Roles of β-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells.
The superficial zone (SFZ) of articular cartilage has unique structural and biomechanical features, is thought to promote self-renewal of articular cartilage, and is thus important for joint long-term function, but the mechanisms regulating its properties remain unclear. Previous studies revealed that Wnt/β-catenin signaling is continuously active in SFZ, indicating that it may be essential for SFZ function. Thus, we examined whether Wnt/β-catenin signaling regulates proliferation and phenotypic expression in SFZ cells. Using transgenic mice, we found that acute activation of Wnt/β-catenin signaling increases SFZ thickness, Proteoglycan 4 (Prg4, also called lubricin) expression and the number of slow-cell cycle cells, whereas conditional ablation of β-catenin causes the opposite. We developed a novel method to isolate SFZ cell-rich populations from the epiphyseal articular cartilage of neonatal mice, and found that the SFZ cells in culture exhibit a fibroblastic cytoarchitecture and higher Prg4 and Ets-related gene (Erg) expression and lower aggrecan expression compared with chondrocyte cultures. Gene array analyses indicated that SFZ cells have distinct gene expression profiles compared with underlying articular chondrocytes. Treatment of Wnt3a strongly stimulated SFZ cell proliferation and maintained strong expression of Prg4 and Erg, whereas ablation of β-catenin strongly impaired proliferation and phenotypic expression. When the cells were transplanted into athymic mice, they formed Prg4- and aggrecan-expressing cartilaginous masses attesting to their autonomous phenotypic capacity. Ablation of β-catenin caused a rapid loss of Prg4 gene expression and strong increases in expression of aggrecan and collagen 10, the latter being a trait of hypertrophic chondrocytes. Together, the data reveal that Wnt/β-catenin signaling is a key regulator of SFZ cell phenotype and proliferation, and may be as important for articular cartilage long-term function.


Design of cocktail peptide vaccine against Cytomegalovirus infection.
Human Cytomegalovirus (HCMV) remains a major morbidity and mortality cause in immuno suppressed patients. Therefore, significant effort has been made towards the development of a vaccine. In this study, the expression of the pp65 and gB fusion peptides and Fc domain of mouse IgG2a as a novel delivery system for selective uptake of antigens by antigen-presenting cells (APCs) in Pichia pastoris yeast system were studied. In this study, four immune dominant sequences in pp65 protein and 3 immuno dominant sequences in gB protein were selected according to literature review. Peptide linker -GGGGS- was used for construction of fusion peptide. This fusion peptide was cloned in the pPICZαA expression vector and transfected into P. pastoris host cells. Dot blot and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) techniques showed that a high level of pp65-gB-Fc fusion peptide was expressed. This CMV pp65-gB-Fc fusion peptide could be a promising candidate for the development of a novel peptide vaccine.


Ideal-Observer Computation with anthropomorphic phantoms using Markov chain Monte Carlo.
In medical imaging, it is widely recognized that image quality should be objectively evaluated based on performance in clinical tasks. To evaluate performance in signal-detection tasks, the ideal observer (IO) is optimal but also challenging to compute in clinically realistic settings. Markov Chain Monte Carlo (MCMC)-based strategies have demonstrated the ability to compute the IO using pre-computed projections of an anatomical database. To evaluate image quality in clinically realistic scenarios, the observer performance should be measured for a realistic patient distribution. This implies that the anatomical database should also be derived from a realistic population. In this manuscript, we propose to advance the MCMC-based approach towards achieving these goals. We then use the proposed approach to study the effect of anatomical database size on IO computation for the task of detecting perfusion defects in simulated myocardial perfusion SPECT images. Our preliminary results provide evidence that the size of the anatomical database affects the computation of the IO.


Conversion of total shoulder arthroplasty to reverse shoulder arthroplasty made possible by custom humeral adapter.
Reverse shoulder arthroplasty (RSA) is increasingly being used to revise anatomical total shoulder arthroplasty cases. This procedure's high complication rate has been reduced by the availability of modular shoulder systems, which allows the humeral component to be preserved during the conversion. This case report describes the revision of an anatomical shoulder implant inserted in 1998. Polyethylene wear and the resulting metal-on-metal contact had caused metallosis. Since the existing humeral implant was not compatible with standard conversion products, the manufacturer provided a custom humeral adapter that allowed the humeral stem to be preserved. This approach greatly simplified the surgical procedure and resulted in good anatomical and clinical outcomes after 9 months of follow-up.


Endometrial study in patients with postmenopausal metrorrhagia.
The aim of the study was to devise a strategy to diagnose malign endometrial pathologies (adenocarcinoma or atypical hyperplasia) that minimizes the number of invasive tests done (hysteroscopy, aspiration biopsy or curettage) with no loss of its detection efficiency. We retrospectively studied the clinical histories of 779 postmenopausal women at the University Hospital Complex of Albacete, for whom an endometrial study had been done (hysteroscopy, aspiration biopsy or curettage) with a 1-year follow-up between 1 March 2006 and 31 March 2008. There were 77 cases of a malignant pathology (66 adenocarcinomas and 11 hyperplasias with atypia); 96.1% had metrorrhagia, and there were only 3 cases of asymptomatic patients (all 3 presented endometrial thickness of > 5 mm: 10, 12 and 15 mm). The sensitivity and specificity of the transvaginal ultrasound, with a 5 mm cut-off point to diagnose a malignant pathology, were 98.4% and 30.1%, respectively; 89.1% and 99.6%, respectively, for aspiration biopsy; 83.9% and 99.1%, respectively, for hysteroscopy without biopsy; and both were 100% for biopsy. Statistical significance was considered at p < 0.05 and confidence intervals were calculated at 95%. In postmenopausal women with metrorrhagia, the first action to take is to do a transvaginal ultrasound, followed by en endometrial study, but only if the endometrium is irregular or endometrial thickness is ≥ 5 mm; in asymptomatic women, the cut-off point should be set at 10 mm. The immediate method of choice is an ambulatory biopsy.


