Strokes and vision: The management of ischemic arterial disease affecting the retina and occipital lobe.
Embolic disease of the anterior or posterior vascular territories may lead to disturbance of vision. Although death from this is uncommon, morbidity remains relatively high: Visual field loss may impair or preclude reading and driving and these are important influences on quality of life. Visual symptoms of stroke mean that patients may present to ophthalmologists with isolated visual symptoms, rather than directly to an emergency department. It is important to diagnose stroke and transient ischemic attacks accurately, as well as to manage them appropriately, as they are important harbingers of further cerebrovascular events. Ophthalmologists are therefore well placed to ensure that these patients receive appropriate acute treatment and secondary prevention. This article reviews the evidence for managing patients presenting with visual symptoms of vascular events. It reviews management of ischemic stroke in general, and compares this with management of events involving the anterior circulation by way of transient monocular visual loss or retinal artery occlusion, and posterior circulation by way of transient binocular visual loss or infarction of the visual cortex.


Albendazole therapy in human lung and liver hydatid cysts: A 13-year experience.
Cystic echinococcosis (CE) is an endemic disease in Iran. This study has aimed to report the efficacy of Albendazole therapy in patients with CE. Among 164 patients with echinococcosis who were referred to the surgery clinic, Ghaem hospital, Mashhad University of Medical Sciences between 2001 and 2013, two were diagnosed with alveolar echinococcosis (AE) and 162 with CE; 43 of whom underwent surgery. The rest 119 patients received medical therapy by Albendazole 15 mg/kg/day for three phases. Each phase included 6 weeks of Albendazole therapy followed by 2 weeks of no medication. The patients were classified according to radiologic evaluations into four groups: (1) cured, (2) improved, (3) unchanged, and (4) worsened or relapsed. Patients who completed more phases had significantly greater chances of better response. Of the 56 patients who completed all three phases, 37 (66.1%) were cured, 15 (26.8%) improved, 4 (7.1%) remained unchanged, and none worsened or relapsed. [Odds ratio (OR):4.78, 95% confidence interval (CI): 2.95-7.74, P < .0001]. Albendazole can be beneficial for inoperable, multiple cysts, and multiple organs CE patients.


Relation of Left Atrial Enlargement to Subsequent Thromboembolic Events in Nonvalvular Atrial Fibrillation Patients With Low to Borderline Embolic Risk.
The current thromboembolic risk stratification of non-valvular atrial fibrillation (NVAF) does not include parameters from transthoracic echocardiography (TTE). We hypothesized that left atrial enlargement (LAE) on TTE could discriminate who require anticoagulation therapy among NVAF patients with low/borderline clinical embolic risk. This single-center cohort study included 6,602 patients with NVAF (median age, 56 years, 70.0% male) with a low to borderline clinical embolic risk (CHA2DS2-VASc score: 0 to 1 in males, 1 to 2 in females). LAE was classified as mild (≥41 mm in males; ≥39 mm in females) or moderate-severe (≥47 mm in males; ≥43 mm in females). The main study outcome was thromboembolic event (ischemic stroke and systemic embolism). Mild and moderate-severe LAE was diagnosed in 26.1% and 32.9% of the cohort, respectively. The patients with moderate-severe LAE showed a higher prevalence of baseline comorbidities and valvular heart disease and had a higher incidence of thromboembolic events than patients with mild or no LAE at 2 years of follow-up (2.5% vs 1.3% vs 1.1%, respectively, p < 0.001). After multivariable adjustment, patients with moderate-severe LAE were at a higher risk of thromboembolic event (hazard ratio, 2.54; 95% CI, 1.65 to 3.90; p < 0.001) compared to those with no LAE. This result persisted in a subgroup analysis of anticoagulant-naïve patients. The rate of thromboembolic events in patients with low clinical embolic risk and moderate-severe LAE was not different to those with high clinical embolic risk without LAE. In conclusion, Moderate-severe LAE on TTE was a significant predictor of thromboembolic events in NVAF patients at low/borderline clinical embolic risk.


Human amnion epithelial cells assemble tenascins and three fibronectin isoforms in the extracellular matrix.
Monoclonal antibodies (MAb) were used to show that cultured human amnion epithelial (HuA) cells produce tenascins (Tn) and isoforms of cellular fibronectin (cFn). Tn polypeptides of M(r) 280,000 and 190,000, assembled into extracellular matrix (ECM) but not secreted into the culture medium by HuA cells, were electrophoretically similar to those produced by human fibroblasts as revealed with domain-specific MAbs. The results suggested that most Fn produced by HuA cells contained the extradomain (ED) A and an oncofetal domain but only a minor fraction EDB. In immunofluorescence Tn and Fn were seen in different cytoplasmic granules upon monensin-induced intracellular accumulation. Tn appeared to be deposited in the ECM in colocalization with Fn but distinctly slower. The present results show that cultured normal human epithelial cells synthesize Tn and three isoforms of cFn and secrete them by using different cytoplasmic pathways.


Levels of prodynorphin mRNA in rat dentate gyrus are decreased during hippocampal kindling.
The effect of hippocampal kindling on the levels of prodynorphin mRNA in rat hippocampus was examined by in situ hybridization using a synthetic oligonucleotide probe. Cryostat tissue sections were hybridised with a 32P-labelled 100 mer DNA probe complementary to the coding region of rat prodynorphin mRNA, and exposed to X-ray film. In rats exhibiting stage 4 seizures, the levels of prodynorphin mRNA in the dentate gyrus were dramatically reduced compared to control animals. This suggests that the development of kindling is accompanied by a reduction in the rate of synthesis of peptides derived from prodynorphin.


Use of plant cell cultures in biotechnology.
Plant cell cultures are being widely used in scientific studies on the physiology, biochemistry and molecular biology of primary and secondary metabolism, developmental regulation and cellular responses to pathogens and stress. In this chapter the significance of plant cell cultures in biotechnology is discussed with special emphasis on commercial production of secondary metabolites and pharmaceuticals, the potential of genetically transformed cell cultures, photosynthetically active cell cultures, production of somatic embryos, and novel assay systems based on the use of plant cells. Future aspects of biotechnical applications with respect to the potentials and limitations of these approaches are assessed, particularly in comparison with the productivity of lower eucaryotes.


Effectiveness of goosestep training or its modification on treating patellar malalignment syndrome: clinical, radiographic, and electromyographic studies.
Imbalanced soft tissue tension between medial and lateral para-patellar structures is the most common pathogenic cause of patellar malalignment syndrome. Despite the fact that an effective technique has not been developed, this disorder is usually treated conservatively. This prospective study tried to identify an effective alternative treatment for patellar malalignment syndrome. Forty female patients (age, 20-40 years) with bilateral patellar malalignment syndrome were randomly divided into two groups. Forty knees in 20 patients were treated with goosestep training without forcefully striking the ground, and 40 knees in other 20 patients were treated with goosestep training with forcefully striking the ground. After 1 month, significant clinical improvement was observed in 72.5% of all patients (P < 0.001). Congruence or lateral patellofemoral angles and VMO/VL (vastus medialis obliquus/vastus lateralis) ratio significantly improved within 1 or 3 months in both groups (P < 0.001 for each comparison). Goosestep training with or without forcefully striking the ground is a feasible method for treating patellar malalignment syndrome. The main advantages include its convenience, simplicity, lack of cost, and demonstrated effectiveness.


Reduction of Animal Sacrifice in Biomedical Science & Research through Alternative Design of Animal Experiments.
Various upcoming techniques can be used in replacement of experiments requiring animal sacrifice or products of animal sacrifice. In many instances these techniques provide more reproducibility and control of parameter, compared to experiments involving animal or animal products. Use of these techniques can avoid the question of the animal sacrifice during experiment and subsequently permission of ethical approval. In silico simulation, informatics, 3D cell culture models, organ-on-chips are some innovative technology which can reduce the number of animals sacrifice. Scientist evolved some innovative culture procedures and production of animal friendly affinity reagents which are free from the product of animal sacrifice. Direct investigation on human body for treatment as well as further research, electronic health record is also helpful in the reduction of animals sacrifice in biomedical investigations. These techniques and strategies of research can be more cost effective as well as more relevant to various issues related to the human health. Some medical blunder has also been reported after the successful testing of drugs on animal's model. Hence, the reliability of animal experiment in context with human health is questionable. Alternative to animal experiments help to reduce the number of animals required for research up to certain extent but is not able to eliminate the need for animals in research completely. Wisely use of animals in teaching & research is expected and the importance of animal experimentation in futuristic development in life science cannot be ignored.


Seasonal and state-dependent changes in brain TRH receptors in hibernating ground squirrels.
Quantitative autoradiography was used to localize and quantify thyrotropin-releasing hormone (TRH) receptors in the brain of hibernating (H), winter euthermic (WE), and summer euthermic (SE) animals to further explore the state-dependent physiological and behavioral effects of TRH in ground squirrels. The pattern of [3H]MeTRH binding (Kd 6.7 +/- 0.1 nM) was heterogeneous and highly concentrated in structures primarily associated with the limbic forebrain. Statistically significant seasonal changes (SE vs. WE) were reflected by decreases in TRH receptor binding in the arcuate nucleus, dorsomedial nucleus, and ventral pallidum of WE animals. Increased binding in WE animals was evident in the suprachiasmatic nucleus and choroid plexus of the lateral ventricles. Significant state-dependent changes (WE vs. H) were characterized by decreases in TRH receptor binding in the hypothalamic paraventricular nucleus, medial preoptic area, ventral tegmental area, and choroid plexus of the lateral ventricles of H animals. Increased binding occurred in the anterior cortical nucleus of the amygdala in H animals. The results suggest that naturally occurring changes in central TRH systems may be important in the mediation of physiological and behavioral processes that undergo seasonal and state-dependent adjustments in hibernating mammals.


