Accuracy in clinical laboratories participating in regional quality control programs.
Few studies have assessed analytic bias (accuracy) in clinical chemistry laboratories. Using the data base of a large regional quality control program, we studied, during a six-year period, analytic bias of participant "all-methods" results, as well as selected commonly used individual methods, for calcium, cholesterol, glucose, potassium, and sodium. Analytic bias was assessed by comparison with "benchmark" measurements by United States Bureau of Standards definitive methods and/or United States Centers for Disease Control clinical reference methods. The all-methods bias at selected clinically relevant analyte levels was +0.1% at 10 mg/dL for calcium; -0.7% for cholesterol at 200 mg/dL; +4.5% for glucose at 120 mg/dL; +0.5% for potassium at 4 mmole/L; and 0% for sodium at 145 mmole/L. There was sufficient agreement between benchmark and participant all-methods results for these analytes to suggest that the all-methods results may be useful analytic bias benchmarks in future regional quality control programs that use similar lyophilized human serum pools.


Evaluation of combination gene therapy with PTEN and antisense hTERT for malignant glioma in vitro and xenografts.
Telomerase activation is a critical event in cell immortalization, and an increase in human telomerase reverse transcriptase (hTERT) expression is the key step in activating telomerase. The phosphatase and tensin homolog (PTEN) gene encodes a double-specific phosphatase that induces cell cycle arrest, inhibits cell growth, and causes apoptotic cell death. Here, we evaluated a combined PTEN and antisense hTERT gene therapy for experimental glioma in vitro and in vivo. We demonstrated that infection with antisense-hTERT and wild-type-PTEN adenoviruses significantly inhibited human U251 glioma cell proliferation in vitro and glioma growth in a xenograft mouse model. The efficacy of therapy was obviously higher in the tumor xenografts infected with both PTEN and antisense hTERT than in the gliomas infected with either agent alone at the same total viral dose. Consistent with these results, we showed that telomerase activity and hTERT protein levels were markedly reduced in the glioma cells following adenovirus infection. In contrast, the levels of PTEN protein expression were dramatically increased in these cells. Our data indicate that combination treatment with antisense hTERT and wild-type PTEN effectively suppresses the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach in glioma gene therapy that warrants further investigation.


Multi-transverse mode operation of alkali vapor lasers: modeling and comparison with experiments.
In high-power diode pumped alkali lasers with stable resonators the radius of the pump beam is usually larger than that of the fundamental laser mode and thus several high order transverse modes of the resonator can participate in the lasing. A simple optical model of multi-transverse mode operation of alkali vapor lasers is reported. The model is based on calculations of the pump and laser beam intensities in the gain medium, where the laser beam intensity is a linear combination of the azimuthally-symmetric Laguerre-Gaussian modes. It was applied to Ti:Sapphire and diode pumped cesium vapor lasers. The model predicts that for low pump power only the fundamental lasing mode oscillates. However, for higher pump powers several transverse modes participate in oscillation. The number and intensities of the oscillating modes as a function of the pump beam power and radius were found. The model predicts linear dependence of the laser power on the pump power, the values of the former being in agreement with the experimental results obtained for diode pumped cesium laser [Electron. Lett.44, 582 (2008)]. The mode-matching efficiency for the multi-transverse mode lasing is ~0.8 - 0.85 which means that in this case almost complete overlap of the laser and pump beams takes place. The laser beam quality factorM2increases with increasing pump power from 1 at the threshold power to 5-6 at maximum values of the pump power resulting in lower beam quality at high powers.


Long-term release and stability of pharmaceutical proteins delivered from solid lipid implants.
Solid lipid implants (SLIs) prepared by twin-screw (tsc) extrusion represent a promising technology platform for the sustained release of pharmaceutical proteins. In this work, we report on two aspects, long-term release and stability of released protein. First, SLIs were produced by tsc-extrusion containing the low melting triglyceride H12 and the high melting triglyceride Dynasan D118. Two different proteins available in a freeze-dried matrix containing hydroxypropyl-β-cyclodextrine (HP-β-CD) were incorporated into the lipid matrix: a monoclonal antibody (mAb) from the IgG1 class and the fab-fragment Ranibizumab (Lucentis®). SLIs, composed of 10% protein lyophilizate and both triglycerides, were extruded at 35°C and 40rpm. Sustained release of both proteins was observed in a sustained manner for approximately 120days. Protein load per implant was increased by three different approaches resulting in a protein load of 3.00mg per implant without affecting the release profiles. The incubation medium containing the released protein was collected, concentrated and analyzed including liquid chromatography (SE-HPLC, IEX, HIC), electrophoresis (SDS-PAGE, on-chip gel electrophoresis) and FT-IR spectroscopy. The mAb showed a monomer loss of up to 7% (SE-HPLC) and IEX analysis revealed the formation of 16% acidic subspecies after 18weeks. FT-IR spectra of mAb indicated the formation of random coil structures towards the end of the release study. Ranibizumab was mainly released in its monomeric form (>95%), and approximately 5% hydrophobic subspecies were formed after 18weeks of release. FT-IR analysis revealed no changes in secondary structure. The release and stability profiles of both proteins underline the potential of SLIs as a delivery system. SLIs provide a promising platform for applications where really long-term release is needed, for example for intraocular delivery of anti-vascular endothelial growth factor (VEGF) drugs for age related macular degeneration (AMD).


Wnt Signaling in Inner Blood-Retinal Barrier Maintenance.
The retina is a light-sensing ocular tissue that sends information to the brain to enable vision. The blood-retinal barrier (BRB) contributes to maintaining homeostasis in the retinal microenvironment by selectively regulating flux of molecules between systemic circulation and the retina. Maintaining such physiological balance is fundamental to visual function by facilitating the delivery of nutrients and oxygen and for protection from blood-borne toxins. The inner BRB (iBRB), composed mostly of inner retinal vasculature, controls substance exchange mainly via transportation processes between (paracellular) and through (transcellular) the retinal microvascular endothelium. Disruption of iBRB, characterized by retinal edema, is observed in many eye diseases and disturbs the physiological quiescence in the retina's extracellular space, resulting in vision loss. Consequently, understanding the mechanisms of iBRB formation, maintenance, and breakdown is pivotal to discovering potential targets to restore function to compromised physiological barriers. These unraveled targets can also inform potential drug delivery strategies across the BRB and the blood-brain barrier into retinas and brain tissues, respectively. This review summarizes mechanistic insights into the development and maintenance of iBRB in health and disease, with a specific focus on the Wnt signaling pathway and its regulatory role in both paracellular and transcellular transport across the retinal vascular endothelium.


Health-related effects of worksite interventions involving physical exercise and reduced workhours.
This study examined the health-related effects of two worksite interventions, physical exercise and reduced workhours, on women employed in dentistry. Six workplaces were randomized to one of the following three conditions: (i) 2.5 hours of weekly, mandatory physical exercise of middle-to-high intensity to be performed during workhours (N=62), (ii) a reduction of full-time weekly workhours from 40 to 37.5 hours (N=50), and (iii) reference. In all, 177 women participated. Biomarkers and self-ratings in questionnaires were obtained before the intervention (T (1)), and six (T (2)) and 12 months (T (3)) after the intervention. The results showed increased levels of physical activity and exercise in all of the groups, the level of physical exercise being significantly greater in the physical exercise group. Repeated-measures analyses of variance using data from T (1)and T (3)for biological measures and all three time points for self-ratings produced significant interaction effects for glucose, waist-to-hip ratio, and work ability and clear trends for general symptoms and upper-extremity disorders. Posthoc analyses showed that the results of the health-related measures differed between the interventions, decreased glucose and upper-extremity disorders in the exercise group, and increased high-density lipoprotein and waist-to-hip ratio among those working reduced hours. These results show that the two interventions had small and varied effects on biomarkers and self-reports of different aspects of health among women. It is suggested that interventions involving a modest reduction in workhours seem to be more effective if these hours are used for physical exercise.


'Carer and gatekeeper' - conflicting demands in nurses' experiences of telephone advisory services.
'Carer and gatekeeper' - conflicting demands in nurses' experiences of telephone advisory services Millions of calls are made to the telephone advisory services in primary health care in Sweden. The patients seem happy with the advice and counselling they receive, but little has been written about nurses' experiences of performing telephone advisory services. Yet, the nurses are expected to be patient, sensitive and have a broad knowledge of medicine, nursing and pedagogy. The aim of this study was to describe how nurses experience the patient encounter when performing telephone advisory services. A strategic sample of five nurses were interviewed and asked to describe how they experienced the central aspects of the patient encounter by telephone. The transcribed interviews were analysed by the Empirical Phenomenological Psychological method. The nurses' experience of the patient encounter when performing telephone advisory services can be characterized in terms of the conflicting demands of being both carer and gatekeeper. The constituents of these conflicting demands were: reading between the lines while pressed for time; educating patients for self-care while fearful of misinterpreting the situation; encountering patients' satisfaction and dissatisfaction. The conflicting demands of being both professional carer and gatekeeper caused stress among the nurses. The organization of the telephone advisory services seems to hinder high-quality care.


Transient Foix-Chavany-Marie syndrome after surgical resection of a right insulo-opercular low-grade glioma: case report.
We describe an atypical case of transient Foix-Chavany-Marie syndrome, or faciopharyngoglossomasticatory diplegia with automatic voluntary dissociation, occurring after surgical resection of a right insulo-opercular glioma. A 26-year-old right-handed man experienced partial seizures that were poorly controlled by antiepileptic drugs during a 2-year period as a result of a right insulo-opercular low-grade glioma, leading to the proposal of surgical resection. In addition, 1 year before the operation, the patient experienced a severe brain injury that resulted in a coma. A computed tomographic scan revealed left opercular contusion. The patient recovered completely within 6 months. Intraoperative corticosubcortical electrical functional mapping was performed along the resection, allowing the identification and preservation of the facial and upper limb motor structures. A subtotal removal of the glioma was achieved. The patient had postoperative anarthria, with loss of voluntary muscular functions of the face and tongue, and he had trouble chewing and swallowing. All of these symptoms resolved within 3 months. These findings provide insight into the use of surgery to treat a right insulo-opercular tumor. First, surgeons must be particularly cautious in cases with a potential contralateral lesion (e.g., history of head injury), even if such a lesion is not visible on magnetic resonance imaging scans; preoperative metabolic imaging and electrophysiological investigations should be considered before an operative decision is made. Second, surgeons must perform intraoperative functional mapping to identify and to attempt to preserve the corticosubcortical facial motor structures. A procedure performed while the patient is awake should be discussed to detect the structures involved in chewing and swallowing in cases of suspected bilateral lesions. Third, the patient must be informed of this particular risk before surgery is performed.


