Analgesic and anti-inflammatory effect of aqueous extract of the stem bark of Allanblackia gabonensis (Guttiferae).
Allanblackia gabonensis (Guttiferae) is a plant used in the African traditional medicine as remedies against pain, rheumatism, inflammations. In the present work, the analgesic effect of aqueous extract has been evaluated using acetic acid, formalin, hot-plate test, tail immersion and paw-pressure test. The anti-inflammatory effect of this extract was also investigated on carrageenan, histamine or serotonin induced by paw oedema. Aqueous extract of stem bark of A. gabonensis administrated p.o. showed significant activity against paw oedema induced by carrageenan, with a maximum percentage of inhibition reaching the 74.01% at the preventive test at a dose of 200 mg/kg. A. gabonensis exhibited a significant reduction of paw oedema induced by both histamine and serotonin with a maximal inhibition of 56.94% (200 mg/kg) and 40.83% (100 mg/kg), respectively. It showed significant protective effects against chemical stimuli (acetic acid and formalin) in the mouse. Administered orally at the doses of 100-400 mg/kg, exhibited protective effect of at least 69.78% on the pain induced by acetic acid and also reduced first (67.18% at 200 mg/kg) and second (83.87% at 400 mg/kg) phase of pain-induced par formalin. It also produced a significant increase of the threshold of sensitivity to pressure and hot plate-induced pain in the rats. These results suggest a peripheral and central analgesic activities as well as an anti-inflammatory effect of the stem bark of A. gabonensis.


Anaerobic and aerobic performance of elite female and male snowboarders.
The physiological adaptation to training is specific to the muscle activity, dominant energy system involved, muscle groups trained, as well as intensity and volume of training. Despite increasing popularity of snowboarding only little scientific data is available on the physiological characteristics of female and male competitive snowboarders. Therefore, the purpose of this study was to compare the aerobic capacity and maximal anaerobic power of elite Polish snowboarders with untrained subjects. Ten snowboarders and ten aged matched students of Physical Education performed two exercise tests. First, a 30-second Wingate test was conducted and next, a cycle ergometer exercise test with graded intensity. In the first test, peak anaerobic power, the total work, relative peak power and relative mean power were measured. During the second test, relative maximal oxygen uptake and lactate threshold were evaluated. There were no significant differences in absolute and relative maximal oxygen uptake between snowboarders and the control group. Mean maximal oxygen uptake and lactate threshold were significantly higher in men than in women. Significant differences were found between trained men and women regarding maximal power and relative maximal power. The elite snowboarders demonstrated a high level of anaerobic power. The level of relative peak power in trained women correlated negatively with maximal oxygen uptake. In conclusion, our results seem to indicate that the demanding competition program of elite snowboarders provides a significant training stimulus mainly for anaerobic power with minor changes in anaerobic performance.


[Modelling of a combined immunodeficiency state by splenectomy and alloimmunization with lymph node antigens].
Autoimmune pathology was modelled in splenectomized animals by allosensitization with lymphoid tissue in association with Freund's adjuvant. It was found that splenectomy in guinea pigs produces stable disorders of homeostasis and morphological picture of the heart, liver, inguinal lymph nodes as well as a imbalance of the autoregulation mechanisms. The authors obtained an experimental model of autoimmune pathology that may be used for investigation of the pathogenesis of these states as well as for developing methods of corrective therapy.


A feedback loop between Wolbachia and the Drosophila gurken mRNP complex influences Wolbachia titer.
Although much is known about interactions between bacterial endosymbionts and their hosts, little is known concerning the host factors that influence endosymbiont titer. Wolbachia endosymbionts are globally dispersed throughout most insect species and are the causative agent in filarial nematode-mediated disease. Our investigation indicates that gurken (grk), a host gene encoding a crucial axis determinant, has a cumulative, dosage-sensitive impact on Wolbachia growth and proliferation during Drosophila oogenesis. This effect appears to be mediated by grk mRNA and its protein-binding partners Squid and Hrp48/Hrb27C, implicating the grk mRNA-protein (mRNP) complex as a rate-limiting host factor controlling Wolbachia titer. Furthermore, highly infected flies exhibit defects that match those occurring with disruption of grk mRNPs, such as nurse cell chromatin disruptions and malformation of chorionic appendages. These findings suggest a feedback loop in which Wolbachia interaction with the grk mRNP affects both Wolbachia titer and grk mRNP function.


Treatment of urinary incontinence with AMS 800 artificial urinary sphincter.
Urinary incontinence has a significant impact on the quality of life for patients. The introduction of the AMS 800 artificial urinary sphincter by American Medical Systems (Minnetonka, MN, USA) has revolutionized the treatment of urinary incontinence due to pure sphincteric incompetence. From April 1989 to October 1997, a total of 52 patients (42 men and 3 women) underwent implantation of the AMS 800 artificial sphincter. Patient age ranged from 31 to 87 years (mean 69.5 years). They all were suffering from urinary incontinence caused by sphincteric damage, always of iatrogenic origin. Follow-up was 5-110 months, with a mean of 35 months. The restoration of continence was complete for 35 patients and allowed them all to return to their normal life. 7 of the patients who had a successful implant died because of other problems. For 2 patients follow-up was not available. Explantation was performed 8 times: in 5 male patients the device was removed because of periprosthetic infections; in 1 female patient with ileal neobladder, because of serious urethral necrosis; and in 2 male patients because of an urethral erosion. The AMS 800 artificial urinary sphincter is the most efficacious treatment currently available for urinary incontinence due to pure sphincteric incompetence. Implanted patients achieved acceptable urinary control. The implantation is associated with 2 distinct complications: surgical and mechanical.


Attention-Diffusion-Bilinear Neural Network for Brain Network Analysis.
Brain network provides essential insights in diagnosing many brain disorders. Integrative analysis of multiple types of connectivity, e.g, functional connectivity (FC) and structural connectivity (SC), can take advantage of their complementary information and therefore may help to identify patients. However, traditional brain network methods usually focus on either FC or SC for describing node interactions and only consider the interaction between paired network nodes. To tackle this problem, in this paper, we propose an Attention-Diffusion-Bilinear Neural Network (ADB-NN) framework for brain network analysis, which is trained in an end-to-end manner. The proposed network seamlessly couples FC and SC to learn wider node interactions and generates a joint representation of FC and SC for diagnosis. Specifically, a brain network (graph) is first defined, where each node corresponding to a brain region is governed by the features of brain activities (i.e., FC) extracted from functional magnetic resonance imaging (fMRI), and the presence of edges is determined by neural fiber physical connections (i.e., SC) extracted from Diffusion Tensor Imaging (DTI). Based on this graph, we train two Attention-Diffusion-Bilinear (ADB) modules jointly. In each module, an attention model is utilized to automatically learn the strength of node interactions. This information further guides a diffusion process that generates new node representations by considering the influence from other nodes as well. After that, the second-order statistics of these node representations are extracted by bilinear pooling to form connectivity-based features for disease prediction. The two ADB modules correspond to the one-step and two-step diffusion, respectively. Experiments on a real epilepsy dataset demonstrate the effectiveness and advantages of our proposed method.


Increased activation and cytokine secretion in B cells stimulated with leptin in aged humans.
Aging is associated chronic inflammation and autoimmunity, and increased levels of leptin. Increased levels of leptin are associated with inflammation and autoimmunity. We have recently reported that leptin activates B cells to induce secretion of proinflammatory and anti-inflammatory cytokines. Role of B cells and leptin in inflammation associated with aging has not been explored. In this study we demonstrate that leptin activates and induces significantly greater amount of IL-6, TNF-α, and IL-10 by B cells from aged humans as compared to young controls. This is associated with increased leptin-induced phosphorylation of STAT3 (signal transducer and activator of transcription-3) in B cells from aged humans as compared to young subjects. These data suggest that leptin-induced B cell-derived proinflammatory cytokines may play a role in chronic inflammation associated with human aging.


Non-host resistance in plants: new insights into an old phenomenon.
SUMMARY Resistance of an entire plant species to all isolates of a microbial species is referred to as non-host or species resistance. An interplay of both constitutive barriers and inducible reactions comprises the basis for this most durable form of plant disease resistance. Activation of inducible plant defence responses is probably brought about by the recognition of invariant pathogen-associated molecular patterns (PAMP) that are characteristic of whole classes of microbial organisms. PAMP perception systems and PAMP-induced signalling cascades partially resemble those known to mediate activation of innate immune responses in animals, suggesting an evolutionarily ancient molecular concept of non-self recognition and immunity in eukaryotes. Genetic dissection has recently provided clues for SNARE-complex-mediated exocytosis and directed vesicle trafficking in executing plant non-host resistance. Recent functional analysis of bacterial effector proteins indicates that establishment of infection in susceptible plants is associated with suppression of plant species resistance.


Femtosecond laser-assisted corneal transplantation.
Corneal transplantation is the only surgical option to improve symptoms and vision in patients with severe corneal opacification. With the evolution and development of keratoplasty techniques, corneal surgeons can perform customized keratoplasty, with complex graft-host junctions to promote wound healing and accelerate visual rehabilitation. Femtosecond laser (FSL) enable customization of the thickness and shape of the graft has been used for trephination of both donor and recipient corneas and for creating special wound configurations. In this review, we have summarized the intraoperative application and postoperative outcomes of FSL-assisted keratoplasties, including penetrating keratoplasty, anterior lamellar keratoplasty (ALK), deep ALK, Descemet stripping automated endothelial keratoplasty (EK), and Descemet membrane EK. Although FSL allows for the customization and precision in keratoplasty, several concerns, such as cost-effectiveness, limit its wider clinical adoption. Hence, more work is required to weigh the advantages and limitations of the FSL applications in corneal transplantation.