Diagnostic yield of upper endoscopy in paediatric patients with Crohn's disease and ulcerative colitis. Subanalysis of the HUPIR registry.
According to Porto Criteria upper gastrointestinal (UGI) endoscopy is recommended in patients with suspected inflammatory bowel disease (IBD). Nevertheless, previous studies revealed frequent involvement of UGI tract even in patients with ulcerative colitis (UC). The aim of the present study was to determine the diagnostic role of esophagogastroduodenoscopy (EGD) and assess the prevalence and different aspects of UGI involvement in children registered in the Hungarian Pediatric IBD Registry (HUPIR) from 1st of January 2007 to 31th of December 2009. Twenty seven institutes provided prospective follow-up data about newly diagnosed IBD patients to HUPIR. The registry was based on detailed questionnaire (76 parameters) involving anamnestic data, laboratory findings, activity indexes, diagnostic procedures, endoscopic examinations (EGD and ileocolonoscopy), and histological data. Localization and phenotype of disease were based on the Montreal classification criteria. During the 3-year period 420 children were diagnosed with IBD, 265 (63%) of them had Crohn's disease (CD), 130 (31%) UC, and 25 (6%) IBD-unclassified (IBD-U). The mean age at diagnosis was 13.2 years (range: 1.2-18 years). EGD was performed in 237 patients (56%), in most cases in patients suffering from CD. Macroscopic lesions on EGD were noted in 64% of patients with CD and 40% of children with UC. Characteristic lesions for CD (ulcer, erosion, aphthous lesion, and granuloma) were noted in 31% of CD patients, however, EGD helped to establish the final diagnosis in 9% of CD patients (diagnostic yield, 9%). There was a high frequency of UGI involvement in children with CD and UC. One third of CD patients showed significant lesions at upper endoscopy and one patient out of ten had real diagnostic help from EGD.


Achieving equity within universal health coverage: a narrative review of progress and resources for measuring success.
Equity should be implicit within universal health coverage (UHC) however, emerging evidence is showing that without adequate focus on measurement of equity, vulnerable populations may continue to receive inadequate or inferior health care. This study undertakes a narrative review which aims to: (i) elucidate how equity is contextualised and measured within UHC, and (ii) describe tools, resources and lessons which will assist decision makers to plan and implement UHC programmes which ensure equity for all. A narrative review of peer-reviewed literature published in English between 2005 and 2013, retrieved from PubMed via the search words, 'universal health coverage/care' and 'equity/inequity' was performed. Websites of key global health organizations were also searched for relevant grey literature. Papers were excluded if they failed to focus on equity (of access, financial risk protection or health outcomes) as well as focusing on one of the following: (i) the impact of UHC programmes, policies or interventions on equity (ii) indicators, measurement, monitoring and/or evaluation of equity within UHC, or (iii) tools or resources to assist with measurement. Eighteen journal articles consisting mostly of secondary analysis of country data and qualitative case studies in the form of commentaries/reviews, and 13 items of grey literature, consisting largely of reports from working groups and expert meetings focusing on defining, understanding and measuring inequity in UHC (including recent drafts of global/country monitoring frameworks) were included. The literature advocates for progressive universalism addressing monetary and non-monetary barriers to access and strengthening existing health systems. This however relies on countries being effectively able to identify and reach disadvantaged populations and estimate unmet need. Countries should assess the new WHO/WB-proposed framework for its ability to adequately track the progress of disadvantaged populations in terms of achieving equitable access, effective coverage and financial risk protection within their own settings. Recently published resources contextualise equity as a measurable component of UHC and propose several useful indicators and frameworks. Country case-studies also provide useful lessons and recommendations for planning and implementing equitable UHC which will assist other countries to consider their own requirements for UHC monitoring and evaluation.


In situ observation of carbon nanotube yarn during voltage application.
Carbon nanotube (CNT) yarns are fabricated by drawing (combined with spinning) from CNT forests and grown on a substrate. Three types of phenomena occur in these CNT yarns with increasing amounts of current: yarn rotation, catalyst evaporation, and breakage of the yarn. These phenomena result from the resistive heating occurring during the current flow, and have been observed in situ under vacuum by transmission electron microscopy. If these CNT yarns are applied to electronic circuits, the rotation and breakage may lead to circuit failure. However, catalyst evaporation is a useful method for purifying CNT yarns without additional treatments prior to yarn fabrication.


Insights into the role of prechlorination in algae-laden raw water distribution process: Algal organic matter and microcystin-LR release, extracellular polymeric substances (EPS) aggregation, and pipeline biofilm communities.
Prechlorination routinely applied for the treatment of algae-laden raw water has received extensive attention due to its influence on water quality and aquatic microbes. In this study, prechlorination experiments with different doses were conducted in sets of model raw water distribution systems. With the elevated dose of chlorine and prolonged hydraulic retention time (HRT), the ratio of intact algal cells decreased, and the stability of water enhanced. Dissolved organic carbon (DOC) and nitrogen (DON) increased when chlorine dose elevated from 0 to 0.5 mg/L but decreased with elevations from 0.5 to 2.0 mg/L, while UV254 showed a monotonically increasing tendency. DOC, DON and extracellular microcystin-LR increase initially and decrease thereafter with the prolonged HRT. Notably, the effects of prechlorination on extracellular polymeric substances aggregation behavior on pipe walls and microbial community composition was revealed, providing more profound understanding of the community dynamics in this engineered system. This study helped optimize strategies to improve the stability and efficiency of pretreatment of algae-laden water.


The mechanism of action of antioxidants against lipoprotein peroxidation, evaluation based on kinetic experiments.
Peroxidation of blood lipoproteins is regarded as a key event in the development of atherosclerosis. Hence, attenuation of the oxidative modification of lipoproteins by natural and synthetic antioxidants in vivo is considered a possible way of prevention of cardiovascular disorders. The assessment of the susceptibility of lipoproteins to oxidation is commonly based on in vitro oxidation experiments. Monitoring of oxidation provides the kinetic profile characteristic for the given lipoprotein preparation. The kinetic profile of peroxidation is characterized by three major parameters: the lag preceding rapid oxidation, the maximal rate of oxidation (V(max)) and the maximal accumulation of oxidation products (OD(max)). Addition of antioxidants alters this pattern, affecting the kinetic parameters of oxidation. In particular, antioxidants may prolong the lag and/or decrease the V(max) and/or decrease the OD(max). Such specific variation of the set of kinetic parameters may provide important information on the mechanism of the inhibitory action of a given antioxidant (scavenging free radicals, metal-binding or other mechanisms). Numerous natural and synthetic compounds were reported to inhibit oxidation of lipoproteins. Based on the analysis of reported effects and theoretical considerations, we propose a simple protocol that relates the kinetic effects of a given antioxidant to the mechanism of its action.


The effect of lifting speed on cumulative and peak biomechanical loading for symmetric lifting tasks.
To determine the influence of lifting speed and type on peak and cumulative back compressive force (BCF) and shoulder moment (SM) loads during symmetric lifting. Another aim of the study was to compare static and dynamic lifting models. Ten male participants performed a floor-to-shoulder, floor-to-waist, and waist-to-shoulder lift at three different speeds [slow (0.34 m/s), medium (0.44 m/s), and fast (0.64 m/s)], and with two different loads [light (2.25 kg) and heavy (9 kg)]. Two-dimensional kinematics and kinetics were determined. A three-way repeated measures analysis of variance was used to calculate peak and cumulative loading of BCF and SM for light and heavy loads. Peak BCF was significantly different between slow and fast lifting speeds (p < 0.001), with a mean difference of 20% between fast and slow lifts. The cumulative loading of BCF and SM was significantly different between fast and slow lifting speeds (p < 0.001), with mean differences ≥80%. Based on peak values, BCF is highest for fast speeds, but the BCF cumulative loading is highest for slow speeds, with the largest difference between fast and slow lifts. This may imply that a slow lifting speed is at least as hazardous as a fast lifting speed. It is important to consider the duration of lift when determining risks for back and shoulder injuries due to lifting and that peak values alone are likely not sufficient.


Characterization and expression analysis of P5CS (Δ1-pyrroline-5-carboxylate synthase) gene in two distinct populations of the Atlantic Forest native species Eugenia uniflora L.
Eugenia uniflora is an Atlantic Forest native species, occurring in contrasting edaphoclimatic environments. The identification of genes involved in response to abiotic factors is very relevant to help in understanding the processes of local adaptation. 1-Pyrroline-5-carboxylate synthetase (P5CS) is one interesting gene to study in this species since it encodes a key enzyme of proline biosynthesis, which is an osmoprotectant during abiotic stress. Applying in silico analysis, we identified one P5CS gene sequence of E. uniflora (EuniP5CS). Phylogenetic analysis, as well as, gene and protein structure investigation, revealed that EuniP5CS is a member of P5CS gene family. Plants of E. uniflora from two distinct environments (restinga and riparian forest) presented differences in the proline accumulation and P5CS expression levels under growth-controlled conditions. Both proline accumulation and gene expression level of EuniP5CS were higher in the genotypes from riparian forest than those from restinga. When these plants were submitted to drought stress, EuniP5CS gene was up-regulated in the plants from restinga, but not in those from riparian forest. These results demonstrated that EuniP5CS is involved in proline biosynthesis in this species and suggest that P5CS gene may be an interesting candidate gene in future studies to understand the processes of local adaptation in E. uniflora.


Changes in Advanced Immunosuppression and Detectable HIV Viremia Among Perinatally HIV-Infected Youth in the Multisite United States HIV Research Network.
Due to successful antiretroviral therapy (ART), perinatally human immunodeficiency virus (PHIV)-infected children are reaching adolescence and young adulthood. Adolescence is characterized by factors (eg, increased risk-taking) that may hamper management. We examined PHIV-infected youth in a multisite US cohort, assessing factors associated with changes in advanced immunosuppression and detectable viremia over time. We conducted a retrospective study of 521 PHIV-infected youth, 12 years and older, followed at 16 HIV clinics in the HIV Research Network between 2002 and 2010. We assessed demographic and clinical factors associated with CD4 <200 cells/mm(3) and viral load ≥2.60 log10 HIV-1 RNA copies/mL using multivariable logistic regression. Between 2002 and 2010, the median age of PHIV-infected youth in care increased from 14 to 18 years. The proportion prescribed ART increased from 67.4% to 84%, with virologic suppression increasing from 35.5% to 63.0% (P trend < .01). Older age, Black and Hispanic race/ethnicity, and increasing viremia were independently associated with CD4 <200 cells/mm(3). Older age, Black race and Hispanic ethnicity were independently associated with higher likelihood of detectable viremia, whereas more recent year of evaluation and being prescribed ART were associated with a lower likelihood. The proportion of PHIV-infected youth on ART has increased. Rates of viremia and advanced immunosuppression have decreased in recent years, but both rates are higher for older PHIV-infected youth. Factors associated with advanced immunosuppression and viremia offer the chance to define strategies to optimize outcomes.