Mechanisms and significance of Ca2+ entry through TRPC channels.
The transient receptor potential (TRP) superfamily of plasma membrane cation channels has been recognized as a signaling hub in highly diverse settings of human physiopathology. In the past three decades of TRP research, attention was focused mainly on the channels Ca2+ signaling function, albeit additional cellular functions, aside of providing a Ca2+ entry pathway, have been identified. Our understanding of Ca2+ signaling by TRP proteins has recently been advanced by a gain in high-resolution structure information on these pore complexes, and by the development of novel tools to investigate their role in spatiotemporal Ca2+ handling. This review summarizes recent discoveries as well as remaining, unresolved aspects of the canonical subfamily of transient receptor potential channels (TRPC) research. We aim at a concise overview on current mechanistic concepts of Ca2+ entry through- and Ca2+ signaling by TRPC channels.


Effect of toothpaste with nano-sized trimetaphosphate on dental caries: In situ study.
This in situ study was to evaluate the remineralizing effect of a fluoride toothpaste supplemented with nano-sized sodium trimetaphosphate (TMP). This blind and cross-over study was performed in 4 phases of 3 days each. Twelve subjects used palatal appliances containing four bovine enamel blocks with artificial caries lesions. Volunteers were randomly assigned into the following treatment groups: Placebo (without F and TMP); 1100 ppm F (1100), 1100 supplemented with 3% micrometric TMP (1100 TMP) and with nano-sized TMP (1100 TMPnano). Volunteers were instructed to brush their natural teeth with the palatal appliances in the mouth during 1min (3 times/day), so that blocks were treated with natural slurries of toothpastes. After each phase, the percentage of surface hardness recovery (%SHR), integrated mineral recovery (IMR) and integrated differential mineral area profile (ΔIMR) in enamel lesions were calculated. F in enamel was also determined. Data were analyzed by ANOVA and Student-Newman-Keuls test. Enamel surface became 20% harder when treated with 1100 TMPnano in comparison with 1100 (p<0.001). 1100 TMPnano showed remineralizing capacity (IMR; ΔIMR) 66% higher when compared with 1100 TMP (p<0.001). Enamel F uptake in the 1100 TMPnano group was 2-fold higher when compared to its counterpart without TMP (p<0.001). The addition of 3% TMPnano to a conventional toothpaste was able to promote an additional remineralizing effect of artificial caries lesions. Toothpaste containing 1100 ppm F associated with TMPnano showed a potential of higher remineralization to 1100 ppm F and 1100 ppm F micrometric TMP.


Rhizosphere control of soil nitrogen cycling: a key component of plant economic strategies.
Understanding how plant species influence soil nutrient cycling is a major theme in terrestrial ecosystem ecology. However, the prevailing paradigm has mostly focused on litter decomposition, while rhizosphere effects on soil organic matter (SOM) decomposition have attracted little attention. Using a dual 13 C/15 N labeling approach in a 'common garden' glasshouse experiment, we investigated how the economic strategies of 12 grassland plant species (graminoids, forbs and legumes) drive soil nitrogen (N) cycling via rhizosphere processes, and how this in turn affects plant N acquisition and growth. Acquisitive species with higher photosynthesis, carbon rhizodeposition and N uptake than conservative species induced a stronger acceleration of soil N cycling through rhizosphere priming of SOM decomposition. This allowed them to take up larger amounts of N and allocate it above ground to promote photosynthesis, thereby sustaining their faster growth. The N2 -fixation ability of legumes enhanced rhizosphere priming by promoting photosynthesis and rhizodeposition. Our study demonstrates that the economic strategies of plant species regulate a plant-soil carbon-nitrogen feedback operating through the rhizosphere. These findings provide novel mechanistic insights into how plant species with contrasting economic strategies sustain their nutrition and growth through regulating the cycling of nutrients by soil microbes in their rhizosphere.


Global characterization of megakaryocytes in bone marrow, peripheral blood, and cord blood by single-cell RNA sequencing.
Megakaryocytes (MK) are mainly derived from bone marrow and are mainly involved in platelet production. Studies have shown that MK derived from bone marrow may have immune function, and that MK from peripheral blood are associated with prostate cancer. Single-cell transcriptome sequencing can help us better understand the heterogeneity and potential function of MK cell populations in bone marrow (BM), peripheral Blood (PB), and cord blood (CB) of healthy and diseased people.We integrated more than 1.2 million single-cell transcriptome data from 132 samples of PB, BM, and CB from healthy individuals and patients from different dataset. We examined the MK (including MK and product of MK) by single-cell RNA sequencing data analysis methods and identification of MK-related protein expression by the Human Protein atlas. We investigate the relationship between the MK subtype and Non-Small Cell Lung Cancer (NSCLC) in 77 non-cancer and 402 NSCLC. We found that MK were widely distributed and the amount of MK in peripheral blood was more than that in bone marrow and there were specificity MK subtypes in peripheral blood. We found classical MK1 with typical MK characteristics and non-classical MK2 closely related to immunity which was the most common subtype in bone marrow and cord blood. Classical MK1 was closely related to Non-Small Cell Lung Cancer (NSCLC) and can be used as a diagnostic marker. MK2 may have potential adaptive immune function and play a role in tumor NSCLC and autoimmune diseases Systemic Lupus Erythematosus. MK have 14 subtypes and are widely distributed in PB, CB, and BM. MK subtypes are closely related to immunity and have potential to be a diagnostic indicator of NSCLC.