Core-shell hybrid upconversion nanoparticles carrying stable nitroxide radicals as potential multifunctional nanoprobes for upconversion luminescence and magnetic resonance dual-modality imaging.
Nitroxide radicals, such as 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and its derivatives, have recently been used as contrast agents for magnetic resonance imaging (MRI) and electron paramagnetic resonance imaging (EPRI). However, their rapid one-electron bioreduction to diamagnetic N-hydroxy species when administered intravenously has limited their use in in vivo applications. In this article, a new approach of silica coating for carrying stable radicals was proposed. A 4-carboxyl-TEMPO nitroxide radical was covalently linked with 3-aminopropyl-trimethoxysilane to produce a silanizing TEMPO radical. Utilizing a facile reaction based on the copolymerization of silanizing TEMPO radicals with tetraethyl orthosilicate in reverse microemulsion, a TEMPO radicals doped SiO2 nanostructure was synthesized and coated on the surface of NaYF4:Yb,Er/NaYF4 upconversion nanoparticles (UCNPs) to generate a novel multifunctional nanoprobe, PEGylated UCNP@TEMPO@SiO2 for upconversion luminescence (UCL) and magnetic resonance dual-modality imaging. The electron spin resonance (ESR) signals generated by the TEMPO@SiO2 show an enhanced reduction resistance property for a period of time of up to 1 h, even in the presence of 5 mM ascorbic acid. The longitudinal relaxivity of PEGylated UCNPs@TEMPO@SiO2 nanocomposites is about 10 times stronger than that for free TEMPO radicals. The core-shell NaYF4:Yb,Er/NaYF4 UCNPs synthesized by this modified user-friendly one-pot solvothermal strategy show a significant enhancement of UCL emission of up to 60 times more than the core NaYF4:Yb,Er. Furthermore, the PEGylated UCNP@TEMPO@SiO2 nanocomposites were further used as multifunctional nanoprobes to explore their performance in the UCL imaging of living cells and T1-weighted MRI in vitro and in vivo.


Diagnosis of iron deficiency: mean corpuscular hemoglobin (MCH) as a predictor of iron deficiency in infants.
Hematologic variables were measured in 240 apparently healthy infants ranging from 1-12 months of age attending a well baby clinic. There were 20 infants for each month of age. Hematologic parameters were measured in each infant by Coulter Counter Model S. Serum iron, total iron binding capacity, free erythrocyte protoporphyrin (FEP) and serum ferritin levels were measured in most infants. Their weights together with their serum iron, total iron binding capacity, and serum ferritin were judged to be independent variables of iron status, whereas the hematologic variables were considered to be response variables indicative of iron status. The correlation coefficients among these variables, after excluding redundant variables and transforming to logarithms, were computed. Canonical correlation analysis was applied to the matrix of correlation coefficients to yield the linear function of the independent variables most highly correlated with a linear function of the response variables. The linear function of the response variables was found to be well approximated by the logarithm of the mean corpuscular haemoglobin, which was highly correlated with each of the independent variables.


Comparison of blood flow after warm and cool ischemia in island flaps: latissimus dorsi myocutaneous and epigastric flaps in the dog.
Cooling has been reported to improve the survival of tissues used in free transfers. Very little has been written about blood flow in flaps following ischemia and about the effect of temperature on flow. In each of 4 dogs, 2 island latissimus dorsi myocutaneous flaps and 2 island epigastric axial flaps were made ischemic for one hour. Flaps were subjected to three temperature conditions during ischemia: warm ischemia, cool ischemia, and cool ischemia followed by rewarming prior to reestablishment of blood flow. Following ischemia, blood flow in the artery of the pedicle was measured using an electromagnetic flowmeter. Both latissimus dorsi and epigastric flaps subjected to warm ischemia experienced a reactive hyperemia, a period lasting several minutes during which blood flow increased severalfold over baseline flow. Cooling the latissimus dorsi flap had no major effect on this hyperemia. However, cooling the epigastric flap attenuated the hyperemic response observed in a warm flap. Both the peak flow attained and the rate of rise to peak flow were decreased. Rewarming the epigastric flap prior to clamp removal gave a hyperemia similar to that observed in the warm flap.


Pulseless Electrical Activity Arrest as the First Symptom of Testicular Cancer with Subsequent Phlegmasia Cerulea Dolens.
Phlegmasia cerulea dolens (PCD) is a severe, rare complication of deep vein thrombosis, which is characterised by compartment syndrome, arterial compromise, venous gangrene, and shock. Prothrombotic states are the primary risk factor for PCD, which, in most cases, is associated with pulmonary embolism and carries a high mortality. A 46-year-old male presented following a pulseless electrical activity (PEA) arrest due to saddle pulmonary embolism (PE). He subsequently developed PCD and venous gangrene secondary to inferior vena cava obstruction, in the setting of a new diagnosis of testicular germ cell tumour. PEA arrest, as the initial presenting problem in malignancy, is rare. It is extreme for the first indication of cancer to be a PEA arrest from massive PE. While hypoxic brain injury from the cardiac arrest precluded intervention in this case, a surgical approach entailing en bloc resection of aortocaval metastasis, with subsequent IVC reconstruction, followed by lower limb venous thrombectomy would have been favoured as it was considered that an endovascular approach would not have been successful. A case of a patient with phlegmasia cerulea dolens secondary to testicular cancer, who presented following PEA arrest is described.


Interpersonal processes: the interplay of cognitive, motivational, and behavioral activities in social interaction.
This analytic review is concerned with the interpersonal processes, and the characteristics of situations and persons that influence them, that lead to the confirmation and disconfirmation of expectations in the course of social interaction. We examine the steps in the chain of events by which the expectations of one person guide and direct the dynamics of social interaction such that the behavior of the target of those expectations comes to confirm or disconfirm those expectations. We further inquire into the motivational and structural foundations of confirmation and disconfirmation in social interaction, using these inquiries to address frequently asked, but rarely answered, questions about expectations and social interaction. Finally, we argue that investigations of expectations in social interaction provide a paradigm for more general theoretical and empirical considerations of interpersonal processes and social relationships.


Predictive value of PD-L1 expression to the efficacy of immune checkpoint inhibitors in advanced triple-negative breast cancer: A systematic review and meta-analysis.
Background: Immune checkpoint inhibitors (ICIs) have been an emerging treatment strategy for advanced triple-negative breast cancer (TNBC). Some studies have shown that high expression of programmed death-ligand 1 (PD-L1) can achieve a better response of clinical efficacy. However, the efficacy of ICIs in advanced TNBC remains controversial. In this meta-analysis, we evaluated the correlation of PD-L1 expression with the efficacy of ICIs in patients with advanced TNBC. Methods: We conducted a systematic search using four databases until March 2022 to obtain eligible randomized controlled trials (RCTs). The quality of the studies was assessed by the Cochrane risk of bias tool. Hazard ratio (HR) was extracted to evaluate the relationship between PD-L1 expression and progression-free survival (PFS) or overall survival (OS) in patients with advanced TNBC. Results: Five randomized controlled clinical trials (RCTs) with 3104 patients were included in this meta-analysis. The results demonstrated that ICIs could significantly improve the OS (HR 0.77, 95% CI 0.60-0.98, p = 0.03) in PD-L1 positive TNBC group. In the subgroup analysis, longer OS was observed (HR: 0.70, 95% CI: 0.60-0.82, p = 0.00001) in PD-L1 positive TNBC patients receiving ICIs alone or ICIs combined with nab-paclitaxel. In terms of PFS, PFS was significantly improved (HR: 0.68, 95% CI: 0.58-0.79, p < 0.00001) in PD-L1 positive patients receiving first-line ICIs and chemotherapy compared to those with ICIs alone. No significant improvement was observed for OS or PFS in PD-L1 negative group. Conclusion: Our study indicated significant improvement for OS in advanced TNBC with ICIs therapy in the PD-L1 positive status, and ICIs alone or ICIs combined with nab-paclitaxel might be a excellent choice in terms of OS. Although PFS has no significant benefit in PD-L1 positive patients, the subgroup analysis showed that ICIs combined with chemotherapy could achieve the PFS benefit in the first-line treatment. However, further clinical studies are needed to validate our conclusions due to limited relevant research.


Oncology nurses' knowledge, attitudes, and experiences regarding advance directives.
To determine oncology nurses' knowledge of, attitudes toward, and experiences with advance directives (ADs). Descriptive, correlation survey. Usable responses from 794 (21% return) of 3,840 randomly selected members of the Oncology Nursing Society. The typical respondent was female, Caucasian, married or living as married, middle-aged, and Christian. A mailed survey using the Knowledge, Attitudinal, and Experiential Survey on Advance Directives instrument. Knowledge, attitudes, experiences, confidence, and ADs. Overall, oncology nurses were most knowledgeable about ADs in general (70% correct) and less knowledgeable about the Patient Self-Determination Act (51% correct) and their state laws (53% correct). The mean total knowledge score based on the three subscales was 17.4 out of a possible 30, or 58% correct. The nurses' experience with ADs was measured using a five-item subscale with a mean score of 4 (SD = 1.11). They were less confident in their ability to assist patients with completing ADs. Respondent attitudes reflected an advocacy role in end-of-life decisions. Attitude items were reviewed individually. Respondents strongly agreed (97%) with the statement that patients should receive sufficient medication to relieve pain even though it may hasten death, which reflects the emphasis in oncology on adequate pain management at the end of life. Nurses' knowledge scores were low. Nurses in the study were not highly confident in their ability to assist patients with ADs. Demographic variables generally did not influence knowledge, confidence, or experience scores. More education related to ADs is needed and could be administered through in-service classes or continuing education. Nurses' responses indicated that they need more time to assist patients with completing ADs. This is difficult in the current practice environment but must be recognized as critically important.


