and myocardium of the frog Rana temporaria].
Using differential centrifugation in sucrose density gradient, from muscles of the frog fractions were obtained which contain fragments of sarcolemma, as well as membranes of T-system tubules and sarcoplasmic reticulum. In isolated membrane fractions, studies were made on the activity of cation-stimulated ATPases (Na+, K+-, Ca2+, Mg2+- and Mg2+-ATPases). Enzymic and electrophoretic analyses showed that the highest content of Mg2+-ATPases is typical of the fractions which are located on the surface of 35% sucrose. The data obtained indicate that Mg2+-ATPase is the enzyme which is specific for the membranes of T-system tubules in skeletal muscles of not only birds but amphibians as well. From cardiac muscle of the frog, membrane fraction was isolated which is similar (with respect to its predominant content of Mg2+-ATPase) to the membranes of T-system tubules. It is suggested that the presence of Mg2+-ATPase in these membranes is a common property of phasic striated muscle fibers in all mature vertebrate animals.


Magnetic PEDOT hollow capsules with single holes.
We demonstrate magnetic capsules with high uptake capacity by combining single-hole hydroxyl-functionalized PEDOT hollow spheres and Fe(3)O(4) nanoparticles; potential applications include pollutant removal and controlled drug delivery.


Editorial Commentary: Pitching a New Curve: Identifying the Etiology of Nontraumatic Throwing Injuries.
Loss of shoulder motion, especially to flexion and external rotation, may increase the risk of nontraumatic shoulder and elbow injuries in elite pitchers. However, the etiology of these injuries is likely mulitifactorial, and before we direct our therapists to abandon sleeper stretches in favor of flexion and external rotation exercises, further research is needed to keep pitchers off the disabled list and on the mound.


Congenital diaphragmatic hernia in neonates: variations in umbilical catheter and enteric tube position.
To evaluate anatomic variations of support apparatus position on radiographs obtained in neonates with congenital diaphragmatic hernia (CDH). The authors evaluated radiographs obtained in 71 neonates with CDH to determine whether nasogastric tubes, umbilical venous catheters, and umbilical arterial catheters deviated from their expected anatomic course. The relationship between deviation patterns and hernia contents was evaluated. Sixty-eight neonates-54 with left-sided CDH and 14 with right-sided CDH-had a nasogastric tube. The tubes in 21 patients with left-sided CDH had a normal anatomic course at radiography. Nineteen of these patients did not have stomach in the hernia. In 13 patients, the tip of the nasogastric tube was lodged at the esophagogastric junction. In 17 patients, the tube was in the left hemithorax. In all 30 of these patients, the stomach was within the CDH. All nasogastric tubes in the 14 patients with right-sided CDH had leftward deviation. Thirty-seven patients-27 with left-sided CDH and 10 with right-sided CDH-had umbilical venous catheters. The catheters in 12 patients with left-sided CDH had apex leftward convexity. The umbilical venous catheter in eight patients with right-sided CDH had rightward shift; all eight patients had liver herniation. The positions of nasogastric tubes and umbilical venous catheters vary in several predictable patterns in neonates with CDH. Knowledge of these variations may be helpful for supporting the diagnosis of CDH in unclear cases and thus avoiding unnecessary apparatus adjustments, and for predicting hernia contents.


[A polymorphism study of the genomic DNA of trematodes at different phases of development].
Polymorphism of the genome DNA in different development stages of trematodes by means of the polymerase chain reaction (PCR) with universal primers was investigated. Interspecific variation in Trichobilharzia ocellata (cercaria) was shown in samples from the Moscow area and some regions in Byelorussia (Naroch Lake). Population groupments of T. ocellata are correlated with migration routes of subpopulation groupments of city populations of the mallard duck (Anas platyrhynchus). The cercariae of T. ocellata from rather distant geographical isolates (Moscow and Naroch Lake) differ by PCR pattern in greater extent than groupments of cercariae within Moscow. These distant isolates are considered to be members of separate populations. The cercariae of T. ocellata emitted from infected snails belonging to the different species (Lymnaea auricularia, L. ovata, L. pusilla pusilla) and during definite period (6 days with 24 h analysis) do not differ by the PCR patterns. T. ocellata cercariae emitted from L. auricularia in autumn period (from molluscs of the new generation in "new" summer infection) are found to be different significantly from the "spring" cercariae of the same year and the "autumn" ones of the previous year. The study of the experimentally reproduced life cycle of Opisthorchis felineus revealed an essential difference of cercariae genome. DNA from that in other development stages. This indicates, that genetic reorganisation in the genome of products of parthenogenetic development took place in the parthenita stage.