Bis[N-(2-hy-droxy-eth-yl)-N-iso-propyl-dithio-carbamato-κ(2) S,S'](piperazine-κN)cadmium: crystal structure and Hirshfeld surface analysis.
The title compound, [Cd(C6H12NOS2)2(C4H10N2)], features a distorted square-pyramidal coordination geometry about the central Cd(II) atom. The di-thio-carbamate ligands are chelating, forming similar Cd-S bond lengths and define the approximate basal plane. One of the N atoms of the piperazine mol-ecule, which adopts a chair conformation, occupies the apical site. In the crystal, supra-molecular layers propagating in the ac plane are formed via hy-droxy-O-H⋯O(hy-droxy), hy-droxy-O-H⋯N(terminal-piperazine) and coordinated-piperazine-N-H⋯O(hy-droxy) hydrogen bonds; the layers also feature methine-C-H⋯S inter-actions and S⋯S [3.3714 (10) Å] short contacts. The layers stack along the b-axis direction with very weak terminal-piperazine-N-H⋯O(hy-droxy) inter-actions between them. An evaluation of the Hirshfeld surfaces confirms the importance of inter-molecular inter-actions involving oxygen and sulfur atoms.


Evaluation of interleukin-10 producing CD19+ B cells in human gingival tissue.
This study aimed to evaluate IL-10 producing CD19+ B cells and to examine the correlation between these cells and the expression levels of IL-1β, TNF-α, RANKL, and IL-10 cytokines in the gingival tissues of individuals with and without chronic periodontitis. Data were obtained from 20 patients with chronic periodontitis and 10 healthy controls. The gingival samples were analyzed by immunofluorescence, while real-time PCR and enzyme-linked immunosorbent assays were performed to determine cytokine levels. The number of IL-10 producing CD19+ B cells and the expression levels of IL-10 were significantly higher in the inflamed gingival tissues than in the healthy tissues. A positive correlation between the expression levels of IL-10 and the number of IL-10 producing CD19+ B cells were observed. IL-1β, TNF-α, and RANKL expression levels were significantly elevated in diseased gingivae compared to healthy tissues, and there was a positive correlation between the expression levels of these pro-inflammatory cytokines and the number of IL-10 producing CD19+ B cells. While IL-10 producing CD19+ B cells are present in the gingival tissues of patients with periodontal disease and of those with a healthy periodontium, the diseased gingival tissues had a much greater number of these cells than the healthy. The mRNA and protein levels of IL-10, IL-1β, and RANKL, as well as mRNA levels of TNF-α, were positively correlated with the number of IL-10 producing CD19+ B cells, which highlights the importance of these factors in the development and progression of periodontitis.


Body size, but neither age nor asymptomatic mitral regurgitation, influences plasma concentrations of dimethylarginines in dogs.
Asymmetric dimethylarginine (ADMA) is a marker of various cardiovascular diseases in man. The aim of the present study was to test if Cavalier King Charles Spaniels (CKCS) with varying degrees of mitral regurgitation (MR) had increased plasma concentration of ADMA and furthermore, characterize the plasma level of ADMA and symmetric dimethylarginine (SDMA) in normal dogs. Seventy-six dogs were included (44 CKCS and 32 dogs of other breeds). The CKCS had various degrees of MR, whereas the remaining dogs had either no or minimal MR. Apart from cardiac murmurs, no dogs showed signs of cardiac or systematic disease. The degree of MR had no significant influence on ADMA (P = 0.33). Body weight was directly associated with ADMA (P = 0.0004) and creatinine was directly associated with SDMA (P<0.0001). Furthermore, the plasma concentration of ADMA was three to four times higher than found in healthy humans.


Mitochondrial DNA mutation underlying Leigh's syndrome: clinical, pathological, biochemical, and genetic studies of a patient presenting with progressive myoclonic epilepsy.
An 18-year-old male patient presented with clinical and radiological evidence of Leigh's syndrome (LS), having developed progressive myoclonic epilepsy and ataxia 11 years previously. Muscle biopsy showed cytochrome oxidase deficiency but no ragged red fibres. Autopsy confirmed the diagnosis of LS; there was additional degenerative change in the cerebellum and dentate and olivary nuclei, and an axonal peripheral neuropathy. Biochemical studies showed reduced activity of complexes I and IV of the respiratory chain in mitochondria from heart, liver and kidney. The mutation of mitochondrial DNA (mtDNA) at position 8344, commonly associated with the syndrome of myoclonic epilepsy and ragged red fibres, was detected in the patient's blood and was present in muscle, brain, liver, heart, and kidney in uniformly high amounts. It is clear that LS is genetically heterogeneous and represents one of the most severe phenotypes of a number of different mtDNA defects.


