A critical updated review of the hydrometallurgical routes for recycling zinc and manganese from spent zinc-based batteries.
This review paper aims to present and analyse data from the most recent literature (between 2007 and 2019) published on the topic of manganese (Mn) and zinc (Zn) recovery from zinc-based spent batteries through hydrometallurgical methods. In a first attempt, a detailed comparative assessment of the metals leaching performance (as well as the experimental variables that influence its performance) reported in the various studies with strong acid or bases, potentially supplemented by complexing or reducing agents, as well as the reactions involved, are reviewed and discussed. All data point out that the use of a reductant is needed to fully solubilize Mn from spent batteries during the leaching process. Comparison of the data seem to indicate that most reductants have similar performance and, therefore, the choice of a reductant should be focused on low cost or even waste materials. In a second attempt, the separative processes mostly described in the literature to recover Mn and Zn from leachates are reviewed emphasizing the strengths and weaknesses of each technique. Solvent extraction is the most widely tested process for this aim. A thorough comparison of existing data indicates that, in general, neutral extractants have higher potential for selective separation of Zn and Mn. Furthermore, although chemical precipitation is a simple process, low pure final metal hydroxide products are expected to be achieved when alkaline precipitation is implemented comparatively to the Mn oxidative precipitation where Mn can be recovered selectively as a solid of manganese (IV) oxide.


Rapid visual detection of benzimidazole resistance in Botrytis cinerea by recombinase polymerase amplification combined with a lateral flow dipstick.
Benzimidazole resistance in Botrytis cinerea is related to point mutations in the target β-tubulin gene (TUB2). Three mutations (E198A, E198K, E198V) at codon 198 account for most of the resistant strains. A rapid on-site diagnostic assay would be useful to detect the presence and monitor further spread of this resistance mechanism. A recombinase polymerase amplification combined with lateral flow detection (RPA-LFD) method was established for the rapid detection of methyl benzimidazole carbamate (MBC) resistance in B. cinerea. Based on the three mutations at TUB2 codon 198, three sets of RPA-LFD primers were designed, and each of these primer sets was able to specifically amplify the DNA containing its corresponding mutation; no amplification was detected with other mutated or wild-type DNA. The assay was optimized for specificity and sensitivity and was shown to detect the presence of 2 × 102 copies μl-1 of target DNA per reaction within 10 min. DNA from eight other common fungal species of small fruit did not yield a signal. The system worked well over a wide range of temperatures from 25 to 45°C. Crude DNA obtained from boiled mycelium and conidia of symptomatic fruit could be used as templates, which simplified the assay process. This study developed a novel assay based on RPA-LFD for the rapid and equipment-free detection of MBC-resistant isolates. In combination with a simple DNA extraction method, the assay could detect B. cinerea MBC-resistant isolates even without specialized equipment within 30 min. Considering its specificity, stability and simplicity, the RPA-LFD assay could be a promising tool for rapid on-site diagnosis of fungicide-resistant isolates. © 2021 Society of Chemical Industry.


Carotid and vertebral arterial fibromuscular dysplasia masquerading as severe preeclampsia: a case report.
Fibromuscular dysplasia is a non-atherosclerotic noninflammatory vascular disease that can affect any vascular bed. Dysplasia of the intima, media, or adventitia layer of the affected arteries causes stenosis and hypertension. Pregnant or post-partum patients may present with hypertension and be mistakenly diagnosed with preeclampsia. A 26 year old Gravida 1 Para 1 female 20 days post partum from a spontaneous vaginal delivery was transported from an outlying facility due to severely elevated blood pressure and transient left arm numbness and left sided facial droop. Upon arrival the patient was begun on intravenous magnesium sulfate and labetalol for a presumptive diagnosis of severe post partum preeclampsia. Her blood pressure and symptoms responded promptly. Due to her neurologic symptoms a magnetic resonance angiogram was ordered revealing 90% stenosis of her bilateral carotid and vertebral arteries. Severe hypertension and minimal neurologic symptoms may be the presenting symptoms for fibromuscular dysplasia. Cranial imaging is warranted in any pregnant or post partum patient who presents with these symptoms to allow appropriate treatment.


Living on the Edge: Neighborhood Boundaries and the Spatial Dynamics of Violent Crime.
Neighborhood boundaries are a defining aspect of highly segregated urban areas. Yet, few studies examine the particular challenges and spatial processes that occur at the bordering region between two neighborhoods. Extending the growing literature on spatial interdependence, this article argues that neighborhood boundaries-defined as sharp changes in the racial or socioeconomic composition of neighborhoods-are a salient feature of the spatial structure with implications for violent crime and other outcomes. Boundaries lack the social control and cohesion of adjacent homogeneous areas, are contested between groups provoking intergroup conflict, and create opportunities for criminal behavior. This article presents evidence linking racial neighborhood boundaries to increased violent crime. The findings illustrate the importance of neighborhood boundaries for our understanding of spatial dimensions of population dynamics above and beyond the characteristics of neighborhoods.


Biochar granulation enhances plant performance on a green roof substrate.
Green roofs have been widely promoted as a means to enhance ecosystem services in cities, but roofs present a harsh growing environment for plants. Biochar is suggested to be a highly beneficial substrate additive for green roof systems due to its low weight, high nutrient and water retention capacity, and recalcitrance. However, biochar is susceptible to wind and water erosion, which may result in biochar loss and negative environmental impacts. Applications of biochar as large particles or in granulated form may mitigate biochar erosion potential, but relevant data on plant performance and substrate properties are lacking. We examined the effects of granulated and conventional biochars at a range of particle sizes on plant performance of the drought-tolerant forb Agastache foeniculum. We found that granulated biochar strongly enhanced plant growth, reproduction, and physiological status, acting to neutralize pH and enhance water retention capacity of the substrate. In contrast, although conventional biochar reduced substrate bulk density and enhanced substrate total porosity and water retention capacity, it suppressed plant growth. Our results also suggest that granulated biochar at intermediate particle sizes (2-2.8 mm) best enhanced plant performance. We conclude that use of granulated biochars on green roofs can strongly promote plant performance while increasing water infiltration and retention.


In situ continuous Dopa supply by responsive artificial enzyme for the treatment of Parkinson's disease.
Oral dihydroxyphenylalanine (Dopa) administration to replenish neuronal dopamine remains the most effective treatment for Parkinson's disease (PD). However, unlike the continuous and steady dopamine signaling in normal neurons, oral Dopa induces dramatic fluctuations in plasma Dopa levels, leading to Dopa-induced dyskinesia. Herein, we report a functional nucleic acid-based responsive artificial enzyme (FNA-Fe3O4) for in situ continuous Dopa production. FNA-Fe3O4 can cross the blood-brain barrier and target diseased neurons relying on transferrin receptor aptamer. Then, FNA-Fe3O4 responds to overexpressed α-synuclein mRNA in diseased neurons for antisense oligonucleotide treatment and fluorescence imaging, while converting to tyrosine aptamer-based artificial enzyme (Apt-Fe3O4) that mimics tyrosine hydroxylase for in situ continuous Dopa production. In vivo FNA-Fe3O4 treatment results in recovery of Dopa and dopamine levels and decrease of pathological overexpressed α-synuclein in PD mice model, thus ameliorating motor symptoms and memory deficits. The presented functional nucleic acid-based responsive artificial enzyme strategy provides a more neuron friendly approach for the diagnosis and treatment of PD.


Biological predictors of cervical cancer response to radiation therapy.
The addition of cisplatin-based chemotherapy to standard radiation therapy reduces the risk of recurrence and disease-related death rates from locally advanced cervical cancers by as much as 50%. However, the absolute gains are relatively small for patients with early tumors, many of whom would have been cured with radiation alone, and recurrence rates are still high for patients who have very large or advanced-stage tumors. As a result, there is a pressing need for more accurate predictors of radiocurability. A variety of types of biomarkers have been shown to correlate with cervical cancer response to radiation therapy. These include traditional clinical and morphologic predictors, non-molecular biomarkers, including hypoxia and fluorodeoxyglucose-positron emission tomography (FDG-PET) avidity, as well as molecular biomarkers, which include single-gene markers or array-based multigene predictors. Multi-gene predictors of response remain immature in cervical cancer, but studies thus far have paved the way for future studies to validate these findings. Methods will need to be standardized and markers will need to be validated on homogeneous patient populations and treatment approaches before they can become useful tools for clinical decision making. In addition, new biomarkers will be of major value only if they add to the predictive value of traditional clinical and morphologic predictors. Ultimately, the most useful biomarkers will identify patients who will benefit from specific molecularly targeted agents in addition to radiation therapy or perhaps identify patient who are at low risk for recurrence, for whom the dose of radiation or chemotherapy can be reduced.


[Quantitative estimation of the modification of mutagenic effect in experiments on mammals using a regression modification index].
A regressive modification index (RMI = beta M - beta/beta.100) is suggested to quantitatively evaluate modification of the mutagenic effect in experiments on mammals. It is based on the correlation of regressive equation "dose mutagen--effects" coefficients beta M and beta in variants with and without modifier, respectively. Regressive modification indices of various doses of phenobarbital are calculated in experiments on rats with cyclophosphamide and fotrin.


Correction: Which New Health Technologies Do We Need to Achieve an End to HIV/AIDS?
[This corrects the article DOI: 10.1371/journal.pbio.1002372.].


Alpha-thalassaemia and globin gene rearrangements in French Polynesia.
The prevalence of alpha-thalassaemia and various globin gene rearrangements was determined in 1992 individuals living on 11 islands in French Polynesia. The gene frequencies for alpha(+)-thalassaemia (almost exclusively the -alpha 3.7III deletion form) range from 5.3% to 19.2%. Haematological indices on 177 heterozygotes and 27 homozygotes for the -alpha 3.7III variant showed considerable overlap with indices of normal individuals; although there was a broad correlation of average indices with alpha-globin genotype, individual values were a poor indication of genotype. A non-deletion form of alpha(+)-thalassaemia (alpha alpha Th), triplicated alpha genes (alpha alpha alpha) and single zeta gene (-zeta) chromosomes were present at low frequencies (< 1%), whereas triplicated gamma gene (gamma gamma gamma) and triplicated zeta (zeta zeta zeta) arrangements were more common (1.1-16.3%). alpha 0-thalassaemia, probably introduced from Southeast Asia in the early part of this century, was observed in a number of individuals of Chinese and Chinese/Polynesian ancestry. Because of the high frequency of alpha(+)-Thalassaemia on some islands, it therefore seems likely that haemoglobin H disease (resulting from the interaction between alpha 0 and alpha(+)-thalassaemia) must occur in parts of French Polynesia.


Performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma, and adrenal insufficiency.
Salivary cortisol has recently been suggested for studies on the hypothalamic-pituitary-adrenal (HPA) axis. The lack of circadian rhythm is a marker of Cushing's syndrome (CS), and some authors have reported that low salivary cortisol levels may be a marker of adrenal insufficiency. The aim of our study was to define the role of salivary cortisol in specific diagnostic settings of HPA axis disease. We analyzed morning salivary cortisol (MSC) and late-night salivary CORTISOL (LNSC) levels in 406 SUBJECTS: 52 patients with Cushing's disease (CD), 13 with ectopic CS, 17 with adrenal CS, 27 with CD in remission (a mean follow-up of 66±39 months), 45 with adrenal incidentaloma, 73 assessed as having CS and then ruled out for endogenous hypercortisolism, 75 with adrenal insufficiency, and 104 healthy subjects. A LNSC value above 5.24 ng/ml differentiated CS patients from controls with high sensitivity (96.3%) and specificity (97.1%); we found higher LNSC levels in ectopic CS patients than in CD patients. We found no difference in MSC and LNSC levels between patients with CD in remission and healthy subjects. Both MSC and LNSC levels were higher in patients with adrenal incidentaloma than in healthy controls. A MSC value below 2.65 ng/ml distinguished patients with adrenal insufficiency from controls with high sensitivity (97.1%) and specificity (93.3%). Salivary cortisol is a useful tool to assess endogenous cortisol excess or adrenal insufficiency and to evaluate stable CD in remission.


Epigenetic modifications in trinucleotide repeat diseases.
Accumulating evidence supports the important role for epigenetic changes in modulating clinical parameters of complex disorders, including neurodegenerative disease. Several conditions, including fragile X syndrome and Huntington's disease are caused by trinucleotide repeat (TNR) expansions in or near specific genes. Highlighting the link between epigenetic disruption and disease phenotype, recent studies have established significant correlations between clinical features, expansion size, gene expression, the chromatin profile, and DNA methylation in regions surrounding the TNR. Given the debilitating and sometimes fatal consequences of TNR disorders, understanding how an altered epigenetic profile impacts clinical outcome warrants further attention, and could provide key insights for developing novel epigenetic therapies and biomarkers. This review presents the current evidence of epigenetic changes in several TNR diseases.


Total enzyme activity constraint and homeostatic constraint impact on the optimization potential of a kinetic model.
The application of biologically and biochemically relevant constraints during the optimization of kinetic models reduces the impact of suggested changes in processes not included in the scope of the model. This increases the probability that the design suggested by model optimization can be carried out by an organism after implementation of design in vivo. A case study was carried out to determine the impact of total enzyme activity and homeostatic constraints on the objective function values and the following ranking of adjustable parameter combinations. The application of constraints on the model of sugar cane metabolism revealed that a homeostatic constraint caused heavier limitations of the objective function than a total enzyme activity constraint. Both constraints changed the ranking of adjustable parameter combinations: no "universal" constraint-independent top-ranked combinations were found. Therefore, when searching for the best subset of adjustable parameters, a full scan of their combinations is suggested for a small number of adjustable parameters, and evolutionary search strategies are suggested for a large number. Simultaneous application of both constraints is suggested.


B lymphoblasts show oxidase activity in response to cross-linking of surface IgM and HLA-DR.
Human B lymphocytes express components of the superoxide generating system of phagocytes, NADPH oxidase. We studied regulation of this 'B-cell oxidase' during in vitro blast transformation, using Lucigenin-amplified chemiluminescence (CL) to detect superoxide release. While freshly isolated tonsil B lymphocytes showed no CL responses, culture with phorbol myristate acetate (PMA) and ionomycin induced susceptibility to CL triggering by anti-IgM and anti-HLA-DR. Maximal effects were observed after 3 days of culture with 0.4 ng/ml PMA + 1 microgram/ml ionomycin. Cells from such B lymphoblast cultures showed no CL responses to opsonized zymosan. In contrast, peripheral blood mononuclear cells, where monocytes are the predominant oxidant source, showed CL responses to opsonized zymosan but not to anti-IgM and anti-HLA-DR, either before or after culture with PMA + ionomycin. Culture of B cells with the surface immunoglobulin cross-linking agent staphylococcus aureus Cowan I also led to emergence of a CL, response to anti-IgM, which was enhanced by interferon-gamma. Interestingly, markedly fewer B blasts than freshly isolated B lymphocytes expressed cytochrome b-558 surface antigen. Thus, the B-cell oxidase is up-regulated during blast transformation and can be triggered via surface IgM and HLA-DR; however, this appears to be restricted to a subset of B lymphoblasts.


Child psychiatric skills in primary healthcare--self-evaluation of Finnish health centre doctors.
To study Finnish general practitioners' (GP's) perceptions of their child psychiatric skills. The study sample consisted of physicians (n=755) working in health centres situated in the special response area of the Tampere University Hospital, Finland. They were requested to assess their competence in 16 areas on a four-step Likert scale. The response rate was 66.1% (n=499). Physicians evaluated their child psychiatric skills as inadequate on many issues. The ability to identify depression was poorer the younger the child in question. Only a minority (14%) felt they were well able to identify a depressed infant. Many physicians considered themselves poorly skilled in assessing the relationship between infant and parents (39.8%), in assessing a child's need for psychiatric treatment (42.7%) and in identifying a child with attention-deficit disorder (40.7%). A majority (75.9%) rated their skills poor in co-operating with daycare personnel or school staff in matters concerning a child with conduct disturbance. Only 26.8% could assess the necessity of taking a child into custody. Women gave higher ratings of their skills in identifying depressed infants and in assessing the infant-parent relationship than men, whereas men assessed their skills as better in cases in which there were problems in co-operation with parents. In order to provide good psychiatric services for children, attention should be paid to the GPs' child psychiatric skills.


Lung clearance index: A new measure of late lung complications of cancer therapy in children.
Childhood cancer survivors (CSs) might face an increased lifelong risk of lung function impairment. The lung clearance index (LCI) has been described as being more sensitive than spirometry in the early stages of some lung diseases. The aim of this study was to evaluate this index in a cohort of patients with a history of childhood cancer for the first time. We evaluated 57 off-treatment CSs aged 0-18 years old and 50 healthy controls (HCs). We used the multiple-breath washout method to study LCI and spirometry. CSs did not show any differences from the controls in ventilation homogeneity (LCI 6.78 ± 1.35 vs. 6.32 ± 0.44; p: not significant [ns]) or lung function (FEV1 99.9 ± 11.3% vs. 103.0 ± 5.9% of predicted; p: ns; FVC 98.2 ± 10.3% vs. 101.1 ± 3.3% of predicted). LCI significantly correlated with the number of years since the last chemotherapy (r = .35, p < .05). Our study describes the trend of LCI in a cohort of CSs and compares it with the results obtained from HCs. The results show that patients maintain both good values of respiratory function and good homogeneity of ventilation during childhood. Moreover, as LCI increases and worsens as the years pass after the end of the treatment could identify the tendency toward pulmonary fibrosis, which is typical of adult CSs, at an earlier time than spirometry.


Isoelectrofocusing of aldolase B from normal human livers and from livers with hereditary fructose intolerance.
By isoelectrofocusing in thin-layer acrylamide-ampholine gel, normal human aldolase B has been resolved into 5 bands. Moreover we were able to specifically stain (after isoelectrofocusing) the mutated aldolase B in livers with hereditary fructose intolerance, and to show that only the 3 most anodic bands are seen. Some different hypotheses are discussed to account for the microheterogeneity of the normal aldolase B, and for the different isoelectrofocusing pattern found in livers with hereditary fructose intolerance.


Promotive effect of elastase on regression of aortic atherosclerosis in cholesterol-fed quails.
In order to test the anti-atherosclerotic function of elastase, 44 Japanese quails, 40 d of age, were used in this study. An atherogenic diet contained 15% corn oil and 2% cholesterol. Elaszym was orally administered at a dose of 6,000 EL units per kg body weight 3 times a week for 3 months. After 3 months feeding the atherogenic diet was discontinued. Moderate hypercholesterolemia and marked lipid-rich aortic lesions were noted in the group which was fed the atherogenic diet for 3 months. The thickened intima was composed of fibroblasts and alpha-1-anti-trypsin, S-100 protein, calmodulin and elastase were strongly demonstrated. Withdrawal of the atherogenic diet resulted in marked improvement of the serum cholesterol level, and slight reduction of the degree of the intimal thickening of the thoracic aorta. Elastase treatment after the withdrawal of atherogenic diet induced significant regression of the aortic lesions of the thoracic aorta. These results suggest that Elaszym possesses the promotive effect on regression of atherosclerotic lesions.


Soil bacterial community composition and diversity respond to soil environment in the Ebinur Lake Wetland.
To understand the relationship between the community structure of bacteria and soil environment, the diversity and composition of soil bacterial communities were investigated, based on 16S rRNA gene clone library, in three different sampling sites (SP1, SP2 and SP3) in the Bortala and Jinghe River basins of Ebinur Lake Wetland. The results showed that the diversity of bacteria among plots was SP2 > SP3 > SP1, and the richness was SP3 > SP2 > SP1. Community composition analysis of bacteria showed that Proteobacteria and Bacteroides accounted for 49.7% and 53.7%, respectively, making them the most dominant phyla observed. In SP1, Proteobacteria was the most dominant phylum, followed by Bacteroides. In SP2 and SP3, Bacteroides was the most dominant phylum, followed by Proteobacteria. At subphyla level, Gammaproteobacteria, Alphaproteobacteria and Deltaproteobacteria accounted for 50%, 51.0%, and 42.2% of the Proteobacteria of SP1, SP2, and SP3, respectively. Betaproteobacteria and Epsilonproteobacteria were found only in SP3. RDA results showed that SOM, SM and EC were the main soil environmental factors affecting bacterial community structure.


Plasmacytoma relapses in the absence of systemic progression post-high-dose therapy for multiple myeloma.
Autologous (ASCT) and allogeneic stem cell transplantations (alloBMT) are well-established therapies for multiple myeloma. However, patients continue to relapse at a constant rate. We present here 15 out of 163 patients who underwent SCT and relapsed with plasmacytomas only without evidence of bone marrow disease progression (14/147 post-ASCT and 1/16 post-alloBMT). The median time from SCT to plasmacytoma relapse was 24 months. The sites of plasmacytoma included bone, skin, rectum, and testicles. Five patients were treated with local radiotherapy, while seven patients received a combination of radiotherapy and chemotherapy or thalidomide, and two patients received chemotherapy alone with or without thalidomide. The recipient of alloBMT was initially treated with VAD-chemotherapy and local radiotherapy followed by a mini-allograft from the original donor. Eleven patients died at a median of 10 months following diagnosis of the plasmacytoma. Four are still alive, 12-20 months post-plasmacytoma diagnosis. These cases of unconventional disease recurrence are likely to be seen due to sub-clinical seeding of tumour cells suggestive of the presence of an extramedullary (EM) clone of plasma cells with a high degree of chemoresistance. We also review all the available data in the literature for the optimal therapy for patients with isolated EM relapse.