Intelligent Metamaterials Based on Nonlinearity for Magnetic Resonance Imaging.
Metamaterials provide a powerful platform to probe and enhance nonlinear responses in physical systems toward myriad applications. Herein, the development of a coupled nonlinear metamaterial (NLMM) featuring a self-adaptive response that selectively amplifies the magnetic field is reported. The resonance of the NLMM is suppressed in response to higher degrees of radio-frequency excitation strength and recovers during a subsequent low excitation strength phase, thereby exhibiting an intelligent, or nonlinear, behavior by passively sensing excitation signal strength and responding accordingly. The nonlinear response of the NLMM enables us to boost the signal-to-noise ratio during magnetic resonance imaging to an unprecedented degree. These results provide insights into a new paradigm to construct NLMMs consisting of coupled resonators and pave the way toward the utilization of NLMMs to address a host of practical technological applications.


Methods for kinetic modeling of temporally resolved hyperspectral confocal fluorescence images.
Elucidating kinetic information (rate constants) from temporally resolved hyperspectral confocal fluorescence images offers some very important opportunities for the interpretation of spatially resolved hyperspectral confocal fluorescence images but also presents significant challenges, these being (1) the massive amount of data contained in a series of time-resolved spectral images (one time course of spectral data for each pixel) and (2) unknown concentrations of the reactants and products at time = 0, a necessary precondition normally required by traditional kinetic fitting approaches. This paper describes two methods for solving these problems: direct nonlinear (DNL) estimation of all parameters and separable least squares (SLS). The DNL method can be applied to reactions of any rate law, while the SLS method is restricted to first-order reactions. In SLS, the inherently linear and nonlinear parameters of first-order reactions are solved in separate linear and nonlinear steps, respectively. The new methods are demonstrated using simulated data sets and an experimental data set involving photobleaching of several fluorophores. This work demonstrates that both DNL and SLS hard-modeling methods applied to the kinetic modeling of temporally resolved hyperspectral images can outperform traditional soft-modeling and hard/soft-modeling methods which use multivariate curve resolution-alternating least squares (MCRALS) methods. In addition, the SLS method is much faster and is able to analyze much larger data sets than the DNL method.


Design and fabrication of continuous-profile diffractive micro-optical elements as a beam splitter.
An optimization algorithm that combines a rigorous electromagnetic computation model with an effective iterative method is utilized to design diffractive micro-optical elements that exhibit fast convergence and better design quality. The design example is a two-dimensional 1-to-2 beam splitter that can symmetrically generate two focal lines separated by 80 microm at the observation plane with a small angle separation of +/- 16 degrees. Experimental results are presented for an element with continuous profiles fabricated into a monocrystalline silicon substrate that has a width of 160 microm and a focal length of 140 microm at a free-space wavelength of 10.6 microm.


Monitoring low-dose warfarin therapy by a central laboratory and implications for clinical trials and patient care. The Coumadin Aspirin Reinfarction (CARS) Pilot Study Group.
The central laboratory provides International Normalized Ratio results in close agreement with the local laboratory for monitoring the anticoagulant effect of low-dose warfarin. A central laboratory may have practical advantages for patients in rural areas that lack laboratory facilities for anticoagulant monitoring.