Investigating the role of interleukin-1 beta and glutamate in inflammatory bowel disease and epilepsy using discovery browsing.
Structured electronic health records are a rich resource for identifying novel correlations, such as co-morbidities and adverse drug reactions. For drug development and better understanding of biomedical phenomena, such correlations need to be supported by viable hypotheses about the mechanisms involved, which can then form the basis of experimental investigations. In this study, we demonstrate the use of discovery browsing, a literature-based discovery method, to generate plausible hypotheses elucidating correlations identified from structured clinical data. The method is supported by Semantic MEDLINE web application, which pinpoints interesting concepts and relevant MEDLINE citations, which are used to build a coherent hypothesis. Discovery browsing revealed a plausible explanation for the correlation between epilepsy and inflammatory bowel disease that was found in an earlier population study. The generated hypothesis involves interleukin-1 beta (IL-1 beta) and glutamate, and suggests that IL-1 beta influence on glutamate levels is involved in the etiology of both epilepsy and inflammatory bowel disease. The approach presented in this paper can supplement population-based correlation studies by enabling the scientist to identify literature that may justify the novel patterns identified in such studies and can underpin basic biomedical research that can lead to improved treatments and better healthcare outcomes.


Experience with urinary undiversion in patients with neurogenic bladder.
Experience in undiversion of the renal tract in thirteen patients with a neurogenic bladder is presented. All cases had what was intended to be a permanent diversion and many were grossly handicapped. Upper renal tract deterioration continued after surgery in only one patient. The commonest indication for surgery was the inability to achieve a satisfactory stoma. All were either dry or only damp postoperatively.


Auricular Reconstruction in Hemifacial Microsomia with an Expanded Two-Flap Method.
Reconstruction of external ear is important for the child/adult with craniofacial deformities to achieve balance and harmony of the face and head. The aim of this study was to investigate the clinical application of an expanded two-flap method for auricular reconstruction in hemifacial microsomia. Between January of 2014 and November of 2015, 111 hemifacial microsomia patients with microtia underwent auricular reconstruction with an expanded two-flap method. The clinical data of these patients were reviewed retrospectively. Thirty-two patients (28.8 percent) underwent auricular reconstruction in combination with simultaneous mandibular lengthening. Microtia was treated by an expanded two-flap method, which includes three stages. In the first stage, the retroauricular skin was expanded using a kidney-shaped tissue expander. In the second stage, the costal cartilage was harvested and the framework was fabricated. The anterior surface of the framework was enveloped by the expanded skin flap. The posterior surface and the helical rim of the framework is covered by a retroauricular fascial flap and a full-thickness skin graft. In the third stage, the tragus was reconstructed, the lobule was formed, and the concha was excavated. The surgical planning and skills of auricular reconstruction-especially for hemifacial microsomia-were described and analyzed. The median duration of follow-up was 8.3 months. There were nine cases (8.1 percent) of complications in our study. During follow-up, 103 patients (92.8 percent) had satisfactory outcomes, seven (6.3 percent) had partially satisfactory outcomes, and one patient (0.9 percent) had an unsatisfactory outcome. Auricular reconstruction using an expanded two-flap method in hemifacial microsomia is safe and effective, with satisfying middle-term results. Therapeutic, IV.


[Influence of corneal astigmatism in final visual acuity after implantation of AcrySof ReSTOR: case report].
Currently, new types of intraocular lenses have been developed aiming to eliminate presbyopia and the use has become more popular. The authors report the case of a patient with bilateral cataract and corneal irregularities and astigmatism higher than 2D in the corneal topography, in which AcrySof ReSTOR intraocular lens was implanted in the left eye associated to relaxing limbal incisions trying to reduce corneal astigmatism. The near and distance postoperative visual acuity were worse than expected, with no improvement with refraction. Apparently, no other reason apart from irregular astigmatism/multifocal lens justified the low vision. After 45 days, with no visual acuity improvement, the intraocular lens was explanted and a monofocal one was implanted. The final corrected visual acuity improved. Thus, the present case emphasizes the need of a correct preoperative selection of patients to implant this type of multifocal lens, with special attention to corneal topography data.


Calciphylaxis: emerging concept in vascular patients.
Calciphylaxis is a small vessel vasculopathy with medial calcification associated with intimal proliferation, fibrosis and thrombosis. This study discusses the clinical features and treatment of calciphylaxis and assesses the prognosis of patients with calciphylaxis. All patients admitted to vascular or renal wards from January 2003 to December 2004 at Royal Perth Hospital, with diagnosis of calciphylaxis confirmed histologically were included in the study. Five patients were included in the study; four male and one female. Three patients had end stage renal failure on haemodialysis and two had normal renal function. All three patients with end-stage renal failure had secondary hyperparathyroidism associated with elevated parathormone and corrected ionised calcium. The two patients with normal renal function had normal calcium, phosphate, and parathormone levels. The diagnosis of calciphylaxis was confirmed in all patients. The wounds of four patients healed and one patient died 8 months after the diagnosis of calciphylaxis had been made. Calciphylaxis is a condition mostly present in patients with end-stage renal failure and can occur in patients with normal renal function. It usually carries a poor prognosis, but in this small series the outcome of patients was good with satisfactory healing of wounds.


Fisheries governance in the face of climate change: Assessment of policy reform implications for Mexican fisheries.
Climate change is driving shifts in the abundance and distribution of marine fish and invertebrates and is having direct and indirect impacts on seafood catches and fishing communities, exacerbating the already negative effects of unsustainably high fishing pressure that exist for some stocks. Although the majority of fisheries in the world are managed at the national or local scale, most existing approaches to assessing climate impacts on fisheries have been developed on a global scale. It is often difficult to translate from the global to regional and local settings because of limited relevant data. To address the need for fisheries management entities to identify those fisheries with the greatest potential for climate change impacts, we present an approach for estimating expected climate change-driven impacts on the productivity and spatial range of fisheries at the regional scale in a data-poor context. We use a set of representative Mexican fisheries as test cases. To assess the implications of climate impacts, we compare biomass, harvest, and profit outcomes from a bioeconomic model under contrasting management policies and with and without climate change. Overall results show that climate change is estimated to negatively affect nearly every fishery in our study. However, the results indicate that overfishing is a greater threat than climate change for these fisheries, hence fixing current management challenges has a greater upside than the projected future costs of moderate levels of climate change. Additionally, this study provides meaningful first approximations of potential effects of both climate change and management reform in Mexican fisheries. Using the climate impact estimations and model outputs, we identify high priority stocks, fleets, and regions for policy reform in Mexico in the face of climate change. This approach can be applied in other data-poor circumstances to focus future research and policy reform efforts on stocks now subject to additional stress due to climate change. Considering their growing relevance as a critical source of protein and micronutrients to nourish our growing population, it is urgent for regions to develop sound fishery management policies in the short-term as they are the most important intervention to mitigate the adverse effects of climate change on marine fisheries.


Congenital auricular anomalies: topographic anatomy, embryology, classification, and treatment strategies.
Congenital auricular anomalies are heterogeneous, with various descriptive and eponymous terms being used. Current classification systems are useful in guiding surgical treatment of severe anomalies. However, they do not generally account for the less severe anomalies, which form the majority of congenital auricular anomalies, nor their contemporary treatment. In this article, the authors review the anatomy and embryology of the external ear and propose a simple classification of congenital auricular anomalies that encompasses all forms of congenital auricular anomalies, facilitates proper diagnosis, and guides treatment. Congenital auricular anomalies should be classified as malformational or deformational anomalies. Malformational auricular anomalies are caused by embryologic maldevelopment that occurs between the fifth and ninth week of gestation resulting in deficient and/or supernumerary auricular components. Deformational auricular anomalies result from in utero or ex utero deformational forces, including those caused by an aberrant insertion of the intrinsic or extrinsic auricular muscles. Malformational auricular anomalies generally require surgical correction during childhood or adolescence. For practical purposes, deformational auricular anomalies have a full complement of chondrocutaneous components that can be digitally manipulated to a normal shape. These anomalies are best treated by auricular molding, which is effective if it is initiated within the first 3 months of life. Deformational auricular anomalies are best regarded as a pediatric public health issue and are best managed nonsurgically. Education of neonatal pediatricians, obstetricians, family doctors, and midwives will allow proper early diagnosis of all congenital auricular anomalies, which is vital to appropriate treatment. These practitioners should be encouraged to manage deformational auricular anomalies early in life so that surgery can be largely avoided in these patients.


Macromolecule synthesis in temperature-sensitive mutants of methanol-utilizing Hansenula polymorpha.
Temperature sensitive (ts) mutants of methanol-utilizing Hansenula polymorpha NTU-AM-P5 were isolated by UV irradiation, EMS and/or NTG treatment. They grow normally at permissive temperature (PT) 38 degrees C, but can not grow at restrictive temperature (RT) 46 degrees C. From chemical composition analysis, it was found that ts mutants NTU-AM-L2 and NTU-AM-L3 had higher RNA content than the others; while ts mutant NTU-AM-E19 had the highest protein content among the isolated strains. Leucinyl-tRNA synthetases activity was the highest among the twenty aminoacyl-tRNA synthetases in both wild type and their ts mutants. When the cells were shifted from PT to RT for 12 h, total aminoacyl-tRNA synthetase activity decreased in all tested strains. Leucinyl-tRNA synthetase of ts mutant NTU-AM-E10 decreased 91.23%. At RT, it was found that ts mutants NTU-AM-E10 and NTU-AM-E20 were defective in DNA synthesis; ts mutants NTU-AM-E15, NTU-AM-E20, NTU-AM-N37 and NTU-AM-m5 were defective in RNA synthesis; ts mutants NTU-AM-E10, NTU-AM-E20 and NTU-AM-m5 were somewhat defective in protein synthesis; while ts mutants NTU-AM-L2 and NTU-AM-L3 did not belong to any one of the above classifications.