Effects of different designs of orthodontic clear aligners on the maxillary central incisors in the tooth extraction cases: a biomechanical study.
Controlling the 3D movement of central incisors during tooth extraction cases with clear aligners is important but challenging in invisible orthodontic treatment. This study aimed to explore the biomechanical effects of central incisors in tooth extraction cases with clear aligners under different power ridge design schemes and propose appropriate advice for orthodontic clinic. A series of Finite Element models was constructed to simulate anterior teeth retraction or no retraction with different power ridge designs. These models all consisted of maxillary dentition with extracted first premolars, alveolar bone, periodontal ligaments and clear aligner. And the biomechanical effects were analysed and compared in each model. For the model of anterior teeth retraction without power ridge and for the model of anterior teeth no retraction with a single power ridge, the central incisors exhibited crown lingual inclination and relative extrusion. For the model of anterior teeth no retraction with double power ridges, the central incisors tended to have crown labial inclination and relative intrusion. For the model of anterior tooth retraction with double power ridges, the central incisors exhibited a similar trend to the first kind of model, but as the depth of the power ridge increased, there was a gradual decrease in crown retraction value and an increase in crown extrusion value. The simulated results showed that von-Mises stress concentration was observed in the cervical and apical regions of the periodontal ligaments of the central incisors. The clear aligner connection areas of adjacent teeth and power ridge areas also exhibited von-Mises stress concentration and the addition of power ridge caused the clear aligner to spread out on the labial and lingual sides. The central incisors are prone to losing torque and extruding in tooth extraction cases. Double power ridges have a certain root torque effect when there are no auxiliary designs, but they still cannot rescue tooth inclination during tooth retraction period. For tooth translation, it may be a better clinical procedure to change the one-step aligner design to two-step process: tilting retraction and root control.


Suitability of patient education materials on proton-pump inhibitors deprescribing: a focused review.
Engaging patients in the process of deprescribing is a necessity. Several patient education materials have been developed for this purpose. The aim of this study was to assess the suitability of the existing patient education materials for proton-pump inhibitors deprescribing. We conducted a targeted inventory of the available materials on scientific literature and known repositories. We evaluated their suitability with the Suitability Assessment of Materials (SAM) instrument. Materials were rated independently by two researchers and then discussed until consensus was reached. Seven patient education materials were identified. Three materials (42.9%) were deemed "superior" and 4 (57.1%) were deemed "adequate". Ratings were generally good in the categories of content, learning stimulation, motivation, typography and layout. The major weaknesses included the use of inappropriate graphics and the too demanding required reading grade level. These may decrease patient attention and comprehension and therefore the effectiveness of education materials. Suitability of the patient education materials on proton-pump inhibitors deprescribing is overall satisfactory. Greater attention on readability, graphics and inclusion of summaries will be needed for development of future materials.


The fibrous structure of coelacanth scales: a twisted 'plywood'.
Isopedin is a network of collagen bundles present in the scales of most fishes. The scales of coelacanths show a remarkable three-dimensional arrangement of this network which is similar to a regularly twisted plywood. The successive fibrous layers cross at an angle which differs slightly from a right angle. It results that the whole system is twisted. The progressive rotation of the fibril direction is right-handed. Certain preferential orientations of fibrils have been observed, namely parallel to the growth rings. Such arrangments also exist in the embryonic cornea of birds and in the cuticle of certain insects, but do not present such an extensive and regular development.


[The future rôle of psychotherapy in medical care from a medicosocial viewpoint (author's transl)].
The difficulties of futurological statement about the role of psychotherapy in the medical care system are seen (1) in the problemacy to define the object, (2) to assess the present state of the situation of psychotherapeutic care, (3) to recognize the environmental conditions of the role of psychotherapy is paramount. The futurological hypotheses are centred on the supposition that psychotherapy is more and more tending not be fixed at medical professional roles.


Development and characterization of 38 polymorphic microsatellite markers from an economically important fruit tree, the Indian jujube.
A total of 38 polymorphic microsatellite loci of the Indian jujube (Ziziphus mauritiana), an economically important fruit tree, were developed to evaluate genetic diversity and aid in the identification of cultivars. The 38 microsatellite markers were isolated from the Indian jujube using a magnetic bead enrichment method, and polymorphisms were identified in 24 Indian jujube cultivars. The number of alleles ranged from two to 13, with expected heterozygosity ranging from 0.261 to 0.898. The polymorphism information content ranged from 0.248 to 0.889, with a mean of 0.616. Of these 38 simple sequence repeat loci, 20 loci from Z. jujuba (Chinese jujube) were successfully amplified using the simple sequence repeat primer sets. These polymorphic loci should be useful in further studies of the genetic diversity and the identification of cultivars of both the Indian jujube and the Chinese jujube.


Differing reactivities of human and guinea-pig complement on haptenized liposomes via the alternative pathway.
Several haptens coupled to dipalmitoylphosphatidylethanolamine (DPPE) were inserted into the liposome membrane with a base composition of an equimolecular mixture of dimyristoylphosphatidylcholine (DMPC) and cholesterol (Chol). Haptens used were trinitrophenyl (TNP)-DPPE, TNP-aminocaproyl (TNP-Cap)-DPPE, dinitrophenyl (DNP)-DPPE, DNP-aminocaproyl (DNP-Cap)-DPPE, fluoresceinthiocarbamyl (Fl)-DPPE, azobenzenarsonate-tyrosyl (ABA-Tyr)-DPPE, dansyl (DNS)-DPPE, dabsyl (DABS)-DPPE, dithiopyridyl (DTP)-DPPE and maleimidobenzoyl (MB)-DPPE. Reactivity of those haptenized liposomes with complement via the alternative pathway was assessed by release of trapped fluorescent marker from the liposomes following incubation with dilutions of guinea-pig and human sera in a diluent containing MgCl2 and ethyleneglycol-bis(beta-aminoethyl ether)N,N'-tetraacetate (EGTA). In the diluent (Mg-EGTA-GVB), complement activation via the alternative pathway proceeds while that via the classical pathway is inhibited. Fl-liposomes were found to be extremely sensitive to guinea-pig complement, being lysed by guinea pig serum dilutions of up to 1:76 in Mg-EGTA-GVB. Guinea-pig serum could lyse TNP-Cap-liposomes, DNP-Cap-liposomes, TNP-liposomes, DTP-liposomes, MB-liposomes, DNP-liposomes and ABA-Tyr-liposomes, with the reactivity of the liposomes decreasing in this order. However, the only haptenized liposomes sensitive to human serum in Mg-EGTA-GVB were DTP- and MB-liposomes; the other liposomes including Fl-liposomes being unreactive via the alternative pathway in reaction with human complement.


Inhibition of release of taurine and excitatory amino acids in ischemia and neuroprotection.
Volume regulated anion channels (VRAC) have been extensively studied in purified single cell systems like cell cultures where they can be activated by cell swelling. This provides a convenient way of analyzing mechanisms and will likely lead to the holy grails of the field, namely the nature or natures of the volume sensor and the nature or natures of VRACs. Important reasons for such an understanding are that these channels are ubiquitous and have important physiological functions which under pathological conditions convert to deleterious effects. Here we summarize data showing the involvement of VRACs in ischemia-induced release of excitatory amino acids (EAAs) in a rat model of global ischemia. Using microdialysis studies we found that reversal of the astrocytic glutamate transporter and VRACs contribute about equally to the large initial release of EAAs and together account for around 80% of the total release. We used the very potent VRAC blocker, tamoxifen, to see if such inhibition of EAA release via VRACs led to significant neuroprotection. Treatment in the focal rat MCA occlusion model led to around 80% reduction in infarct size with an effective post initiation of ischemia therapeutic window of three hours. However, the common problem of other effects for even the most potent inhibitors pertains here, as tamoxifen has other, potentially neuroprotective, effects. Thus it inhibits nitrotyrosine formation, likely due to its inhibition of nNOS and reduction of peroxynitrite formation. Although tamoxifen cannot therefore be used as a test of the "VRAC-excitotxicity" hypothesis it may prove successful for translation of basic stroke research to the clinic because of its multiple targets.


Impact of histopathological diagnosis with ancillary immunohistochemical studies on lung cancer subtypes incidence and survival: a population-based study.
The aim of this study was to assess the impact of immunohistochemical- (IHC-) studies on incidence and survival of lung cancer histotypes. Lung cancers occurred in southern Switzerland between 1996 and 2010 were selected by the Ticino Cancer Registry and categorised into adenocarcinoma (AC), squamous-cell-carcinoma (SqCC), small-cell-carcinoma (SmCC), and large-cell carcinoma/non-small-cell lung cancer (LCC/NSCLC). Incidence rates, annual-percentage-change (APC), and two-year overall survival (OS) (follow-up: 31.12.2010) were performed. 2467 cases were selected: 997 (40.4%) AC; 522 (21.2%) LCC/NSCLC, 378 (15.3%) SmCC, and 570 (23.1%) SqCC. Trend-analysis showed significant increase in AC (APC: 4.6; 95% CI: 3.1; 6.0) and decrease of LCC/NSCLC, with significant joinpoint in 2003 (APC: -14.7; 95% CI: -21.6; -7.1). Improved OS and decreased OS were detected in SqCC and LCC/NSCLC, respectively. This study highlights that diagnosis with ancillary immunohistochemical studies will change incidence and survival of precisely defined lung cancer subtypes. It calls attention to the need for cautious interpretation of studies and clinical trials, where the diagnosis was based on histology unaccompanied by IHC studies, and to the need of standardised diagnostic procedures.