Distribution of type III secretion gene clusters in Burkholderia pseudomallei, B. thailandensis and B. mallei.
Burkholderia pseudomallei, the causative agent of melioidosis, carries a cluster of genes closely related in organisation to the type III secretion (TTS) system gene clusters of the plant pathogens Ralstonia solanacearum and Xanthomonas spp. The TTS gene cluster (TTS1) is present only in B. pseudomallei and not in avirulent B. thailandensis. Adjacent to the gene cluster encoding putative secreton structural proteins lie a number of open reading frames (ORFs) encoding putative proteins with little or no homology to known proteins, with the exception of one predicted protein with homology to Pseudomonas syringae HrpK. In both R. solanacearum and Xanthomonas spp., genes in this location encode secreted effector proteins. RT-PCR analysis indicated that TTS genes, including two of these ORFs, are expressed in broth at 37 degrees C. Analysis of genome sequence data identified a second cluster of TTS genes (TTS2) present in both B. pseudomallei and B. mallei (99% identity). However, B. mallei appears to lack the TTS1 gene cluster. PCR assays indicated that TTS2 was also present in B. thailandensis. TTS1 and TTS2 are similar in gene organisation, but nucleotide sequences are sufficiently divergent to suggest that the two TTS systems may have different roles.


[Acipimox (Olbetam) as a secondary hypolipemic agent in combined hypertriglyceridemia and hyperlipidemia].
32 patients with hypertriglyceridemia, excessive hypertriglyceridemia, and combined hyperlipidemia, were treated with the nicotinic acid derivative acipimox (Olbetam). First line treatment with bezafibrate, or statins in some with combined hyperlipidemia, had failed. In 10 acipimox was discontinued due to side effects or absence of clinical response. The other 22 completed 6 months of treatment with no side effects. Acipimox caused a significant 54% decrease in triglyceride levels, a 23% decrease in total cholesterol, and a 12% increase in HDL-cholesterol. LDL-cholesterol was difficult to calculate because of the high triglyceride levels, so no results are presented. Although acipimox was much better tolerated than nicotinic acid, it also had side effects, but fewer. Acipimox can therefore be used as a second-line drug, mainly in those with combined hyperlipidemia and hypertriglyceridemia.


Machine learning combined with Geodetector quantifies the synergistic effect of environmental factors on soil heavy metal pollution.
The critical prerequisite for the prevention and control of soil heavy metal (HM) pollution is the identification of factors that influence soil HM accumulation. The dominant factors have been individually identified and apportioned in existing studies. However, the accumulation of soil HMs results from a combination of multiple factors, and the influence of a single factor is less than the interaction of multiple parameters on soil HM pollution. In this study, we employed Geodetector to delve into the interaction effect of the influencing factors on the variations of soil HMs. We performed partial dependence plot to depict how these factors interact with each other to affect the HM content. We found that both individually and interactively, pH and agricultural activities significantly impact soil HM content. Except for Hg and Cu, the pairs with the most significant interaction effects all involve pH. For Pb, As and Zn, interaction with pH has the most significant driving force compared to the other factors. For Cu, Hg, and Ni, all environmental factor interactions increased their explanatory power, while for Cr, the single most significant driver decreased its driving power when interacting with other factors. Additionally, the study area exhibited a widespread prevalence of changes in HM concentration being governed by the synergistic effect of two factors. For the response of HMs to the interaction of pH and fertilizer, soil HM concentration was sensitive to pH, while fertilizer had less effect. These results provide a dependable method of investigating the interaction of environmental factors on soil HM content and put forth efficacious and potent tactical measures for soil HM pollution prevention and control based on the interaction type.


Dynamic imaging of coherent sources: Studying neural interactions in the human brain.
Functional connectivity between cortical areas may appear as correlated time behavior of neural activity. It has been suggested that merging of separate features into a single percept ("binding") is associated with coherent gamma band activity across the cortical areas involved. Therefore, it would be of utmost interest to image cortico-cortical coherence in the working human brain. The frequency specificity and transient nature of these interactions requires time-sensitive tools such as magneto- or electroencephalography (MEG/EEG). Coherence between signals of sensors covering different scalp areas is commonly taken as a measure of functional coupling. However, this approach provides vague information on the actual cortical areas involved, owing to the complex relation between the active brain areas and the sensor recordings. We propose a solution to the crucial issue of proceeding beyond the MEG sensor level to estimate coherences between cortical areas. Dynamic imaging of coherent sources (DICS) uses a spatial filter to localize coherent brain regions and provides the time courses of their activity. Reference points for the computation of neural coupling may be based on brain areas of maximum power or other physiologically meaningful information, or they may be estimated starting from sensor coherences. The performance of DICS is evaluated with simulated data and illustrated with recordings of spontaneous activity in a healthy subject and a parkinsonian patient. Methods for estimating functional connectivities between brain areas will facilitate characterization of cortical networks involved in sensory, motor, or cognitive tasks and will allow investigation of pathological connectivities in neurological disorders.


Resolution improvement in two-photon fluorescence microscopy with a single-mode fiber.
The dependence of spectral broadening of an ultrashort-pulsed laser beam on the fiber length and the illumination power is experimentally characterized in order to deliver the laser for two-photon fluorescence microscopy. It is found that not only the spectral width but also the spectral blue shift increases with the fiber length and illumination power, owing to the nonlinear response in the fiber. For an illumination power of 400 mW in a 3-m-long single-mode fiber, the spectral blue shift is as large as 15 nm. Such a spectral blue shift enhances the contribution from the short-wavelength components within the pulsed beam and leads to an improvement in resolution under two-photon excitation, whereas the efficiency of two-photon excitation is slightly reduced because of the temporal broadening of the pulsed beam. The experimental measurement of the axial response to a two-photon fluorescence polymer block confirms this feature.


Antitumor Activity of Thermosensitive Hydrogels Packaging Gambogic Acid Nanoparticles and Tumor-Penetrating Peptide iRGD Against Gastric Cancer.
Gambogic acid (GA) is proved to have anti-tumor effects on gastric cancer. Due to poor solubility, non-specific biological distribution, toxicity to normal tissues and short half-life, it is hard to be applied into the clinic. To overcome these issues, we developed a thermosensitive and injectable hydrogel composed of hydroxypropyl cellulose, silk fibroin and glycerol, with short gelling time, good compatibility and sustained release, and demonstrated that the hydrogel packaged with gambogic acid nanoparticles (GA-NPs) and tumor-penetrating peptide iRGD could improve the anti-tumor activity. The Gelling time and micropore size of the hydrogels were regulated through different concentrations of glycerol. Controlled release characteristics of the hydrogels were evaluated with a real-time near-infrared fluorescence imaging system. Location of nanoparticles from different carriers was traced by confocal laser scanning microscopy. The in vivo antitumor activity of the hydrogels packaging GA-NPs and iRGD was evaluated by investigating tumor volume and tumor size. The thermo-sensitive properties of hydrogels were characterized by 3-4 min, 37°C, when glycerol concentration was 20%. The hydrogels physically packaged with GA-NPs and iRGD showed higher fluorescence intensity than other groups. The in vivo study indicated that the co-administration of GA-NPs and iRGD by hydrogels had higher antitumor activity than the GA-loaded hydrogels and free GA combining with iRGD. Free GA group showed few antitumor effects. Compared with the control group, the body weight in other groups had no obvious change, and the count of leukocytes and hemoglobin was slightly decreased. The hydrogel constructed iRGD and GA-NPs exerted an effective anti-tumor effect possibly due to retention effect, local administration and continuous sustained release of iRGD promoting the penetration of nanoparticles into a deep part of tumors. The delivery system showed little systemic toxicity and would provide a promising strategy to improve anti-gastric cancer efficacy.


Insights into the Role of MicroRNAs in the Onset and Development of Diabetic Neuropathy.
Diabetic neuropathy is a serious complication of chronic hyperglycemia in diabetes patients. This complication can involve both peripheral sensorimotor and autonomic nervous system. The precise nature of injury to the peripheral nerves mediated by chronic hyperglycemia is unknown; however, several mechanisms have been proposed including polyol pathway activation, enhanced glycation of proteins and lipids, increased oxidative stress, and cytokine release in the site of injury. MicroRNAs (miRNAs) are small non-coding RNAs that mediate RNA interference by post-transcriptionally modulating gene expression and protein synthesis. Therefore, they have been implicated in several developmental, physiological, and pathophysiological processes where they modulate the expression of different proteins. Recently, miRNAs gained an increasing attention also for their role as diagnostic test in many diseases due to their stability in serum and their easy detection. Furthermore, recent studies suggest that miRNAs may be involved in diabetic neuropathy although their role in the onset and the development of this complication is not fully understood. In this review, we discuss the most recent literature providing evidence for miRNAs role in diabetic neuropathy opening new pathways to improve both early diagnosis and treatment of this complication.


[Notifications to the Netherlands Pharmacovigilance Foundation Lareb of the expulsion of a vaginal contraceptive ring (NuvaRing) and of pregnancy during the use of it].
Netherlands Pharmacovigilance Foundation Lareb expulsion of the vaginal contraceptive ring NuvaRing was reported 8 times between February 2003 and April 2004. Moreover, in two of these reports pregnancy was reported. In that same period, Lareb received 10 more reports of pregnancy during the use of the ring, in which expulsion was not mentioned explicitly. Additional information on these cases was collected by questionnaire. Expulsion of the ring is described in the product information. The ring should then be placed back within 3 h. However, the Lareb reports show that expulsion of the ring is not always noticed by the user. In those cases the contraceptive efficacy of this method is questionable. The physician should be alert to pre-existing risk factors that increase the chance of expulsion of the ring, and should provide extra detailed advice about the right way of placing the ring, the risk of expulsion and the importance of replacing it in time.