Comparison of broiler performance when fed diets containing corn grain with insect-protected (corn rootworm and European corn borer) and herbicide-tolerant (glyphosate) traits, control corn, or commercial reference corn.
A 42-d feeding experiment with growing Ross x Ross 508 broilers showed that the nutritional value of insect-protected and herbicide-tolerant corn was comparable to that of the genetically similar control and 5 commercial reference corn hybrids. MON 88017 provides protection from feeding damage by coleopteran pest corn rootworm and is tolerant to the action of glyphosate, the active ingredient in the Roundup family of agricultural herbicides. MON 88017 x MON 810 was developed by the traditional breeding of MON 88017 with MON 810, which provides protection from the European corn borer and other lepidopteran pests. A randomized complete block design was used with 8 dietary treatments in each of 5 replicated blocks of pens. No differences among diets were observed (P > 0.05) in performance (final live weights, feed intake, feed conversion, and adjusted feed conversion), carcass yield (chill, fat pad, breast, thigh, wing, and drum weight), or percentage of moisture, protein, and fat in breast meat and moisture and fat in thigh meat. Thigh protein was similar (P > 0.05) in broilers fed diets containing MON 88017 x MON 810 and conventional control or all commercial reference corns; however, differences (P < 0.05) were noted for the percentage of thigh protein among broilers fed the control and 2 of the 5 reference diets, attributable to biological variability among the conventional corn hybrids. Broilers overall performed consistently and had similar carcass yield and meat composition when fed diets containing MON 88017 or MON 88017 x MON 810 as compared with those fed the conventional control and commercial diets, supporting a conclusion of nutritional equivalence.


Remote Determination of Critical Speed and Critical Power in Recreational Runners.
This study aimed to compare estimations of critical speed (CS) and work completed above CS (D'), and their analogies for running power (critical power [CP] and W'), derived from raw data obtained from habitual training (HAB) and intentional maximal efforts in the form of time trials (TTs) and 3-minute all-out tests (3MTs) in recreational runners. The test-retest reliability of the 3MT was further analyzed. Twenty-three recreational runners (4 female) used a foot pod to record speed, altitude, and power output for 8 consecutive weeks. CS and D', and CP and W', were calculated from the best 3-, 7-, and 12-minute segments recorded in the first 6 weeks of their HAB and in random order in weeks 7 and 8 from 3 TTs (3, 7, and 12 min) and three 3MTs (to assess test-retest reliability). There was no difference between estimations of CS or CP derived from HAB, TT, and 3MT (3.44 [0.63], 3.42 [0.53], and 3.76 [0.57] m · s-1 and 281 [41], 290 [45], and 305 [54] W, respectively), and strong agreement between HAB and TT for CS (r = .669) and CP (r = .916). Limited agreement existed between estimates of D'/W'. Moderate reliability of D'/W' was demonstrated between the first and second 3MTs, whereas excellent reliability was demonstrated for CS/CP. These data suggest that estimations of CS/CP can be derived remotely, from either HAB, TT, or 3MT, although the lower agreement between D'/W' warrants caution when using these measures interchangeably.


Predictors of Preventive Health Practices, Chronic Disease Burden and Health Status Among Underserved Bangladeshi Americans in Michigan.
The Bangladeshi American community in Michigan is growing rapidly. Little is known about the correlates of health status and preventive health services among Bangladeshi Americans. The purpose of this study was to examine the relationships between demographic factors, preventive health practices, chronic conditions and health status of this population. Data were collected through self-administered surveys during community events in Hamtramck, Michigan and analyzed using descriptive statistics and multiple linear regression. The surveys were completed by 166 Bangladeshi Americans. A majority reported not having an up-to-date physical/dental exams, colorectal, cervical, or breast cancer screening. The length of U.S. residency was associated with cancer screening utilization while employment status was correlated with self-reported health status. Our results demonstrate a need for development and implementation of language-appropriate and cultural interventions to address the unique healthcare needs of this growing population.


Endocannabinoid modulation of fear responses: learning and state-dependent performance effects.
Recently, disruption of the endogenous cannabinoid (endocannabinoid, eCB) system was found to impair extinction in delay and contextual fear conditioning models. However, conditioning procedures used in that work precluded investigation of possible eCB effects on acquisition of learned fear. We therefore examined the role of eCBs in modulating fear responses using multiple-trial versions of trace (hippocampal-dependent) and delay (amygdala-dependent) Pavlovian fear conditioning. By administering the CB1 receptor antagonist AM251 (5 mg/kg, i.p) to C57/Bl/6 mice at various times, we systematically identified the stages of learning and memory (i.e. acquisition, consolidation, recall and extinction) that are modulated by eCB signaling. During tone (CS) - footshock (US) conditioning, AM251 enhanced acquisition of freezing behavior for both trace- and delay-conditioning protocols. CB1 antagonism also enhanced generalized fear (baseline freezing) and cued (CS) freezing during memory recall tests in a state-dependent manner for both trace and delay conditioned animals. Furthermore, in trace-conditioned animals, AM251 impaired extinction performance of both cued and generalized fear. CB1 antagonism did not affect short-term memory (STM) or long-term memory (LTM) consolidation processes. Together, these results suggest that during acquisition and recall of aversive learning, eCBs prevent the expression and retention of inappropriate generalized and learned responses. These findings have important implications for the therapeutic use of CB1 antagonists.


Optical coherence tomography (OCT) angiography of central retinal artery occlusion in the patent cilioretinal artery: a case report.
Here we report the case of a 78-year-old male patient with a 2-day history of low visual acuity and fundus and who was diagnosed with central retinal artery occlusion. In addition, the patient had an allergy to fluorescein. A fundus examination of the left eye found a pink optic disc with blurred margins, diffuse pallor in the retina with arterial attenuation, and a normal band of the retinal area in the macular region. Optical coherence tomography revealed increased thickness of the inner retina. Optical coherence tomography angiography (OCT-A) revealed a decreased flow signal in the superficial layers, with reduced flow signal in the choriocapillaris. OCT-A is a valuable alternative during the follow-up period in patients with central retinal artery occlusion, particularly in those with an allergy to contrast agents. The use of this as a non-invasive examination can improve the prognosis of patients and future studies investigating the treatment of central retinal artery occlusion.


Immune rejection of tumor cells: in vivo significance of anti-tumor in vitro immune reactions.
The mechanism of immune tumor rejection remains poorly understood. The respective roles of antibodies, macrophages, cytolytic T cells (CTL) and that of "K" cells or any other cell which could be involved in antibody dependant cell mediated cytotoxicity are still unknown. It is probable that the CTL play some role in tumor rejection but the "in vivo" relevance of the other, "in vitro" detected phenomena, is less clear. The correlations between "in vivo" tumor rejection and "in vitro" detected reactions are very difficult to establish, specially for the following two reasons: a) the different methods used in vitro do not explore identical phenomena ; b) some of them provide both specific and non-specific reactions.


Comparison of Chalquest and Hayflick media, with and without ammonium reineckate, for isolating Mycoplasma pulmonis from rats.
Chalquest and Hayflick media with and without ammonium reineckate were compared for isolation of Mycoplasma pulmonis from the nasopharyngeal ducts, tracheobronchial trees, and middle ears of 66 naturally infected rats. The results show that 92% (366 of 396) of the samples were positive for M. pulmonis in Chalquest medium with and without ammonium reineckate and 66% (260 of 396) were positive in Hayflick medium with and without ammonium reineckate (P less than 0.001). An enhancing effect of ammonium reineckate on M. pulmonis isolation was observed only in Hayflick medium; the isolation rate was 76% (151 of 198) in Hayflick medium with ammonium reineckate as compared with 55% (109 of 198) in Hayflick medium without ammonium reineckate (P less than 0.03). No significant differences in isolation rates were observed between Chalquest medium with and without ammonium reineckate. The mean growth time of M. pulmonis on Chalquest medium was 3.4 days as compared with 5.1 days in Hayflick medium, indicating that M. pulmonis can be detected earlier on Chalquest medium than on Hayflick medium. These data indicate that Chalquest medium is superior to Hayflick medium for M. pulmonis isolation from rats.


Cultured bovine endothelial cells produce both urokinase and tissue-type plasminogen activators.
Cell extracts and conditioned media (CM) from cultured bovine aortic endothelial cells (BAEs) were fractionated by PAGE in the presence SDS, and plasminogen activator (PA) activity was localized by fibrin autography. Multiple molecular weight forms of PA were detected in both preparations. Cell-associated PAs had Mr of 48,000, 74,000, and 100,000 while secreted PAs showed Mr of 52,000, 74,000, and 100,000. A broad zone of activity (Mr 80,000-100,000) also was present in both cellular fractions. In addition, PAs of Mr 41,000 and 30,000 appeared upon prolonged incubation or repeated freezing and thawing of the samples, and probably represent degradation products of higher molecular weight forms. This complex lysis pattern was not observed when CM was subjected to isoelectric focusing. Instead, only two classes of activator were resolved, one at pH 8.5, the other at 7.6. Analysis of focused samples by SDS PAGE revealed that the activity at pH 8.5 resulted exclusively from the Mr 52,000 form; all other forms were recovered at pH 7.6. The activity of the Mr 52,000 form was neutralized by anti-urokinase IgG but was not affected by antitissue activator IgG indicating that it is a urokinaselike PA. The activities of the Mr 74,000-100,000 forms were not affected by anti-urokinase. They were blocked by antitissue activator suggesting that all the forms in this group were tissue-type PAs. The multiple forms of PA were differentially sensitive to inactivation by diisopropylfluorophosphate (DFP). Treatment of CM with 10 mM DFP for 2 h at 37 degrees C only partially inhibited the 52,000-dalton form. However, it completely inactivated the 74,000-dalton partially inhibited the 52,000-dalton form. However, it completely inactivated the 74,000-dalton PA. The activity of the Mr 100,000 form was not affected by this treatment, or by treatment with 40 mM DFP. Thus, cultured BAEs produce multiple, immunologically distinct forms of PA which differ in size, charge, and sensitivity to DFP. These forms include both urokinaselike and tissue-activator-like PAs. The possibility that one of these forms is a zymogen is discussed.