Comparative study of functional capacity and quality of life among obese and non-obese elderly people with knee osteoarthritis.
The association between osteoarthritis (OA) and obesity can lead to a reduced functional capacity, compromising the quality of life (QoL) of the elderly. To compare the functional capacity and QoL of obese and non-obese older adults with knee OA. The sample consisted of 35 subjects with OA divided into two groups, obese and non-obese subjects, according to their body mass index. To assess functional capacity, performance tests such as Timed Up and Go (TUG), gait speed test, and the six-minute walk test (6 MWT) were carried out. To assess QoL, WOMAC and SF-36 questionnaires were administered. We performed descriptive and inferential statistics using SPSS software version 20.0. Elderly patients with OA were divided into two groups (obese, n=16; non-obese, n=19). Socio-demographic characteristics were similar between groups (p>0.05). The obese group showed a worst performance in TUG, brisk walking speed and 6 MWT. A more severe pain was found in the following items: "performing heavy housework chores", "going down stairs", "bending to floor" and "getting up from bed" in the obese group (p<0.05). In addition, the obese group had more difficulty to perform tasks for the following items: "going down stairs", "rising from a chair", "standing" and "getting on/off toilet" (p<0.05). There was no statistically significant difference in the assessed domains of SF-36 between groups (p>0.05). OA associated with obesity caused a negative impact on functional capacity; however, quality of life scores were low, and no difference in obese and non-obese subjects was found.


Efficacy and Mechanism Study of 6S-5-Methyltetrahydrofolate-Calcium Against Telencephalon Infarction Injury in Zebrafish Model of Ischemic Stroke.
Ischemic stroke is a heterogeneous brain injury with complex pathophysiology and it is also a time sensitive neurological injury disease. At present, the treatment options for ischemic stroke are still limited. 6S-5-methyltetrahydrofolate-calcium (MTHF-Ca) is the calcium salt of the predominant form of dietary folate in circulation. MTHF-Ca has potential neuroprotective effect on neurocytes, but whether it can be used for ischemic stroke treatment remains unknown. We established zebrafish ischemic stroke model through photothrombotic method to evaluate the protective effect of MTHF-Ca on the ischemic brain injury of zebrafish. We demonstrated that MTHF-Ca reduced the brain damage by reducing motor dysfunction and neurobehavioral defects of zebrafish with telencephalon infarction injury. MTHF-Ca counteracted oxidative damages after Tel injury by increasing the activities of GSH-Px and SOD and decreasing the content of MDA. RNA-seq and RT-qPCR results showed that MTHF-Ca played a neuroprotective role by alleviating neuroinflammation, inhibiting blood coagulation, and neuronal apoptosis processes. Overall, we have demonstrated that MTHF-Ca has neuroprotective effect in ischemic stroke and can be used as a potential treatment for ischemic stroke.


Segmental pedicle screwing for idiopathic scoliosis using computer-assisted surgery.
Retrospective clinical study. To evaluate the accuracy of computer-assisted surgery for idiopathic scoliosis. Segmental pedicle screw fixation has been proven to enable enhanced correction of scoliotic deformities. However, both neurovascular and visceral structures are at potential risk from screw misplacement due to pedicle drift. No reports exist on the accuracy and benefits of computer-assisted surgery for pedicle screwing in scoliosis surgery. A total of 40 consecutive patients with idiopathic scoliosis were evaluated. Postoperative computed tomography was assessed for the accuracy of pedicle screw placement in 20 cases treated without a navigation system and 20 cases with a computed tomography-based navigation system. Correlations between registered levels and pedicle perforation were investigated. Pedicle violation was observed in 28.0% of the control group and 11.4% of the navigation group, with significant differences. No screw misplacements at the registered levels were seen, and the longer the distance between the registered level and level of screw insertion, the higher the rate of pedicle violation. No intraoperative complications caused by pedicle perforation occurred. In the navigation group, a tendency to lateral perforation at the concave side and medial perforation at the convex side was noted, like in the control group. Use of the navigation system significantly reduced the screw misplacement rate for rotated vertebrae as compared with the control group. Separate registration is recommended for rotated vertebrae when possible.


Effect of a sensory diet smartphone application on the symptoms of children with attention deficit hyperactivity disorder (ADHD): A feasibility study.
Sensory integration and sensory diet can improve the symptoms of children with attention deficit/hyperactivity disorder (ADHD). This feasibility study aimed to evaluate the effect of using a sensory diet smartphone application by mothers on the main symptoms of their children with ADHD, including hyperactivity, attention deficit, and impulsivity. We conducted a need assessment study with the collaboration of 15 occupational therapists, developed an Android-based prototype, and evaluated it in terms of usability with the participation of 12 available mothers of children with ADHD. 12 other selected children were divided into control and experimental groups. At first, these children were evaluated using the hyperactivity subscale of the fourth version of the Pediatric Symptoms Questionnaire, and after two months of using the application by the mothers of the children in the experimental group, both groups were re-evaluated using the same questionnaire. We compared the mean score of this questionnaire before and after the mothers' use of the application. The application included 105 sensory diet exercises presented in animated format with accompanying text explanations. According to mothers' feedback, the usability of the application was rated at a high level with an average score of 8.35 out of 9. In the experimental group, attention deficit significantly improved compared to the pre-intervention stage (Mean ± SD = 13.67 ± 6.86 vs. 22 ± 6.13, P-value<0.0001) and compared to the control group after the intervention (P-value = 0.048). Additionally, after the intervention, the experimental group showed significant improvements in impulsivity (mean difference = -1.33) and hyperactivity (mean difference = -4.67) compared to the pre-intervention (P-value = 0.025 and 0.034, respectively). However, these improvements were not statistically significant when compared to the control group (P-value = 0.937 and 0.58, respectively). The findings suggest that sensory diet smartphone applications have the potential to help alleviate symptoms related to attention deficit in children with ADHD.


Pharmacokinetic based study on "lagged stimulation" of Curcumae Longae Rhizoma - Piper nigrum couplet in their main active components' metabolism using UPLC-MS-MS.
Curcumae Longae Rhizoma is one of the commonly used traditional Chinese medicines, which has multiple biological activities such as relieving stagnation and stasis, pain alleviation, curing amenorrhea and wounds. However, its main active component-curcumin has poor absorption and very fast metabolism in body. To solve this problem, Piper nigrum was introduced for its ability to strengthen bioavailability of other compounds. In most cases of TCM couplets, all ingredients were prepared and taken simultaneously, which in our opinion did not take full advantage of their interactions. Therefore, order of administration should be adjusted according to pharmacokinetic parameters of the ingredients, which the ones act as supplement can first be taken, and main therapeutic components followed when the former reached its peak. the extract of Piper nigrum (containing at least 95% piperine) was taken by rats 6h before taking Curcumae Longae Rhizoma extract (containing at least 95% curcumin). Then, a UPLC-MS-MS method was developed to determine their content in plasma simultaneously. Determination was carried out by on a C18 column within 5min by isocratic elution using 0.2% formic acid and acetonitrile (50:50, v/v). Tandem mass detection was conducted by selective reaction monitoring (SRM) via electrospray ionization (ESI) source in positive mode. Samples were pre-treated by liquid-liquid extraction (LLE), and verapamil was used as internal standard (IS). For both curcumin and piperine, the proposed method had good linearity (r2=0.999) within the concentration range of 1-1000ng/ml, with good recovery, precision and stability. The lower limit of quantification (LLOQ) was 1ng/ml. As pharmacokinetic data indicated, Maximum concentration (Cmax) of curcumin increased significantly to 394.06; the time reach maximum concentration (Tmax) and elimination half-life (T1/2) were 0.5 and 0.67h, respectively; CONCLUSION: The results provide a good strategy for the investigation of TCM formula especially the couplets, as well as a fast, selective and sensitive UPLC-MS-MS method determining active components in-vivo. Furthermore, the finding of "lagged stimulation" suggested that the use of complex formula should take pharmacokinetics into much more careful consideration.


Partial purification of a prostatic growth factor.
A 5-step fractionation procedure was used to isolate a prostatic growth factor from a tissue homogenate of human benign prostatic hyperplasia. The procedure made use of the property of prostatic growth factor to occur predominately as a large molecule (greater than 67,000) in low ionic strength solution (Tris with 0.05 M NaCl) but as a smaller molecule (less than 33,000) in high salt buffer (Tris with 1.55 M NaCl). The fractionation scheme consisted of ammonium sulfate precipitation, gel filtration (low ionic strength) and DEAE chromatography. The growth factor activity was eluted from DEAE with high ionic strength buffer followed by 2 gel filtration steps in high ionic strength buffer. The fractionation scheme produced greater than a 200-fold increase in prostatic growth factor activity and 10 per cent recovery. Additional separation steps will be required to purify prostatic growth factor to homogeneity.


Noncutaneous neoplasms after kidney transplantation: analysis at single center.
Malignancy is the third most cause of death among kidney transplantation recipients after cardiovascular events and infection. The aim of this study was to investigate the types of and risk factors for cancer excluding skin lesions among kidney transplantation (KT) patients in Portugal. We studied retrospectively the 1695 patients who underwent KT between 1983 and 2009. Malignancies post-KT were considered if diagnosed at least 1 year after KT. The results were compared with a group of cancer free patients. During the follow-up period to June 2010, which included a median duration of 118.49 months (interquartile range 53.34 to 182.46), 60 patients (3.5%) developed 66 malignancies, which were the cause of death in 17. Compared with patients without cancer, the affected ones were older (P < .001), and had a longer duration of graft function (P = .002). There were no significant differences regarding gender, follow-up time, actue rejection episodes, donor type, number of KT, immunosuppressive regimen. The most frequent malignancy was colorectal cancer (21.2%), followed by malignant lymphoma (16.7%) and breast cancer (13.6%). The mean age of patients at diagnosis was 53.9 ± 11.5 years. The average time for development of a cancer was 8.3 ± 5.7 years with 42.4% detected between 1 and 5 years. In total, 16 patients were converted to sirolimus. Patient survival was significantly lower among subjects with cancer; censored graft survival was significantly higher in this group. A multivariate logistic regression analysis identified risk factors for malignancy post-KT to be recipient age and duration of follow-up. In conclusion, our data showed a significant number of tumors that generally not described to be higher lesions among KT. We achieved an early diagnosis and a lack of impact on death-censored graft survival.


Leydig's and sertoli cells. Their fine structures in three cases of Klinefelter's syndrome.
Testicular biopsy specimens obtained from three patients with Klinefelter's syndrome were studied by light and electron microscopy. Of note in the ultrastructural findings were the absence of annulate lamellae in the Sertoli cells and the abnormal mitochondria, the presence of microcrystalline formations, and the absence of the crystals of Reinke in Leydig's cells. It is suggested that the impaired hormonal function of the testes in Klinefelter's syndrome may be related to the absence of annulate lamella in the Sertoli cells and the presence of microcrystal formations in Leydig's cells.