Cardiovascular, endocrine, and renal effects of urodilatin in normal humans.
Effects of urodilatin (5, 10, 20, and 40 ng. kg-1. min-1) infused over 2 h on separate study days were studied in eight normal subjects with use of a randomized, double-blind protocol. All doses decreased renal plasma flow (hippurate clearance, 13-37%) and increased fractional Li+ clearance (7-22%) and urinary Na+ excretion (by 30, 76, 136, and 99% at 5, 10, 20, and 40 ng. kg-1. min-1, respectively). Glomerular filtration rate did not increase significantly with any dose. The two lowest doses decreased cardiac output (7 and 16%) and stroke volume (10 and 20%) without changing mean arterial blood pressure and heart rate. The two highest doses elicited larger decreases in stroke volume (17 and 21%) but also decreased blood pressure (6 and 14%) and increased heart rate (15 and 38%), such that cardiac output remained unchanged. Hematocrit and plasma protein concentration increased with the three highest doses. The renin-angiotensin-aldosterone system was inhibited by the three lowest doses but activated by the hypotensive dose of 40 ng. kg-1. min-1. Plasma vasopressin increased by factors of up to 5 during infusion of the three highest doses. Atrial natriuretic peptide immunoreactivity (including urodilatin) and plasma cGMP increased dose dependently. The urinary excretion rate of albumin was elevated up to 15-fold (37 +/- 17 micrograms/min). Use of a newly developed assay revealed that baseline urinary urodilatin excretion rate was low (<10 pg/min) and that fractional excretion of urodilatin remained below 0.1%. The results indicate that even moderately natriuretic doses of urodilatin exert protracted effects on systemic hemodynamic, endocrine, and renal functions, including decreases in cardiac output and renal blood flow, without changes in arterial pressure or glomerular filtration rate, and that filtered urodilatin is almost completely removed by the renal tubules.


A(2b) receptors mediate the antimitogenic effects of adenosine in cardiac fibroblasts.
Adenosine inhibits growth of cardiac fibroblasts; however, the adenosine receptor subtype that mediates this antimitogenic effect remains undefined. Therefore, the goals of this study were to determine which adenosine receptor subtype mediates the antimitogenic effects of adenosine and to investigate the signal transduction mechanisms involved. In rat left ventricular cardiac fibroblasts, PDGF-BB (25 ng/mL) stimulated DNA synthesis ((3)H-thymidine incorporation), cellular proliferation (cell number), collagen synthesis ((3)H-proline incorporation), and MAP kinase activity. The adenosine receptor agonists 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, but not N(6)-cyclopentyladenosine, 4-aminobenzyl-5'-N-methylcarboxamidoadenosine, or CGS21680, inhibited the growth effects of PDGF-BB, an agonist profile consistent with an A(2B) receptor-mediated effect. The adenosine receptor antagonists KF17837 and 1,3-dipropyl-8-p-sulfophenylxanthine, but not 8-cyclopentyl-1,3-dipropylxanthine, blocked the growth-inhibitory effects of 2-chloroadenosine and 5'-N-methylcarboxamidoadenosine, an antagonist profile consistent with an A(2) receptor-mediated effect. Antisense, but not sense or scrambled, oligonucleotides to the A(2B) receptor stimulated basal and PDGF-induced DNA synthesis, cell proliferation, and collagen synthesis. Moreover, the growth-inhibitory effects of 2-chloroadenosine, 5'-N-methylcarboxamidoadenosine, and erythro-9-(2-hydroxy-3-nonyl) adenine plus iodotubericidin (inhibitors of adenosine deaminase and adenosine kinase, respectively) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A(2B) receptor. Our findings strongly support the hypothesis that adenosine causes inhibition of CF growth by activating A(2B) receptors coupled to inhibition of MAP kinase activity. Thus, A(2B) receptors may play a critical role in regulating cardiac remodeling associated with CF proliferation. Pharmacologic or molecular biological activation of A(2B) receptors may prevent cardiac remodeling associated with hypertension, myocardial infarction, and myocardial reperfusion injury after ischemia.


Kidney Autotransplantation for Renal Artery Aneurysm: Case Series and a Systematic Review.
Renal artery aneurysm (RAA) is a rare vascular disease. Kidney autotransplantation (KAT) is the treatment option when endovascular approach is not available. However, the evidence on KAT for RAA is mostly limited to small case series or reports. Here, we describe our 2 center experience of KAT for RAA, and provide the results of our systematic literature review to evaluate the outcomes. A retrospective 2 center study was conducted in patients undergoing KAT for RAA between 2010 and 2018. Moreover, a systematic review was performed on medical databases to evaluate the outcomes of KAT for RAA. Nine patients were surgically treated at our institutions: eight with laparoscopic nephrectomy (LN), and 1 with open followed heterotopic KAT. All RAAs were ex-vivo reconstructed, and in 3 cases a vein graft was used for reconstruction. There were 2 postoperative major complications including 1 graft loss. In the systematic review, 102 studies with 355 patients were included. In 35 patients (9.9%) a minimal invasive approach was performed. The incidence of postoperative major complications and graft loss was 9.4% and 4.1%. Our experiences showed that laparoscopic approach for nephrectomy followed heterotopic KAT was feasible with good postoperative outcomes. KAT is an effective treatment for RAA when endovascular approach is not feasible for interpretation of the outcomes, the quality and sample size of the evidence should be taken into consideration.


Ethanol-glycerin fixation with thymol conservation: a potential alternative to formaldehyde and phenol embalming.
Anatomical fixation and conservation are required to prevent specimens from undergoing autolysis and decomposition. While fixation is the primary arrest of the structures responsible for autolysis and decomposition, conservation preserves the state of fixation. Although commonly used, formaldehyde has been classified as carcinogenic to humans. For this reason, an adequate substitute was developed. Ethanol-glycerin fixation and thymol conservation are described and compared with formaldehyde and phenol in this technical report. The setup, tissue qualities, financial aspects, and health concerns of this method are discussed. Ethanol-glycerin fixation and thymol conservation provide outstanding haptic and optic tissue qualities. Typical formaldehyde and phenol effects, such as skin, airway, and eye irritation, as well as carcinogenic effects, can be circumvented by using ethanol-glycerin and thymol instead. Ethanol-glycerin fixation is more expensive than formaldehyde and requires an explosion-proof facility. However, the absence of health effects and its convincing tissue qualities balance these higher costs. Therefore, ethanol-glycerin fixation and thymol conservation provide a potential alternative and complement established fixation techniques. The use of carcinogenic formaldehyde and toxic phenol can be effectively restricted through the use of the described method.


Modification of humoral responses by the combination of leflunomide and cyclosporine in Lewis rats transplanted with hamster hearts.
Vigorous antibody-mediated responses prevent the successful engraftment of hamster hearts transplanted into Lewis rats. Early antibody responses mediating acute rejection of the xenograft are T cell-independent and resistant to the T-cell immunosuppressant, cyclosporine (CsA). Immunosuppression with the combination of leflunomide plus CsA completely prevents xenograft rejection, but when such immunosuppression is stopped the hamster heart is rejected by a process that we term late xenograft rejection. We report here on some of the immunological features of late xenograft rejection. Lewis rats transplanted with hamster hearts were treated with leflunomide (5 mg/kg/day by gavage) for 14-21 days and CsA (20 mg/kg/day by gavage) continuously from the day of transplant. Serum was harvested and the functional activities of the xenoreactive antibodies were quantitated by in vivo passive transfer of sera, flow cytometry, in vitro C3 deposition assays, and Western blotting. CsA alone prevented late xenograft rejection and the accompanying production of xenoreactive antibodies. The xenoreactive antibodies accompanying acute or late xenograft rejection were predominantly IgM, but only serum from rats undergoing acute xenograft rejection was able to induce hyperacute rejection. The ability of serum to induce hyperacute rejection correlated with its ability to induce C3 deposition on hamster lymphocytes in vitro. The repertoire of hamster antigens recognized by IgM in the serum of rats undergoing late xenograft rejection is more restricted than that of IgM in the serum of rats undergoing acute xenograft rejection. We additionally demonstrate that long-term graft survival is not dependent on graft accommodation. These studies demonstrate that a brief treatment with the combination of leflunomide and CsA profoundly modifies the humoral xenoreactivity in the recipient, converting it from a T-independent into a T cell-dependent response. Differences in functional activity of sera from acute or late xenograft rejection suggest that antigenic specificity defines the ability of IgM to induce complement activation and hyperacute rejection.


The effect of human embryonic stem cells (hESCs) long-term normoxic and hypoxic cultures on the maintenance of pluripotency.
The maintenance of pluripotency of human embryonic stem cells (hESCs) requires a high efficiency of self-renewal. During in vitro propagation, however, spontaneous differentiation occurs frequently, and there is also a risk of chromosomal changes. In this study, we assessed the properties of hESCs after long-term culture at ambient air and 5% oxygen growth conditions. The hESC lines were grown for up to 42 and 18 mo in normoxic and hypoxic conditions, respectively, and their proliferation; expression of Oct4, SSEA1, Nanog, and Notch1; karyotype; telomerase activity; and differentiation potential in vitro were evaluated. In contrast to cultures at 20% oxygen, where the central zones of the colonies underwent spontaneous differentiation, during exposure to 5% oxygen, the hESC colonies maintained a homogenous and flat morphology that was consistent with the presence of Oct4-positive undifferentiated phenotype. Irrespective of oxygen concentration, the undifferentiated cells expressed high levels of Nanog and Oct4 transcripts, normal karyotype, and high telomerase activity. When assayed for differentiation potential, they yielded derivatives of all three embryonic germ layers. Our data thus indicate that hypoxic exposure has the capacity to sustain enhanced long-term self-renewal of hESCs. The hESC lines described in the current paper can be obtained for research purposes from the Laboratory for Stem Cell Research, Aalborg University.


A meiotic mutant affecting recombination in female Drosophila melanogaster.
mei-S282 is a female meiotic mutant isolated from a natural population of Drosophila melanogaster. It is a recessive mutation located at approximately map position 5 on the third chromosome which has two major effects. It causes a nonuniform decrease in recombination which is most drastic in distal chromosome regions and nondisjunction of all chromosome pairs is elevated at the first meiotic division. Nondisjunctional events are positively correlated; furthermore, nondisjoining chromosomes, themselves nonrecombinant, are preferentially recovered from cells in which nonhomologs are preferentially recovered from cells in which nonhomologs are also non-recombinant.-It is concluded that mei-S282 is a defect which occurs early in meiosis I prior to the time of exchange. In the mutant, the frequency of no-exchange tetrads for each of the major chromosomes is increased-and in cells which contain two or more no-exchange tetrads, an interaction between these chromosomes leads to correlated nondisjunction. mei-S282(+) then, is an exchange precondition necessary for the normal frequency and distribution of exchanges.