Reproduction-related interactions and loads induce continuous turn alternation leading to linearity in a terrestrial isopod.
Turn alternation (TA) is the tendency to turn in the opposite direction of an immediately preceding turn when moving forward, resulting in an overall linear trajectory. TA has been observed in many animals, and terrestrial isopods are considered model organisms for studying TA. Optimizing their fleeing speed and trajectory helps isopods efficiently escape from predatory threats. However, since reproduction induces morphological and physiological changes, individuals might adjust their trajectories depending on their altered mobility. In this study, we investigated the effect of reproduction-related factors on the frequency of TA, which enables linearity, in the common rough woodlouse Porcellio scaber. The results showed that breeding females enhanced their linearity more than nonbreeding females and males. Furthermore, females without access to a potential mate enhanced their linearity more than females and males with access to a potential mate and maintained a high linearity for approximately 40 days. In terrestrial isopods, continuous TA for linearity may be used to avoid reproductive failure because of lack of encounters with the potential mate or to compensate for low running ability due to physical or physiological loads. Conversely, individuals that do not need to worry about reproductive failures or individuals with small loads could perform the random turn that does not require learning or memory. This is the first study to show that the events involved in reproduction affect the linearity shown by continuous TA in terrestrial isopods.


Incarceration and Current Tobacco Smoking Among Black and Caribbean Black Americans in the National Survey of American Life.
We examined the relationship between having a history of incarceration and being a current smoker using a national sample of noninstitutionalized Black adults living in the United States. With data from the National Survey of American Life collected between February 2001 and March 2003, we calculated individual propensity scores for having a history of incarceration. To examine the relationship between prior incarceration and current smoking status, we ran gender-specific propensity-matched fitted logistic regression models. A history of incarceration was consistently and independently associated with a higher risk of current tobacco smoking in men and women. Formerly incarcerated Black men had 1.77 times the risk of being a current tobacco smoker than did their counterparts without a history of incarceration (95% confidence interval [CI] = 1.20, 2.61) in the propensity score-matched sample. The results were similar among Black women (prevalence ratio = 1.61; 95% CI = 1.00, 2.57). Mass incarceration likely contributes to the prevalence of smoking among US Blacks. Future research should explore whether the exclusion of institutionalized populations in national statistics obscures Black-White disparities in tobacco smoking.


Map of spinal neurons activated by chemical stimulation in the nucleus raphe magnus of the unanesthetized rat.
The expression of the proto-oncogene c-fos was used as a cellular marker of spinal cord neurons activated by microinjection of kainic acid into the medullary nucleus raphe magnus of awake and drug-free Sprague-Dawley rats. The c-FOS protein was detected by immunocytochemistry. We found increased immunoreactivity bilaterally in laminae I-VI of the dorsal horn. The strongest c-FOS expression was observed within the inner layer of lamina II near its border with lamina III. In the ventral horn no c-FOS immunoreactivity was observed. Thus, the present results provide evidence for a descending excitation of neurons predominantly in inner lamina II, possibly mediating nucleus raphe magnus-induced inhibition of neurons in other laminae.


Minimally Invasive Technique (Nummular Craniotomy) for Mesial Temporal Lobe Epilepsy: A Comparison of 2 Approaches.
To describe our series of a minimally invasive technique using a small scalp incision and keyhole craniotomy for the removal of mesial temporal lobe structures through a transcortical approach in patients with medically intractable mesial temporal lobe epilepsy (MTLE). Studies that directly compare the clinical outcomes between minimally invasive and conventional techniques are scarce, and this information is lacking in the literature. The study enrolled 73 consecutive patients with refractory MTLE and unilateral hippocampal sclerosis; 30 patients were operated on with standard frontotemporal craniotomy between 2010 and 2013 and 43 patients were operated with a minimally invasive craniotomy (nummular craniotomy) between 2014 and 2016. The preoperative evaluation included clinical history, physical examination, video-electroencephalography, neuropsychologic assessment, and magnetic resonance imaging including thin-section coronal sequences. There were no deaths in either group. Postoperative complications in the standard frontotemporal craniotomy group included temporal muscle atrophy (n = 4; 13.3%), cerebrospinal fluid leakage (n = 1; 3.3%), and wound infection (n = 1; 3.3%). No complications were observed in the keyhole craniotomy group. There was no between-group difference in postoperative seizure control. The mean Engel class I seizure-free outcome was 90.4% in the standard frontotemporal craniotomy group and 90.7% in the nummular craniotomy group (P > 0.05). Lengths of hospitalization (2.81 vs. 4.37 days, P < 0.001) and operative time (85.79 vs. 142.73 minutes, P < 0.001) were lower in the keyhole than in the standard frontotemporal craniotomy group, respectively. The nummular technique was associated with faster recovery, early hospital discharge, and fewer complications than the standard technique. No differences were observed in postoperative seizure control. Keyhole craniotomy is a safe, easy, and effective treatment option for medically intractable MTLE.


Neonatal agonism of ERalpha masculinizes serotonergic (5-HT) projections to the female rat ventromedial nucleus of the hypothalamus (VMN) but does not impair lordosis.
Serotonin (5-HT) is known to play a role in the suppression of the lordosis response in males. We have previously shown that there is a sex difference in the density of 5-HT immunoreactive (5-HT-ir) fibers in the ventrolateral division of the adult ventromedial nucleus of the hypothalamus (VMNvl) and that neonatal administration of estradiol (E2) increases 5-HT-ir in the female VMNvl to male-typical levels. Here we demonstrate that postnatal administration of the ERalpha agonist 1,3,5-tris(4-Hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), but not the ERbeta agonist diarylpropionitrile (DPN), also masculinizes 5-HT-ir in the female VMNvl, suggesting a mechanistic role for ERalpha in this process. Sexual receptivity, as ascertained by the lordosis quotient, was unaffected by either PPT or DPN treatment but nearly abolished by estradiol benzoate (EB), a synthetic estrogen with high affinity for both ERalpha and ERbeta. Collectively, these observations show that postnatal estrogens increase the density of 5-HT projections to the VMNvl via an ERalpha dependent mechanism, but that this increased inhibitory input is not sufficient to suppress the lordosis response.