Purification and optimization of functional reconstitution on the surface of leukemic cell lines of GPI-anchored Fc gamma receptor III.
Purified glycosyl phosphatidyl inositol (GPI)-anchored cell surface proteins can be reincorporated spontaneously into the cell membrane by incubating the cells with these proteins. This unique property provides a novel way of introducing cell surface receptors on live cell membranes without the use of gene transfection. Since any classical transmembrane cell surface protein can be converted to a GPI anchored protein by recombinant techniques, this method provides a means of studying ectodomain associated receptor functions on various cell types. Moreover, in some circumstances, it can be used to correct deficient cellular functions resulting from lack of cell surface protein expression. Using GPI-anchored Fc gamma receptor III (CD16B), a low affinity Fc gamma receptor, we have systematically studied the optimal conditions for reconstitution of a functional receptor on nucleated cells. CD16B is purified to homogeneity from neutrophil lysates by single step immunoaffinity chromatography. The purified CD16B is functionally active as evidenced by its ability to bind IgG opsonized erythrocytes. CD16B incorporation on nucleated cells is temperature dependent with an optimum of 37 degrees C. The level of expression of incorporated CD16B is also depend on the concentration of CD16B available and the duration of incubation. The incorporated CD16B retains its ability to bind ligand and also mediates endocytosis of the bound ligand. In summary, our results demonstrate that purified, functionally active GPI-anchored receptors can be expressed on desired cells in a controlled manner and retain some functional properties.


Improving the touchscreen-based food approach-avoidance task: remediated block-order effects and initial findings regarding validity.
Approach biases to foods may explain why food consumption often diverges from deliberate dietary intentions. Yet, the assessment of behavioural biases with the approach-avoidance tasks (AAT) is often unreliable and validity is partially unclear. The present study continues a series of studies that develop a task based on naturalistic approach and avoidance movements on a touchscreen (hand-AAT). In the hand-AAT, participants are instructed to respond based on the food/non-food distinction, thereby ensuring attention to the stimuli. Yet, this implies the use of instruction switches (i.e., 'approach food - avoid objects' to 'avoid food - approach objects'), which introduce order effects. The present study increased the number of instruction switches to potentially minimize order effects, and re-examined reliability. We additionally included the implicit association task (IAT) and several self-reported eating behaviours to investigate the task's validity. Results replicated the presence of reliable approach biases to foods irrespective of instruction order. Evidence for validity, however, was mixed: biases correlated positively with external eating, increase in food craving and aggregated image valence ratings but not with desire to eat ratings of the individual images considered within participants or the IAT. We conclude that the hand-AAT can reliably assess approach biases to foods that are relevant to self-reported eating patterns.


Relatively semi-conservative replication and a folded slippage model for short tandem repeats.
The ubiquitous presence of short tandem repeats (STRs) in virtually all genomes implicates their functional relevance, while a widely-accepted definition of STR is yet to be established. Previous studies majorly focus on relatively longer STRs, while shorter repeats were generally excluded. Herein, we have adopted a more generous criteria to define shorter repeats, which has led to the definition of a much larger number of STRs that lack prior analysis. Using this definition, we analyzed the short repeats in 55 randomly selected segments in 55 randomly selected genomic sequences from a fairly wide range of species covering animals, plants, fungi, protozoa, bacteria, archaea and viruses. Our analysis reveals a high percentage of short repeats in all 55 randomly selected segments, indicating that the universal presence of high-content short repeats could be a common characteristic of genomes across all biological kingdoms. Therefore, it is reasonable to assume a mechanism for continuous production of repeats that can make the replicating process relatively semi-conservative. We have proposed a folded replication slippage model that considers the geometric space of nucleotides and hydrogen bond stability to explain the mechanism more explicitly, with improving the existing straight-line slippage model. The folded slippage model can explain the expansion and contraction of mono- to hexa- nucleotide repeats with proper folding angles. Analysis of external forces in the folding template strands also suggests that expansion exists more commonly than contraction in the short tandem repeats. The folded replication slippage model provides a reasonable explanation for the continuous occurrences of simple sequence repeats in genomes. This model also contributes to the explanation of STR-to-genome evolution and is an alternative model that complements semi-conservative replication.


Two-Dimensional Polycyclic Photovoltaic Molecule with Low Trap Density for High-Performance Photocatalytic Hydrogen Evolution.
Typical organic semiconductors show a high trap density of states (1016 -1018 cm-3 ), providing a large number of centers for charge-carrier recombination, thus hindering the development of photocatalytic hydrogen evolution. Here, we design and synthesize a two-dimensional polycyclic photovoltaic material, named as TPP, to reduce the trap density to as low as 2.3×1015 cm-3 , which is 1-3 orders of magnitude lower than those of typical organic semiconductors. Moreover, TPP exhibits a broad and strong absorption, ordered molecular packing with a large crystalline coherence length and enhanced electron mobility. Then, the bulk heterojunction nanoparticles (BHJ-NPs) based on a blend of polymer donor (PM6) and TPP exhibit an average hydrogen evolution rate (HER) of 64.31 mmol h-1 g-1 under AM1.5G sunlight (100 mW cm-2 ), and 72.75 mmol h-1 g-1 under 330-1100 nm illumination (198 mW cm-2 ) higher than that of the control NPs based on typical PM6 : Y6 (62.67 mmol h-1 g-1 ).


Model for spatial microtubule oscillations.
Under particular in vitro conditions, oscillating spatial and temporal waves of assembled microtubules can be observed. A reaction-diffusion model is presented to reproduce these results. This model is based on a set of chemical reaction equations and extended to include spatial dependence and diffusion. The basic properties of the model are presented and the results are demonstrated to connect the observable waves with turbidimetric measurements. The results of the model are consistent with experimental findings.


Automated high through-put colocalization analysis of multichannel confocal images.
The laser scanning confocal microscope (LSCM) generates images of multiple labelled fluorescent samples. Colocalization of fluorescent labels is frequently examined. Here we present an example where localization of fluorescent analogues of cloned protein were referenced to fluorescent antibodies directed against the proteins of cellular compartments. Colocalization is usually evaluated by visual inspection of signal overlap or by using commercially available software tools, but there are limited possibilities to automate the analysis of large amounts of data. We developed a simple tool using Matlab to automate the colocalization procedure and to exclude the biased estimations resulting from visual inspections of images. The script in Matlab language code automatically imports confocal images and converts them into arrays. The contrast of all images is uniformly set by linearly reassigning the values of pixel intensities to use the full 8-bit range (0-255). Images are binarized on several threshold levels. The area above a certain threshold level is summed for each channel of the image and for colocalized regions. As a result, count of pixels above several threshold levels in any number of images is saved in an ASCII file. In addition Pearson's r correlation coefficient is calculated for fluorescence intensities of both confocal channels. Using this approach quick quantitative analysis of colocalization of hundreds of images is possible. In addition, such automated procedure is not biased by the examiner's subject visualization.


Long-term safety study of colistimethate sodium (Colobreathe®): Findings from the UK Cystic Fibrosis Registry.
As part of the risk management plan in Europe, a long-term observational study was conducted to monitor the safety of colistimethate sodium dry powder for inhalation (CMS-DPI) compared to other inhaled antibiotics. A cohort of CMS-DPI patients and a matched cohort were identified from the UK Cystic Fibrosis Registry (UKCFR) from 2014-2018. The primary outcome was a composite endpoint, defined as adverse events (AEs) or new cystic fibrosis (CF) complications. Other outcomes included pulmonary exacerbations and treatment discontinuations. Of 1466 and 3503 patients in the CMS-DPI and comparator cohorts, respectively, 82.7% and 79.4% had AEs. Among the most common new CF complications were osteopenia, CF-related diabetes, and increased liver enzymes. The adjusted event rate ratio (ERR) for the primary outcome was 1.25 (95% confidence interval [CI]: 1.18-1.33, p<0.001). After excluding new CF complications, there was no difference between cohorts (ERR=1.04, 95% CI: 0.79-1.38, p=0.785). Pulmonary exacerbations were common in CMS-DPI and comparator cohorts (78.0% and 79.9% of patients, respectively), with adjusted ERR of 1.02 (95% CI: 0.95-1.10, p=0.523). Rates of discontinuation were similar in the CMS-DPI and Tobramycin inhalation powder comparator cohorts (37.8% and 39.8% of patients, respectively). There was no difference in the rate of adverse events between CMS-DPI and comparator cohorts. The safety profile of CMS-DPI is similar to those of other inhaled antibiotics, supporting its long-term safety in people with CF. The UKCFR has developed a successful model for partnership with industry to conduct long-term studies aimed at assessing drug safety.


No increased susceptibility to breast cancer from combined CHEK2 1100delC genotype and the HLA class III region risk factors.
CHEK2 is low-penetrance breast cancer susceptibility gene. The 1100delC mutation may interact with variants/mutations in other breast cancer susceptibility loci. We identified a risk haplotype in the HLA class III region in breast cancer patients [de Jong MM, Nolte IM, de Vries EGE, et al. The HLA class III subregion is responsible for an increased breast cancer risk. Hum Mol Genet 2003, 12, 2311-2319] and tested whether it interacted with 1100delC mutation. The CHEK2 1100delC mutation was analysed in the same series of patients and controls as in the HLA breast cancer study. In 962 unselected breast cancer patients, the 1100delC mutation was observed in 2.9% and in 367 controls in 1.4% (NS). The highest 1100delC frequency occurred in high-risk (4.4%), followed by moderate-risk (3.8%), and lowest in low genetic risk patients (2.4%, P(trend) 0.029). In HLA risk haplotype carriers no increased breast cancer risk was observed in the presence of 1100delC mutation. Patients more often had one than both genetic risk factors. The 1100delC mutation and the HLA risk haplotype confer increased breast cancer risks, but an interactive effect on breast cancer between both factors is unlikely. In contrast, the effect of 1100delC mutation on breast cancer risk was limited to individuals without HLA risk haplotype, suggesting a mutual excluding effect between these risk factors.


[Avoidance of complications during Kimray-Greenfield filter implantation].
In 9 out of 24 cases we experienced complications when implanting the Kimray-Greenfield-Filter. As a result of this the introduction of this filter is now performed by a guide wire. To obtain maximum results the introducer and the filter itself should be improved.