Ciguatera fish poisoning in the Caribbean islands and Western Atlantic.
Ciguatera fish poisoning (ciguatera), a common poisoning caused by fish ingestion, is reviewed in the Western Atlantic and the Caribbean waters. It is endemic from Florida coasts (northern limit) to Martinique Island (southern limit), with outbreaks occurring from time to time. In the Caribbean, ciguatera causes a polymorphic syndrome with gastrointestinal, cardiovascular, and neurological signs and symptoms. Neurological and muscular dysfunctions can be treated by intravenous injection of D-mannitol. The lipid-soluble toxins involved are ciguatoxins that are likely produced by the dinoflagellate Gambierdiscus toxicus. G. toxicus strains are endemic in the Caribbean Sea and in theWestern Atlantic. Although it is likely that blooms of G. toxicus are ingested by herbivorous fishes, they are not implicated in ciguatera in the Caribbean. Rather, large carnivores (barracudas, jacks, snappers, groupers), consumers of smaller benthic fish, are often involved in ciguatera. Fish toxicity depends on fishing area and depth, fish size and tissues, and climatic disturbances. Ciguatoxins have been isolated and purified from Caribbean fish species. The structure of two epimers, C-CTX-1 and C-CTX-2 from horse-eye jack, comprise 14 trans-fused ether-linked rings and a hemiketal in terminal ring. Caribbean ciguatoxins are mainly detected in the laboratory by chicken, mouse, mosquito, or cell bioassays, and by analytical HPLC/tandem mass spectrometry down to parts per billion (ppb). A ciguatera management plan that integrates epidemiology, treatment, and a simple method of detection is required to ensure the protection of consumers.


The ability of women to recall their oral contraceptive histories.
Self-reported contraceptive histories were obtained at interview from 99 women and compared with prospectively collected data from the Oxford-Family Planning Association cohort study. The effect of different memory aids was evaluated and an assessment was made of the completeness and accuracy of contraceptive histories recorded in general practice notes. Accuracy of recall of total duration of use was sufficiently good to establish the presence or otherwise of a duration-response relationship and could be improved by the use of a contraceptive calendar. Recall of specific brands used was less accurate. In studies where accurate information on use of particular preparations is required, the use of a photo album is recommended, supplemented by data obtained from general practice records to improve the accuracy of dates. General practice records on their own are not sufficiently complete to be used as a sole source of exposure data in studies in which it is important to obtain a complete oral contraceptive history.


Relapse patterns in early-PET negative, limited-stage Hodgkin lymphoma (HL) after ABVD with or without radiotherapy-a joint analysis of EORTC/LYSA/FIL H10 and NCRI RAPID trials.
In the H10 and RAPID randomised trials, chemotherapy+radiotherapy (combined modalities treatment, CMT) was compared with chemotherapy (C) in limited-stage Hodgkin lymphoma (HL), with negative early positron emission tomography (ePETneg). We analysed patterns of relapses in the H10 trial, validated findings in the RAPID trial and performed a combined analysis stratified by trial. The impact of radiotherapy (RT) on risk of relapse was studied using adjusted Cox models, with time-varying effects. In H10, 1,059 ePETneg patients were included (465 European Organisation for Research and Treatment of Cancer (EORTC) favourable [F], 594 unfavourable [U]). Among the F patients, 2/227 (1%) relapsed after CMT, 30/238 (13%) after C: of these relapses, 21/30 (70%) occurred in less than 2 years and 25/30 (83%) affected originally involved areas. Among the U group, 16/292 (5%) relapsed after CMT: 8/16 (50%) in less than 2 years, 11/16 (69%) in originally involved areas. After C 30/302 (10%) relapsed: 27/30 (90%) in less than 2 years, and 26/30 (87%) in originally involved areas. Similar results were observed in 419 ePETneg RAPID patients (241 F, 128 U, 50 unclassified): among F patients, 6/118 (5%) relapsed after CMT; 13/123 (11%) after C: 11/13 (85%) in less than 2 years and 11/13 (85%) affecting originally involved areas. In U patients, 3/65 (5%) relapsed after CMT and 5/63 (8%) after C. In both trials, omitting RT in ePETneg HL resulted in more early relapses, mainly affecting originally involved areas. RT significantly reduced risk of early relapses in the combined stratified analysis.


Is severe obesity a form of addiction? Rationale, clinical approach, and controlled clinical trial.
For many, obesity is just a problem of energy input and expenditure: more energy input than expenditure. However, the clinical practice and epidemiological data clearly show that weight control is more complex than expected by this simple equation. This is particularly true in morbid obesity, a form of severe obesity in which a person's Body Mass Index (BMI, kg/m(2)) is over 40. If we compare the definitions and diagnostic criteria for "dependence" and "addiction" with the situation of many severe obese subjects, it is apparent that they match very well. Further, different neurological studies confirm this similarity: both addiction and obesity patients have a deficiency of dopamine receptors. Nevertheless, when we compare many of the actual obesity treatments with the ones used in the area of addictions it is possible to find relevant differences: obesity treatments neither consider different levels of type and intensity of care, nor a multidimensional approach. To overcome these limitations, in this paper we propose a bio-psychosocial approach in which the genetic influence (lack of dopamine receptors) is matched by psychosocial issues (pressure for thinness and diet as main body image dissatisfaction treatment). Further, the paper outlines how this approach may influence the treatment options, by focusing both on the lessons coming from actual addiction treatment and the opportunities offered by virtual reality. Finally, the paper presents and discusses the outcome of a controlled trial, based on the proposed approach, including a 6-month follow-up (211 morbid obese females with a BMI of >40 and a documented history of failures.


The effect of chronic stress and obesity on sperm quality and testis histology in male rats; a morphometric and immunohistochemical study.
Stress and obesity lead structural and functional abnormalities in many organs. This research investigated the effect of these two risk factors on sperm parameters and histologic structure of testis in rat model. Twenty-four male rats were divided into four groups with six rats in each group as control, stress, obesity, and stress-obesity groups. The rats of obesity and stress-obesity groups were fed high-fat diet for 12-week and obesity was created. Control and stress groups were given standard rat chow for the same time. Through last 4-week, stress and stress-obesity groups were applied to chronic mild stress procedure. At the end of the experiment, epididymal sperm was collected from vas deferens and testes were harvested from sacrificed animals. Sperm samples were evaluated in terms of concentration and motility by using Makler Chamber. Sperm smears were stained with Eosin-Y stain for morphological evaluation, and also histochemically for GABA transporter-1 (GAT1) expression assessment. Testis sections were dyed with Hematoxylin-Eosin and Johnsen scores were assessed. GAT1 expression was detected in testis sections by immunohistochemistry, and TUNEL method was used for determining apoptosis in testis. In comparison with the control samples in stress, obesity, and stress-obesity groups sperm concentration and motility decreased, and also the number of sperm with abnormal morphology increased. Stress, obesity, and stress-obesity groups showed a significantly decreased in sperm concentration and motility in comparison with the control group, and also in these groups had significantly increased number of abnormal sperm compared to control. Additionally, the testicular structure was deteriorated, and Johnsen scores decreased. And also GAT1 expression and apoptosis were prominent. These negative results, especially, testicular weight, sperm concentration, and Johnsen score were more observed in the stress-obesity group. Stress and obesity may induce male infertility by disrupting both sperm quality and testis histology. When stress and obesity are coexisting, these adverse effects are more severe. And also, increased GAT1 expression may be associated with these effects.


Dose dependency of canthaxanthin crystals in monkey retina and spatial distribution of its metabolites.
To establish the threshold level of canthaxanthin crystals in the retina of cynomolgus monkeys. To correlate the spatial distribution of all-trans canthaxanthin and its metabolites with the grade of crystals. Monkeys were orally administered 0, 0.2, 0.6, 1.8, 5.4, 16.2, and 48.6 mg/kg body wt canthaxanthin daily for 2.5 to 3 years. A second group of monkeys were administered 200 and 500 mg/kg body wt/d for 5 years. Ophthalmoscopy, electroretinography (ERG), retina and carotenoid analysis were performed as previously reported. Crystals in the retina periphery were observed by ophthalmoscopy preterminally only in the extreme high doses of 200 to 500 mg/kg body wt/d. There were no adverse effects on visual functions as measured by ERG. Crystals in the peripheral retina, and/or in the macula, were detected microscopically in all canthaxanthin treated groups except at the lowest dose of 0.2 mg/kg body wt/d. The grade of crystals increased up to a dose of 16.2 mg/kg body wt/d. Dose-dependent increases in canthaxanthin content also were noted in the retina, the liver, and in plasma. All-trans canthaxanthin was the major compound in the peripheral and paracentral retina of very highly dosed animals, where its concentration correlated largely with the grade of inclusions. In the macula, 4'-OH-echinenone was the dominant canthaxanthin metabolite. The grade of crystals in monkey retinas was dose dependent with a threshold level at 0.6 mg canthaxanthin/kg body wt/d. It correlated in the retinal periphery with the concentrations of all-trans-canthaxanthin and in the macula with its metabolites.


ICFSR Task Force Perspective on Biomarkers for Sarcopenia and Frailty.
Biomarkers of frailty and sarcopenia are essential to advance the understanding of these conditions of aging and develop new diagnostic tools and effective treatments. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force - a group of academic and industry scientists from around the world -- met in February 2019 to discuss the current state of biomarker development for frailty and sarcopenia. The D3Cr dilution method, which assesses creatinine excretion as a biochemical measure of muscle mass, was suggested as a more accurate measure of functional muscle mass than assessment by dual energy x-ray absorptiometry (DXA). Proposed biomarkers of frailty include markers of inflammation, the hypothalamic-pituitary-adrenal (HPA) axis response to stress, altered glucose insulin dynamics, endocrine dysregulation, aging, and others, acknowledging the complex multisystem etiology that contributes to frailty. Lack of clarity regarding a regulatory pathway for biomarker development has hindered progress; however, there are currently several international efforts to develop such biomarkers as tools to improve the treatment of individuals presenting these conditions.