Gaming Against Violence: A Grassroots Approach to Teen Dating Violence.
Teen dating violence is a pervasive problem that affects millions of adolescents worldwide. Although there have been various approaches to addressing this problem, using videogames had not been employed before 2008, when Jennifer Ann's Group, an Atlanta, GA-based nonprofit organization, created an annual competition. The Life.Love. Game Design Challenge rewards game developers for creating videogames about teen dating violence without using any violence in the games themselves. The resulting videogames have increased awareness about teen dating violence and provided educational information to assist adolescents, parents, and teachers in identifying abusive relationships.


[HB's-antigen and anti-HBs in hospital staff (author's transl)].
In 826 employees from six hospitals and three theoretical clinical institutes of Düsseldorf University HBs-antigen and anti-HBs were determined. HBs-antigen was not significantly more frequent than in a control group. On the other hand anti-HBs was much more common in hospital staff. In probands with histories of liver disease and blood transfusions there was a significantly higher incidence of anti-HBs. Different occupations within the hospitals showed different anti-HBs frequencies.


Homeopathic treatment of patients with psoriasis--a prospective observational study with 2 years follow-up.
Design Prospective multicentre observational study. Objective To evaluate details and effects of homeopathic treatment in patients with psoriasis in usual medical care. Methods Primary care patients were evaluated over 2 years using standardized questionnaires, recording diagnoses and complaints severity, health-related quality of life (QoL), medical history, consultations, all treatments, and use of other health services. Results Forty-five physicians treated 82 adults, 51.2% women, aged 41.6 +/- 12.2 (mean +/- SD) years. Patients had psoriasis for 14.7 +/- 11.9 years; 96.3% had been treated before. Initial case taking took 127 +/- 47 min. The 7.4 +/- 7.4 subsequent consultations (duration: 19.4 +/- 10.5 min) cumulated to 169.0 +/- 138.8 min. Patients received 6.0 +/- 4.9 homeopathic prescriptions. Diagnoses and complaints severity improved markedly with large effect sizes (Cohen's d= 1.02-2.09). In addition, QoL improved (SF-36 physical component score d = 0.26, mental component score d = 0.49), while conventional treatment and health service use were considerably reduced. Conclusions Under classical homeopathic treatment, patients with psoriasis improved in symptoms and QoL.


Efficacy of halcinonide cream, 0.1 percent, in the treatment of moderate and severe dermatoses.
The efficacy of halcinonide cream, 0.1 percent, was evaluated in 101 patients with moderate or severe dermatoses. Conditions of these patients included contact dermatitis, atopic dermatitis, nummular eczema, neurodermatitis, stasis dermatitis, dyshidrosis, and various combinations of these disorders. Halcinonide cream was prescribed twice or three times a day for three weeks, and patients were followed-up weekly during this period. Sixteen patients stopped treatment after two weeks because their lesions had cleared. By the end of three weeks, the condition in 46 of the patients had completely resolved, the condition in 39 showed marked improvement, the condition in 10 had improved moderately, the condition in 5 showed mild improvement, and the condition in 1 did not show any improvement. No local or systemic side effects were reported. We conclude that halcinonide cream is an effective and safe topical therapy in the short-term treatment of a variety of moderate to severe steroid-responsive dermatoses.


Clinical evaluation of Toxi.Prep: a semiautomated solid-phase extraction system for screening of drugs in urine.
A prototype Toxi.Prep (TP) system that utilizes solid-phase extraction (SPE) has been developed as a method for broad-spectrum drug screening and identification of tetrahydrocannabinol (THC) metabolites in urine. TP can simultaneously extract up to seven specimens while automating the process of sample extraction, washing, and elution onto a chromatogram. TP was compared with the Toxi. Lab A (TL-A) system for extraction of basic drugs only. In a blind study, 33 distinct drugs and metabolites were detected in 55 urines over 13 runs. Of the drug occurrences, 68.8% (141 of 205) were detected on both TP and TL-A. Of the 13 runs, quinidine and quinine, nortriptyline metabolites, and diphenhydramine were noted more frequently on TP than TL-A, whereas nicotine and metabolites, morphine, and methadone metabolites were more frequently noted on TL-A. Twenty specimens were analyzed for THC metabolites. Of the cases positive for THC metabolites, 100% (16 of 16) were positive by both methods. Time and motion studies for all runs proved an overall labor reduction for extraction and spotting by approximately 40%.


Girls Just Wanna Have Fun: a process evaluation of a female youth-driven physical activity-based life skills program.
Integrating a positive youth development framework into physical activity programming has become popular as it is believed that this integration can create the development of both physical and psychosocial skills. However, there has been a lack of intervention fidelity research within the field of positive youth development. The Girls Just Wanna Have Fun program was designed in response to increased calls for physical activity programs for female youth and is a theoretically-grounded physical activity-based life skills program that aims to empower female youth. The purpose of this paper was to provide a detailed description of the program and a process evaluation of the first year of program implementation. From interviews with youth and leaders, as well as documentation from the leaders' weekly online log of each implemented session, themes emerged regarding the successes. Findings from this study indicated that program goals were attained and it appears that the program was implemented, for the most part, as designed. The themes related to successes included using activities to facilitate relational time, providing intentional opportunities for leadership, having communicative program leaders who supported one another, and engaging youth in different types of physical activity. The themes related to challenges included difficulties with facility and transportation, some activities being too much like schoolwork, and social distractions and cliques. Included in the paper is a discussion of practical implications and recommendations for community programmers, as well as future directions for the program. Overall, this process evaluation represents an important step in responding to calls for increased evaluation in community-based programs and aids in understanding the process in which positive youth development programs can be effectively implemented.


The nuclear import machinery is a determinant of influenza virus host adaptation.
After viral entry into the cell, the nuclear envelope poses a major cellular barrier that needs to be overcome upon adaptation of highly pathogenic avian influenza viruses (HPAIV) to the new host. To ensure efficient viral transcription and replication in the nucleus of the host cell, the viral polymerase complex of avian influenza viruses needs to switch from recognition of avian to mammalian components of the nuclear import machinery. Recent evidence suggests that influenza viruses have evolved different mechanisms to utilize importin-α isoforms as components of this machinery, bridging pre- and post-nuclear import on both sides of the nuclear envelope.


Sex differences in the circulatory responses to an isocapnic cold pressor test.
What is the central question of this study? Do sex differences exist in the cardiorespiratory responses to an isocapnic cold pressor test (CPT)? What is the main finding and its importance? During the CPT, there were no sex differences in the respiratory response; however, females demonstrated a reduced mean arterial pressure and reduced dilatation of the common carotid artery. Given that the CPT is predictive of future cardiovascular events, these data have clinical implications for improving the utility of the CPT to determine cardiovascular health risk. Sex differences should be taken into consideration when conducting and interpreting a CPT. The cold pressor test (CPT) elicits a transient increase in sympathetic nervous activity, minute ventilation ( V ̇ E ), mean arterial pressure (MAP) and common carotid artery (CCA) diameter in healthy individuals. Although the extent of dilatation of the CCA in response to the CPT has been used as a clinical indicator of cardiovascular health status, the potential sex differences have yet to be explored. In response to a CPT, we hypothesized that elevations in V ̇ E and MAP and dilatation of the CCA would be attenuated in females compared with males. In 20 young, healthy participants (10 females), we measured the respiratory, cardiovascular and CCA responses during a CPT, which consisted of a 3 min immersion of the right foot into 0-1 ice water. Blood pressure (via finger photoplethysmography), heart rate (via electrocardiogram) and CCA diameter and velocity (via Duplex ultrasound) were simultaneously recorded immediately before and during the CPT. During the CPT, while controlling end-tidal gases to baseline values, the main findings were as follows: (i) no sex differences were present in absolute or relative changes in V ̇ E (P = 0.801 and P = 0.179, respectively); (ii) the relative MAP and CCA diameter response were reduced in females by 51 and 55%, respectively (P = 0.008 and P = 0.029 versus males, respectively); and (iii) the relative MAP responses was positively correlated with the dilatation of the CCA in males (r = 0.42, P = 0.019), in females (r = 0.43, P = 0.019) and in males and females combined (r = 0.55, P < 0.001). Given that the CPT is used as a clinical tool to assess cardiovascular health status, sex differences should be considered in future studies.


Pharmacologic considerations for antiviral drug development.
To discuss pharmacologic considerations for the development of antiviral agents. English-language literature pertaining to the development and clinical evaluation of antiviral compounds, primarily agents targeted against herpes group viruses and HIV. Pertinent information, as judged by the author, was selected for discussion. Drug development of antiviral agents presents unique problems compared with that of antimicrobial and other agents. Understanding the mechanism of action and both pharmacokinetic and pharmacodynamic considerations is critical to developing a rational dosing strategy and safe, effective use. The lack of standardized methods for antiviral susceptibility testing and the influence of factors such as strain of virus, host cell type, culture medium, inoculum size, end point, and method of measurement on the results obtained illustrate factors that complicate preclinical pharmacologic analysis of antiviral agents. Acyclovir offers a model for clinical drug development. Its mechanism of action, pharmacokinetics, and pharmacodynamics have been studied extensively. Rational guidelines for usage are available, including guidelines in special patient populations such as kidney transplant recipients and neonates. A pregnancy registry has allowed evaluation of the incidence of birth defects in fetuses exposed to systemic acyclovir. Several pitfalls in antiviral drug development are associated with inadequate pharmacologic information. The development of dextran sulfate and fialuridine provides two examples. Integration of pharmacokinetic and pharmacodynamic analyses using modern sampling and analysis techniques may facilitate more rapid development of antiviral agents and more informed dosage regimens to achieve the highest probability of therapeutic success.