[Selection of priorities in public health (author's transl)].
Identification of priorities is a major factor in an public health programme. We should avoid making a selection of priorities on a subjective basis, or basing a decision on temporary situations or the desire of influential personalities confusing personal interests with true priorities. The choice of priorities in health care must take into account two essential factors: 1) The impact of a disease on the population. It can be evaluated by studying:--the mortality rate and the increased life expectation resulting from the suppression of the disease;--the incidence of the disease;--the temporary or the permanent disablement it causes;--the incidence of complications. 2) The possibility of success of health programmes. The possibility of success depends on many factors: technical, logistic, political and psychological, which should be analysed in depth before establishing any priority programme. A public health programme can only be given priority rating when it combines maximum impact on the population with the highest chance of success. Priority rating can be attributed to a public health programme only when long term impact on the population and successful achievement can be combined.


Testosterone in prostate cancer: the Bethesda consensus.
• Androgen stimulation of prostate cancer (PCa) cells has been extensively studied. The increasing trend of using serum testosterone as an absolute surrogate for castration state means that the diagnostic measurement of testosterone and the values potentially influencing prognosis must be better understood. This is especially important when PCa progresses from an endocrine to an intracrine status. • We performed a literature review using the MEDLINE database for publications on: (i) hormonal changes with androgen deprivation therapy (ADT); (ii) monitoring hormonal therapy with testosterone measurement; (iii) the efficacy of intermittent androgen deprivation (IAD) compared with continuous androgen deprivation; (iv) the underlying mechanisms of castration-resistance; and (v) novel treatments for castration-resistant PCa (CRPCa). • The optimum serum castration levels to be achieved with ADT are still debated. Recently, the 50 ng/dL threshold has been questioned because of reports indicating worse outcomes when levels between 20 and 50 ng/dL were studied. Instead, a 20 ng/dL threshold for serum testosterone after ADT in patients with advanced prostate cancer was recommended. • Understanding the mechanisms of androgen biosynthesis relating to PCa as well as prognostic implications might achieve a consensus regarding the role of ADT for both the androgen-sensitive and -insensitive disease state.


A new algorithm for the simulation of sodium dodecil sulfate two-dimensional polyacrylamide gel electrophoresis data sets.
A new algorithm for generating simulated sodium dodecil sulfate two-dimensional polyacrylamide gel electrophoresis (SDS 2D-PAGE) map images was developed. To choose the simulation strategy able to provide realistic 2D-PAGE maps, several parameters that characterize the statistical features of the images and data sets of images were taken into account, such as the distribution of size, intensity, and volume of the spots and their changes of position and volume along different replications of the same 2D-PAGE map. In this way, also the low reproducibility of replications of the same SDS 2D-PAGE maps was taken into account. The present algorithm can be usefully employed for the development of new classification and/or image analysis algorithms applied to bidimensional electrophoretic data sets, given the usually small number of experimental replications available.


Relationship of absorption, depersonalisation, and self-focused attention in subjects with and without hallucination proneness.
The purpose of this work was to study the relationship of absorption, depersonalisation, and self-focused attention in subjects prone to hallucination. A sample of 218 healthy subjects was given the LSHS-R Hallucination Scale (Bentall & Slade, 1985). Three groups, subjects with high, medium, and low hallucination proneness, were formed from this sample. The Tellegen Absorption Scale (TAS; Tellegen & Atkinson, 1974), Cambridge Depersonalisation Scale (CDS; Sierra & Berrios, 2000), and Self-Absorption Scale (SAS; McKenzie & Hoyle, 2008) were also given to all the participants. The Metacognitions Questionnaire (MCQ-30; Wells & Cartwright-Hatton, 2004) was used as a covariant to control for the effects of emotional vulnerability on the dependent variables studied. The results showed that subjects highly prone to hallucinations had significantly higher absorption, depersonalisation, and self-focused attention than the subjects in the other two groups. A hierarchical regression analysis showed that absorption and depersonalisation predict hallucination proneness. The importance of the absorption, depersonalisation, and self-focused attention variables for understanding the aetiology of hallucinations is discussed in the Conclusions, where some approaches to its treatment are also suggested.