The Effects of Remdesivir and Dexamethasone on Renal Sirtuin-1 Expression and Renal Function in Male Rats.
Remdesivir (REM) and dexamethasone (DEX) both have been used to treat coronavirus disease 2019 (COVID-19). The present study aimed to evaluate the effects of REM and DEX on kidney structure and function with particular focus on the probable renal sirtuin-1 (SIRT1) expression alteration in rats. Twenty-four male Wistar rats were divided into four groups, as follows: group A (control) received normal saline (5 mL/kg/day for 10 days); group B (REM) received REM (17 mg/kg/day on the first day, and 8.5 mg/kg/day on the 2nd-10th days); group C (REM + DEX) received both REM (17 mg/kg/day on the first day, and 8.5 mg/kg/day on the 2nd-10th days) and DEX (7 mg/kg/day, for 10 days); group D (DEX) received DEX (7 mg/kg/day for 10 days). Renal SIRT1 expression and kidney structure and function-related factors were evaluated by standard methods. The mean levels of urea in the REM + DEX group (60.83 ± 6.77, mg/dL) were significantly higher than in the control (48.33 ± 3.01, mg/dL; p = 0.002) and DEX (51.22 ± 4.99, mg/dL; p = 0.018) groups. The mean levels of creatinine in the REM (0.48 ± 0.08, mg/dL) and REM + DEX (0.50 ± 0.04, mg/dL) groups were higher than in the control group (48.33 ± 3.0 mg/dL) significantly (p = 0.022 and p = 0.010, respectively). The renal SIRT1 expression was significantly (p = 0.018) lower in the REM + DEX group (0.36 ± 0.35) than in the control group (1.34 ± 0.48). Tubulointerstitial damage (TID) scores in REM + DEX-treated rats (2.60 ± 0.24) were significantly higher than in the control (0.17 ± 0.17, p = 0.001) and DEX (0.50 ± 0.29, p = 0.005) groups. The administration of DEX and REM might lead to kidney injury associated with SIRT1 downregulation.


Patient-reported symptom burden and impact on daily activities in chronic graft-versus-host disease.
Chronic graft-versus-host disease (GVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) treatment for hematologic malignancies. There are limited patient-reported data concerning symptom burden and effects on activities of daily living (ADL). The cross-sectional Living With Chronic GVHD Patient Survey was administered online in the United States (May-August 2020) to participants aged ≥18 years who underwent allogeneic HSCT, were diagnosed with chronic GVHD by a healthcare provider, and self-reported active chronic GVHD (within past 5 years). Information on patient demographics, disease characteristics, symptom burden, and ability to perform ADL was collected. Symptom burden was assessed using the validated Lee Symptom Scale (range from 0-100 with higher scores indicating greater burden). All data were summarized using descriptive statistics; no formal statistical comparisons were conducted. Out of 580 participants who entered the survey screener, 165 participants (28.4%) across 33 states fulfilled all study eligibility criteria, completed the entire survey, and were included (age: mean [SD], 53.7 (13.8) years; median [range], 57.0 [18-78] years; female, n = 105 [63.6%]; White, n = 137 [83.0%]). Respondents described their chronic GVHD severity primarily as moderate (n = 54 [32.7%]) or severe (n = 102 [61.8%]) at the time when symptoms were at their worst. One-third of respondents (33.9%) indicated that their chronic GVHD symptoms were at their worst for ≥1 year in duration. Mean (SD; range) Lee Symptom Scale score was 44.8 (19.4; 2-100); 44% of respondents considered "dry eye" the most burdensome symptom. Almost half of respondents (n = 73 [44.2%]) rated their overall quality of life (QoL) as poor. Participants reported a detrimental impact of symptoms on ADL, including basic activities (eg, eating, personal hygiene, dressing). Survey respondents self-reported high chronic GVHD symptom burden and felt that their symptoms severely interfered with physical function and ADL. Effective strategies to mitigate chronic GVHD symptoms are needed to improve QoL among HSCT survivors.


Correction to: Inflammatory bowel disease (IBD) position statement of the Italian Society of Colorectal Surgery (SICCR): general principles of IBD management.
The affiliation of the author Silvio Danese has been incorrectly published in the original publication. The complete correct affiliation should read as follows.


Inhibition of JK184-Induced Cytoprotective Autophagy Potentiates JK184 Antitumor Effects in Breast Cancer.
Breast cancer (BCa) is the most common aggressive tumor with limited curative therapeutic options available among women worldwide. JK184 is a potent Hedgehog inhibitor that regulates the glioma-dependent transcriptional activity. Although some studies have indicated that JK184 can kill BCa cells, it remains unclear whether there are any events that limit the use of JK184 in BCa therapy. Here, we report that JK184 intervention induces BCa cell death involving the dysregulation of autophagy in a dose- and time-dependent manner. The induction of autophagy compromises the antiproliferative effect of JK184. Mechanistically, JK184 induces autophagy via inhibiting the Akt/mTOR pathway in BCa cells. Taken together, our findings unravel a novel mechanism for JK184 treatment in BCa, suggesting that JK184 in combination with autophagy inhibitor may be a potential therapeutic strategy for the clinical treatment of BCa.


Adipose tissue TSH as a new modulator of human adipocyte mitochondrial function.
Recent studies indicate a possible role of TSH/TSHR signalling axis on adipogenesis and adipose tissue physiology. Here, we aimed to investigate the relationship between adipose tissue TSHB and adipose tissue physiology-related gene expression. Subcutaneous and visceral adipose tissue TSHB gene expression was analysed in two independent cohorts [Cohort1 (N = 96) and Cohort2 (N = 45)] and after bariatric surgery-induced weight loss [Cohort3 (N = 22)]. Adipose tissue TSH protein expression was also analysed in a subgroup of participants from Cohort 1 (N = 16). The effects of recombinant TSH on human subcutaneous preadipocytes and adipocytes were investigated. In cohort 1, both visceral and subcutaneous adipose tissue TSHB gene expression was positively correlated with the expression of mitochondrial function (PPARGC1A, ISCA2, CISD1, SIRT1, NFE2L2, NRF1) and fatty acid mobilization (CAV1, ENGL1), but not with adipogenic-related genes. Of note, adipose tissue TSH protein levels were also associated with some of these markers of mitochondrial function and fatty acid mobilization. These associations were replicated in cohort 2. Bariatric surgery-induced weight loss resulted in increased subcutaneous adipose tissue TSHB in parallel to increased PPARGC1A. In human subcutaneous adipocytes, rh-TSH administration led to increased mitochondrial respiratory capacity in parallel to increased mitochondrial function- and adipogenic-related gene expression, but no significant effects were observed during differentiation of human preadipocytes. These data point to a possible role of adipose tissue TSH in the maintenance of adipocyte mitochondrial function.


Study of nasopharyngeal bacterial flora. Variations in nasopharyngeal bacterial flora in schoolchildren and adults when administered antimicrobial agents.
Changes in nasopharyngeal bacterial flora in adults with acute upper respiratory tract infection on administration of antimicrobial agents were investigated, and how these changes contrasted with those in children. Many patients with acute sinusitis due to allergies, and patients with malignancy and diabetes mellitus were included in the investigation. The detection rates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, the major bacteria of acute otitis media (AOM), were 22%, 10%, and 7% respectively, which were significantly lower than those for children. Gram stain examination of nasopharyngeal swab samples showed a significant relation between leukocyte infiltration and the detection amount of S. pneumoniae (P = 0.0086). A significant relation (P = 0.0134) was also observed when H. influenzae was simultaneously detected. No significant change in the three major AOM bacteria present in nasopharyngeal bacterial flora after administration of antimicrobial agents was observed. However, all S. pneumoniae and H. influenzae detected after antimicrobial agent administration had the beta-lactam-resistance gene. It was observed that a significant improvement in leukocyte infiltration occurred 6 to 10 days after antimicrobial agent administration. In contrast, a significant improvement in children was observed at 2 to 5 days. In the adult subjects, this improvement was probably due to spontaneous remission rather than the effect of the antimicrobial agents. Although investigation of the long-term administration of antimicrobial agents was also conducted, its benefits for the patients were not elucidated.


Highly sensitive immunosensing platform for one-step detection of genetically modified crops.
The wide cultivation of genetically modified (GM) insect-resistant crops has raised concerns on the risks to the eco-environment resulting from a release of Cry proteins. Therefore, it is vital to develop a method for the quantification of GM crops. Herein, A highly sensitive immunosensing platform has been developed for both colorimetric and chemiluminescent (CL) detection of Cry 1Ab using dual-functionalized gold nanoparticles (AuNPs) as signal amplification nanoprobes for the first time. In this work, anti-Cry 1Ab monoclonal antibody and horseradish peroxidase (HRP) are simultaneously functionalized on the surface of AuNPs with an exceptionally simple synthesis method. Combined with immunomagnetic separation, this immunosensing platform based on colorimetric method could detect Cry 1Ab in one step in a linear range from 1.0 to 40 ng mL-1 within 1.5 h, with a limit of detection of 0.50 ng mL-1. The sensitivity of fabricated nanoprobes was 15.3 times higher than that using commercial HRP-conjugated antibody. Meanwhile, the fabricated nanoprobes coupled with CL detection was successfully applied for Cry 1Ab detection with a minimum detection concentration of 0.050 ng mL-1 within a linear range of 0.10-20 ng mL-1. The proposed approach was validated with genuine GM crops, and the results showed a good correlation coefficient of 0.9906 compared to those of a commercial ELISA kit. Compared with ELISA, the developed immunosensing platform significantly simplified the assay procedure and shortened the analytical time, thus providing a new platform for the detection of genetically modified crops with high sensitivity, rapidity and simplicity.


Targeting the Microbiome in Inflammatory Bowel Disease: Critical Evaluation of Current Concepts and Moving to New Horizons.
Microorganisms present in the intestine possess proinflammatory or anti-inflammatory activities which may modulate inflammatory bowel disease (IBD). The concepts followed by researchers in trying to target the microbiota in IBD were to decrease pathogens or pathobionts, or only the microbial load, and more recently, to favor growth and persistence of favorable microorganisms. We review, here, those concepts and critically analyze the clinical data (especially randomized controlled trials) obtained using antibiotics and probiotics. We eventually present and criticize the rational and data obtained so far following new research strategies including the use of new probiotics, genetically modified organisms and fecal transplantation.


Circulating macroprolactin exhibits molecular heterogeneity and is not exclusively an antibody complex.
Macroprolactin (macPRL) is considered to be solely a prolactin antibody complex. We examined macPRL heterogeneity in samples from thirteen patients suspected of macroprolactinemia. Polyethylene glycol (PEG) precipitation, gel permeation (GPC), protein-G affinity, and Lectin affinity chromatography were used to investigate the nature of macPRL. Using PEG, 8, 3, and 2 samples were macPRL positive, negative, and indeterminate respectively. Using GPC, prolactin appeared at high (H) (≥150 kDa), mid (M) (≥30 < 150 kDa), and low (L) (<30 k Da) forms. For macPRL positive samples, 52.3 to 95.0%, 3.6 to 34.1%, and 1.4 to 34.5% appeared at the (H), (M), and (L) regions respectively, compared with samples negative for macPRL with 1.2 to 5.1%, 60.0 to 79.4%, and 15.4 to 38.9% prolactin activity respectively. macPRL positive samples showed 30.4 to 86.5% binding to protein G column compared with negative samples at 1.2 to 5.1%. GPC-separated forms showed macPRL is heterogenous being either antibody bound (protein G studies) or glycosylated aggregates (lectin studies). Samples with identified macPRL forms were analysed using 4 immunoassay analysers. Samples with (H) and (M) macPRL forms showed significant positive bias in 2 immunoassays. The study is limited by the small number of samples and a larger scale study is required.