Genetic Inactivation of Chlamydia trachomatis Inclusion Membrane Protein CT228 Alters MYPT1 Recruitment, Extrusion Production, and Longevity of Infection.
Chlamydia trachomatis is an obligate intracellular pathogen with global health and economic impact. Upon infection, C. trachomatis resides within a protective niche, the inclusion, wherein it replicates and usurps host cell machinery and resources. The inclusion membrane is the key host-pathogen interface that governs specific protein-protein interactions to manipulate host signaling pathways. At the conclusion of the infection cycle, C. trachomatis exits the host cell via lysis or extrusion. Extrusion depends on the phosphorylation state of myosin light chain 2 (MLC2); the extent of phosphorylation is determined by the ongoing opposing activities of myosin phosphatase (MYPT1) and myosin kinase (MLCK). Previously, it was shown that MYPT1 is recruited to the inclusion and interacts with CT228 for regulation of host cell egress. In this study, we generated a targeted chromosomal mutation of CT228 (L2-ΔCT228) using the TargeTron system and demonstrate a loss of MYPT1 recruitment and increase in extrusion production in vitro. Mutation of CT228 did not affect chlamydial growth in cell culture or recruitment of MLC2. Moreover, we document a delay in clearance of L2-ΔCT228 during murine intravaginal infection as well as a reduction in systemic humoral response, relative to L2-wild type. Taken together, the data suggest that loss of MYPT1 recruitment (as a result of CT228 disruption) regulates the degree of host cell exit via extrusion and affects the longevity of infection in vivo.


Mycobacterium avium Complex Extracellular Vesicles Attenuate Inflammation via Inducing IL-10.
Mycobacterium avium complex (MAC) is an ubiquitous acid-fast bacterium. MAC cell wall and membrane release extracellular vesicles (EVs) into different media. The immunogenic effects of EVs isolated from MAC remain unknown. The aim of this study was to determine the EVs effect on macrophage cytokine production. MAC EVs were extracted and purified using differential centrifuges also known as Claassen's method, with some modifications. After protein analysis of EVs, and scanning electron microscopy (SEM), the EVs were injected into BALB/c mice for in vivo experiments. The concentration of interferon gamma (IFN-γ) and interleukin 10 (IL-10) in the spleen immune cell culture was measured by sandwich ELISA. We for the first time showed that MAC can naturally produce EVs. The extraction method was technically-feasible, efficient and affordable. The SEM analysis showed that EVs diameter was similar to other studies on mycobacteria, and EVs maintained their spatial characterization. The results of the cytokine assays indicated that EV-treated cells secreted IL-10 (P = 0.034) but not IFN-γ (P = 0.037). Our findings suggest that EVs of M. avium could have anti-inflammatory effects. They can be used as a suppressor or regulator of inflammation via IL-10. The replication of the anti-inflammatory response of MAC EVs in future studies may indicate a new therapeutic agent for inflammation.


Heat shock proteins in protein folding and membrane translocation.
Constitutively expressed heat-shock proteins of the hsp60 and hsp70 families, classified as 'molecular chaperones', have important functions in the folding and intracellular sorting of newly-synthesized proteins. Recent studies of protein translocation across subcellular membranes have shown: (1) Proteins traverse membranes in extended conformations. (2) Cytosolic hsp70 proteins maintain newly-synthesized precursors destined for translocation in a loosely-folded, translocation-competent state. (3) Hsp 70 proteins on the trans-side of the membrane are required for efficient translocation. (4) In the case of mitochondria, the newly-imported polypeptides are transferred to the 'foldase' hsp60, the homologue of the E. coli groEL, which mediates their folding and oligomeric assembly. Hsp70 and hsp60 fulfill these various functions by their abilities, (1) to recognize an unknown structural element(s) which is transiently exposed in unfolded or incompletely folded polypeptides, and (2) to allow cycles of binding and (step-wise) release of the substrate protein catalyzed by ATP-hydrolysis.


Identification of CGI-121, a novel PRPK (p53-related protein kinase)-binding protein.
PRPK (p53-related protein kinase) has been reported as a novel protein kinase which binds to the tumor suppressor protein p53 and induces phosphorylation of p53 at Ser 15. To identify novel binding partners of PRPK, we performed a yeast two-hybrid screening and isolated an expressed sequence tag CGI-121 by which a 20-kDa protein was encoded. We demonstrated the protein-protein interaction of CGI-121 with PRPK in vivo and in vitro. The protein expression of CGI-121 was observed in many cell lines and was immunocytochemically identified in both the nucleus and cytosol. Although PRPK interacted with both CGI-121 and p53, several attempts to demonstrate an association between CGI-121 and p53 were unsuccessful. In addition, coprecipitation of p53 using recombinant PRPK was inhibited by adding recombinant CGI-121 in vitro, suggesting that CGI-121 could act as a potent inhibitor of the binding of PRPK to p53.


Clinical and microbial evaluation of dental scaling associated with subgingival minocycline in chronic periodontitis subjects.
The aims of this double-blind randomized clinical trial were to evaluate the presence of periodontal pathogens and the clinical response of periodontal pockets treatment to scaling and root planing (SRP) associated with subgingival minocycline (SM). A total of 36 subjects, 26 to 60 years old (40.7 +/- 9.1), who had been previously diagnosed with chronic periodontitis, were included in the present study. Eighteen subjects were selected for the test group (TG), who were treated with SRP plus SM (new treatment), and 18 subjects for the control group (CG) who received SRP plus vehicle (current treatment). Two homologous sites in each subject with a probing depth (PD) > or = 6 mm were chosen. To evaluate the clinical response after treatment, PD was measured at baseline and at 90 days. Microbiological evaluation was performed to detect 7 periodontal pathogens using polymerase chain reaction at baseline, 30, and 120 days. A mean reduction in PD of 2.8 and 2.1 mm was observed in the TG and CG, respectively. At baseline, P. gingivalis was the most prevalent organism in both test (65.8%) and control (48.6%) groups. After 120 days it fell to 30.8% in TG and to 23.1% in CG. There were no statistically significant differences between the test and control groups concerning PD (p > 0.05 by Wilcoxon test) or presence of periodontal pathogens (p > 0.05 by Wilcoxon and chi-square; p > 0.01 by Signal test). The results observed showed that the new treatment was as effective as the current treatment in reducing periodontal pathogens and PD among chronic periodontitis subjects.


Sub-clinical middle ear malfunctions in elderly patients; prevalence, pattern and predictors.
Little is known about functioning of the middle ear with advancing age. To estimate the prevalence and describe tympanometric patterns of sub-clinical middle ear malfunctions,( S-MEM) in elderly patients. It also assessed clinical factors that could predict S-MEM. Cross-sectional, analytical study of patients aged ≥ 60 years in a tertiary hospital in Nigeria between 2011-2014. Pure tone audiometry (PTA), tympanometry and acoustic reflexes were recorded. S-MEM was based on audiometric and tympanometric evident abnormalities. Descriptive, univariate and multivariate analyses performed to detect independent clinical predictors of S-MEM at p-value of <0.05. 121 patients , M: F of 1.1:1. Mean age was 70.1 ± 6.2 years, 77.7% were married. Prevalence of S-MEM was 21.5%. Abnormal tympanometric tracings were type AS>C>B>AD. The parameters that were statistically-significant on univariate analyses were subjected to logistic regression analysis which confirmed previous head injury, diabetes, osteoarthritis of knee joint, and absent acoustic reflex as clinical predictors for S-MEM. 21.5% of elderly Africans had subclinical abnormalities in their middle ear functioning, mostly with type AS tympanogram. Independent clinical predictors of S-MEM included previous head injury, diabetes, history of osteoarthritis of knee joints, and absent acoustic reflex.


Ostreid herpesvirus OsHV-1 μVar in Pacific oysters Crassostrea gigas (Thunberg 1793) of the Wadden Sea, a UNESCO world heritage site.
The Wadden Sea is an extensive wetland area, recognized as UNESCO world heritage site of international importance. Since the mid-1990s, the invasive Pacific oyster Crassostrea gigas (Thunberg 1793) population in the area has grown exponentially, having a distinct impact on the ecosystem. The recent spread of the emerging oyster pathogen Ostreid herpesvirus OsHV-1 μVar worldwide and specifically in the oyster culture areas in the south of the Netherlands raised the question whether the virus may also be present in the Wadden Sea. In the summer of 2012 juvenile Pacific oysters were collected from five locations in the Dutch Wadden Sea. The virus was shown to be present in three of the five locations by real-time PCR and sequencing. It was concluded that OsHV-1 μVar has settled itself in Pacific oyster reefs in the Wadden Sea. These results and the recent discoveries of OsHV-1 microvariants in Australia and Korea indicate that OsHV-1 μVar and related variants might be more widespread than can be deduced from current literature. In particular in regions with no commercial oyster culture, similar to the Wadden Sea, the virus may go undetected as wild beds with mixed age classes hamper the detection of mortality among juvenile oysters.


The book of opposites: the role of the nuclear receptor co-regulators in the suppression of epidermal genes by retinoic acid and thyroid hormone receptors.
Transcriptional regulation by nuclear receptors occurs through complex interactions that involve DNA response elements, co-activators/co-repressors, and histone modifying enzymes. Very little is known about how molecular interplay of these components may determine tissue specificity of hormone action. We have shown previously that retinoic acid (RA) and thyroid hormone (T3) repress transcription of a specific group of epidermal keratin genes through a novel mechanism that utilizes receptors homodimers. In this paper, we have analyzed the epidermal specificity of RA/T3 action by testing the role of co-repressors and co-activators in regulation of epidermal genes. Using transient co-transfections, northern blots, antisense oligonucleotides, and a histone deacetylase (HDAC) inhibitor, trichostatin A, we found that in the context of specific keratin RE (KRE), co-activators and histone acetylase become co-repressors of the RA/T3 receptors in the presence of their respective ligands. Conversely, co-repressors and HDAC become co-activators of unliganded T3Ralpha. The receptor-co-activator interaction is intact and occurs through the NR-box. Therefore, the role of co-activator is to associate with liganded receptors whereas the KRE-receptor interaction determines specific transcriptional signal, in this case repression. This novel molecular mechanism of transcriptional repression conveys how RA and T3 target specific groups of epidermal genes, thus exerting intrinsic tissue specificity.