Developmental switches of sericin mRNA splicing in individual cells of Bombyx mori silkgland.
Four mRNA of 10.5, 9.0, 4.0, and 2.8 kb are made from the sericin Ser1 gene by alternative maturation of a unique mRNA precursor. By means of RNA blots and in situ hybridization, we investigated variations in the distribution of these mRNA during the last larval instar in different territories of the middle silkgland. Taken together, the results from these two techniques show that 150 out of the 266 cells of this region of the organ express the Ser1 gene, but accumulate distinct mature mRNA species. Of these 150 cells 42 are specialized in a processing pathway resulting in the production of the 2.8-kb Ser1 mRNA throughout the larval instar. The 108 others perform successively three distinct splicing pathways leading to a development-dependent accumulation of, respectively, the 4.0-, the 10.5-, and the 9.0-kb mRNA. This suggests the occurrence of two switches in the splicing capacities of these cells during the fifth instar. The middle silkgland cells also express another sericin gene (Ser2) which encodes two mRNA of 5.4 and 3.1 kb, also arising by differential splicing. At the beginning of development, all the middle silkgland cells express this gene but, as development proceeds, expression becomes restricted to only the anterior cells. The biological consequence of this topological and temporal regulation of the mode of expression of these two genes is the sequential secretion and layering of the different sericins around the silk thread.


Alveolar epithelial responses in experimental streptococcal pneumonia.
We describe an experimental model of pneumonia in Wistar rats evoked by Streptococcus sanguis. The lesion developed rapidly as a confluent bronchopneumonia of the single-lobed left lung. Except at the extreme base, where an abscess formed, the pneumonic process thereafter resolved, and most of the lung appeared microscopically and ultrastructurally normal 8 days after infection. Sequential electron microscopic studies revealed that in the areas of lung which subsequently resolved, damage was restricted to type 1 pneumocytes. Within 24 h of infection, the unaffected type 2 pneumocytes were observed to proliferate, transform into elongated pneumocytes of intermediate morphology, and then undermine and strip off the damaged type 1 cells from the subjacent basement membrane. Thereafter, the intermediate type pneumocytes completed their transformation into definitive type 1 cells, thus completing the repair process. We hypothesize that this represents an accelerated form of the normal type 1 replacement mechanism, and that uncomplicated epithelial repair following acute alveolar damage is possible if type 2 pneumocytes escape significant damage, so that they retain their capacity to proliferate and differentiate into type 1 epithelium.


[Lipid storage myopathy--a contribution to the problem of the differential diagnosis of muscle dystrophy (Duchenne)].
A case of a lipid myopathy in a 12-year-old boy is reported. The clinical picture was like a muscle-dystrophy (Duchenne) The histochemical investigations demonstrated the lipidmyopathy combined with a neurogenic atrophy.


Sumoylation is critical for DJ-1 to repress p53 transcriptional activity.
Sumoylation is an important post-translational modification, which is also involved in the pathogenesis of many neurodegenerative diseases. We previously reported that DJ-1 decreases Bcl-2 associated X protein expression through repressing p53 transcriptional activity. Here we show that DJ-1(K130R), the non-sumoylatable mutant form of DJ-1, shifts from nucleus to cytoplasm, fails to repress p53 transcriptional activity and loses its protective function against ultraviolet induced cell death. Our findings suggest that sumoylation is critical for DJ-1 to repress p53 transcriptional activity.


Auxin transport: a field in flux.
Polar auxin transport is crucial for plant growth and development. Auxin moves between plant cells through a combination of membrane diffusion and carrier-mediated transport. Several classes of membrane proteins that facilitate auxin uptake and efflux have recently been identified in Arabidopsis. The relative contribution to auxin transport made by the different facilitators and by membrane diffusion is unclear. In this Opinion article, we assess the significance of auxin diffusion versus carrier-mediated transport and then discuss the physiological importance of the transport facilitators within the context of the multiple trans-cellular auxin fluxes recently described in the Arabidopsis root apex.


Highly convergent synthesis of C3- or C2-symmetric carbohydrate macrocycles.
[structure: see text] A highly convergent strategy for the synthesis of C3- or C2-symmetric oligosaccharide macrocycles is reported. Molecular modeling indicates these macrocycles possess sterically congested cavities. Weak host-guest interactions are observed that should be beneficial for applications such as functionalized molecular pores.