A continuous curriculum for general practice? Proposals for undergraduate-postgraduate collaboration.
The development of a seamless general practice 'spiral' curriculum, in which topics may be revisited at different levels of intensity and complexity during the learning process, has been discussed in the context of undergraduate-postgraduate co-operation. Although the lifelong curriculum for all doctors contains a number of core competencies that aim to produce a 'stem' doctor, concerns remain about the effects of excessive reductionism. It is therefore essential that the content and delivery of the spiral curriculum ensure that intellectual interest is nurtured, by containing both taught theory and training in a hospital context. The opportunity for generalists to teach core competencies such that general practice is at the centre of the undergraduate curriculum--emphasising working within primary health care teams in teaching and training practices--is an ideal area for undergraduate-postgraduate co-operation. The use of the directly observed measures of performance would bring the undergraduate approach to assessment closer to that used in postgraduate general practice. However, supporting the tutors' network is crucial in undergraduate departments where much can be gained by joint working with postgraduate colleagues.


[Effect of storage of the thermotolerant actinomycete Thermoactinomyces vulgaris on its enzymic activity].
Various methods of storage (as soil cultures, in peptonecorn agar, and in the freeze-dried state) of the thermotolerant actinomycete Thermoactinomyces vulgaris RA II-4a, protease producer, were studied. The best method providing a high level of proteolytic activity was shown to be freeze-drying and subsequent selection of the most active variants. The optimal temperature for the storage of the freeze-dried culture was 4 degrees C. During a prolonged (12 months) storage of the actinomycete under the above conditions its proteolytic activity grew by 84.6%.


ClpC and MecA, components of a proteolytic machine, prevent Spo0A-P-dependent transcription without degradation.
In Bacillus subtilis, a proteolytic machine composed of MecA, ClpC and ClpP degrades the transcription factor ComK, controlling its accumulation during growth. MecA also inhibits sporulation and biofilm formation by down-regulating spoIIG and sinI, genes that are dependent for their transcription on the phosphorylated protein Spo0A-P. Additionally, MecA has been shown to interact in vitro with Spo0A. Although the inhibitory effect on transcription requires MecA's binding partner ClpC, inhibition is not accompanied by the degradation of Spo0A, pointing to a previously unsuspected regulatory mechanism involving these proteins. Here, we further investigate the MecA and ClpC effects on Spo0A-P-dependent transcription. We show that MecA inhibits the transcription of several Spo0A-P activated genes, but fails to de-repress several Spo0A-P repressed promoters. This demonstrates that MecA and ClpC do not act by preventing the binding of Spo0A-P to its target promoters. Consistent with this, MecA by itself has no effect in vitro on the transcription from PspoIIG while the addition of both MecA and ClpC has a strong inhibitory effect. A complex of MecA and ClpC likely binds to Spo0A-P on its target promoters, preventing the activation of transcription. Thus, components of a degradative machine have been harnessed to directly repress transcription.


Leprosy in the Netherlands. A review of leprosy patients registered at the Department of Dermatology, University of Amsterdam in the years 1972-1976.
Recently, there has been a sharp increase in the number of leprosy patients in The Netherlands, due to an increased immigration from Surinam where leprosy is hyperendemic. The patients registered at the Dermatological Department of the University of Amsterdam during the years 1972-1976 were reviewed. It was found that 28% of the untreated patients had recently suffered a relapse. A substantial percentage took the medication irregularly or discontinued treatment prematurely and quite a few patients required other types of treatment besides chemotherapy, such as surgical treatment and physiotherapy.


The aerodynamics and hydrodynamics of plants.
Because they grow away from their substratum to compete for light, plants have to withstand hydrodynamic or aerodynamic drag. Both water and land plants reconfigure in response to this drag, and this is presumed to reduce the risk of mechanical failure. However, there is little unequivocal evidence of drag reduction in large trees as a result of reconfiguration. Land plants must also transport water internally to their tissues, and many have developed xylem tracheids and vessels that help speed up this process. Recent evidence that tree height is limited by water supply suggests that water transport efficiency must be a crucial element in tree design. However, the resistance of many parts of the xylem is still unknown. More focused work is urgently required to shed light on the evolution and ecology of plants in relation to the flow of fluids.


A New Pedestrian Crossing Level of Service (PCLOS) Method for Promoting Safe Pedestrian Crossing in Urban Areas.
Crosswalks are critical locations in the urban transport network that need to be designed carefully as pedestrians are directly exposed to vehicular traffic. Although various methods are available to evaluate the level of service (LOS) at pedestrian crossings, pedestrian crossing facilities are frequently ignored in assessing crosswalk conditions. This study attempts to provide a comprehensive framework for evaluating crosswalks based on several essential indicators adopted from different guidelines. A new pedestrian crossing level of service (PCLOS) method is introduced in this research, with an aimto promote safe and sustainable operations at such locations. The new PCLOS employs an analytical point system to compare existing street crossing conditions to the guidelines' standards, taking into account the scores and coefficients of the indicators. The quantitative scores and coefficients of indicators are assigned based on field observations and respondent opinions. The method was tested to evaluate four pedestrian crosswalks in the city of Putrajaya, Malaysia. A total of 17 indicators were selected for the study after a comprehensive literature review. Survey results show that the provision of a zebra crossing was the most critical indicator at the pedestrian crossings, while drainage near crosswalks was regarded as the least important. Four indicators had a coefficient value above 4, indicating that these are very critical pedestrian crossing facilities and significantly impact the calculation of LOS for pedestrian crossings. Four crosswalks were evaluated using the proposed method in Putrajaya, Malaysia. The crosswalk at the Ministry of Domestic Trade Putrajaya got the "PCLOS A". In contrast, the midblock crossing in front of the Putrajaya Corporation was graded "PCLOS C". While the remaining two crosswalks were graded as "PCLOS B" crosswalks. Based on the assigned PCLOS grade, the proposed method could also assist in identifying current design and operation issues in existing pedestrian crossings and providing sound policy recommendations for improvements to ensure pedestrian safety.


Preoperative venous intimal hyperplasia, postoperative arteriovenous fistula stenosis, and clinical fistula outcomes.
Arteriovenous fistulas often fail to mature, and nonmaturation has been attributed to postoperative stenosis caused by aggressive neointimal hyperplasia. Preexisting intimal hyperplasia in the native veins of uremic patients may predispose to postoperative arteriovenous fistula stenosis and arteriovenous fistula nonmaturation. This work explored the relationship between preexisting venous intimal hyperplasia, postoperative arteriovenous fistula stenosis, and clinical arteriovenous fistula outcomes in 145 patients. Venous specimens obtained during arteriovenous fistula creation were quantified for maximal intimal thickness (median thickness=22.3 μm). Postoperative ultrasounds at 4-6 weeks were evaluated for arteriovenous fistula stenosis. Arteriovenous fistula maturation within 6 months of creation was determined clinically. Postoperative arteriovenous fistula stenosis was equally frequent in patients with preexisting venous intimal hyperplasia (thickness>22.3 μm) and patients without hyperplasia (46% versus 53%; P=0.49). Arteriovenous fistula nonmaturation occurred in 30% of patients with postoperative stenosis versus 7% of those patients without stenosis (hazard ratio, 4.33; 95% confidence interval, 1.55 to 12.06; P=0.001). The annual frequency of interventions to maintain arteriovenous fistula patency for dialysis after maturation was higher in patients with postoperative stenosis than patients without stenosis (0.83 [95% confidence interval, 0.58 to 1.14] versus 0.42 [95% confidence interval, 0.28 to 0.62]; P=0.008). Preexisting venous intimal hyperplasia does not predispose to postoperative arteriovenous fistula stenosis. Postoperative arteriovenous fistula stenosis is associated with a higher arteriovenous fistula nonmaturation rate. Arteriovenous fistulas with hemodynamically significant stenosis frequently mature without an intervention. Postoperative arteriovenous fistula stenosis is associated with an increased frequency of interventions to maintain long-term arteriovenous fistula patency after maturation.


Simian-human immunodeficiency virus containing a human immunodeficiency virus type 1 subtype-E envelope gene: persistent infection, CD4(+) T-cell depletion, and mucosal membrane transmission in macaques.
The envelope (env) glycoprotein of human immunodeficiency virus type 1 (HIV-1) determines several viral properties (e.g., coreceptor usage, cell tropism, and cytopathicity) and is a major target of antiviral immune responses. Most investigations on env have been conducted on subtype-B viral strains, prevalent in North America and Europe. Our study aimed to analyze env genes of subtype-E viral strains, prevalent in Asia and Africa, with a nonhuman primate model for lentivirus infection and AIDS. To this end, we constructed a simian immunodeficiency virus/HIV-1 subtype-E (SHIV) recombinant clone by replacing the env ectodomain of the SHIV-33 clone with the env ectodomain from the subtype-E strain HIV-1(CAR402), which was isolated from an individual in the Central African Republic. Virus from this recombinant clone, designated SHIV-E-CAR, replicated efficiently in macaque peripheral blood mononuclear cells. Accordingly, juvenile macaques were inoculated with cell-free SHIV-E-CAR by the intravenous or intravaginal route; virus replicated in these animals but did not produce hematological abnormalities. In an attempt to elicit the pathogenic potential of the recombinant clone, we serially passaged this viral clone via transfusion of blood and bone marrow through juvenile macaques to produce SHIV-E-P4 (fourth-passage virus). The serially passaged virus established productive infection and CD4(+) T-cell depletion in juvenile macaques inoculated by either the intravenous or the intravaginal route. Determination of the coreceptor usage of SHIV-E-CAR and serially passaged SHIV-E-P4 indicated that both of these viruses utilized CXCR4 as a coreceptor. In summary, the serially passaged SHIV subtype-E chimeric virus will be important for studies aimed at developing a nonhuman primate model for analyzing the functions of subtype-E env genes in viral transmission and pathogenesis and for vaccine challenge experiments with macaques immunized with HIV-1 env antigens.