Quantifying pesticide emissions for drift deposition in comparative risk and impact assessment.
Estimating emissions of chemical pesticides used in agriculture is an essential component in evaluating the potential toxicity-related impacts on humans and ecosystems in various comparative risk and impact assessment frameworks, such as life cycle assessment, environmental footprinting, chemical substitution, and risk prioritization. Emissions related to drift deposition-usually derived from drift experiments-can reach non-target areas, and vary as a function of crop characteristics and application technique. We derive cumulative drift deposition fractions for a wide range of experimental drift functions for use in comparative and mass-balanced approaches. We clarify that cumulative drift deposition fractions require to integrate the underlying drift functions over the relevant deposition area and to correct for the ratio of deposition area to treated field area to arrive at overall mass deposited per unit mass of applied pesticide. Our results show that for most crops, drift deposition fractions from pesticide application are below 0.03 (i.e. 3% of applied mass), except for grapes and fruit trees, where drift fractions can reach 5% when using canon or air blast sprayers. Notably, aerial applications on soybeans can result in significantly higher drift deposition fractions, ranging from 20% to 60%. Additionally, varying the nozzle position can lead to a factor of five differences in pesticide deposition, and establishing buffer zones can effectively reduce drift deposition. To address remaining limitations in deriving cumulative drift deposition fractions, we discuss possible alternative modelling approaches. Our proposed approach can be implemented in different quantitative and comparative assessment frameworks that require emission estimates of agricultural pesticides, in support of reducing chemical pollution and related impacts on human health and the environment.


Hypoxia Inducible Factor-1α Potentiates Jagged 1-Mediated Angiogenesis by Mesenchymal Stem Cell-Derived Exosomes.
Insufficient vessel growth associated with ischemia remains an unresolved issue in vascular medicine. Mesenchymal stem cells (MSCs) have been shown to promote angiogenesis via a mechanism that is potentiated by hypoxia. Overexpression of hypoxia inducible factor (HIF)-1α in MSCs improves their therapeutic potential by inducing angiogenesis in transplanted tissues. Here, we studied the contribution of exosomes released by HIF-1α-overexpressing donor MSCs (HIF-MSC) to angiogenesis by endothelial cells. Exosome secretion was enhanced in HIF-MSC. Omics analysis of miRNAs and proteins incorporated into exosomes pointed to the Notch pathway as a candidate mediator of exosome communication. Interestingly, we found that Jagged1 was the sole Notch ligand packaged into MSC exosomes and was more abundant in HIF-MSC than in MSC controls. The addition of Jagged1-containing exosomes from MSC and HIF-MSC cultures to endothelial cells triggered transcriptional changes in Notch target genes and induced angiogenesis in an in vitro model of capillary-like tube formation, and both processes were stimulated by HIF-1α. Finally, subcutaneous injection of Jagged 1-containing exosomes from MSC and HIF-MSC cultures in the Matrigel plug assay induced angiogenesis in vivo, which was more robust when they were derived from HIF-MSC cultures. All Jagged1-mediated effects could be blocked by prior incubation of exosomes with an anti-Jagged 1 antibody. All together, the results indicate that exosomes derived from MSCs stably overexpressing HIF-1α have an increased angiogenic capacity in part via an increase in the packaging of Jagged1, which could have potential applications for the treatment of ischemia-related disease. Stem Cells 2017;35:1747-1759.


Low-molecular-weight heparin in the treatment of pulmonary embolism.
Unfractionated heparin is the traditional treatment of choice for patients presenting with submassive pulmonary embolism. However, newer low-molecular-weight heparins have been developed and tested in several clinical trials in the last 2 decades because of the many limitations of unfractionated heparin. The pharmacologic properties of the low-molecular-weight heparins allow them to be administered subcutaneously in fixed, weight-adjusted doses without need for laboratory monitoring. Different studies have recently proved their efficacy in the treatment of patients with deep vein thrombosis. Because there is good evidence that deep vein thrombosis and pulmonary embolism are 2 expressions of a single disease, the use of low-molecular-weight heparins has been extended to patients presenting with clinically stable pulmonary embolism. In particular, the results of 2 important clinical trials, the Columbus and the Thésée, have conclusively proved that the low-molecular-weight heparins are as safe and effective as unfractionated heparin. In some centers, approximately 80% of patients with deep vein thrombosis are treated at home. This suggests that carefully selected patients with clinically stable pulmonary embolism can receive home treatment with low-molecular-weight heparins.


An Integrative Biomedical Informatics Approach to Elucidate the Similarities Between Pre-Eclampsia and Hypertension.
Pre-eclampsia is a pregnancy condition affecting 5-10% of pregnancies, and it is the leading cause of death in pregnancy associated with increased risk of cardiovascular disease later in life. Despite research, the pathogenesis of pre-eclampsia is still poorly understood. In this paper, we investigate the overlapping pathogenic mechanisms between pre-eclampsia and adult hypertension using an integrative biomedical informatics strategy that combined text mining techniques to identify genes and proteins, with geneset analyses, generating knowledge on the pathways and mechanisms involved in these conditions. We identified several overlapping pathogenic pathways/systems including metabolic pathways, developmental biology pathways, immune system, haemostasis, tyrosine kinase pathways, extracellular matrix and oxidative stress pathways. This bioinformatics approach could be applied for investigating mechanistic pathways of other disorders.


Community care of patients with schizophrenia: the role of the primary health care team.
Schizophrenia is a severe, chronic mental disorder that usually begins in early adulthood. Recurrent relapse leading to long-term psychological and social disability means that patients may require intensive community support. Despite a recent fall in the overall numbers of patients consulting their general practitioner with mental disorders, presentations by those suffering from severe mental disorders have risen. This review encompasses the role of general practitioner in the management of schizophrenia, considering in turn drug and psychological therapies, family interventions, innovations in care, the effects of community care developments, and the liasion between primary health care and mental health professionals. There is a need for further research in the area of family-practice-based interventions involving general practitioners and the practice team.


Compute Tomography Radiomics Analysis on Whole Pancreas Between Healthy Individual and Pancreatic Ductal Adenocarcinoma Patients: Uncertainty Analysis and Predictive Modeling.
Radiomics is a rapidly growing field that quantitatively extracts image features in a high-throughput manner from medical imaging. In this study, we analyzed the radiomics features of the whole pancreas between healthy individuals and pancreatic cancer patients, and we established a predictive model that can distinguish cancer patients from healthy individuals based on these radiomics features. Methods: We retrospectively collected venous-phase scans of contrast-enhanced computed tomography (CT) images from 181 control subjects and 85 cancer case subjects for radiomics analysis and predictive modeling. An attending radiation oncologist delineated the pancreas for all the subjects in the Varian Eclipse system, and we extracted 924 radiomics features using PyRadiomics. We established a feature selection pipeline to exclude redundant or unstable features. We randomly selected 189 cases (60 cancer and 129 control) as the training set. The remaining 77 subjects (25 cancer and 52 control) as a test set. We trained a Random Forest model utilizing the stable features to distinguish the cancer patients from the healthy individuals on the training dataset. We analyzed the performance of our best model by running 5-fold cross-validations on the training dataset and applied our best model to the test set. Results: We identified that 91 radiomics features are stable against various uncertainty sources, including bin width, resampling, image transformation, image noise, and segmentation uncertainty. Eight of the 91 features are nonredundant. Our final predictive model, using these 8 features, has achieved a mean area under the receiver operating characteristic curve (AUC) of 0.99 ± 0.01 on the training dataset (189 subjects) by cross-validation. The model achieved an AUC of 0.910 on the independent test set (77 subjects) and an accuracy of 0.935. Conclusion: CT-based radiomics analysis based on the whole pancreas can distinguish cancer patients from healthy individuals, and it could potentially become an early detection tool for pancreatic cancer.


Studies on the mechanism of activation and inactivation of pyruvate, phosphate dikinase. A possible regulatory role for the enzyme in the C4 dicarboxylic acid pathway of photosynthesis.
1. The activity of pyruvate,P(i) dikinase in leaves of maize and Amaranthus palmeri rapidly falls on transferring illuminated plants to darkness. Illumination of dark-treated plants results in an immediate rapid increase in activity of the enzyme, the final activity reached being dependent on the intensity of the incident light. 2. Activation of the enzyme in extracts of dark-treated maize leaves after gel filtration on Sephadex G-25 requires a thiol and P(i). The P(i) requirement for activation can be replaced by arsenate. Activation of the enzyme is inhibited by AMP and GMP and possibly also by ADP and ATP. Activation of the enzyme after gel filtration on Sephadex G-200 also requires a heat-labile component that is excluded by Sephadex G-25. 3. The active enzyme isolated from illuminated leaves is inactivated by ADP in the presence of a thiol, the rate of inactivation being very much faster in air than in an oxygen-free atmosphere. Reactivation of the ADP-inactivated enzyme requires a thiol, P(i) and a component excluded by Sephadex G-25 but considerably retarded by Sephadex G-200. 4. The active enzyme is rapidly and irreversibly inactivated in the absence of a thiol. Inactivation is accelerated by both sodium diethyldithiocarbamate and tetraethylthiuram disulphide, and the enzyme inactivated by these reagents is completely reactivated by incubation with dithiothreitol. This reactivation does not require P(i). The inactive enzyme from dark-treated leaves is stabilized by diethyldithiocarbamate and can be partially activated by dithiothreitol alone; complete reactivation requires both dithiothreitol and P(i). 5. The enzyme activity is markedly inhibited by the thiol reagents p-chloromercuribenzoate, gamma-(p-arsenophenyl)-n-butyrate and an equimolar mixture of arsenite and 2,3-dimercaptopropan-1-ol. 6. The processes of activation and inactivation observed in vitro are discussed in relation to the regulation of pyruvate,P(i) dikinase activity in the leaf.


Multiclass Imbalance Problems: Analysis and Potential Solutions.
Class imbalance problems have drawn growing interest recently because of their classification difficulty caused by the imbalanced class distributions. In particular, many ensemble methods have been proposed to deal with such imbalance. However, most efforts so far are only focused on two-class imbalance problems. There are unsolved issues in multiclass imbalance problems, which exist in real-world applications. This paper studies the challenges posed by the multiclass imbalance problems and investigates the generalization ability of some ensemble solutions, including our recently proposed algorithm AdaBoost.NC, with the aim of handling multiclass and imbalance effectively and directly. We first study the impact of multiminority and multimajority on the performance of two basic resampling techniques. They both present strong negative effects. "Multimajority" tends to be more harmful to the generalization performance. Motivated by the results, we then apply AdaBoost.NC to several real-world multiclass imbalance tasks and compare it to other popular ensemble methods. AdaBoost.NC is shown to be better at recognizing minority class examples and balancing the performance among classes in terms of G-mean without using any class decomposition.