Tetanus toxoid provides efficient T-cell help for the induction of HA-1(H) cytotoxic T cells.
In vitro generation and expansion of leukemia-reactive T cells may improve the efficacy and specificity of cellular immunotherapy against hematologic malignancies in the context of allogeneic stem cell transplantation. Since the expression of minor histocompatibility antigen HA-1(H) is limited to hematopoietic cells, ex vivo generated HA-1(H)-specific CD8+ cytotoxic T lymphocytes (CTLs) can be used for adoptive immunotherapy. Numerous studies have shown that primary CTL induction from naïve precursors requires professional antigen-presenting cells. Here, the feasibility of ex vivo induction of HA-1(H)-specific CD8+ CTLs is demonstrated from unfractionated peripheral blood mononuclear cells (PBMNCs) from healthy blood donors when CD4+ T-cell help is provided during primary stimulation. As a stimulus for the induction of T-cell help, tetanus toxoid (TT) was used. After the second restimulation cycle, approximately 1 percent of CD8+ T cells stained positively with the HLA-A*0201/HA-1(H) pentamer. Positive T cells were further expanded more than 1000-fold by antigen-independent stimulation with anti-CD3/CD28 monoclonal antibodies. HA-1(H)-induced T cells showed the classical phenotype for CD8+ memory effector cells: the phenotype changed from a mixed CD45RA/RO phenotype to an activated phenotype characterized by high expression of CD45RO and no expression of CCR7. The generated T cells revealed a very potent CTL response, even at low E:T ratios. This study demonstrates that TT provides a very potent and cost-effective tool for the in vitro induction of antigen-specific CTLs from precursor PBMNCs that can easily be adapted to GMP conditions for translational purposes.


RORing toward immunoregulation in glomerulonephritis?
CD4+ T cells that express forkhead box protein 3 are important in maintaining tolerance and restraining effector responses. Herrnstadt et al. use a model of rapidly progressive glomerulonephritis to examine the nature and role of forkhead box protein 3-positive and retinoid acid-related orphan receptor γt-positive regulatory T cells. These cells are prominent in experimental glomerulonephritis, both locally and systemically, and are present in kidneys of people with anti-neutrophil cytoplasmic antibody-associated vasculitis. Functionally, despite their expression of retinoid acid-related orphan receptor γt, associated with T-helper cell 17 cells, they regulate cellular immunity, both systemically and within the kidney.


Issues to address in burn care for ethnic minority children: a qualitative study of the experiences of health care staff.
Numerous studies have shown that ethnic minority children in the developed world are at greater risk of sustaining burns compared to children from non-ethnic minority backgrounds. However, little is known about the experiences of hospital health care staff with ethnic minority children and parents. A qualitative interview study was conducted to gain more insight into burn care for ethnic minority children and the potential challenges this presents. Semi-structured interviews on burn care for ethnic minority children were conducted in 2009 with health care staff (N=17) working in two burn centers in the Netherlands. Interviews were transcribed and analyzed using a framework method. Health care staff identified the following issues in burn care for ethnic minority children and their parents: (1) linguistic barriers to communication with parents about pressure garments, dressing changes, skin grafting procedures, and psychosocial support; (2) biological/genetic features of differing pigmentation of skin and skin healing; (3) cultural differences between parents and health care staff; (4) insecurity or irritation about linguistic and cultural barriers. Burn health care staff should have knowledge of biological/genetic features of dark skin, awareness of cultural differences, and transcultural communication skills to deliver culturally competent care tailored to the needs of ethnic minority children and their parents.


Spina bifida occulta in isthmic spondylolisthesis: a surgical trap.
An 11-year-old girl presented with symptomatic grade IIB isthmic type spondylolisthesis, with an elongated pars, confirmed on magnetic resonance imaging (MRI). Posterolateral in situ fusion of L5/S1 was performed. At surgery, a significant bony defect in the posterior aspect of S1 was noted. Awareness of this possible co-existence is paramount if iatrogenic damage to neural elements is to be avoided during surgery.


Partial gastric wrap-around as an alternative procedure in the treatment of hiatal hernia.
The Allison, Belsey, and Nissen antireflux operations have been widely used over the last 15 yr. A number of problems have followed from these procedures that have prompted us under certain circumstances to seek alternative operations. In the last 2 yr, in selected patients, we have done a partial gastric wrap-around (Dor-Nissen) operation on 16 children from age 2 wk to 13 yr for the following reasons: failed Allison and Nissen repairs, two infants with such a small stomach that only a partial stomach wrap-around was possible, with a Heller cardiomyotomy, and for reflux with or without an accompanying hiatal hernia. All of these Dor-Nissen partial wrap-around operations were technically easy to do and all the postoperative patients have been problem-free both clinically and radiologically. Moreover, the gass bloat syndrome seen with the Nissen fundoplication has not been encountered. We recommended this partial wrap-around antireflux operation as a primary procedure, an alterative to one of the more widely used operations, or when re-operating for recurrence of gastroesophageal reflux.


Menopause and the aging female reproductive system.
Only in this century have so many women lived beyond reproductive age. Cultural upheavals in industrial nations have made reproduction an option, a hygienic issue, and the ending of reproductive capacity a crisis of aging. A woman's hormonal milieu changes during her climacteric and beyond with multiple potential symptomatic consequences. Treatment with hormones can ameliorate the symptoms of menopause and potentially decrease the risk for the long-term consequences of the menopause. Objective scientific data for absolutes regarding hormone replacement therapy are lacking, but, increasingly, this epoch in the physical and emotional life of a woman is being defined by new cultural expectations.


Tea polyphenols inhibit the growth and virulence properties of Fusobacterium nucleatum.
Fusobacterium nucleatum plays a key role in creating the pathogenic subgingival biofilm that initiates destructive periodontitis. It is also a common resident of the human gastrointestinal tract and has been associated with inflammatory bowel disease. The aim of the present study was to investigate the effects of green and black tea extracts as well as two of their bioactive components, EGCG and theaflavins, on the growth and virulence properties of F. nucleatum. The tea extracts and components displayed various degrees of antibacterial activity that may involve damage to the bacterial cell membrane and the chelation of iron. They also prevented biofilm formation by F. nucleatum at concentrations that did not interfere with bacterial growth. In addition, the treatment of a pre-formed F. nucleatum biofilm with the green tea extract and EGCG caused a time-dependent decrease in biofilm viability. The green and black tea extracts, EGCG, and theaflavins decreased the adherence of F. nucleatum to oral epithelial cells and matrix proteins. Moreover, these tea components also attenuated F. nucleatum-mediated hemolysis and hydrogen sulfide production, two other virulence factors expressed by this bacterium. In summary, this study showed that tea polyphenols may be of interest for treating F. nucleatum-associated disorders.