Selective incorporation of architectural proteins into terminally differentiated molluscan gill cilia.
Incubation of excised gills from the bay scallop Aequipecten irradians with 3H-leucine demonstrates that many ciliary structural proteins can attain a degree of labeling approaching that previously reported for sea urchin or surf clam embryos undergoing ciliary turnover or regeneration. This labeling is not a consequence of any predominant incorporation into new cilia at the meristematic growth tips of the gill since tissue regions of varying maturity incorporate label into the same proteins at similar levels, with the most mature region having the highest incorporation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorographic analysis of isolated cilia, separated into detergent-soluble membrane/matrix and detergent-insoluble 9+2 axoneme fractions, reveals that 1) tubulin in the membrane/matrix fraction is labeled whereas tubulin in the axoneme is not; 2) no labeled dynein heavy chains are seen in either fraction; 3) the most heavily labeled axonemal components do not appear to any significant extent in the membrane/matrix fraction; and 4) after thermal depolymerization of the microtubules, nearly all labeled proteins reside in the in-soluble ninefold ciliary remnant, the most prominent being tektin A, an integral component of outer doublet microtubules. Further fractionation of the remnant with sarkosyl-urea to produce tektin filaments demonstrates two solubility classes of tekin A, only the more soluble of which is labeled. Very similar selective architectural protein labeling patterns have been reported for steady-state cilia of sea urchin embryos, and this may indicate a widespread turnover or exchange mechanism characteristic of cilia heretofore considered static.


Oral intake of selenium has no effect on the serum concentrations of growth hormone, insulin-like growth factor-1, insulin-like growth factor-binding proteins 1 and 3 in healthy women.
The administration of large doses of selenium (Se) to rats leads to reduced serum levels of somatotropin (growth hormone) and insulin-like growth factor-1 (IGF-1), followed by growth retardation. Similar experiments in humans have been contradictory. The effects of wheat Se and selenomethionine supplementation were investigated in healthy, Norwegian women. In study 1, the participants (n = 18) were given Se-rich bread with 100, 200 and 300 micrograms Se daily for 6 weeks. Initial serum Se concentration were 1.5 +/- 0.2 mumol/l (mean +/- SD). Serum Se increased in a dose-dependent manner in the three groups (p < 0.001). There was no effect on somatotropin and IGF-1 at any of the Se doses given. In study 2 (n = 24), the effects of 400 micrograms selenomethionine daily for 15 weeks were studied in a placebo controlled study. In the treatment group, serum Se concentrations increased by more than 100%. There was, however, no effect on serum somatotropin and IGF-1 concentrations, nor was there any effect on IGF-binding proteins 1 and 3. Our results indicate that at normal or slightly increased intakes, Se has no effect on the serum concentrations of these two hormones in healthy individuals.


Ultrastructural characterization and Fourier analysis of fiber cell cytoplasm in the hyperbaric oxygen treated guinea pig lens opacification model.
The structural characteristics of differentiated fiber cells in control and hyperbaric oxygen (HBO)-treated guinea pig lenses were examined by transmission electron microscopy (TEM). Emphasis was placed on cell damage, membrane integrity, and cytoplasmic texture. Given the faint gross opacities observed in HBO-treated lenses in previous studies, it was hypothesized that subtle but significant morphological differences due to oxidative damage exist between control and treated animals. Experimental animals received either 70 or 85 treatments with HBO (2.5 atm of 100% O(2) for 2.5 hr, 3 times per week for 5-7 months). All specimens were obtained within 24 hr of death. Freshly cut Vibratome lens sections were fixed and processed for low and high-magnification thin-section TEM analysis. Cytoplasmic texture was analyzed using Fourier and autocorrelation image processing techniques. Low-magnification analysis revealed relatively insignificant differences in general appearance between the fiber cells of the inner fetal and embryonic nuclei in control and HBO-treated guinea pigs. Both groups demonstrated cells of similar morphology with equivalent membrane complexity and homogeneous cytoplasmic texture. Evidence of any major cellular damage or extracellular space debris was not obvious. High-magnification analysis of the cytoplasm of the treated lenses exhibited a mild, yet detectable increase in texture compared with controls and was confirmed by Fourier analysis. Cytoplasmic texture increased in complexity with additional treatments. The absence of major cellular damage in the lenses of HBO-treated animals suggests a less conspicuous source of light scattering. The small changes in cytoplasmic organization observed between treated and control animals may entirely account for the increase in nuclear light scattering observed by slit lamp. The results obtained with this guinea pig/HBO model parallel many of the morphological data associated with human nuclear cataracts. The high-angle scattering observed in the lens of the HBO-treated guinea pig may represent the type of cytoplasmic reorganization that occurs with mild oxidation, effectively making it a valuable model for human lens aging.