ROS homeostasis and metabolism: a dangerous liason in cancer cells.
Tumor cells harbor genetic alterations that promote a continuous and elevated production of reactive oxygen species. Whereas such oxidative stress conditions would be harmful to normal cells, they facilitate tumor growth in multiple ways by causing DNA damage and genomic instability, and ultimately, by reprogramming cancer cell metabolism. This review outlines the metabolic-dependent mechanisms that tumors engage in when faced with oxidative stress conditions that are critical for cancer progression by producing redox cofactors. In particular, we describe how the mitochondria has a key role in regulating the interplay between redox homeostasis and metabolism within tumor cells. Last, we will discuss the potential therapeutic use of agents that directly or indirectly block metabolism.


Vascular contribution of adrenomedullin to microcirculatory improvement in experimental colitis.
The effect of adrenomedullin (AM), a peptide that has demonstrated vasodilatory activity, was studied in the colon and small mesenteric arteries of rats in a chronic model of inflammatory bowel disease. AM (50 ng/kg/day) was administered i.p. daily, starting 24h after trinitrobenzensulfonic acid (TNBS, 30 mg) instillation. After 14 days, rats were sacrificed, colons were macroscopically analyzed and biochemical parameters (myeloperoxidase activity, cytokines, cyclooxygenase-2 (COX-2) as well as inducible nitric oxide synthase (iNOS) expression) were determined. Vascular function of small mesenteric arteries was assessed by addition of phenylephrine (10⁻⁸ to 10⁻⁴ mol/L) and participation of COX and NOS pathways was also evaluated by using different inhibitors: indomethacin, NS-398, L-NNA, and 1400 w. Chronic AM treatment significantly reduced colonic macroscopic damage and inflammation markers. TNBS instillation induced COX-2 and iNOS expressions in colon and small mesenteric arteries; AM treatment decreased COX-2 expression only in microvessels from rats with colitis. An attenuation of phenylephrine-induced contraction was detected in small mesenteric arteries from both TNBS and AM-treated rats. COX and NOS inhibitors altered the contractile ability of phenylephrine in small mesenteric arteries from TNBS rats, suggesting the involvement of COX-2 and iNOS derived factors in the deleterious effect of TNBS on vascular reactivity; AM administration was able to reduce such alteration. Finally, treatment with the peptide significantly reduced colonic nitric oxide (NO) levels, without affecting plasma concentration. In conclusion, AM showed beneficial effects in the restoration of vascular function through the regulation of vasoactive products derived from COX-2 and iNOS.


Arginine vasopressin-binding peptides derived from the bovine and rat genomes differ in their abilities to block arginine vasopressin modulation of murine immune function.
Previously we reported on a nonapeptide (binding peptide) derived by reading the complementary DNA strand of the bovine arginine vasopressin (AVP) gene in the 3'5' direction that specifically blocks the AVP helper signal for gamma-interferon (IFN gamma) production by helper cell-depleted mouse spleen cultures. Bovine 5'3' AVP-binding peptide, however, did not block AVP activity. We report here on the relative abilities of 5'3' and 3'5' AVP-binding peptides derived from the bovine and rat AVP genes to block the AVP helper signal for IFN gamma production. The sequences of the bovine and rat 5'3' AVP-binding peptides differ by two amino acids, whereas the 3'5' AVP-binding peptides derived from both genes are the same. In contrast to the lack of blocking activity of the bovine 5'3' AVP-binding peptide, the rat 5'3' AVP-binding peptide was almost as effective as the 3'5' AVP-binding peptide in blocking AVP function. No effect was seen with a 9-amino acid control peptide consisting of a 'scrambled' 3'5' AVP-binding peptide sequence. Further, polyclonal anti-rat 5'3' AVP-binding peptide antibodies blocked AVP activity, whereas polyclonal anti-bovine 5'3' AVP-binding peptide antibodies had no significant effect. Polyclonal antibodies generated against the 3'5' AVP-binding peptide also blocked AVP activity. These antibodies possibly blocked AVP function by interaction with the lymphocyte AVP receptor, since AVP specifically displaced binding of the antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)


Molecular Mechanisms for Krüppel-Like Factor 13 Actions in Hippocampal Neurons.
Krüppel-like factors (KLFs) play key roles in nervous system development and function. Several KLFs are known to promote, and then maintain neural cell differentiation. Our previous work focused on the actions of KLF9 in mouse hippocampal neurons. Here we investigated genomic targets and functions of KLF9's paralog KLF13, with the goal of understanding how these two closely related transcription factors influence hippocampal cell function, proliferation, survival, and regeneration. We engineered the adult mouse hippocampus-derived cell line HT22 to control Klf13 expression with doxycycline. We also generated HT22 Klf13 knock out cells, and we analyzed primary hippocampal cells from wild type and Klf13-/- mice. RNA sequencing showed that KLF13, like KLF9, acts predominantly as a transcriptional repressor in hippocampal neurons and can regulate other Klf genes. Pathway analysis revealed that genes regulated by KLF13 are involved in cell cycle, cell survival, cytoarchitecture regulation, among others. Chromatin-streptavidin sequencing conducted on chromatin isolated from HT22 cells expressing biotinylated KLF13 identified 9506 genomic targets; 79% were located within 1-kb upstream of transcription start sites. Transfection-reporter assays confirmed that KLF13 can directly regulate transcriptional activity of its target genes. Comparison of the target genes of KLF9 and KLF13 found that they share some functions that were likely present in their common ancestor, but they have also acquired distinct functions during evolution. Flow cytometry showed that KLF13 promotes cell cycle progression, and it protects cells from glutamate-induced excitotoxic damage. Taken together, our findings establish novel roles and molecular mechanisms for KLF13 actions in mammalian hippocampal neurons.


[Establishment of molecular markers linked to sex in Schisandra sphenanthera].
To establish the gender-related RAPD markers in Schisandra sphenanthera. The genomic DNA was extracted from the young leaves of male and female Schisandra sphenanthera by modified CTAB method. The gender differences in the genome were studied by RAPD which was optimized by the single factor and orthogonal experiments. 25 microL total volume included Mg2+ of 2.5 mmol/L, dNTPs of 0.08 mmol/L, primer of 0.6 micromol/L, Taq enzyme 1.5 U, DNA template 60 ng, annealing temperature 41.3 degrees C, 35 cycles. In 400 random primers, only a male specific band 541 bp was generated by S353. The marker can be used as the basis of gender identification.


Intestinal γδ T-cell lymphomas are most frequently of type II enteropathy-associated T-cell type.
Enteropathy-associated T-cell lymphoma includes type I cases and distinctive type II cases that, according to 2008 and 2010 World Health Organization descriptions, are T-cell receptor β+. Although T-cell receptor γδ enteropathy-associated T-cell lymphomas are reported, it is unknown if they have distinctive features and if they should be categorized as enteropathy-associated T-cell lymphoma or as a mucocutaneous γδ T-cell lymphoma. To address these questions, the clinicopathologic, immunophenotypic, molecular, and cytogenetic features of 5 γδ-enteropathy-associated T-cell lymphomas were investigated. Only 1 patient had celiac disease and had type I enteropathy-associated T-cell lymphoma, and the others fulfilled the histopathologic criteria for type II enteropathy-associated T-cell lymphoma. All lacked cutaneous involvement. A celiac disease-associated HLA type was found in the patient with CD and one of four others. All were T-cell receptor γ+, T-cell receptor δ+, βF1-, CD3+, CD7+, CD5-, CD4-, and TIA-1+ with variable staining for CD2 (3/5), CD8 (2/5), Granzyme B (1/5), and CD56 (4/5). Fluorescence in situ hybridization demonstrated 9q34 gains in 4 cases, with 9q33-34 gains by single nucleotide polymorphism in 3 of these. Single nucleotide polymorphism analysis also demonstrated gains in 5q34-q35.1/5q35.1 (4/5), 8q24 (3/5), and in 32 other regions in 3 of 5 cases. Vδ1 rearrangements were identified in 4 of 4 cases with documented clonality showing the same clone in normal-appearing distant mucosa (3/3 tested cases). Thus, γδ-enteropathy-associated T-cell lymphomas share many features with other enteropathy-associated T-cell lymphoma and are mostly of type II. Their usual nonactivated cytotoxic phenotype and Vδ1 usage are features unlike many other mucocutaneous γδ T-cell lymphomas but shared with hepatosplenic T-cell lymphoma. These findings support the conclusion that a γδ T-cell origin at extracutaneous sites does not define a specific entity.


New directions in laser therapy: combination of carbon dioxide laser resurfacing and incisional cosmetic facial surgery.
As clinicians enter a time of increasingly greater patient demand for quality of surgery, superior results, and efficient time use, the plastic surgeon should have as many tools as possible to accomplish these ends. Patient safety should never be compromised, however. A thorough analysis of the patient regarding physical complaints and social and medical history is of utmost importance. The guidelines that have been enumerated are just that-guidelines. Still, the plastic surgeon must use all of his or her experience and knowledge to formulate the best and most appropriate surgical plan for each individual patient.


Evolution of the organization of epicardial activation patterns during ventricular fibrillation.
This study quantified how the organization of epicardial activation changes during the first 40 seconds of ventricular fibrillation (VF). Unipolar potentials were mapped from a 504 (24 x 21) electrode array (2-mm interelectrode spacing) on the anterior right ventricle (RV) and left ventricle (LV) epicardium. The array covered approximately 20% of the epicardial surface. In each of seven pigs, six episodes of VF were induced by premature stimulation. One-half second epochs of VF were analyzed, starting 0, 10, 20, 30, and 40 seconds post induction and using novel pattern analysis algorithms. Eight parameters were quantified: (1) the number of wavefronts; (2) the epicardial area activated by wavefronts; (3) the fraction of wavefronts arising from epicardial breakthrough or from a focus; (4) the fraction of wavefronts terminated by conduction block; (5) the multiplicity index (number of distinct activation pathways in the rhythm); (6) the repeatability index (number of times activation pathways are traversed); (7) the activation rate; and (8) the wavefront propagation velocity. The results showed that VF patterns were less organized at 10 than at 0 seconds, with more, smaller wavefronts traversing a larger variety of pathways for fewer repetitions. VF activation patterns then gradually reorganized up to 40 seconds, but by a different mechanism: the spatial size of subpatterns grew, but the dynamics otherwise appeared unchanged. During both transitions, both activation rate and propagation velocity slowed monotonically. Thus, changes in organization during VF can occur by multiple mechanisms.