Interfacial effect on the ability of peptide-modified gold nanoclusters to inhibit hIAPP fibrillation and cytotoxicity.
Deposit of amyloid peptides in the cells is related to various amyloidosis diseases. A variety of nanomaterials have been developed to resist amyloid deposit. Most of the research on the inhibition of nanomaterials against amyloid aggregation are undertaken in solution, while the membranes that may mediate fibrillar aggregation and affect interaction of inhibitors with amyloid peptides in biotic environment are little taken into account. In this study, we synthesized three kinds of gold nanoclusters modified with cysteine (C@AuNCs), glutathione (GSH@AuNCs) and a peptide derived from the core region of hIAPP fibrillation (C-HL-8P@AuNCs), and investigated their inhibitory activities against hIAPP fibrillation in the absence and presence of lipid vesicles (POPC/POPG 4:1 LUVs) by the experiments of ThT fluorescence kinetics, AFM and CD. We also explored the inhibitions of hIAPP-induced membrane damage and cytotoxicity by peptide@AuNCs using fluorescent dye leakage and cell viability assays. Our study revealed that the inhibitory efficiency of these peptide@AuNCs against hIAPP fibrillation follows C-HL-8P@AuNCs≅GSH@AuNCs>C@AuNCs in lipid-free solution and C-HL-8P@AuNCs≫GSH@AuNCs>C@AuNCs in lipid membrane environment. Compared with the results obtained in lipid-free solution, the inhibitions of hIAPP fibrillation observed in lipid membrane environment were more associated with the inhibitions of hIAPP-induced damages of lipid vesicles and INS-1 cells (C-HL-8P@AuNCs≫GSH@AuNCs>C@AuNCs). An additional hydrophobic interaction with the homologous core region of hIAPP, which is only provided by C-HL-8P@AuNCs and largely suppressed in lipid-free solution, enhanced in the membrane environment and therefore made C-HL-8P@AuNCs much more powerful than GSH@AuNCs and C@AuNCs in the inhibitions of hIAPP fibrillation and cytotoxicity.


Treatment outcomes, quality of life, and impact of hemophilia on young adults (aged 18-30 years) with hemophilia.
The Hemophilia Experiences, Results and Opportunities (HERO) initiative assessed psychosocial issues reported by people with moderate to severe hemophilia and was led by a multidisciplinary international advisory board. This analysis reports data from young adult respondents (aged 18-30 years), including both US and overall global (including US respondents) results, and investigates treatment outcomes, quality of life, and impacts of hemophilia on relationships. More young adults in HERO received prophylaxis than on-demand treatment, although a majority reported not using factor products exactly as prescribed, and 50% of global respondents and 26% of US respondents reported issues with access to factor replacement therapy in the previous 5 years. Many young adults with hemophilia reported comorbidities, including bone/skeletal arthritis, chronic pain, and viral infections, and nearly half of young adults reported anxiety/depression. Most reported pain interference with daily activities in the past 4 weeks, although a majority reported participating in lower-risk activities and approximately half in intermediate-risk activities. Most young adults were very or quite satisfied with the support of partners/spouses, family, and friends, although roughly one-third reported that hemophilia affected their ability to develop close relationships with a partner. A majority of young adults reported that hemophilia has had a negative impact on employment, and 62% of global respondents and 78% of US respondents were employed at least part-time. Together these data highlight the psychosocial issues experienced by young adults with hemophilia and suggest that increased focus on these issues may improve comprehensive care during the transition to adulthood.


Effect of thickness of cavity wall on fracture strength of pulpotomized primary molar teeth with class II amalgam restorations.
This was to evaluate the effect of different thicknesses of cavity walls on fracture strength of pulpotomized primary molar teeth with class II amalgam restorations. 80 carious extracted human primary molar teeth were selected for pulpotomy preparation. The teeth were divided into four groups. Mesio- or disto-occlusal (20 teeth) and mesio-occluso-distal (20 teeth); cavities were prepared in both first and second primary molar teeth. Each group was divided into two subgroups of ten teeth according to the thickness of their walls (1.5 or 2.5 mm). After restoring teeth with amalgam, all groups were stored in distilled water at 37 degrees C for seven days. They were then thermo cycled 1,000 times between 5 degrees to 55 degrees C. The specimens were then subjected to a compressive axial load in a universal testing machine at a crosshead speed of 0.5 mm min(-1). The t-test was used for statistical analysis. Mean fracture resistances of the first and second molar teeth were 975.5 +/- 368.8 and 1049.2 +/- 540.1, respectively. In the first molars, fracture resistance of 2-surface cavities was significantly more than 3-surface cavities (p=0.001), but this difference was not statistically significant in second molars. In second molars, fracture strength in 2- and 3-surface cavities with a 2.5 mm thickness in the walls was more than those with 1.5 mm thickness. However, in first molars this difference was only statistically significant in 3-surface cavities (p=0.045). The fracture strength in pulpotomized primary molar teeth with amalgam restorations was high, more than maximum bite forces in primary teeth, even in extensive 3- surface cavities.