Self-control of dysmenorrheic symptoms through pain management training.
An adaptation of Anxiety Management Training was evaluated as a means of teaching women to use relaxation in order to control menstrual pain and discomfort. After reporting their menstrual symptoms for two successive baseline periods, spasmodic and congestive dysmenorrheic subjects received four individual sessions of pain management training. Following treatment, these subjects reported significant reductions in pain, discomfort, interference, and time loss due to dysmenorrheic symptoms relative to their own baselines and to an untreated control group. These effects were still in evidence 18 months after treatment and appeared to have generalized to behavioral, attentional and autonomic symptoms that might be considered secondary sequelae of dysmenorrhea. With one minor exception, there was no differential response to treatment by spasmodic as opposed to congestive subjects.


Medical experimentation on prisoners (part 6): Situation in Africa, Middle East and part of the Arab world (Tunisia in particular).
The developing World has the largest number of prisoners globally, but their situation is considered «opaque». In recent years, there has been a growing interest from pharmaceutical companies in this part of the world. A growing number of voices is denouncing the spectrum of medical exploitation of prisoners. In Tunisia, there is a great legislative effort to ensure the protection of this vulnerable population. The present history note, the sixth in a series on medical experimentation on prisoners, intended to discuss the situation of medical experimentation in prisons in Africa, the Middle East and part of the Arab world, Tunisia in particular.


Chronic Pain And Health-Related Quality Of Life In Women With Autism And/Or ADHD: A Prospective Longitudinal Study.
To investigate the prevalence of chronic pain and its association with health-related quality of life (HRQoL) in a group of women, diagnosed with autism spectrum disorder (ASD) and/or attention deficit hyperactive disorder (ADHD) in childhood. Prospective longitudinal 16-19 years follow-up study of 100 Swedish females diagnosed with ASD and/or ADHD in childhood/adolescence. Seventy-seven of the women were included in the current sub-study, using validated measures of pain perception and quality of life. A large majority of the women (76.6%) reported chronic pain. HRQoL was low overall and lower still for those reporting chronic pain. Women with ADHD who had ongoing treatment with stimulants reported a significant lower prevalence of chronic widespread pain (CWP) than those not treated. Comorbidity with chronic pain is common in women with ASD and/or ADHD and important to address in the clinic since it is associated with an already low HRQoL. Treatment for ADHD might reduce the pain in some cases.


[New treatments of infectious diseases over the last ten years].
This review focuses on new antibiotics, particularly for gram-positive infections, new antiretroviral drugs, new treatment of fungal infections and indications of miltefosine in the treatment of leishmaniasis.


Structure determination of aligned systems by solid-state NMR magic angle spinning methods.
Single crystal rotational echo double resonance (REDOR) experiments can be used to determine the three-dimensional orientation of heteronuclear bond vectors in an amino acid, as well as the crystal's orientation relative to the rotor fixed frame (RFF). We also demonstrate that for samples uniaxially aligned along the rotor axis, the polar tilt angle of a bond vector relative to the RFF can be measured by use of an analytical expression that describes the REDOR curve for that system. These bond orientations were verified by X-ray indexing of the single crystal sample, and were shown to be as accurate as +/- 1 degrees .


Concomitant Imaging Dose and Cancer Risk in Image Guided Thoracic Radiation Therapy.
Kilovoltage cone beam computed tomography (CT) (kVCBCT) imaging guidance improves the accuracy of radiation therapy but imposes an extra radiation dose to cancer patients. This study aimed to investigate concomitant imaging dose and associated cancer risk in image guided thoracic radiation therapy. The planning CT images and structure sets of 72 patients were converted to CT phantoms whose chest circumferences (Cchest) were calculated retrospectively. A low-dose thorax protocol on a Varian kVCBCT scanner was simulated by a validated Monte Carlo code. Computed doses to organs and cardiac substructures (for 5 selected patients of various dimensions) were regressed as empirical functions of Cchest, and associated cancer risk was calculated using the published models. The exposures to nonthoracic organs in children were also investigated. The structural mean doses decreased monotonically with increasing Cchest. For all 72 patients, the median doses to the heart, spinal cord, breasts, lungs, and involved chest were 1.68, 1.33, 1.64, 1.62, and 1.58 cGy/scan, respectively. Nonthoracic organs in children received 0.6 to 2.8 cGy/scan if they were directly irradiated. The mean doses to the descending aorta (1.43 ± 0.68 cGy), left atrium (1.55 ± 0.75 cGy), left ventricle (1.68 ± 0.81 cGy), and right ventricle (1.85 ± 0.84 cGy) were significantly different (P<.05) from the heart mean dose (1.73 ± 0.82 cGy). The blade shielding alleviated the exposure to nonthoracic organs in children by an order of magnitude. As functions of patient size, a series of models for personalized estimation of kVCBCT doses to thoracic organs and cardiac substructures have been proposed. Pediatric patients received much higher doses than did the adults, and some nonthoracic organs could be irradiated unexpectedly by the default scanning protocol. Increased cancer risks and disease adverse events in the thorax were strongly related to higher imaging doses and smaller chest dimensions.


Eating from the wild: diversity of wild edible plants used by Tibetans in Shangri-la region, Yunnan, China.
Locally harvested wild edible plants (WEPs) provide food as well as cash income for indigenous people and are of great importance in ensuring global food security. Some also play a significant role in maintaining the productivity and stability of traditional agro-ecosystems. Shangri-la region of Yunnan Province, SW China, is regarded as a biodiversity hotspot. People living there have accumulated traditional knowledge about plants. However, with economic development, WEPs are threatened and the associated traditional knowledge is in danger of being lost. Therefore, ethnobotanical surveys were conducted throughout this area to investigate and document the wild edible plants traditionally used by local Tibetan people. Twenty-nine villages were selected to carry out the field investigations. Information was collected using direct observation, semi-structured interviews, individual discussions, key informant interviews, focus group discussions, questionnaires and participatory rural appraisal (PRA). Information about 168 wild edible plant species in 116 genera of 62 families was recorded and specimens were collected. Most species were edible greens (80 species) or fruits (78). These WEPs are sources for local people, especially those living in remote rural areas, to obtain mineral elements and vitamins. More than half of the species (70%) have multiple use(s) besides food value. Some are crop wild relatives that could be used for crop improvement. Several also have potential values for further commercial exploitation. However, the utilization of WEPs and related knowledge are eroding rapidly, especially in the areas with convenient transportation and booming tourism. Wild food plants species are abundant and diverse in Shangri-la region. They provide food and nutrients to local people and could also be a source of cash income. However, both WEPs and their associated indigenous knowledge are facing various threats. Thus, conservation and sustainable utilization of these plants in this area are of the utmost importance. Documentation of these species may provide basic information for conservation, possibly further exploitation, and will preserve local traditional knowledge.


Evaluation of trace heavy metal levels of some fish species sold at retail in Kayseri, Turkey.
Cd, Ni, Cr, Zn, Cu and Pb concentrations of muscle tissue of 61 fish samples belonging to six fish species (Sparus auratus, Pomatomus saltatrix, Sarda sarda, Engraulis encrasicholus, Sander lucioperca, Scomber scombrus) retailed in Kayseri, Turkey were determined by flame atomic absorption spectrometry after wet digestion. Cd concentrations of at least 31 fish samples (50.8%) and Pb concentrations of at least six fish samples (9.8%) exceeded the corresponding Turkish permissible limit of 0.05 and 0.2 mg kg(-1) respectively whereas Zn concentrations of 11 fish samples (18%) exceeded the Turkish Food Codex limits of 50 mg kg(-1) for Zn. Cu concentrations of all fish species analyzed (100%) were below the corresponding Turkish legislations of 20 mg kg(-1). No limits were established concerning Ni and Cr concentrations in fish by the Turkish governmental authorities.


Effect of Dose and Timing of Preoperative Statins on Mortality After Coronary Artery Bypass Surgery.
Preoperative statin administration is associated with reduced mortality risk after a coronary artery bypass graft operation. However, the optimal dose and timing are unknown. We retrospectively reviewed data from 3,025 primary isolated coronary artery bypass graft surgery patients at our institution. Patients were divided into three groups, according to timing of their preoperative statin: 24 hours or less (n = 1,788), 24 to 72 hours (n = 452), or more than 72 hours before operation or no dose (n = 781). We then grouped patients by preoperative dose: no statin (n = 739), 20 mg or less (n = 920), or more than 20 mg (n = 1,284) atorvastatin or equivalent. Primary outcome was 30-day all-cause postoperative mortality. Thirty-day all-cause mortality was significantly lower for patients taking a statin 24 hours or less preoperatively (1.7%) compared with 24 to 72 hours (2.9%), more than 72 hours, or no dose (3.8%). Multivariate analysis of a propensity-matched cohort showed taking statins 24 hours or less preoperatively was associated with reduced 30-day all-cause mortality (odds ratio 0.52, 95% confidence interval: 0.28 to 0.98, p = 0.04) versus more than 24 hours or no dose. For preoperative statin dose, 30-day all-cause mortality was significantly lower when taking 20 mg or less(1.8%) or more than 20 mg atorvastatin or equivalent (2.1%) than when taking none (3.8%). In multivariate analysis of the propensity-matched cohort, more than 20 mg preoperative dose was associated with a 68% reduction of 30-day all-cause mortality (odds ratio 0.32, 95% confidence interval: 0.13 to 0.82, p = 0.02) compared with no preoperative statin. However, a 20 mg or less preoperative dose showed no mortality reduction. Both statin use 24 hours or less preoperatively and preoperative statin dose of more than 20 mg were independently associated with decreased 30-day all-cause mortality after coronary artery bypass graft surgery.


A primary pulmonary glomus tumor complicated with hyperpyrexia and anemia.
Pulmonary glomus tumors are extremely rare, with only 19 cases having been reported worldwide. The glomus body is considered to be related to the regulation of body temperature, but the reported cases were not associated with hyperpyrexia. Here, we describe a 28-year-old man with hyperpyrexia and anemia complicated with a coin lesion of the right lung. After resection of the upper lobe of the right lung by video-assisted thoracoscopic surgery, all of the patient's symptoms disappeared. The pathologic analysis reported a rare pulmonary glomus tumor. The disease had not recurred by 1 year after operation.