Characteristics, risk factors and management of venous thromboembolism in immune thrombocytopenia: a retrospective multicentre study.
An increased risk of thrombosis has been reported in immune thrombocytopenic purpura (ITP), but the characteristics, risk factors of occurrence, recurrence and management of venous thromboembolic events (VTE) have been poorly investigated. To describe VTE and ITP characteristics, distribution of VTE risk factors and their impact on VTE features and recurrence. A retrospective study of patients with ITP and VTE registered in databases of three reference French centres of ITP. Among 49 patients, 66 VTE were recorded. The platelet count at the time of the first VTE was <100 × 109 /L for 28/43 (65%) patients. In total, 19/48 (40%) patients had at least one positive antiphospholipid test result. For the 10 VTE occurring in eight patients with platelet count <50 × 109 /L, ITP treatment was efficient in 7. One haemorrhagic complication associated with anticoagulant (AC) therapy was recorded. For 31/49 (63%) patients, long-term AC therapy could have been discussed after the first VTE, but only 13 received it. A second VTE occurred in 13 (27%) patients. The risk of recurrence was increased in patients with unprovoked VTE before ITP diagnosis or active cancer. VTE in ITP mainly occurred in the presence of multiple risk factors of TE. A low platelet count does not protect against VTE. Management with AC therapy despite persistently low platelet count seems possible. Risk of VTE recurrence is high, particularly with a history of unprovoked VTE or active cancer. In this setting, indefinite AC therapy could be discussed.


Localization of the gene for uridine monophosphate synthase to human chromosome region 3q13 by in situ hybridization.
The bifunctional enzyme uridine monophosphate (UMP) synthase catalyzes the last two steps in de novo pyrimidine biosynthesis. A genetic deficiency in the activity of this enzyme causes the inherited human disease orotic aciduria. We used a human cDNA probe to localize the gene for UMP synthase to human chromosome region 3q13 by the technique of in situ hybridization.


Epicardial ultrasonography: a potential method for intraoperative quality assessment of coronary bypass anastomoses?
Intraoperative quality assessment in coronary artery bypass surgery confirms graft patency and enables revision of failing grafts. The aim of this study was to evaluate graft quality intraoperatively by epicardial ultrasonography and to compare this technique with transit time flow measurements and intraoperative angiography, and to evaluate the ability of these methods to predict long-term patency as described by follow-up angiography. Thirty-nine patients with mean age of 66 years (SD 9.5) who underwent off-pump coronary artery bypass surgery with internal mammary artery graft to the left anterior descending coronary artery were included. Epicardial ultrasonography and transit time flow measurement were performed after completion of the anastomoses, and coronary angiography after closure of the chest. Follow-up angiography was carried out after 156 days (SD 50). Diameter measurements obtained by epicardial ultrasonography correlated poorly with the same diameter measurements obtained by angiography. Epicardial ultrasonography revealed 5 abnormal grafts (13%), transit time flow measurements none, and intraoperative angiography 9 (23%). At follow-up angiography, 4 grafts (11%) were pathologic. Epicardial ultrasonography and transit time flow measurements indicated no need for graft revision; intraoperative angiography suggested need for revision in 3 cases. Epicardial ultrasonography could be a useful method for intraoperative assessment of graft anastomosis quality, but needs to demonstrate its ability to predict grafts in need of revision. Angiography must be considered the gold standard in intraoperative imaging.


Analogs of thyrotropin-releasing hormone using an aminoglycine-based template.
Novel thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH2) analogs, made by solid phase, were derived from the general scaffold pGlu-(D/L)Agl(X)-Pro-NH2 where Agl = aminoglycine. Analogs ranged from X being a proton to an acylating agent derived from substituted (aromatic heterocyclic rings) formic or acetic acids or an aminotriazolyl moiety (3'-amino-1H-1',2',4'-triazolyl) built on N(alpha) of aminoglycine or Nbeta of alpha,beta-diaminoproprionic acid (Dpr). X was expected to mimic the electronic and structural characteristics of the imidazole ring of histidine. Analogs were purified by HPLC, characterized by mass spectrometry and isolated as either diastereoisomeric mixtures or pure isomers. Analogs, tested for their binding affinity to mouse pituitary TRH receptors, have apparent equilibrium inhibitory constants > 1 microM.


Targeting IAP proteins in combination with radiotherapy.
The efficacy of radiotherapy critically depends on the activation of intrinsic cell death programs in cancer cells. This implies that evasion of cell death, a hallmark of human cancers, can contribute to radioresistance. Therefore, novel strategies to reactivate cell death programs in cancer cells are required in order to overcome resistance to radiotherapy. Since Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in multiple cancers and block cell death induction at a central point, therapeutic targeting of IAP proteins represents a promising approach to potentiate the efficacy of radiotherapy. The current review discusses the concept of targeting IAP proteins in combination with radiotherapy.


Death from Ingestion of E-Liquid.
The use of e-liquids is becoming more prevalent. There is a risk that such liquids may be ingested by mouth rather than being vaped/ inhaled. Due to the high concentration of drugs such as nicotine in these liquids, there may be toxic, and possibly fatal consequences. We report the death of a 32-year-old male who ingested nicotine-containing e-liquid while under the influence of alcohol. A serum sample taken 24 h after collapse contained nicotine at a concentration of 1600 ng/mL of nicotine. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Death secondary to e-liquid ingestion is still very rare, but has the potential for causing deaths due to the easy access of such liquids to the general public. Such toxicity should be considered in individuals who present in the early phases with symptoms of stimulant toxicity, but also in the latter phase where there may be autonomic depressive effects.


Reduced expression of NGEP is associated with high-grade prostate cancers: a tissue microarray analysis.
New gene expressed in prostate (NGEP) is a newly diagnosed prostate-specific gene that is expressed only in normal prostate and prostate cancer cells. Discovery of tissue-specific markers may promote the development of novel targets for immunotherapy of prostate cancer. In the present study, the staining pattern and clinical significance of NGEP were evaluated in a series of prostate tissues composed of 123 prostate cancer, 19 high-grade prostatic intraepithelial neoplasia and 44 samples of benign prostate tissue included in tissue microarrays using immunohistochemistry. Our study demonstrated that NGEP localized mainly in the apical and lateral membranes and was also partially distributed in the cytoplasm of epithelial cells of normal prostate tissue. All of the examined prostate tissues expressed NGEP with a variety of intensities; the level of expression was significantly more in the benign prostate tissues compared to malignant prostate samples (P value <0.001). Among prostate adenocarcinoma samples, a significant and inverse correlation was observed between the intensity of NGEP expression and increased Gleason score (P = 0.007). Taken together, we found that NGEP protein is widely expressed in low-grade to high-grade prostate adenocarcinomas as well as benign prostate tissues, and the intensity of expression is inversely proportional to the level of malignancy. NGEP could be an attractive target for immune-based therapy of prostate cancer patients as an alternative to the conventional therapies particularly in indolent patients.


In-hospital care, complications, and 4-month mortality following a hip or proximal femur fracture: the Spanish registry of osteoporotic femur fractures prospective cohort study.
We have characterised 997 hip fracture patients from a representative 45 Spanish hospitals, and followed them up prospectively for up to 4 months. Despite suboptimal surgical delays (average 59.1 hours), in-hospital mortality was lower than in Northern European cohorts. The secondary fracture prevention gap is unacceptably high at 85%. To characterise inpatient care, complications, and 4-month mortality following a hip or proximal femur fracture in Spain. Design: prospective cohort study. Consecutive sample of patients ≥ 50 years old admitted in a representative 45 hospitals for a hip or proximal femur fragility fracture, from June 2014 to June 2016 and followed up for 4 months post-fracture. Patient characteristics, site of fracture, in-patient care (including secondary fracture prevention) and complications, and 4-month mortality are described. A total of 997 subjects (765 women) of mean (standard deviation) age 83.6 (8.4) years were included. Previous history of fracture/s (36.9%) and falls (43%) were common, and 10-year FRAX-estimated major and hip fracture risks were 15.2% (9.0%) and 8.5% (7.6%) respectively. Inter-trochanteric (44.6%) and displaced intra-capsular (28.0%) were the most common fracture sites, and fixation with short intramedullary nail (38.6%) with spinal anaesthesia (75.5%) the most common procedures. Surgery and rehabilitation were initiated within a mean 59.1 (56.7) and 61.9 (55.1) hours respectively, and average length of stay was 11.5 (9.3) days. Antithrombotic and antibiotic prophylaxis were given to 99.8% and 98.2% respectively, whilst only 12.4% received secondary fracture prevention at discharge. Common complications included delirium (36.1 %) and kidney failure (14.1%), with in-hospital and 4-month mortality of 2.1% and 11% respectively. Despite suboptimal surgical delay, post-hip fracture mortality is low in Spanish hospitals. The secondary fracture prevention gap is unacceptably high at > 85%, in spite of virtually universal anti-thrombotic and antibiotic prophylaxis.


Heterogeneity of a crude synaptosomal preparation, studied by affinity partitioning using hexaethonium-poly(ethylene glycol).
The heterogeneity of a synaptosomal preparation was studied by the use of affinity partitioning in combination with centrifugal counter-current distribution. Hexaethonium-poly(ethyleneglycol) was used as the extracting agent. The fractions were analyzed for: light scattering, protein, choline acetyltransferase, L-glutamate decarboxylase, glutamine synthetase, 2',3'-cyclicnucleotide-3'-phosphohydrolase, acetylcholinesterase and succinate dehydrogenase. The material was fractionated into three main fractions which differed in their content of marker-enzymes.


Engineering and utilization of reporter cell lines for cell-based assays of transmembrane receptors.
Transmembrane receptors, a subset of integral membrane proteins, are the receivers that transduce an extracellular chemical message into an intracellular response. Accordingly, these proteins are of particular interest in the scientific community and are probably best studied as part of a cellular system. Herein, we detail the engineering of a fluorescent and bioluminescent reporter cell line for a transmembrane receptor and how to employ it in a directed evolution screen that identifies peptide regulators of receptor activity.