The role of health anxiety in online health information search.
This article is one of the first to empirically explore the relationship between health anxiety and online health information search. Two studies investigate how health anxiety influences the use of the Internet for health information and how health anxious individuals respond to online health information. An exploratory survey study with 104 Dutch participants indicates that health anxiety is related to an increase in online health information search. Moreover, results suggest that health anxious individuals experience more negative consequences from online health information search. Findings from an experimental study (n=120) indicate that online health information results in greater worries among health anxious individuals compared to nonhealth anxious individuals only if the information stems from a trustworthy governmental Web site. Information from a less trustworthy online forum does not lead to greater worries among health anxious individuals. In sum, the Internet appears to play a pivotal role in the lives of health anxious individuals.


Getting drunk and growing up: trajectories of frequent binge drinking during the transition to young adulthood.
The purpose of this study was: (1) to identify different trajectories of frequent binge drinking during the transition to young adulthood; (2) to validate the trajectories by relating them to behaviors and attitudes concerning alcohol and other drug use; and (3) to distinguish among the trajectories according to demographic characteristics and lifestyle experiences typical of the transition to young adulthood. Four waves of national panel data were obtained from the Monitoring the Future project; 9,945 weighted cases from the 1976-85 high school senior year cohorts were surveyed at biennial intervals between ages 18 and 24. Frequent binge drinking was defined as having five or more drinks in a row at least twice in the past two weeks. Six distinct frequent binge drinking trajectory groups were specified a priori and confirmed with cluster analysis: Never, Rare, Chronic, Decreased, Increased and "Fling." Repeated measures ANOVAS revealed that the trajectories corresponded to patterns of change and stability in problems with alcohol, attitudes about heavy drinking, peer heavy drinking and illicit drug use. Results from logistic regression analyses predicting diverging and converging trajectories provided some support for the general hypothesis that trajectories of Chronic and Increased frequent binge drinking over time are associated with difficulties in negotiating the transition to young adulthood. The findings provide strong evidence for wide developmental variation in drinking patterns in the population, variation that is obscured by more aggregate-level considerations. The developmental variation in frequent binge drinking during the transition to young adulthood reflects systematic variation in success and difficulties with negotiating the transition.


Genetic Blood Disorders Survey in the Sultanate of Oman.
The Genetic Blood Disorders Survey is the first community-based survey in the Arabic world and the Middle East to determine the prevalence of the most common genetic blood disorders. The objective of the survey was to determine the prevalence of the most common genetic blood disorders reported among Omani children under 5 years of age in order to provide the planners and policy-makers with reliable information suitable for formulating health policies, planning, and evaluation. The survey was designed, executed, and financed by the Ministry of Health of the Sultanate of Oman. To reduce costs and save effort and time, data collection for the survey was implemented with the Gulf Family Health Survey (GFHS). The GFHS in the Sultanate of Oman is a research project undertaken by the Council of Health Ministers of the Gulf Co-operation Council States. The six member countries have participated in this GFHS project. A total of 6103 households were interviewed. From these households 6342 children under 5 years of age were taken by their parents to neighbourhood hospitals or health centres for blood collection. Fifty-one per cent of the sample were male and 49 per cent were female. Among the child respondents, 17.9 per cent were in the age group 0 to < 1 year, 20.3 per cent were in the age group 1 to < 2 years, 21.1 per cent were in the age group 2 to < 3 years, 20.5 per cent were in the age group 3 to < 4 years, and 20.2 per cent were in the age group 4 to 5 years. Fifty-five per cent of the mothers of the children studied were illiterate, 9 per cent could read and write but had less than primary education, 20 per cent had completed primary school, 9 per cent had attended preparatory school, 5 per cent had attended secondary school, 1 per cent had had intermediate education, while 0.6 per cent had completed university or higher education. The results of this survey revealed that haemoglobinopathies are prevalent in Oman; the prevalence of sickle cell trait was 6 per cent, and of beta-thalassaemia 2 per cent. The prevalence of sickle cell and homozygous beta-thalassaemia were 0.2 and 0.07 per cent, respectively. Other abnormal haemoglobins (Hb) have been detected in this survey; HbD (0.6 per cent), HbE (0.3 per cent), HbC (0.02 per cent). Combination of sickle cell with other abnormal Hb was also detected at low prevalence. Glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency had a high prevalence in Oman, being 25 per cent in males and 10 per cent in females. Among the children studied, three-quarters (74.5 per cent) were found to be free from haemoglobinopathies and G6PD normal, the rest (25.5 per cent), either had haemoglobinopathies (7.5 per cent), G6PD deficiency (16 per cent) or a combination of G6PD deficiency with at least one abnormal Hb (2 per cent). The prevalence of total haemoglobinopathies in Oman was 9.5 per cent. The prevalence of sickle cell trait varied between regions, North Sharqiya had the highest prevalence of 10 per cent. Dakhiliya (9 per cent), followed by Muscat and South Batinah 8 and 7.9 per cent, respectively. The prevalence of sickle cell trait declined by a half in Musandam, South Sharqiya, Dhahira, and North Batinah (4.7, 3.9, 3.9, and 2.9 per cent respectively). Dhofar had the lowest prevalence of 0.2 per cent and no cases of sickle cell trait were found in the Al-Wousta region in the sample selected. The prevalence of beta-thalassaemia trait ranged from 3.9 to 0.2 per cent. Three regions had high rates: North Batinah (3.9 per cent), Muscat (2.8 per cent), and Dakhiliya (2 per cent). The other five regions in the Sultanate have lower rates: Dhahira (1.7 per cent), Musandam (1.6 per cent), South Batinah (1.5 per cent), South Sharqiya (1.2 per cent), and North Sharqiya (1.1 per cent). The prevalence of beta-thalassaemia trait in Dhofar was 0.2 per cent and no cases were detected in the Al-Wousta region. The prevalence of G6PD deficiency reached 29 per cent in Dakhiliya, 26 per cent in South Batinah, 21 per cent in Dhahira, 19 per cent in Muscat and 17 per cent in North Sharqiya and North Batinah. The prevalence declined to 10 per cent in Musandam, 9 per cent in South Sharqiya, Dhofar had the lowest prevalence of 2 per cent and no cases of G6PD deficiency were found in Al-Wousta. The male to female ratio was 2.5:1. In all regions of the Sultanate, prevalence of G6PD deficiency in males were more than twice those in females. From the above rates, it could be calculated that in the whole Sultanate 44,733 children under 5 years of age have G6PD deficiency, 14,306 have sickle cell trait, 474 have sickle cell disease, 5393 have beta-thalassaemia trait, and 175 have beta-thalassaemia major. The study showed that the mean Hb level of children under 5 years of age was 10.9 g/dl for both males and females; the mean Hb level for males was 10.89 g/dl and for females 10.99 g/dl, the difference between males and females was significant. The study revealed that half of the children under 5 years of age were anaemic. Mild anaemia was predominant (46 per cent), while moderate and severe anaemia were 4 and 0.2 per cent respectively. The status of anaemia among children improved with age; mild anaemia was prevalent in 65 per cent of children between ages 0 to < or = 1 years then decreased with age until it reached 30 per cent at 4-5 years of age. The survey produced the first normal haematological indices for children under 5 years of age to be used as a reference in the country. The blood picture of the normal subjects in the survey showed that the mean Hb value for males was 11.9 g/dl and for females 11.8 g/dl. The children had reduced values of MCH and MCV compared to normal international values, the reason for this could be alpha-thalassaemia or iron deficiency. The children maintained high values of HbF (more than 1.2 per cent) even after their first birthday. HbF reached its normal level at 5 years of age. Marriage of first cousins among the parents of the children studied under 5 years of age was 34 per cent. Total consanguinity rate including second cousin relationships and beyond was 58 per cent. We recommend that a national prevention programme for genetic blood disorders be formulated by the authorities. The programme could be included in the Ministry of Health 5-year health development programme for prevention of non-communicable diseases which already exists.


Intraerythrocytic Mycoplasma-like organism diagnosed ultrastructurally as an agent of anaemia in laboratory-reared cyprinid hybrids.
A study targeting the etiology of severe anaemia that sporadically occurred in laboratory-bred cyprinid hybrids resulted in a diagnosis of a Mycoplasma-like organism selectively invading the cytoplasm of erythrocytes. Despite the fact that there was a concurrent yeast infection in moribund anaemic hybrids, the primary role in the development of anaemia was assigned to the Mycoplasma-like organism due to its regular occurrence in erythrocytes of both the moribund hybrids and hybrids that were free of yeast infection yet showed early to advanced symptoms of the disease. Novel data on the Mycoplasma-like organism's cytoskeleton were obtained from ultrathin sections of affected erythrocytes. An ultrastructural study of the concurrent yeast infection in moribund hybrids manifesting the most advanced anaemia revealed the presence of Titan cells in ascitic fluid. The original findings presented in this study underline the diagnostic relevance of transmission electron microscopy in the research of similar infections.


Clinical evaluation of biofiltration in uremic patients undergoing chronic hemodialysis.
The clinical efficiency of biofiltration (BF) was evaluated in six hemodialysis patients with poor clinical tolerance for standard hemodialysis. Three were adults (mean age 34 years, mean body weight 67 kg) and three adolescents (mean age 17 years, mean body weight 38 kg). Mean maintenance hemodialysis time was 90.5 months (range 49-132). BF treatments lasted three hours in all cases, for a total of nine hours weekly, with AN69 S membranes and infusion of 3 liters of HCO3 solution (100 mEq/l for the adults, 80 mEq/l for the adolescents). We recorded intra- and inter-dialytic symptoms daily, hematological values and acid-base status monthly. Multimodality evoked potentials were recorded after 3 and 9 months. Biochemical values reached a steady state 9 months from the beginning of the study, metabolic acidosis was corrected more efficiently in both groups at the end of dialysis, but only in the adult patients, were pre-dialysis plasma bicarbonates within normal limits. A clear drop in the number of episodes of intradialytic hypotension was noticed in both groups, but the adolescent patients' tolerance for dialysis did not improve. In conclusion our data show that in adult patients with poor tolerance BF offers a dependable alternative to standard hemodialysis, and the length of treatment can be reduced.