Enhancing the Production of the Fungal Pigment Aurofusarin in Fusarium graminearum.
There is an increasing demand for products from natural sources, which includes a growing market for naturally-produced colorants. Filamentous fungi produce a vast number of chemically diverse pigments and are therefore explored as an easily accessible source. In this study we examine the positive regulatory effect of the transcription factor AurR1 on the aurofusarin gene cluster in Fusarium graminearum. Proteomic analyses showed that overexpression of AurR1 resulted in a significant increase of five of the eleven proteins belonging to the aurofusarin biosynthetic pathway. Further, the production of aurofusarin was increased more than threefold in the overexpression mutant compared to the wild type, reaching levels of 270 mg/L. In addition to biosynthesis of aurofusarin, several yet undescribed putative naphthoquinone/anthraquinone analogue compounds were observed in the overexpression mutant. Our results suggest that it is possible to enhance the aurofusarin production through genetic engineering.


Phase II study of amrubicin as second-line therapy in patients with platinum-refractory small-cell lung cancer.
Amrubicin is a synthetic anthracycline with potent topoisomerase II inhibition. This phase II study was conducted to confirm safety and activity of amrubicin in the treatment of refractory small-cell lung cancer (SCLC). Patients with refractory SCLC (either with progressive disease as best response or progression within 90 days of first-line therapy) received amrubicin (40 mg/m(2)/d for 3 every 21 days). The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), and change in left ventricular ejection fraction (LVEF). Seventy-five patients with a median progression-free interval after first-line therapy of 38 days were enrolled; 69 patients received a median of four amrubicin cycles (range, one to 12 cycles). The ORR was 21.3% (95% CI, 12.7% to 32.3%), with one complete response (1.3%) and 15 partial responses (20%). Median PFS and OS were 3.2 months (95% CI, 2.4 to 4.0 months) and 6.0 months (95% CI, 4.8 to 7.1 months), respectively. The ORR in 43 patients who never responded to first-line therapy was 16.3% (95% CI, 6.8% to 30.7%). Most commonly reported grade 3 or 4 adverse events included neutropenia (67%), thrombocytopenia (41%), and anemia (30%), with febrile neutropenia in 12%. There was no decrease in mean LVEF with cumulative amrubicin doses exceeding 750 mg/m(2). Single-agent amrubicin showed promising activity with a 21.3% ORR and an acceptable safety profile when used as second-line therapy patients with platinum-refractory SCLC. Amrubicin did not induce early cardiotoxicity, but its long-term effects are unknown.


Expression of ASC in renal tissues of familial mediterranean fever patients with amyloidosis: postulating a role for ASC in AA type amyloid deposition.
Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever and serositis; in some cases, ensuing amyloidosis results in kidney damage. Treatment with colchicine reduces the frequency and severity of FMF attacks and prevents amyloidosis, although the mechanisms behind these effects are unknown. Pyrin, the protein product of the MEFV gene, interacts with ASC, a key molecule in apoptotic and inflammatory processes. ASC forms intracellular speck-like aggregates that presage cell death. Here we show that cell death after ASC speck formation is much slower in nonmyeloid cells than in myeloid cells. Additionally, we demonstrate that colchicine prevents speck formation and show that specks can survive in the extracellular space after cell death. Because we also found that ASC is expressed in renal glomeruli of patients with FMF but not in those of control patients, we posit that high local ASC expression may result in speck formation and that specks from dying cells may persist in the extracellular space where they have the potential (perhaps in association with pyrin) to nucleate amyloid. The fact that speck formation requires an intact microtubule network as shown here could potentially account for the ability of prophylactic colchicine to prevent or reverse amyloidosis in patients with FMF.


Expressive writing interventions in cancer patients: a systematic review.
Decades of research have suggested that expressive writing produces physical and psychological benefits in controlled laboratory experiments among healthy college students. This work has been extended to clinical and medical populations, including cancer patients. Although expressive writing could be a promising and inexpensive intervention for this population, the effects have not been systematically examined in oncology samples. A systematic review using PRISMA guidelines was conducted for experimental trials of cancer patients who participated in an expressive writing intervention. PsycINFO and PubMed/Medline were searched for peer-reviewed studies. Thirteen articles met the inclusion/exclusion criteria. Although the majority of the intervention effects were null, there were several main effects for expressive writing on sleep, pain, and general physical and psychological symptoms. Several moderators were identified, suggesting that expressive writing may be more or less beneficial based on individual characteristics such as social constraints. The reviewed studies were limited due to representativeness of the samples, performance, detection and patient-reported outcomes biases, and heterogeneity of the intervention protocol and writing prompts. Future studies with rigorous designs are needed to determine whether expressive writing is therapeutically effective in cancer patients.


Twin-Image-Free Holography: A Compressive Sensing Approach.
Holographic reconstruction is troubled by the phase-conjugate wave front arising from Hermitian symmetry of the complex field. The so-called twin image obfuscates the reconstruction in solving the inverse problem. Here we quantitatively reveal how and how much the twin image affects the reconstruction and propose a compressive sensing (CS) approach to reconstruct a hologram completely free from the twin image. Using the canonical basis, the incoherence condition of CS is naturally satisfied by the Fourier transformation associated with wave propagation. With the propagation kernel function related to the distance, the object wave diffracts into a sharp pattern while the phase-conjugate wave diffracts into a diffuse pattern. An iterative algorithm using a total variation sparsity constraint could filter out the diffuse conjugated signal and overcome the inherent physical symmetry of holographic reconstruction. The feasibility is verified by simulation and experimental results, as well as a comparative study to an existing phase retrieval method.


Lenalidomide-induced interstitial lung disease.
Lenalidomide is a more potent and less toxic oral analog of thalidomide. The drug is indicated for treatment of multiple myeloma and other hematologic disorders and has rarely been associated with pulmonary toxicity. We describe a 73-year-old woman who received lenalidomide therapy for multiple myeloma. Nine weeks after starting the drug, she developed progressive dyspnea, cough, and constitutional symptoms, and was found to be hypoxic. A computed tomography scan of the chest showed bilateral interstitial infiltrates. Bronchoalveolar lavage was negative for infection, but transbronchial biopsy showed an organizing pneumonia. The patient was diagnosed with lenalidomide-induced interstitial lung disease after other causes were excluded. Clinical and radiologic resolution occurred after lenalidomide was discontinued and a tapering course of corticosteroids was begun. Use of the Naranjo adverse drug reaction probability indicated a high probability (score of 7) that this adverse drug reaction was caused by lenalidomide. Lenalidomide inhibits prostaglandin E(2) (PGE(2)) secretion by cells. If fibroblast PGE(2) synthesis is impaired in the lung, the mitogenic action of cysteinyl leukotrienes may be unmasked, promoting fibroblast proliferation and collagen synthesis, eventually leading to interstitial lung disease. Another potential mechanism may be an immunologic one similar to that seen in the interstitial pulmonary process in patients with hypersensitivity pneumonitis. To our knowledge, only one other case of lenalidomide-induced pulmonary toxicity has been reported in the literature. Although lenalidomide-induced pulmonary toxicity is uncommon, clinicians should consider this potential adverse drug reaction in the differential diagnosis in patients receiving lenalidomide who present with symptoms of interstitial lung disease for which alternative causes have been excluded.


Measuring hospital qualities. A preliminary investigation on Health Impact Assessment possibilities for evaluating complex buildings.
World Health Organization states that is possible evaluating projects' qualities via Health Impact Assessment (HIA) but there are not specific HIA tools on hospital buildings assessment. Researchers show significant relationships between built environment and health. The research purpose is investigating how existing tools for healthcare building assessment are encouraging the development of possible hospital HIA evaluation. Based on previous works, 13 assessment tools have been included and a comparison of the criteria has been conducted to understand which the most prevalent topics are. The tools have been analyzed through literature, technical manuals and official websites. The authors identified 12 thematic categories where criteria from different tools have been clustered and discussed. The most prevalent criteria are related to Indoor Environmental Quality (IEQ) (20%). In the oldest tools the evaluation was mainly on technical features while in recent instruments several indicators are related to Architectural features and innovation (48%), Education (23%) and Food (11%). There is growing interest in tools capable of addressing healthy hospitals encouraging IEQ, physical activity and healthy food provision related to occupants' health outcomes. This preliminary study set the basis for further development on hospital facility HIA tools.


Evaluation of cardiac surgery mortality rates: 30-day mortality or longer follow-up?
The aim of our study was to investigate early mortality after cardiac surgery and to determine the most adequate follow-up period for the evaluation of mortality rates. Information on all adult cardiac surgery procedures in 10 of 16 cardiothoracic centres in Netherlands from 2007 until 2010 was extracted from the database of Netherlands Association for Cardio-Thoracic Surgery (n = 33 094). Survival up to 1 year after surgery was obtained from the national death registry. Survival analysis was performed using Kaplan-Meier and Cox regression analysis. Benchmarking was performed using logistic regression with mortality rates at different time points as dependent variables, the logistic EuroSCORE as covariate and a random intercept per centre. In-hospital mortality was 2.94% (n = 972), 30-day mortality 3.02% (n = 998), operative mortality 3.57% (n = 1181), 60-day mortality 3.84% (n = 1271), 6-month mortality 5.16% (n = 1707) and 1-year mortality 6.20% (n = 2052). The survival curves showed a steep initial decline followed by stabilization after ∼60-120 days, depending on the intervention performed, e.g. 60 days for isolated coronary artery bypass grafting (CABG) and 120 days for combined CABG and valve surgery. Benchmark results were affected by the choice of the follow-up period: four hospitals changed outlier status when the follow-up was increased from 30 days to 1 year. In the isolated CABG subgroup, benchmark results were unaffected: no outliers were found using either 30-day or 1-year follow-up. The course of early mortality after cardiac surgery differs across interventions and continues up to ∼120 days. Thirty-day mortality reflects only a part of early mortality after cardiac surgery and should only be used for benchmarking of isolated CABG procedures. The follow-up should be prolonged to capture early mortality of all types of interventions.