Structure and genomic organization of the human AUF1 gene: alternative pre-mRNA splicing generates four protein isoforms.
The steady-state levels of many mRNAs are determined in part by their turnover rates. Turnover rates, in turn, are usually controlled by proteins that bind cis-acting sequence elements in mRNAs. One class of cis-acting instability determinants is composed of A + U-rich elements present in the 3'-UTRs of many labile mRNAs. Many A + U-rich elements are bound by the AUF1 family of RNA-binding proteins, which may target these mRNAs for rapid decay. cDNA cloning and immunoblot analyses suggest that the AUF1 family consists of at least four isoforms. Previous genomic cloning combined with FISH and Southern analyses of a panel of monochromosomal mouse/human or hamster/human somatic cell hybrids localized two AUF1 loci to human 4q21.1-q21.2 and Xq12 (B. Wagner et al., 1996, Genomics 34: 219-222). In the present study AUF1 gene organization was examined. The results suggest that the four known AUF1 isoforms are generated by alternative pre-mRNA splicing of a transcript encoded by the chromosome 4 locus. Functionally, this creates isoforms with different RNA-binding affinities and specificities. Thus, alternative pre-mRNA splicing may serve to create functional versatility within the AUF1 family of proteins.


Candidate autoantigens in multiple sclerosis.
Multiple sclerosis is an inflammatory demyelinating CNS disease of putatively autoimmune origin. Novel models of experimental autoimmune encephalomyelitis (EAE) have demonstrated that T cells specific for various myelin and even nonmyelin proteins are potentially encephalitogenic. The encephalitogenic T cell response directed against different CNS antigens not only determines the lesional topography of CNS inflammation but also the composition of the inflammatory infiltrates. The heterogeneity of the lesional distribution seen in EAE might therefore be useful for the understanding of the various clinical subtypes seen in MS. In this review the possible candidate autoantigens in MS are discussed with special regard to the human T cell and B cell responses against various myelin and nonmyelin proteins.


Parotid acinar cells transiently change to duct-like cells during epithelial-mesenchymal transition.
Hyposecretion of saliva and consequent dry mouth lead to severe caries and periodontal disease. Therapeutic radiation for head and neck cancer and sialadenitis result in atrophy and fibrosis of salivary glands, but the mechanism is not clear. As a model for dysfunction of salivary glands, we examined the change of gene expression patterns in primary cultured parotid acinar cells. The expression levels of acinar markers such as amylase and aquaporin-5 rapidly decreased during culture. At the same time, ductal markers began to be expressed although their expression was transient. In the late phase of culture, markers of epithelial-mesenchymal transition began to be expressed and increased. Inhibitor for Src or p38 MAP kinase suppressed these changes. These results suggest that parotid acinar cells transiently change to duct-like cells during epithelial-mesenchymal transition and that these changes are induced by signal transduction via Src-p38 MAP kinase pathway. There is a possibility that parotid acinar cells retain a plasticity of differentiation.