Telomerase RNA in Hymenoptera (Insecta) switched to plant/ciliate-like biogenesis.
In contrast to the catalytic subunit of telomerase, its RNA subunit (TR) is highly divergent in size, sequence and biogenesis pathways across eukaryotes. Current views on TR evolution assume a common origin of TRs transcribed with RNA polymerase II in Opisthokonta (the supergroup including Animalia and Fungi) and Trypanosomida on one hand, and TRs transcribed with RNA polymerase III under the control of type 3 promoter, found in TSAR and Archaeplastida supergroups (including e.g. ciliates and Viridiplantae taxa, respectively). Here, we focus on unknown TRs in one of the largest Animalia order - Hymenoptera (Arthropoda) with more than 300 available representative genomes. Using a combination of bioinformatic and experimental approaches, we identify their TRs. In contrast to the presumed type of TRs (H/ACA box snoRNAs transcribed with RNA Polymerase II) corresponding to their phylogenetic position, we find here short TRs of the snRNA type, likely transcribed with RNA polymerase III under the control of the type 3 promoter. The newly described insect TRs thus question the hitherto assumed monophyletic origin of TRs across Animalia and point to an evolutionary switch in TR type and biogenesis that was associated with the divergence of Arthropods.


Effect of extraction or nonextraction orthodontic treatment modality on favorability of eruption of impacted third molars.
The objective of the study is to determine if extraction of permanent teeth, for orthodontic purpose, causes a change in third molar angulation and also to determine if extraction of permanent teeth causes an increase in eruption space available for third molars. This systematic review includes retrospective cohort studies which evaluated the change in third molar angulation or eruption space available for third molars among orthodontic patients treated by a fixed appliance with either extraction or nonextraction protocol. Search engines used were MEDLINE, IndMED, Web of Science, Cochrane, EMBASE, and Google Scholar from the year 1975 to 2015. Separate data collection forms were used to extract data from the studies. The Cochrane Risk of Bias Assessment Tool was used to assess the studies included in the systematic review. Fifteen studies included in the systematic review proved that third molar angulation and eruption space improved in patients treated with extraction treatment modality. However, two studies concluded that change in third molar angulation and eruption space occurred irrespective of the type of treatment involved. The angulation and eruption space of third molar improved following extraction of premolar or molar. Nonextraction treatment modality did not cause any adverse effects.


The Importance of Systematically Reporting and Reflecting on eHealth Development: Participatory Development Process of a Virtual Reality Application for Forensic Mental Health Care.
The use of electronic health (eHealth) technologies in practice often is lower than expected, mostly because there is no optimal fit among a technology, the characteristics of prospective users, and their context. To improve this fit, a thorough systematic development process is recommended. However, more knowledge about suitable development methods is necessary to create a tool kit that guides researchers in choosing development methods that are appropriate for their context and users. In addition, there is a need for reflection on the existing frameworks for eHealth development to be able to constantly improve them. The two main objectives of this case study were to present and reflect on the (1) methods used in the development process of a virtual reality application for forensic mental health care and (2) development model that was used: the CeHRes Roadmap (the Centre for eHealth Research Roadmap). In the development process, multiple methods were used to operationalize the first 2 phases of the CeHRes Roadmap: the contextual inquiry and value specification. To summarize the most relevant information for the goals of this study, the following information was extracted per method: (1) research goal, (2) explanation of the method used, (3) main results, (4) main conclusions, and (5) lessons learned about the method. Information on 10 methods used is presented in a structured manner. These 10 methods were stakeholder identification, project team composition, focus groups, literature study, semistructured interviews, idea generation with scenarios, Web-based questionnaire, value specification, idea generation with prototyping, and a second round of interviews. The lessons learned showed that although each method added new insights to the development process, not every method appeared to be the most appropriate for each research goal. Reflection on the methods used pointed out that brief methods with concrete examples or scenarios fit the forensic psychiatric patients the best, among other things, because of difficulties with abstract reasoning and low motivation to invest much time in participating in research. Formulating clear research questions based on a model's underlying principles and composing a multidisciplinary project team with prospective end users appeared to be important in this study. The research questions supported the project team in keeping the complex development processes structured and prevented tunnel vision. With regard to the CeHRes Roadmap, continuous stakeholder involvement and formative evaluations were evaluated as strong points. A suggestion to further improve the Roadmap is to explicitly integrate the use of domain-specific theories and models. To create a tool kit with a broad range of methods for eHealth development and further improve development models, studies that report and reflect on development processes in a consistent and structured manner are needed.


Implementing supported employment as an evidence-based practice.
Supported employment for people with severe mental illness is an evidence-based practice, based on converging findings from eight randomized controlled trials and three quasi-experimental studies. The critical ingredients of supported employment have been well described, and a fidelity scale differentiates supported employment programs from other types of vocational services. The effectiveness of supported employment appears to be generalizable across a broad range of client characteristics and community settings. More research is needed on long-term outcomes and on cost-effectiveness. Access to supported employment programs remains a problem, despite their increasing use throughout the United States. The authors discuss barriers to implementation and strategies for overcoming them based on successful experiences in several states.


Control of ribonucleic acid synthesis in eukaryotes. 3. The effect of cycloheximide and edeine on rna synthesis in yeast.
The addition of cycloheximide to a thermosensitive conditional yeast mutant (ts-187) before and after transfer to the nonpermissive temperature (36 degrees C) for initiation of protein synthesis produces the uncoupling of the RNA and protein synthetic machineries. Since the drug can produce this relaxation in the presence and absence of protein synthesis, it is concluded that the coupling of protein and RNA synthesis, which a temperature shift produces, is not exclusively related to the inhibition of protein synthesis. Support for this assumption has been obtained using the parental (A364A) strain. Transferring this strain to 36 degrees C produces inhibition of RNA synthesis in the presence of stimulation of protein synthesis. Furthermore, cycloheximide and edeine prevent this inhibtion of RNA synthesis that temperature shift produces. It is, therefore, postulated that this inhibition of RNA synthesis results from the synthesis or activation of a factor(s) elicited by the increase in temperature whose function is to repress the transcriptional apparatus. Cycloheximide or edeine can prevent the function of this repressor-like factor by binding to the factor or by preventing its synthesis. The fact that inhibition of protein synthesis either by cycloheximide action or temperature shift in ts-187 produces inhibition of RNA synthesis in isolated nuclei indicates that, in addition to the aforementioned repressor, other factor(s) having a promoter function may exist. Since a slight inhibition of protein synthesis produces nuclear template restrictions, it is postulated that the promoter-like factor(s) is a polypeptide different from the RNA polymerase and, at least in yeast, has a high turnover.


Intramyocardial hematoma after coronary perforation during percutaneous coronary intervention--anticipated and treated.
Coronary perforation is an uncommon complication of percutaneous coronary intervention and the subset of patients developing a subepicardial hematoma without hemopericardium is even rarer. Subepicardial (or intramyocardial) hematomas are often associated with catastrophic events. These hematomas are reported mainly in those with prior coronary artery bypass grafting (CABG). To date, only 2 cases have been reported in non-CABG patients. Ours is such a case where the perforation failed to resolve. Despite the absence of pericardial effusion or hemodynamic instability, we anticipated the possibility of a dissecting myocardial hematoma and proceeded with preemptive surgery. Perioperative findings confirmed the presence of a large intramyocardial hematoma, conservative treatment of which may well have led to potentially lethal consequences. We then review the scant literature on the subject.


Can Tele-Health Support Self-Care and Empowerment? A Qualitative Study of Hip Fracture Patients' Experiences With Testing an "App".
Telemedicine or tele-health is increasingly used to help meet challenges in health care linked to demographic changes and an aging population. This study aimed to investigate whether a tele-health solution, an "app" presented on a tablet, can assist patients in their recovery following a hip fracture and accommodate individual learning and health literacy needs to support them in self-care and empowerment. Twenty patients with a hip fracture were informed and educated using an app during hospital admission and for 3 to 4 weeks after discharge. A qualitative approach employed field observation and individual interviews with patients and their relatives. Data were analyzed using qualitative content analysis. Patients found that the app supported their ability to perform self-care and their desire for autonomy. They would not have downloaded the app by themselves but found the use of the app presented on a tablet very supportive in their everyday life while rehabilitating after a hip fracture. Findings indicate that health-care professionals can support information and education for patients with a hip fracture using an app that accommodates different learning styles. This demonstrates that apps used for the dissemination of health knowledge can be used by elderly hip fracture patients even if they are not used to technology.


Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus.
We here investigated endothelial nitric oxide synthase (eNOS) expression after 10 minutes of forebrain ischemia. Real-time polymerase chain reaction, immunoblots and immunohistochemical studies revealed up-regulation of eNOS expression in the hippocampal CA1 subfield of gerbil. Immunoreactivity of eNOS significantly increased in endothelium but neither in neurons nor astrocytes after 6 to 168 hours of reperfusion. An increased Akt activity preceded the postischemic eNOS up-regulation. Intracerebroventricular injection (i.c.v.) of wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI-3K), significantly inhibited the increases in both eNOS mRNA and its protein with concomitant inhibition of Akt activation. The significant increase in the eNOS expression was also evident following preconditioning 2-minute ischemia. Both eNOS up-regulation and acquisition of ischemic tolerance observed at 3 days after preconditioning ischemia were significantly inhibited by pretreatment with wortmannin. Administration (i.c.v.) of N-nitro-L-arginine methyl ester, but not 7-nitroindazole, 30 minutes prior to lethal 10-minute ischemia, significantly abolished the acquired tolerance. Intraperitoneal injections of aminoguanidine at immediately after, 24, and 48 hours after preconditioning had no effects on the tolerance. These results suggest that eNOS expression is up-regulated in the endothelium via PI-3K pathways after transient forebrain ischemia, and that preconditioning-induced eNOS expression plays an important role in neuroprotection in the ischemic tolerance.


Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report.
Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.