Mental health literacy in higher education students.
With approximately 50% of young people aged 18-24 in tertiary education, these are potential settings for programmes to improve mental health literacy. A survey was carried out with students and staff of a tertiary education institution to investigate recognition of depression, help-seeking intentions, beliefs about interventions and stigmatizing attitudes. Students of an Australian metropolitan university (with staff as a comparison group) participated in a telephone interview. They answered questions relating to mental health literacy. Of the completed interviews, 774 (65%) were students and 422 (35%) were staff. Over 70% of students and staff were able to recognize depression in a vignette, with greater likelihood of recognition in students associated with older age, female gender, being born in Australia and a higher level of education. Over 80% of respondents said they would seek help if they had a problem similar to that of the vignette. However, rates of specific help-seeking intentions for students were relatively low, with only 26% nominating a general practitioner and only 10% nominating a student counsellor. Factors associated with stigmatizing attitudes included male gender, younger age, lower level of education, being born outside Australia and lack of recognition of depression. There is a need for mental health literacy interventions targeted at students, particularly those who are younger, male, born outside Australia and of a lower level of education. As rates of specific help-seeking intentions for students were relatively low, there is a need for further exploration of the barriers to help seeking from professional sources.


Heteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration.
Frontotemporal lobar degeneration (FTLD) is a common cause of young onset dementia and is characterised by focal neuropathology. The reasons for the regional neuronal vulnerability are not known. Mitochondrial mechanisms have been implicated in the pathogenesis of FTLD, raising the possibility that frontotemporal regional mutations of mitochondrial DNA (mtDNA) are contributory causes. Here we applied dual sequencing of the entire mtDNA at high depth to identify high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements in post mortem brain tissue of people affected by FTLD and age-matched controls. Both mtSNVs and mtDNA rearrangements were elevated in the temporal lobe, with the greatest burden seen in FTLD. mtSNVs found in multiple brain regions also reached a higher heteroplasmy levels in the temporal lobe. The temporal lobe of people with FTLD had a higher burden of ribosomal gene variants predicted to affect intra-mitochondrial protein synthesis, and a higher proportion of missense variants in genes coding for respiratory chain subunits. In conclusion, heteroplasmic mtDNA variants predicted to affect oxidative phosphorylation are enriched in FTLD temporal lobe, and thus may contribute to the regional vulnerability in pathogenesis.


Comparison of monooxygenase activities and cytochrome P-450 isozyme concentrations in human liver microsomes.
Concentrations of three human liver microsomal cytochrome P-450 isozymes and 20 different monooxygenase activities were determined in human liver microsomal preparations. The results of correlation analysis suggest that: there are important variations in the amounts of the three cytochrome P-450 isozymes measured, particularly P-450(8) and P-450(9); aldrin epoxidase, d-benzphetamine N-demethylase, and S-warfarin 4-hydroxylase activities are linked to cytochrome P-450(5); aryl hydrocarbon (benzo(a)pyrene) hydroxylase and 4-nitroanisole-O-demethylase activities are linked to P-450(8); hydroxylations at the 4'-, 6-, 7-, and 8-positions of R-warfarin are closely linked to each other but are not correlated with other measured monooxygenase activities or P-450 isozyme levels; and P-450(9) is not related to any of the catalytic activities tested. Thus, certain monooxygenase activities can be attributed to specific cytochrome P-450 isozymes. This approach should be useful in suggesting the roles of different cytochromes P-450 in drug metabolism in man which can be further examined using in vitro and in vivo methods.


Micro-trichome as a class I homeodomain-leucine zipper gene regulates multicellular trichome development in Cucumis sativus.
Plant trichomes serve as a highly suitable model for investigating cell differentiation at the single-cell level. The regulatory genes involved in unicellular trichome development in Arabidopsis thaliana have been intensively studied, but genes regulating multicellular trichome development in plants remain unclear. Here, we characterized Cucumis sativus (cucumber) trichomes as representative multicellular and unbranched structures, and identified Micro-trichome (Mict), using map-based cloning in an F2 segregating population of 7,936 individuals generated from a spontaneous mict mutant. In mict plants, trichomes in both leaves and fruits, are small, poorly developed, and denser than in the wild type. Sequence analysis revealed that a 2,649-bp genomic deletion, spanning the first and second exons, occurred in a plant-specific class I homeodomain-leucine zipper gene. Tissue-specific expression analysis indicated that Mict is strongly expressed in the trichome cells. Transcriptome profiling identified potential targets of Mict including putative homologs of genes known in other systems to regulate trichome development, meristem determinacy, and hormone responsiveness. Phylogenic analysis charted the relationships among putative homologs in angiosperms. Our paper represents initial steps toward understanding the development of multicellular trichomes.


The use of bispectral analysis in patients undergoing intravenous sedation for third molar extractions.
The bispectral (BIS) index has been used to interpret electroencephalogram (EEG) recordings to predict the level of sedation and loss of consciousness in patients undergoing general anesthesia. It was the purpose of this project to assess the usefulness of BIS technology in determining the level of sedation in patients undergoing third molar extraction under conscious sedation. Twenty-five subjects undergoing third molar extraction in an outpatient setting were analyzed. The EEG activity was recorded continually during surgery using a microcomputer (Aspect-1050 Monitor; Aspect Co, Natick, MA) with real-time bispectral data obtained by EEG skin electrodes through a frontotemporal montage. The Observer's Assessment of Alertness and Sedation (OAA/S) scale was used to subjectively assess the level of sedation observed by the anesthetist before initiating the sedation procedure and then at 5-minute intervals until the end of the procedure. The BIS level was simultaneously recorded. The initial sedation was accomplished using a standard dose of midazolam (0.05 mg/kg) and fentanyl (1.5 microg/kg) followed by a 10- to 30-mg bolus of propofol until a level of sedation at which the patient's eyes were closed and he or she was responsive only to vigorous stimulation or repeated loud calling of their name (OAA/S level of 1 to 2). Local anesthesia was then administered. Additional doses of sedative medication (midazolam or propofol) were given during the procedure to maintain the desired level of sedation (an OAA/S level of 2 to 3). The time and dose of the drug given were recorded. The level of sedation based on a single anesthetist's interpretation (OAA/S) and the BIS readings were then compared. A strong positive relationship between the BIS index and OAA/S readings was found (P < .0001). Pairwise comparisons of mean BIS index and its corresponding OAA/S level were significantly different from each other (P < .003) except for OAA/S levels 2 and 3 (P = .367). BIS technology offers an objective, ordinal means of assessing the depth of sedation. There was a strong relationship between the objective BIS values and subjective assessment (OAA/S scale) of the depth of anesthesia. This can be invaluable in providing an objective assessment of sedation in oral and maxillofacial surgery where it may be difficult to determine the level of sedation clinically.


The effect of hormonal secretion on survival in adrenocortical carcinoma: A multi-center study.
Current evidence suggests that cortisol secreting adrenocortical carcinoma has worse prognosis compared to non-secreting adrenocortical carcinoma. However, the effect of other secretory subtypes is unknown. This multicenter study within the American-Australian-Asian Adrenal Alliance included adults with adrenocortical carcinoma (1997-2020). We compared overall survival and disease-free survival among cortisol secreting, mixed cortisol/androgen secreting, androgen secreting, and non-secreting adrenocortical carcinoma. Of the 807 patients (mean age 50), 719 included in the secretory subtype analysis: 24.5% were cortisol secreting, 13% androgen secreting, 28% mixed cortisol/androgen, 32.5% non-secreting, and 2% were mineralocorticoid secreting. Median overall survival and disease-free survival for the entire cohort were 60 and 9 months, respectively. Median overall survival was 36 months for cortisol, 30 for mixed, 60 for androgen secreting, and 115 for non-secreting adrenocortical carcinoma, P < .01. Median disease-free survival was 7 months for cortisol, 8 for mixed, 10 for androgen, and 12 for non-secreting adrenocortical carcinoma, P = .06. On multivariable analysis of age, sex, Ki67%, secretory subtype, stage, resection, and adjuvant therapy, predictors of worse overall survival were older age, higher Ki67%, stage IV, mixed secreting, R1, and no adjuvant therapy, P < .05. On subgroup analysis of R0 resection, predictors of worse overall survival included older age and higher Ki67%. Ki67% ≥40, stage III and cortisol secretion were associated with worse disease-free survival. Mixed cortisol/androgen secreting adrenocortical carcinoma was associated with worse overall survival, while cortisol or androgen secreting alone were not. Notably, among patients after R0 resection, secretory subtype did not affect overall survival. Cortisol secreting adrenocortical carcinoma demonstrated worse disease-free survival. Ki67% remained a strong predictor of worse overall survival and disease-free survival independent of stage.


Dietary AGEs as Exogenous Boosters of Inflammation.
Most chronic modern non-transmissible diseases seem to begin as the result of low-grade inflammation extending over prolonged periods of time. The importance of diet as a source of many pro-inflammatory compounds that could create and sustain such a low-grade inflammatory state cannot be ignored, particularly since we are constantly exposed to them during the day. The focus of this review is on specific components of the diet associated with inflammation, specifically advanced glycation end products (AGEs) that form during thermal processing of food. AGEs are also generated in the body in normal physiology and are widely recognized as increased in diabetes, but many people are unaware of the potential importance of exogenous AGEs ingested in food. We review experimental models, epidemiologic data, and small clinical trials that suggest an important association between dietary intake of these compounds and development of an inflammatory and pro-oxidative state that is conducive to chronic diseases. We compare dietary intake of AGEs with other widely known dietary patterns, such as the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) diets, as well as the Dietary Inflammation Index (DII). Finally, we delineate in detail the pathophysiological mechanisms induced by dietary AGEs, both direct (i.e., non-receptor-mediated) and indirect (receptor-mediated).


[Isolation of the mRNA for interferon and its integration into the genome of a foreign host].
The study of superinduction and translation of interferon mRNA (mRNA-IF) in four cell systems was the experimental basis for tests on the establishment in mouse and monkey cells (L-1210 and BSC) of the capacity for long-term production of biologically active chicken interferon after their inoculation with chicken mRNA-IF. The interferon was tested and identified by the species-specificity, thermostability and antigenic specificity. During 3 months (the observation period) after a single inoculation of chicken mRNA-IF the L-1210 and BSC cells in response to induction with poly: C produced the homologous (mouse or monkey) and heterologous (chicken) interferons without any signs of decline of the latter's production. Titres of the heterologous interferon exceeded those of homologous interferon by approximately 10-fold. The dynamics of production of chicken interferon after induction and the sensitivity of this process to actinomycin D permit a conclusion on similar mechanisms of transcription and translation of homologous and heterologous interferons. It is suggested that integration of the genetic information for synthesis of chicken interferon with the genome of heterogenous cells may be a possible mechanism of this phenomenon.