The SGLT2 Inhibitor Empagliflozin for the Treatment of Type 2 Diabetes Mellitus: a Bench to Bedside Review.
The treatment of type 2 diabetes mellitus (T2DM) continues to pose challenges for clinicians and patients. The dramatic rise in T2DM prevalence, which has paralleled the rise in obesity, has strained the healthcare system and prompted the search for therapies that not only effectively treat hyperglycemia, but are also weight neutral or promote weight loss. In most clinical situations after diagnosis, patients are advised to adopt lifestyle changes and metformin is initiated to help control blood glucose levels. However, metformin may not be tolerated, or may not be sufficient for those with higher glucose levels at diagnosis. Even among those who have initial success with metformin, the majority eventually require one or more additional agents to achieve their treatment goals. Because T2DM is a progressive disease, the requirement for combination treatment escalates over time, driving the need for therapies with complementary mechanisms of action. Online public resources were searched using "empagliflozin", identifying 32 articles in PubMed, and 12 abstracts presented at the 2013 American Diabetes Association meeting. Peer-reviewed articles and abstracts describing preclinical studies and clinical trials were retrieved, and relevant publications included in this review. Trials registered on clinicaltrials.gov were searched for ongoing empagliflozin studies. The sodium-glucose co-transporter 2 (SGLT2) inhibitors are of great interest since they provide a novel, insulin-independent mechanism of action. The SGLT2 inhibitor empagliflozin has demonstrated promising pharmacodynamic and pharmacokinetic properties. In clinical trials, empagliflozin has demonstrated a good efficacy and safety profile in a broad range of patients with T2DM, and appears to be an attractive adjunct therapeutic option for the treatment of T2DM. Ongoing trials, including patients with T2DM and comorbidities such as hypertension, are expected to provide important additional data, which will further define the role of empagliflozin in a growing movement toward individualized approaches to diabetes care.


Erythrocyte membrane lipid peroxidation before and after vitamin E supplementation in children with cholestasis.
In 10 children with chronic cholestasis and without neurologic signs, we evaluated lipid peroxidation and vitamin E levels in serum and in the erythrocytes before and after a therapeutic trial with alpha-tocopherol. We also studied the effects of vitamin E administration on hematocrit and hemoglobin values and on reticulocyte and erythrocyte counts. Plasma and erythrocyte malonyldialdehyde (MDA) values were significantly higher compared with normal control values, whereas plasma and erythrocyte tocopherol measurements were lower. Oral administration of high doses of vitamin E (300 mg/day for 15 days) resulted in lower serum MDA levels, whereas serum vitamin levels did not change significantly. In erythrocytes, the MDA decreased but not to control levels, and vitamin E increased but to lower values than normal. Hematologic values also improved. We conclude that longer treatment might be necessary to completely reverse the oxidative damage associated with vitamin E deficiency in children with cholestasis.


Design and synthesis of monocyclic beta-lactams as mechanism-based inhibitors of human cytomegalovirus protease.
Mechanism based inhibitors of HCMV protease have been designed based on the monocyclic beta-lactam nucleus, which have been shown to acylate the viral enzyme in a time dependent manner. SAR in a series of monocyclic beta-lactam N-ureas, has defined the size and relative stereochemistry of the C-3 substituent producing a low micromolar inhibitor 17b with good aqueous stability and selectivity over the mammalian serine proteases.


Transluminal vascular stent for ostial atherosclerotic renal artery stenosis.
We implanted transluminal stents in 24 hypertensive patients with a critical atherosclerotic ostial renal artery stenosis (28 arteries). Immediate revascularisation was successful in all. Follow-up angiography at 6 months, available in 18 patients, revealed restenosis twice. In another patient restenosis was suspected and confirmed by angiography at 2 months. Hence, the total restenosis rate was 3 of 19 patients (16%) and 3 of 23 arteries (13%). Two patients developed renal insufficiency due to cholesterol embolism. In the remaining 22 patients renal function improved (n = 8) or stabilised (n = 14). Although all had to resume antihypertensive treatment, blood pressure normalised in 15 patients, improved in one, remained unchanged in five and worsened in one.


New Strategies for Clinical Trials in Autism Spectrum Disorder.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that poses several challenges in terms of clinical diagnosis and investigation of molecular etiology. The lack of knowledge on the pathogenic mechanisms underlying ASD has hampered the clinical trials that so far have tried to target ASD behavioral symptoms. In order to improve our understanding of the molecular abnormalities associated with ASD, a deeper and more extensive genetic profiling of targeted individuals with ASD was needed. The recent availability of new and more powerful sequencing technologies (third-generation sequencing) has allowed to develop novel strategies for the characterization of comprehensive genetic profiles of individuals with ASD. In particular, this review will describe integrated approaches based on the combination of various omics technologies that will lead to a better stratification of targeted cohorts for the design of clinical trials in ASD. In order to analyze the big data collected by assays such as the whole genome, epigenome, transcriptome, and proteome, it is critical to develop an efficient computational infrastructure. Machine learning models are instrumental to identify non-linear relationships between the omics technologies and, therefore, establish a functional informative network among the different data sources. The potential advantage provided by these new integrated omics-based strategies is better characterization of the genetic background of ASD cohorts, to identify novel molecular targets for drug development, and ultimately offer a more personalized approach in the design of clinical trials for ASD.


Transposable elements as tools for reshaping the genome: it is a huge world after all!
Transposable elements (TEs) are discrete pieces of DNA that can move from one site to another within genomes and sometime between genomes. They are found in all major branches of life. Because of their wide distribution and considerable diversity, they are a considerable source of genomic variation and as such, they constitute powerful drivers of genome evolution. Moreover, it is becoming clear that the epigenetic regulation of certain genes is derived from defense mechanisms against the activity of ancestral transposable elements. TEs now tend to be viewed as natural molecular tools that can reshape the genome, which challenges the idea that TEs are natural tools used to answer biological questions. In the first part of this chapter, we review the classification and distribution of TEs, and look at how they have contributed to the structural and transcriptional reshaping of genomes. In the second part, we describe methodological innovations that have modified their contribution as molecular tools.


GTV differentially impacts locoregional control of non-small cell lung cancer (NSCLC) after different fractionation schedules: subgroup analysis of the prospective randomized CHARTWEL trial.
To evaluate the impact of fractionation schedule on the size of the gross tumour volume (GTV) effect on tumour control after radiotherapy of NSCLC. A subgroup analysis on 163 patients treated in a randomized phase III trial of CHARTWEL (continuous hyperfractionated accelerated radiotherapy-weekend less) vs conventional radiotherapy was performed. The influence of GTV and other baseline factors on local failure (LF), disease-free survival (DFS), distant metastases (DM), and overall survival (OS) was estimated using the Cox Proportional Hazards model. Superior local control was achieved by CHARTWEL compared to conventional radiotherapy (HR 0.54, p=0.015). The hazard of LF increased with increasing GTV for both conventional fractionation and CHARTWEL, however the increase for the latter was less pronounced and not significant. Highly accelerated CHARTWEL treatment was significantly more effective than conventional radiotherapy for locoregional control of NSCLC. GTV had a significant effect on locoregional control after conventional fractionation, an effect that was not significant with CHARTWEL. This is the first study to demonstrate that the magnitude of the time factor of fractionated radiotherapy increases with tumour volume.


Impact of combination therapy with repeat surgery and temozolomide for recurrent or progressive glioblastoma multiforme: a prospective trial.
The purpose of this study is to evaluate the feasibility of repeat surgery combination with postoperative TMZ for adults with recurrent or progressive GBMs. Of 35 patients who had diagnoses of GBM between 2002 and 2005, 7 (20%) underwent second surgeries and TMZ for recurrent or progressive disease. We examined the case histories of these 7 patients and determined the location of tumor and extent of their surgical procedures. Using the KPS, we assessed each patient's neurologic state before and after initial and repeat surgery. We calculated survival times from time of initial surgery and compared actual survival with statistically predicted survival times for each patient. Median survival rates were higher than predicted: The statistical risk estimate for median survival time after repeat surgery for these patients was 9 months; the actual survival time from initial operation until time of death averaged 15.1 months. The neurologic status before and after second surgery also averaged 76 points on KPS. Survival time did not depend on removing the entire tumor at initial and second surgery. Combination with repeat surgery and TMZ improved overall survival of these GBM patients.


A Critical Appraisal of Short-Term End Points in Acute Heart Failure Clinical Trials.
The prevalence of heart failure continues to grow, and this is accompanied by an increase in hospitalization for acute heart failure. Hospitalization for heart failure results in a trajectory shift of the syndrome and is associated with worsening outcomes, increased mortality risk, and high costs. Numerous clinical trials over the past 2 decades have had limited success, with no single agent shown to improve mortality risk. The lack of success is multifactorial and in part related to inadequate targets and end points selected for intervention, underscoring the need to better understand and define the pathophysiology of acute heart failure. To better inform future drug development, this review critically explores the short-term end points and outcomes that previous phase III acute heart failure trials have examined.


Surface EMG shows distinct populations of muscle activity when measured during sustained sub-maximal exercise.
Muscle activity patterns were measured from the rectus femoris, biceps femoris, tibialis anterior and gastrocnemius medialis muscles using electromyography (EMG). Recordings were made from six runners while they ran for 30 mm around a track at a constant, self-selected pace. They were made from three sites along each muscle belly, and for ten consecutive steps on each 450 m lap completed. The intensity of the myoelectric signals was resolved into components in time and frequency space using wavelet analysis. Distinct populations of high- (170-220 Hz) and low-frequency (40-60 Hz) components could be seen in the frequency spectra. There was no significant effect of the electrode position on the rates of change of EMG intensity for any of the muscles, and there was no significant difference in these rates between a 150-ms window at the end of the swing phase and a 150-ms window during the stride phase of running. There were significant differences in the way in which each subject responded to the task, and the way in which the FMG intensities changed at the different frequency bands. There was a significant reduction in EMG intensity at low frequencies and a significant increase at high frequencies, and these changes were ubiquitous for all four muscles tested. The frequencies that showed the greatest changes coincided with the frequencies where distinct populations of activity occurred within the signal. These changes in muscle activity are different from those seen for maximal fatiguing contractions. However, they suggest that the patterns of muscle recruitment may change during sustained sub-maximal exercise.