Nanosystems for Skin Delivery: From Drugs to Cosmetics.
Skin delivery is an exciting and challenging area. There are numerous skin delivery systems available on the market. However, this market still remains limited to a narrow range of substances. Thus, several strategies have been developed to improve the performance of those substances, including the development of nanosystems. The aim of this review is to elucidate the nanosystems applied to the skin. Thus, we undertook a structured search of bibliographic databases for peer-reviewed research literature. In order to contextualize this subject, anatomy and physiology of the skin will be first briefly described and then general concepts and the various examples of these nanosystems, both cosmetic and pharmaceutical field, will be also accessed. As demonstrated, the use of nanosized carrier systems for drugs or active ingredients has gathered the attention of the most famous cosmetic and pharma industries. In fact, those nanosystems can easily establish a special interaction with skin structures, achieving deeper layers and obtaining a controlled release of the encapsulated substances. The findings of this review confirm the importance of skin delivery and the applications of nanotechnology in this area. Although those nanosystems have a high potential and applicability, there are still some limitations mainly because some of those studies are inconclusive in terms of risk of the nanomaterials and further toxicological investigations could address those issues in order to make these products more functional and attractive to consumers.


Oral repeat dose and reproductive toxicity of the chlorinated flame retardant Dechlorane Plus.
This study consisted of a 28-day oral repeat dose (repeat dose toxicity [RDT]) phase and a developmental and reproductive (developmental and reproductive toxicity [DART]) phase with rats. Rats were treated with Dechlorane Plus at doses of 0, 750, 1500, or 5000 mg/kg by gavage. For the RDT phase, no effects were observed on in-life parameters or clinical or anatomic pathology. In the DART phase, no effects were observed on reproductive or fertility indices, or fetal development through lactation day (LD) 4. No effects were noted on gestation day (GD) 20 implantation data, fetal indices, or external and visceral examinations. Mortalities occurred across all dose groups, although these were gavage-related errors and not compound related. Microscopic evidence of gavage-related errors included adhesions, inflammation, and fibrosis in the thoracic and pleural cavities. These findings were not test article related as they were observed only in animals with evidence of gavage injury. The no-observable-effect level (NOEL) in both phases of study was 5000 mg/kg.


[Analgesic nephropathy].
Analgesic nephropathy is a slowly progressive disease caused by the chronic abuse of analgesic mixtures containing two analgesic components combined with potentially addictive substances (coffeine and/or codeine). Pathologically, the nephropathy is characterized by renal papillary necrosis with calcification and chronic interstitial nephritis sometimes in association with transitional-cell carcinoma of the uroepithelium. In the early stage, the clinical characteristics are polyuria, sterile pyuria, sometimes renal colic and haematuria. With further progression of the disease, there are the nonspecific symptoms of advanced renal failure. The incidence of classic analgesic nephropathy among Hungarian patients on chronic renal replacement therapy has proven. There is an urgent need for the estimation of analgesic nephropathy among patients with chronic renal disease and among patients with chronic pain presumably regularly taking analgesics in Hungary. As long as analgesic mixtures containing phenacetin or paracetamol and/or nonsteroidal antiinflammatory drugs and addictive substances are available "over-the-counter", analgesic nephropathy will continue to be a problem also in our country.