Enantioselective Iodine(III)-Mediated Synthesis of α-Tosyloxy Ketones: Breaking the Selectivity Barrier.
The development of practical methods to access chiral nonracemic α-substituted ketones is of particular importance due to their ubiquitous nature. Unprecedented levels of enantioselectivity are reported for the synthesis of α-tosyloxy ketones, using enol esters and chiral iodine(III) reagents. The reaction can be performed under both stoichiometric and catalytic conditions. These results suggest widely different reaction mechanisms for the reaction of ketones versus enol esters, supporting recent computational insights.


Optimizing Fe Nutrition for Algal Growth.
Chlamydomonas is an excellent reference system for dissecting the impact of iron (Fe) nutrition on photosynthetic and other metabolisms. The operational definition of four stages of Fe nutrition is described and a guide to the practical use of these stages is offered, specifically the preparation of media and growth of mixotrophic cultures. A key consideration is the impact of carbon metabolism on the expression of Fe-containing enzymes and hence the Fe quota. The absolute concentration of Fe in the medium is less determinative of gene expression than the Fe available on a per-cell basis. In nature, algal cells may transition from Fe-replete to -deficient to -limited during a bloom.


Statistical analysis of fractal-based brain tumor detection algorithms.
Fractals are geometric objects that have a noninteger fractal dimension (FD). The FD has been exploited for various biomedical recognition applications such as breast tumor and lung tumor detection. Our previous work shows that the FD is useful in the detection of brain tumors when a reference nontumor image is available. In this work, we extend our previous work by statistically validating the results of FD analysis on a set of 80 real MR and CT images. Our half-image technique requires that the tumor is located in one half of the brain whereas our whole-image technique does not. Furthermore, we alleviate the need for a reference (control) nontumor image to compute the tumor FD, which was necessary in our previous work. We also compare the brain tumor detection performance of our algorithms with other fractal-based algorithms in the literature and statistically validate our results against manually segmented tumor images. We find that the tumor region offers a statistically significant lower FD compared with that of the nontumor area for most of the FD algorithms studied in this work. Thus, our statistical analysis suggests that these FD algorithms may be exploited successfully to determine the possible presence and location of brain tumors in MR and CT images.


Provision of HIV prevention and care services to farmworkers in sub-Saharan African countries.
To summarise data on human immunodeficiency virus (HIV) services available to farmworkers in sub-Saharan Africa (SSA). We conducted a systematic review to understand which HIV prevention and care services were accessed by farm workers in SSA. MEDLINE (PubMed), Embase, CINAHL (EBSCO Host), Cochrane library, African Index Medicus, Scopus, Google Scholar, Open Grey, and Web of Science Proceedings Citation Index were searched. Studies were eligible for inclusion if they measured or reported on the presence of HIV workplace policy frameworks, guidelines, or programmes for HIV prevention, treatment and care services, and other treatment modalities specifically targeting farmworkers. Nine studies published between 2005 and 2019 were included in the review. Six themes emerged from included studies, which include HIV policy, HIV prevention (awareness, education, and condom supply), voluntary counselling and testing, antiretroviral therapy (ART), linkage to care, and mobile clinic. Though availability of an HIV policy was inadequate, a significant positive impact of the HIV policy in influencing behaviour change was reported. Most of the farm workers could access HIV education and condom supply in their places of work. Access to ART, treatment support, and linkage to care was inadequate, but community outreach programmes and mobile clinics showed success in reaching a high number of workers with HIV testing and treatment. A majority of farm workers faced barriers in accessing government health facilities. The findings suggest that there is poor access to HIV services for farmworkers in SSA. There is a dire need to scale up HIV services and programmes, including mobile health facilities, in agricultural settings. Due to high labour migration patterns among farmworkers, we recommend cross-country HIV programmes that allow continuity of care across borders.


A respiratory function jacket for measuring tidal volume and changes in FRC.
We describe a simple application of a mercury-in-rubber strain gauge in a jacket used to measure tidal volume in paralyzed, mechanically ventilated rabbits. The jacket produces a record with a straight base line. Shifts of this base line can be used to assess changes in functional residual capacity (FRC).


Impact of a patient-centered, computer-based health information/support system.
Consumer health information systems potentially improve a patient's quality of life and activate patient self-care. Test a computerized system (CHESS: Comprehensive Health Enhancement Support System), which, in this application, provided HIV-positive patients with information, decision support, and connections to experts and other patients. Would patients given in-home access to computers use the system, improve their quality of life, reduce health-risk behaviors, and use medical services more efficiently? Randomized controlled trial: CHESS computers in experimental subjects' homes in Madison or Milwaukee, Wisconsin, for 3 or 6 months; controls received no intervention. Subjects were compensated for self-report surveys completed before, during, and after CHESS installation. Of 204 HIV-positive patients recruited (90% male, 84% white, average education some college, and 65% experiencing HIV-related symptoms), 90% completed the study. Self-reports of quality of life and frequency and duration of use of medical services. CHESS was used daily with little difference between demographic subgroups. While CHESS was in the home, its users reported quality-of-life improvements: active life, negative emotions, cognitive function, social support, and participation in health care. They also reported spending less time during ambulatory care visits, making more phone calls to providers, and experiencing fewer and shorter hospitalizations. A computer-based personal health support system can improve a patient's quality of life and promote more efficient use of health care.


The mechanism of Qijing Mingmu decoction on cellular senescence of conjunctivochalasis.
Qijing Mingmu decoction (QJMM), a compound Chinese medicine preparation, which consists of Lycium barbarum, Polygonatum, Ophiopogon japonicus, Poria cocos, Glycyrrhiza, Eclipta prostrata and Ligusticum striatum, has been confirmed to be effective for the treatment of conjunctivochalasis (CCH) in clinic and reduce cellular senescence. However, the underlying mechanism is still unknown. Our previous study revealed that p38-mediated cellular senescence contributed to the pathogenesis of CCH. To explore whether p38 might be the potential therapeutic target of QJMM for CCH, CCH fibroblasts were treated with QJMM granule and then the effect of QJMM granule on the expression and promoter activity of p38α was determined by western blot and dual luciferase reporter gene assay, respectively. Meanwhile, the influence of QJMM granule on cell proliferation, oxidative stress, cellular senescence and the expression of the cellular senescence-associated genes were measured by corresponding methods. QJMM granule significantly decreased the protein expression of p38α and p-p38α in CCH fibroblasts in a dose-dependent manner and inhibited p38α promoter activity. QJMM granule as well as the p38 inhibitor SB203580 reduced the level of reactive oxygen species and increased the activity of superoxide dismutase in CCH fibroblasts. QJMM granule and SB203580 promoted cell proliferation and reduced the percentage of SA-β-Gal-positive cells. The mRNA and protein expression of p53 and p21 was remarkably down-regulated by QJMM granule as well as SB203580 and that of SMP30 was up-regulated in CCH fibroblasts. Our findings demonstrated that QJMM granule was effective for alleviating cellular senescence of CCH fibroblasts by p38 MAPK signaling and the followed p53/p21 signaling.


Analytical methods for the characterization and diagnosis of infection with Pseudomonas aeruginosa: A critical review.
The recent increase in outbreaks of pathogenic bacteria and antimicrobial resistance represent major public health problems. Being the leading cause of death in humans, the bacterial infections need to be accurately and quickly diagnosed. Hence, the development of fast, cost-effective, sensitive and specific strategies for the detection of the targeted bacterium is of utmost importance. This review presents a systematic, critical evaluation of the recent analytical methods for the characterization and diagnosis of infections caused by Pseudomonas aeruginosa. The clinical manifestations, incidence and treatment of the P. aeruginosa infection and the associated quorum sensing, biofilm formation and virulence factors are also discussed. An overview of a variety of analytical methods for the detection of P. aeruginosa is provided, including whole-cell detection (microbiological methods, biosensors), antigens, DNA, and relevant markers (quorum sensing molecules, virulence factors) detection. The latest trends in analytical methods, especially sensors, are the orientation towards portability and on-site detection. The efforts made so far to achieve these goals in the detection of P. aeruginosa and its markers are also presented and discussed in this review. The strengths and weaknesses of the current detection methods are evaluated, while exploring potential routes for further development.


The emotional and behavioral process of staff nurse turnover.
Nurses who leave their jobs proceed through stages of disengagement, some of which are quite intense. Yet 88% of the nurses in this study say that an appropriate managerial intervention early in their leave-taking decision process would have halted their decision to leave. The authors describe stages of nurses' leave-taking decisions, their experiences, and their behaviors.


Effects of epidermal growth factor receptor inhibitor on proliferative cholangitis in hepatolithiasis.
There is currently no effective medication to prevent stone recurrence after choledochoscopic lithotomy or to treat proliferative cholangitis (PC), which is the pathologic basis of hepatolithiasis. This study aimed to investigate whether gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, inhibited cholangio hyperplasia and lithogenesis in PC. After cholangioscopic lithotomy, indwelling catheters were placed in the diseased bile duct lumens in 94 patients with hepatolithiasis. Subsequently, 49 of the 94 patients were treated with 250 mg gefitinib solution via a catheter twice a week, and they were subjected to choledochoscopic biopsy at 6 and 12 weeks. The rest 45 hepatolithiasis patients without gefitinib treatment served as controls. The expressions of EGFR, PCNA and procollagen I were significantly reduced in the patients treated with gefitinib in 12 weeks compared with those in the control group. Patients in the gefitinib group had a much lower degree of hyperplasia of the biliary epithelium, submucosal glands and collagen fibers compared with those in the control group. Gefitinib treatment significantly decreased mucin 3 expression and beta-glucuronidase activity. Postoperative gefitinib treatment could significantly inhibit PC-mediated hyperplasia and lithogenesis, which might provide a novel strategy for the prevention of biliary restenosis and stone recurrence in patients with hepatolithiasis.


Treatment strategy after non-curative endoscopic resection of early gastric cancer.
Endoscopic resection (ER) is indicated for patients with early gastric cancer who have a negligible risk of lymph node metastasis (LNM). Histological examination of the resected specimen may indicate a possible risk of LNM or a positive resection margin. These patients are considered to have undergone non-curative ER. The aim of this study was to determine the appropriate treatment strategy for such patients. A total of 298 patients who had non-curative ER were classified into those with a positive lateral margin only (group 1; 72 patients) and those with a possible risk of LNM (group 2; 226 patients). Surgery was performed within 6 months of non-curative ER in 19 patients in group 1 and 144 in group 2. In group 1, nine patients were found to have local residual tumours, all limited to the mucosal layer without LNM. In Group 2, 13 patients had residual disease, including four local tumours without LNM, two local tumours with LNM and seven cases of LNM alone. The rate of LNM after surgery was 6.3 per cent in group 2. Surgery remains the standard treatment after non-curative ER in patients with a possible risk of LNM.


Evaluation of the International Society for Animal Genetics bovine single nucleotide polymorphism parentage panel in South African Bonsmara and Drakensberger cattle.
A panel of 200 single nucleotide polymorphisms (SNPs) have been recommended by the International Society for Animal Genetics (ISAG) for use in parentage verification of cattle. While the SNPs included on the ISAG panel are segregating in European Bos taurus and Bos indicus breeds, their applicability in South African (SA) Sanga cattle has never been evaluated. This study, therefore, assessed the usefulness of the ISAG panel in SA Bonsmara (BON) and Drakensberger (DRB) cattle. Genotypes of 185 ISAG SNPs from 64 BON and 97 DRB sire-offspring pairs were available, all of which were validated with 119,375 SNPs. Of the 185 ISAG SNPs, 14 and 18 in the BON and DRB, respectively (9 in common to both breeds), were either monomorphic, exhibited at least one discordance between validated sire-offspring pairs, or had poor call rate or clustering issue. The mean minor allele frequency of the 185 ISAG SNPs was 0.331 in the BON and 0.359 in the DRB. The combined probability of parentage exclusion (PE) was the same (99.46%) for both breeds, while the probability of identity varied from 1.61 × 10-48 (BON) to 1.11 × 10-54 (DRB). Fifteen (23.4%) and 32 (33%) of the already validated sire-offspring pairs for the BON and DRB, respectively, were determined by the ISAG panel to be false-negatives based on a threshold of having at least two discordant SNPs. In comparison to sire discovery using the 119,375 SNPs, sire discovery using only the ISAG panel identified correctly 44 (out of 64 identified using the 119,375 SNPs) unique sire-offspring BON pairs and 62 (out of 97 identified using the 119,375 SNPs) unique sire-offspring DRB when all sires were masked. Five BON and three DRB offspring had > 1 sire nominated. This study demonstrated that the use of the ISAG panel may result in incorrect exclusions and multiple candidate sires for a given animal. Selection of more informative SNPs is, therefore, necessary in the pursuit of a low-cost and effective SNP panel for indigenous cattle breeds in SA.


Radio-frequency identification (RFID) tag localisation of non-palpable breast lesions a single centre experience.
The purpose of this study is to report the surgical experience and outcomes with pre-operative localisation of non-palpable breast lesions using the RFID tag system. The cohort for this prospective study included patients over the age of 18 with biopsy proven, non-palpable indeterminate lesions, DCIS or breast cancer requiring pre-operative localisation before surgical excision between September 2020 and July 2022. A total of 312 RFID tags were placed in 299 consecutive patients. Indications for localisation included non-palpable invasive cancer in 255 (85.3%) patients, in situ disease in 38 (12.7%) and indeterminate lesions requiring surgical excision in 6 (2.0%). Both in situ and invasive lesions had a median size of 13 mm (range 4-100 mm) on pre-operative imaging. The RFID tags were in situ for a median time of 21 days before surgery (range 0-233 days). Of the 213 tags, 292 (93.6%) were introduced using ultrasound (USS) guidance and stereotactically in 20 (6.4%). In 3 (1.0%) cases the RFID tag was either not satisfactorily deployed at the intended target or retrieved intra-operatively. Following discussion of post-operative histology by the multi-disciplinary team, further surgery for close or involved margins was for 26 (8.7%) patients. The Hologic RFID tag system can be used for accurate pre-operative localisation of non-palpable masses as well as diffuse abnormalities such as mammographic distortions and calcifications. It has advantages of flexibility for scheduling image-guided insertion independently of scheduled operating lists and can be placed to localise lesions prior to initiating neoadjuvant systemic treatment.


C1q binding to mitochondria: a possible artefact?
Mitochondrial preparations, obtained from human tonsils and from rat spleen, liver, heart, and kidney tissues, bound [125I]C1q with affinities of 10(7)-10(8)M-1. The binding of C1q was not affected by treatment of the mitochondrial preparations with pronase, trypsin, or phospholipase D, but it was lowered 5-6-fold following treatment of the mitochondria with DNase and RNase. Binding of C1q to mitochondrial preparations was also greatly diminished by limited chemical modification of C1q with cyclohexane-1,2-dione. It is suggested that the reported binding of C1q to mitochondria may have arisen from the protein binding to DNA and/or RNA contaminating the mitochondrial preparations.


Endocrine Toxicities of Antineoplastic Therapy: The Adrenal Topic.
Immune checkpoint inhibitors (ICIs) have improved survival in patients affected by several solid tumours at the cost of new autoimmune adverse events. Endocrine toxicity is frequently reported in patients treated with these agents, mainly as thyroid dysfunction and hypophysitis. Primary adrenal insufficiency is reported in 1-2% of patients receiving a single ICI, but its rate is approximately 5% in patients treated with a combination of two ICIs. The clinical presentation of adrenal insufficiency may be insidious due to symptoms that are not specific. The same symptoms in cancer patients are frequently multifactorial, rendering the early diagnosis of adrenal insufficiency challenging in this group of patients. As adrenal insufficiency can be fatal if not rapidly diagnosed and treated, oncologists should be aware of its clinical presentations to timely involve endocrinologists to offer patients the appropriate management. In parallel, it is essential to educate patients, their caregivers, and relatives, providing them with detailed information about the risk of adrenal insufficiency and how to manage alarming symptoms at their onset. Finally, large collaborative trials are needed to develop appropriate tests to assess better the personal risk of drug-induced adrenal insufficiency and its early diagnosis and treatment, not only in cancer patients.


Topology of P-glycoprotein as determined by epitope mapping of MRK-16 monoclonal antibody.
There is growing evidence for the direct role of P-glycoprotein mediating multidrug resistance in tumor cells. P-glycoprotein is thought to function as an energy-dependent drug efflux pump. The monoclonal antibody MRK-16 binds to an external domain of P-glycoprotein and partially inhibits drug efflux in multidrug-resistant cells. As an approach toward elucidating the mechanism by which MRK-16 affects drug transport, we undertook the definition of the precise binding site of this antibody. In this study we have mapped the epitope of MRK-16 monoclonal antibody to a resolution of a single amino acid using a series of overlapping synthetic peptides. We demonstrate that MRK-16 recognizes only the class I isoform (MDR1) of human P-glycoprotein and that its epitope encompasses at least two (first and fourth) of the six predicted extracellular peptide loops. These results suggest that the epitope of MRK-16 is discontinuous and that the sequences involved which are separated by about 625 amino acids in the linear sequence must be spatially situated in close proximity in the native protein. Based on these results, we present a model for transmembrane alpha-helical packing of P-glycoprotein in the lipid bilayer. This may have implications for understanding the function of P-glycoprotein in drug transport.


Progesterone effects upon dopamine release from the corpus striatum of female rats. I. Evidence for interneuronal control.
In the present experiment, we examined whether progesterone modifies dopamine (DA) release from superfused corpus striatal (CS) tissue fragments of ovariectomized estrogen-primed rats as result of a direct interaction with dopaminergic nerve terminals or through interneurons within the CS. In Expt. I, an in vitro pulsatile infusion of progesterone (2 ng/ml) directly into superfusion chambers containing CS fragments resulted in a statistically significant increase in DA release (P less than 0.008). No such stimulation was obtained following a continuous progesterone infusion or during control superfusions receiving no progesterone. In an effort to examine a direct action of progesterone on DA terminals in Expt. II, tetrodotoxin (TTX, 1 microM) was added to the Superfusion medium to block the activity of interneurons within the CS. TTX completely abolished the effect of pulsatile progesterone on DA release. These results indicate that the stimulatory action of progesterone on in vitro DA release from CS fragments is apparently exerted through activation of interneurons which discriminately respond to a specific (pulsatile) mode of progesterone infusion.


Why the Photochemical Reaction of Phenol Becomes Ultrafast at the Air-Water Interface: The Effect of Surface Hydration.
Photochemical reactions at the air-water interface can show remarkably different rates from those in bulk water. The present study elucidates the reaction mechanism of phenol characteristic at the air-water interface by the combination of molecular dynamics simulation and quantum chemical calculations of the excited states. We found that incomplete hydrogen bonding to phenol at the air-water interface affects excited states associated with the conical intersection and significantly reduces the reaction barrier, resulting in the distinctively facilitated rate in comparison with the bulk phase. The present study indicates that the reaction dynamics can be substantially different at the interfaces in general, reflecting the difference in the stabilization energy of the electronic states in markedly different solvation at the interface.


A determination of the volumes of the layers of the rat hippocampal region.
The absolute volumes of the hippocampal and subicular cortical layers in the rat were determined. The boundaries of the various layers were defined on series of sections made through the entire hippocampal region of five rats and stained according to the Timm sulfide silver technique. Coordinates representing the boundaries of the layers on selected sections were fed into a mini-computer programmed to calculate the volume of the layers from the areas of the profiles and the distances between the sections. The distribution of the layers indicates that they constitute the same proportion of the volume of the dorsal and ventral divisions of the hippocampal region, with the exception of the structures lying in regio inferior and regio superior. Although the combined regio superior and regio inferior components of the layers of Ammon's horn occupy the same percentage of the volume of the dorsal and ventral hippocampal regions, the regio superior components occupy a larger percentage of Ammon's horn in the dorsal region than they do in the ventral region. The inter-animal variations in the volumes of the various layers indicate that it is possible to describe quantitatively the subdivisions of the hippocampal region with a precision that is compatible with comparative studies.