To Include or Not to Include: The Impact of Gene Filtering on Species Tree Estimation Methods.
With the increasing availability of whole genome data, many species trees are being constructed from hundreds to thousands of loci. Although concatenation analysis using maximum likelihood is a standard approach for estimating species trees, it does not account for gene tree heterogeneity, which can occur due to many biological processes, such as incomplete lineage sorting. Coalescent species tree estimation methods, many of which are statistically consistent in the presence of incomplete lineage sorting, include Bayesian methods that coestimate the gene trees and the species tree, summary methods that compute the species tree by combining estimated gene trees, and site-based methods that infer the species tree from site patterns in the alignments of different loci. Due to concerns that poor quality loci will reduce the accuracy of estimated species trees, many recent phylogenomic studies have removed or filtered genes on the basis of phylogenetic signal and/or missing data prior to inferring species trees; little is known about the performance of species tree estimation methods when gene filtering is performed. We examine how incomplete lineage sorting, phylogenetic signal of individual loci, and missing data affect the absolute and the relative accuracy of species tree estimation methods and show how these properties affect methods' responses to gene filtering strategies. In particular, summary methods (ASTRAL-II, ASTRID, and MP-EST), a site-based coalescent method (SVDquartets within PAUP*), and an unpartitioned concatenation analysis using maximum likelihood (RAxML) were evaluated on a heterogeneous collection of simulated multilocus data sets, and the following trends were observed. Filtering genes based on gene tree estimation error improved the accuracy of the summary methods when levels of incomplete lineage sorting were low to moderate but did not benefit the summary methods under higher levels of incomplete lineage sorting, unless gene tree estimation error was also extremely high (a model condition with few replicates). Neither SVDquartets nor concatenation analysis using RAxML benefited from filtering genes on the basis of gene tree estimation error. Finally, filtering genes based on missing data was either neutral (i.e., did not impact accuracy) or else reduced the accuracy of all five methods. By providing insight into the consequences of gene filtering, we offer recommendations for estimating species tree in the presence of incomplete lineage sorting and reconcile seemingly conflicting observations made in prior studies regarding the impact of gene filtering.


Feasibility of prenatal diagnosis and carrier detection in South African haemophilia A patients.
The feasibility of DNA diagnosis for haemophilia A was tested in South African patients and families by screening for the common inversion mutation in the factor VIII gene and for the intragenic microsatellite markers in introns 13 and 22. The allele frequencies at the two microsatellite loci were significantly different, with informativity being higher in the Negroid (100%) than the Caucasoid group (67%). In severely affected haemophiliacs the inversion was found in 43% (6/14) of Negroids but in only 32% (13/41) of Caucasoids. Presence of a second common unidentified mutation may account for the low frequency in the latter. Haplotype analysis shows a disproportionately high frequency of an (AC)20 intron 13-(AC)26 intron 22 inversion negative Caucasoid haemophilia chromosome, supporting a founder effect.


A United States marine presenting with hemoptysis after push-ups.
We present an unusual case of right lower lobe intralobar pulmonary sequestration in a previously healthy and physical active 27-year-old U.S. Marine, who presented with new onset hemoptysis after doing push-ups. Diagnosis was obtained by chest X-ray and contrast computed tomography scan. Preoperatively the patient underwent fluoroscopy-guided embolization of the aberrant systemic artery supplying the sequestration. The segmental resection of the sequestration was then successfully performed through a muscle-sparing thoracotomy.


Innovative pH sensors developed from ultrafine fibers containing açaí (Euterpe oleracea) extract.
This work describes the development of ultrafine fibers with açaí (Euterpe oleracea Mart.) extract (AE) for use as pH sensors with potential applications in the food industry. The fibers were produced by electrospinning with polymeric solutions composed of 7% (w v-1) polycaprolactone, 2% (w v-1) polyethylene oxide and 3% (w v-1) AE solubilized in chloroform and methanol (3:1). The mean diameter of the fibers was 1635 ± 277 nm, with hydrophilic characteristics (contact angle < 90°), a melting point of 58 °C and a maximum degradation temperature of 408 °C. The total color difference (ΔΕ) of the colorimetric response was greater than 5, corresponding to the human ability for color differentiation. This new material can be used as a pH sensor for foods such as pork and fish to ensure quality and safety for the consumer, who can visually check the condition of the products.


St Georg modular knee prosthesis. A two-and-a-half to six-year follow-up.
The St Georg modular knee replacement has been studied in 59 cases with an observation period ranging from 28 to 73 months. In 47% of the knees both compartments were replaced; five of the six poor results were in this group. These were revised to a hinge arthroplasty or, in one case, to an arthrodesis. Other complications were few and insignificant. There were no infections. We concluded that unicompartmental knee arthroplasty can be recommended when joint involvement is localised to one compartment only. With more generalised joint disease we prefer a semiconstrained total condylar prosthesis.