Peptide hormone isoforms: N-terminally branched PYY3-36 isoforms give improved lipid and fat-cell metabolism in diet-induced obese mice.
The prevalence of obesity is increasing with an alarming rate worldwide and there is a need for efficacious satiety drugs. PYY3-36 has been shown to play a role in hypothalamic appetite regulation and novel analogs targeting the Y2 receptor have potential as drugs for the treatment of obesity. We have designed a series of novel PYY3-36 isoforms, by first adding the dipeptide Ile-Lys N-terminal to the N(α) of Ser-13 in PYY13-36 and then anchoring the N-terminal segment, e.g. PYY3-12, to the new Lys N(ε)-amine. We hypothesized that such modifications would alter the folding of PYY, due to changes in the turn motif, which could change the binding mode to the Y receptor sub-types and possibly also alter metabolic stability. In structure-affinity/activity relationship experiments, one series of PYY isoforms displayed equipotency towards the Y receptors. However, an increased Y2 receptor potency for the second series of PYY isoforms resulted in enhanced Y receptor selectivity compared to PYY3-36. Additionally, acute as well as chronic mice studies showed body-weight-lowering effects for one of the PYY isoforms, which was also reflected in a reduction of circulating leptin levels. Interestingly, while the stability and pharmacokinetic profile of PYY3-36 and the N-terminally modified PYY3-36 analogue were identical, only mice treated with the branched analogue showed marked increases in adiponectin levels as well as reductions in non-esterified free fatty acids and triglycerides.


Potential distribution of invasive crop pests under climate change: incorporating mitigation responses of insects into prediction models.
Climate change facilitates biological invasions globally. Predicting potential distribution shifts of invasive crop pests under climate change is essential for global food security in the context of ongoing world population increase. However, existing predictions often omit the capacity of crop pests to mitigate the impacts of climate change by using microclimates, as well as through thermoregulation, life history variation and evolutionary responses. Microclimates provide refugia buffering climate extremes. Thermoregulation and life history variation can reduce the effects of diurnal and seasonal temperature variability. Evolutionary responses allow insects to adapt to long-term climate change. Neglecting these ecological processes may lead to overestimations in the negative impacts of climate change on invasive pests whereas in turn cause underestimations in their range expansions. To improve model predictions, we need to incorporate the fine-scale microclimates experienced by invasive crop pests and the mitigation responses of insects to climate change into species distribution models.


Construction of FLAG tagging vectors for Candida albicans.
We have constructed three new vectors for Candida albicans (pFLAG-Act1, pFLAG-Mal2, and pFLAG-Met3). The proteins can be expressed as C-terminal FLAG-tagged proteins under the control of different promoters (ACT1, MAL2, and MET3). To confirm the protein expression, we used the Renilla reniformis luciferase and the drug efflux pump Cdr1p of Candida albicans as reporters. The luciferase protein expressed by the MET3 promoter was found to have the strongest activity of the three promoters when cultured in a methionine-depleted synthetic medium. Cdr1p was expressed as a C-terminal FLAG-tagged protein using either these vectors or PCR-mediated integration. The fluconazole resistance was increased by the Cdr1p expression in a CDR1 homozygous disruptant. The expressed proteins were detected by Western blotting using the anti-FLAG antibody. We also constructed a Cdr1p-FLAG expressing strain, in which we directly tagged Cdr1p with FLAG on the genome loci, using a PCR-based integrative marker cassette that was amplified using the pFLAG vector. We then confirmed the protein expression by Western blotting. Thus, these new vectors are useful as C. albicans genetic tools.


Autoantibodies against the insulin receptor. Dissociation of the acute effects of the antibodies from the desensitization seen with prolonged exposure.
The effect of antibodies against the insulin receptor (anti-R) found in a patient with the type B syndrome of insulin resistance and acanthosis nigricans was characterized using 3T3-L1 cultured fat cells. Anti-R acutely mimicked the action of insulin by stimulating deoxyglucose uptake. With more prolonged exposure, this insulinomimetic effect decayed, glucose metabolism returned to basal levels, and the cells became severely resistant to the actions of insulin. As seen with anti-R from a previous patient, desensitization consisted of both a dramatic decrease in the maximal responsiveness of the cells to insulin and a shift in the dose-response curve for insulin-stimulated glucose oxidation. The acute and chronic effects of anti-R were then compared. The concentration of anti-R required to half-maximally inhibit insulin binding averaged more than twice that required for half-maximal stimulation of deoxyglucose uptake, consistent with the amount of spare receptors in 3T3-L1 cells. After prolonged exposure, the insulinomimetic activity was completely lost at all concentrations of anti-R, even at those that did not completely induce insulin resistance. Thus, loss of the insulinomimetic activity of anti-R is necessary, but not sufficient, to cause desensitization. Less anti-R was required to desensitize cells to insulin than would have been predicted on the basis of the acute inhibition of binding and the number of spare receptors.(ABSTRACT TRUNCATED AT 250 WORDS)


GSK3β suppression inhibits MCL1 protein synthesis in human acute myeloid leukemia cells.
Previous studies have shown that glycogen synthase kinase 3β (GSK3β) suppression is a potential strategy for human acute myeloid leukemia (AML) therapy. However, the cytotoxic mechanism associated with GSK3β suppression remains unresolved. Thus, the underlying mechanism of N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea (AR-A014418)-elicited GSK3β suppression in the induction of AML U937 and HL-60 cell death was investigated in this study. Our study revealed that AR-A014418-induced MCL1 downregulation remarkably elicited apoptosis of U937 cells. Furthermore, the AR-A014418 treatment increased p38 MAPK phosphorylation and decreased the phosphorylated Akt and ERK levels. Activation of p38 MAPK subsequently evoked autophagic degradation of 4EBP1, while Akt inactivation suppressed mTOR-mediated 4EBP1 phosphorylation. Furthermore, AR-A014418-elicited ERK inactivation inhibited Mnk1-mediated eIF4E phosphorylation, which inhibited MCL1 mRNA translation in U937 cells. In contrast to GSK3α, GSK3β downregulation recapitulated the effect of AR-A014418 in U937 cells. Transfection of constitutively active GSK3β or cotransfection of constitutively activated MEK1 and Akt suppressed AR-A014418-induced MCL1 downregulation. Moreover, AR-A014418 sensitized U937 cells to ABT-263 (BCL2/BCL2L1 inhibitor) cytotoxicity owing to MCL1 suppression. Collectively, these results indicate that AR-A014418-induced GSK3β suppression inhibits ERK-Mnk1-eIF4E axis-modulated de novo MCL1 protein synthesis and thereby results in U937 cell apoptosis. Our findings also indicate a similar pathway underlying AR-A014418-induced death in human AML HL-60 cells.


Minocycline as an adjunct for treatment-resistant depressive symptoms: study protocol for a pilot randomised controlled trial.
Depression is one of the leading causes of disability worldwide. A high proportion of patients do not respond to standard drug treatments. Recent evidence has suggested that anti-inflammatory treatment may have beneficial effects in major depression. Minocycline is a tetracycline antibiotic with good CNS penetration that exerts effects on multiple interacting symptoms implicated in the pathophysiology of mood disorders. Open-label studies have suggested that minocycline is effective as an adjunct drug in improving depressive symptoms. This is a multi-centre, 3-month, double-blind, placebo-controlled, pilot trial of minocycline added to treatment as usual for patients suffering from DSM-IV major depressive disorder. This will be a double-blind, randomised, controlled, two parallel-arm study with 20 participants in each arm, giving a total of 40 participants. There will be a screening visit, a randomization visit and four follow-up visits. Clinical assessments using the Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ -9) and the Generalised Anxiety Disorder scale (GAD-7) will be carried out at every visit. Side effects checklists will also be undertaken at each visit. Biomarkers (inflammatory cytokines and CRP) will be measured at baseline and at the end of the treatment phase. Minocycline will be started at 100 mg once daily (OD) and will be increased to 200 mg at two weeks. Anti-inflammatory treatments have been shown to have some beneficial effects in the treatment of major depressive disorder. The aim of this pilot randomised controlled trial is to establish the degree of improvement in depressive symptoms with the addition of minocycline to treatment as usual. ClinicalTrials.gov NCT02263872 registered 10 October 2014.


Site-specific endonucleolytic cleavages and the regulation of stability of E. coli ompA mRNA.
The stability of ompA mRNA is growth-rate dependent. We show that the 5' noncoding region of this mRNA provides a target for site-specific endonucleases. The rate of degradation of ompA mRNA parallels the rate of these endonucleolytic cleavages, implying that endonucleolytic rather than exonucleolytic attack is the initial step in ompA mRNA degradation. Thus the 5' noncoding region appears to be a determinant of mRNA stability, and endonucleolytic cleavages in the 5' noncoding region may well regulate expression of the ompA gene.


Whole Soy Flour Incorporated into a Muffin and Consumed at 2 Doses of Soy Protein Does Not Lower LDL Cholesterol in a Randomized, Double-Blind Controlled Trial of Hypercholesterolemic Adults.
Soy protein may reduce coronary heart disease (CHD) risk by lowering LDL cholesterol, but few studies have assessed whether whole soy flour displays a similar effect. The aim of this study was to assess the dose effect of whole soy flour incorporated into muffins on plasma LDL cholesterol in hypercholesterolemic adults. Adults aged 30-70 y (n = 243) with elevated LDL cholesterol (≥3.0 and ≤5.0 mmol/L) were stratified by LDL cholesterol and randomly assigned to consume 2 soy muffins containing 25 g soy protein [high-dose soy (HDS)], 1 soy and 1 wheat muffin containing 12.5 g soy protein and 12.5 g whey protein [low-dose soy (LDS)], or 2 wheat muffins containing 25 g whey protein (control) daily for 6 wk while consuming a self-selected diet. Fasting blood samples were collected at weeks 0, 3, and 6 for analysis of plasma lipids [total, LDL, and HDL cholesterol and triglycerides (TGs)], glucose, insulin, C-reactive protein (CRP), and isoflavones. Blood pressures also were measured. Dietary intake was assessed at weeks 0 and 4 with the use of 3 d food records. Treatment effects were assessed with the use of intention-to-treat analysis with multiple imputation and LDL cholesterol as the primary outcome. In total, 213 (87.6%) participants completed the trial. Participants were primarily Caucasian (83%) and mostly female (63%), with a mean ± SD body mass index (in kg/m2) of 28.0 ± 4.6 and systolic and diastolic blood pressures of 122 ± 16 and 77 ± 11 mm Hg, respectively. Despite a dose-dependent increase in plasma isoflavones (P < 0.001), neither HDS nor LDS had a significant effect on LDL cholesterol compared with control (mean ± SEM changes: control, -0.04 ± 0.05 mmol/L; HDS, 0.01 ± 0.05 mmol/L; and LDS, -0.04 ± 0.06 mmol/L). There were no significant treatment effects on total or HDL cholesterol, TGs, CRP, homeostatic model assessment of insulin resistance, blood pressure, or the Framingham 10-y CHD risk score. Consuming 12.5 or 25 g protein from defatted soy flour incorporated into muffins does not reduce LDL cholesterol or other CHD risk factors in hypercholesterolemic adults. This trial was registered at clinicaltrials.gov as NCT01547585.


The performance of prostate specific antigen, prostate specific antigen density and transition zone density in the era of extended biopsy schemes.
Prostate specific antigen, prostate specific antigen density and transition zone density have been previously identified as prostate cancer detection tools. Recent studies suggest that prostate specific antigen may be increasingly accurate for detecting clinically significant high grade prostate cancer (Gleason grade 7 or greater). We defined the performance of these measures in a referral based population undergoing an extended prostate biopsy scheme. We retrospectively reviewed prospectively collected data on 1,708 men referred for prostate needle biopsy. All participants were men who had not undergone biopsy in the past. From these data ROC curves were constructed for prostate specific antigen, prostate specific antigen density and transition zone density for the presence of cancer, high grade (Gleason 3 + 4 or greater) and high volume (50% or greater of cores positive) disease. Prostate specific antigen density had a statistically higher AUC than prostate specific antigen for detecting all prostate cancers (0.737 vs 0.633, p <0.001) as well as high grade (0.766 vs 0.673, p <0.001) and high volume (0.843 vs 0.755, p <0.001) disease. Additionally, prostate specific antigen and prostate specific antigen density performed better for detecting high grade and high volume disease compared to overall prostate cancer detection. The performance of transition zone density was similar to that of prostate specific antigen density. Prostate specific antigen and prostate specific antigen density show improved performance characteristics for detecting clinically significant high grade and high volume prostate cancer in referral populations undergoing extended scheme prostate needle biopsy. Prostate specific antigen density shows better performance characteristics than prostate specific antigen. No advantage was seen when using transition zone density over prostate specific antigen density.


Morphological abnormalities in gonads of the Baltic herring (Clupea harengus membras): Description of types and prevalence in the northern Baltic Sea.
Due to heavy anthropogenic influence and variation of the environmental conditions in the Baltic Sea, reproductive disorders are becoming a major environmental concern. We show here an increasing prevalence of gonadal malformations in the Baltic herring (Clupea harengus membras), a key species of the Baltic ecosystem and important in commercial fishery. During 1987-2014, the spawning herring population in the Archipelago Sea (AS) (North Baltic Sea, Finland) was monitored annually and analyzed for gross morphology of the gonads [total number (n) of analyzed fish = 38 284]. Four different types of malformations were repeatedly found and named as asymmetric, rudimentary, segmented, and branched gonads, but also hermaphroditic gonads and miscellaneous (unidentified) disorders were recorded. In 2013, additional samplings (n of fish analyzed = 541) showed similar malformations in herring from the Bothnian Sea. In some gonad types, histological examination revealed disintegration of seminiferous tubules and hyperplasia of the interstitial tissue. In 2014, the overall prevalence of malformations was still relatively low in the AS (frequency = 0-3.4 %; n = 750) and had apparently minimal effect on population recruitment. However, an increasing trend in the time-series (GLM; F = 32.65; p < 0.001) and a significantly higher prevalence in the Bothnian Sea (frequency = 0.7-5.0 %; n = 541; χ (2) = 6.24; p < 0.05) suggest that gonadal malformations may become a new threat for fish in the Baltic Sea. The observed gonad atrophies may be due to environmental endocrine disruption; however, also other explanations may exist and potential explanations are discussed.


High reliability transformation of the wheat pathogen Bipolaris sorokiniana using Agrobacterium tumefaciens.
Bipolaris sorokiniana, the causal agent of spot blotch of wheat, significantly reduces grain yield worldwide. In order to study pathogenic mechanisms of the fungus, conditions for efficient transformation using Agrobacterium-mediated transformation were investigated. To study different stages of hyphal fusion and pathogenic mechanisms of the fungus, two fluorescence markers viz. the red fluorescent protein (DsRed-Express) and the green fluorescent protein (EGFP1) were constitutively expressed. Southern hybridizations confirmed the presence of T-DNA in all hygromycin B or geneticin resistant transformants, and also showed random and single copy integration. Fluorescence microscopy suggested the high level expression of both DsRed and EGFP fluorescent proteins in spores and mycelia. The results signify that DsRed and EGFP can be used as efficient reporter gene for monitoring B. sorokiniana hyphal fusion as well as colonization in the host tissues. This work will be useful to develop methodologies for understanding the mechanisms of Bipolaris-wheat interaction and functional genomics of B. sorokiniana for various applications including insertional mutagenesis, targeted disruption of specific genes, ectopic complementation of loss-of-function strains and over-expression.


A rationale for opiate withdrawal symptomatology.
The discovery of opioid peptide transmitters and the delineation of their interactions with the noradrenergic locus ceruleus (LC) has led to our proposing that opiate effects on mood and physiological responses result from the opiate-induced inhibition of the LC. Withdrawal of opiates removes this "tonic" inhibition of the LC and could readily result in a piperoxane-like release from inhibition. The hypothesis that noradrenergic hyperactivity underlies the physiologic and affective changes seen in opiate withdrawal and spontaneous panic seen in man can be readily tested in man by evaluating the efficacy of drugs which inhibit the LC and block piperoxane- and LC-elicited increases in specific behaviors for the treatment of opiate withdrawal and naturally occurring panic-anxiety states in man.


Submicroscopic Ca2+ diffusion mediates inhibitory coupling between individual Ca2+ channels.
Dihydropyridine-sensitive Ca2+ channels in heart demonstrate an important negative feedback property: they close, or inactivate, in response to prior Ca2+ entry. We now find that Ca2+ influx through one channel can selectively contribute to the inactivation of another adjacent channel, without a generalized elevation of bulk intracellular Ca2+ concentration. Intracellular application of the Ca2+ chelator BAPTA greatly diminishes such negative interactions within Ca2+ channel pairs. These findings demonstrate that Ca2+ currents are controlled not only by intrinsic channel properties, but also by local diffusive interactions among neighboring channels. Such inhibitory coupling among channels provides a concrete example of localized Ca2+ signaling, long proposed to exist on the basis of theoretical calculations.


Locomotion in virtual environments predicts cardiovascular responsiveness to subsequent stressful challenges.
Individuals differ in their physiological responsiveness to stressful challenges, and stress potentiates the development of many diseases. Heart rate variability (HRV), a measure of cardiac vagal break, is emerging as a strong index of physiological stress vulnerability. Thus, it is important to develop tools that identify predictive markers of individual differences in HRV responsiveness without exposing subjects to high stress. Here, using machine learning approaches, we show the strong predictive power of high-dimensional locomotor responses during novelty exploration to predict HRV responsiveness during stress exposure. Locomotor responses are collected in two ecologically valid virtual reality scenarios inspired by the animal literature and stress is elicited and measured in a third threatening virtual scenario. Our model's predictions generalize to other stressful challenges and outperforms other stress prediction instruments, such as anxiety questionnaires. Our study paves the way for the development of behavioral digital phenotyping tools for early detection of stress-vulnerable individuals.


Surgical Interest of an Accurate Real-World Prediction of Primary Systemic Therapy Response in HER2 Breast Cancers.
Human epidermal growth factor receptor 2 (HER2)-enriched breast cancers (BC) present the highest rates of pathological response to primary systemic therapy (PST), but they are also the ones that tend to be larger at diagnosis, with microcalcifications and, often, with axillary involvement. If we do not have a reliable method to predict the degree of response, we may not be able to transfer the benefits of PST to surgery. The post-PST surgery planning is guided by the findings in the magnetic resonance imaging (MRI), whose predictive capacity, although high, is far from optimal. Thus, it seems interesting to find other variables to improve it. A retrospective observational study including women with HER2 BC treated with PST and further surgery was conducted. Information regarding clinical, radiological, and histopathological variables was gathered from a total of 132 patients included. Radiological complete response (rCR) was achieved in 65.9% of the sample, and pathological complete response (pCR), according to Miller and Payne criteria, in 58.3% of cases. A higher Ki67 value, the absence of Hormonal Receptors expression, and an rCR was significantly related to a pCR finding. This information impacts directly in surgery planning, as it permits adjustment of the breast resection volume.


Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report.
Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman's rho: - 0.86, p < 0.001. To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.


Sialoadenectomy enhances hepatic injury induced by lipopolysaccharide/galactosamine in mice.
Submandibular salivary glands (SMGs) synthesize, accumulate and secrete a large amount of epidermal growth factor (EGF) in mice. It is known that surgical removal of SMG (sialoadenectomy) alters cell turnover in the liver and exacerbates liver injury induced by lipopolysaccharide/galactosamine (LPS/GalN). Here we show that such increased hepatotoxicity is not the consequence of the lack of EGF production from SMG. On the contrary, it appears to be the consequence of an inadequate cytokine production by the liver of sialoadenectomized mice. Thus, we found that the increase of plasma tumour necrosis factor-alpha and interleukin-6 was slower in sialoadenectomized than in sham-operated mice. This is because of a decreased rate of production of both cytokines by the liver. We found that the increase of plasma corticosterone (CS) concentration is lower in sialoadenectomized than that in sham-operated mice. Adrenalectomy exacerbated liver injury induced by LPS/GalN. In these animals, sialoadenectomy did not further increase the effect of LPS/GalN. Our results suggest that the effect of sialoadenectomy on LPS/GalN-induced liver toxicity may be the consequence of an altered cytokine production by the liver and a reduced CS release from adrenal glands.