LFIRE-1/HFREP-1, a liver-specific gene, is frequently downregulated and has growth suppressor activity in hepatocellular carcinoma.
We have previously identified several novel genes, which are differentially expressed among human normal liver and hepatocellular carcinomas (HCCs). The full-length liver fibrinogen-related gene-1 (LFIRE-1) cDNA was cloned from the human normal liver cDNA library. LFIRE-1 is highly homologous to HFREP-1 with discrepancy at 5' untranslated region (UTR) and encodes the same fibrinogen-related protein, which suggest that these two sequences might be alternative splicing forms of the same gene, LFIRE-1/HFREP-1, located at human chromosome 8p22. The LFIRE-1 and HFREP-1 are specifically expressed in normal human liver tissue, but reduced or undetectable in most of HCC specimens at both RNA and protein level. Furthermore, the reduction or nonexpression of LFIRE-1/HFREP-1 is significantly associated with the degree of tumor differentiation. Loss of heterozygosity (LOH) analysis revealed allelic loss of LFIRE-1/HFREP-1 on chromosome 8p22 in 57.1% (24/42) of HCC specimens. We detected three inactivation mutations among 45 cases of HCC specimens examined, two of which lost the remaining allele and the third had a replacement of conserved cysteine residue with glycine residue. Notably, the downregulation of LFIRE-1/HFREP-1 expression is frequently associated with allelic loss. The reduction of LFIRE-1/HFREP-1 expression by antisense approach enhances cancer cell proliferation and colony formation in soft agar. Moreover, restoration of exogenous wild-type LFIRE-1/HFREP-1 expression but not LFIRE-1/HFREP-1 missense mutations in human HCC cells inhibited their anchorage-dependent or -independent growth in vitro, and suppressed their tumorigenicity in nude mice. In conclusion, our data demonstrated that liver-specific gene LFIRE-1/HFREP-1 was frequently downregulated and might possess growth suppressor activity in HCC.


Phorbol esters induce immediate-early genes and activate cardiac gene transcription in neonatal rat myocardial cells.
The mechanisms which transduce intracellular signals for the accumulation of myofibrillar protein during the onset of myocardial cell hypertrophy are unknown. Although previous studies in skeletal muscle cells have suggested that the activation of protein kinase C induces de-differentiation, including the selective disassembly of myofibrils and inhibition of myofibrillar protein synthesis, the present study demonstrates that phorbol esters which activate protein kinase C lead to the accumulation of an individual contractile protein, myosin light chain-2 (MLC-2) and produce several features of myocardial cell hypertrophy. Utilizing immunoblotting and indirect immunocytofluorescence with MLC antisera, the present study demonstrates a several-fold increase in the content of MLC-2, and a marked increase in the assembly of MLC into organized contractile units in individual neonatal rat myocardial cells following treatment with phorbol 12-myristate 13-acetate (PMA). The concentration of PMA required to elicit this response and the lack of a response with an inactive phorbol ester is consistent with the activation of a protein kinase C dependent pathway. Furthermore, PMA treatment results in the rapid induction of a program of immediate-early gene expression (including the c-fos and c-jun proto-oncogenes, and an inducible zinc finger containing gene, egr-l), and activates cardiac gene transcription as assessed by nuclear run-on analyses. The results of the present study suggest the possibility that a protein kinase C dependent pathway may be involved in the up-regulation of myofibrillar protein content and the activation of cardiac gene transcription during growth and hypertrophy of neonatal rat myocardium, and that the induction of a program of immediate-early gene expression may be linked to this response.


The relation between left ventricular global longitudinal strain and troponin levels in patients hospitalized with COVID-19 pneumonia.
Left ventricular global longitudinal strain (LVGLS) from two-dimensional speckle-tracking echocardiography (2D-STE) provides a more accurate estimation of subclinical myocardial dysfunction. In patients with COVID-19, elevated high sensitive troponin (hs-TnI) levels are frequent independent from the underlying cardiovascular disease. However, the relationship between high troponin levels and LVGLS in such patients remains unknown. We aimed to investigate the relation between troponin levels and LVGLS values in patients with COVID-19. A total of thirty-eight patients diagnosed with COVID-19 pneumonia who underwent echocardiography examination within the first week of hospital admission were enrolled in our study. Patients were divided into two groups according to their hs-TnI levels. Conventional left venticular (LV) function parameters, including ejection fraction, LV diastolic and systolic volumes were obtained and LVGLS was determined using 2D-STE. Frequency of hypertension, diabetes mellitus and current smoking were similar among groups. Compared with the patients in the negative troponin group, those in the positive troponin group were more likely to have a higher age; higher levels of D-dimer, C-reactive protein and ferritin; higher need for high-flow oxygen, invasive mechanical ventilation therapy or both; and a higher number of intensive care unit admissions. There was no statistically significant difference in LVGLS and ejection fraction values between the two groups.(- 18.5 ± 2.9, - 19.8 ± 2.8, p = 0.19; 55.2 ± 9.9, 59.5 ± 5.9, p = 0.11 respectively). Despite troponin increase is highly related to in-hospital adverse events; no relevance was found between troponin increase and LVGLS values of COVID-19 patients.


N2,N2,7-trimethylguanine, a new trimethylated guanine natural product from the New Zealand ascidian, Lissoclinum notti.
From the New Zealand ascidian, Lissoclinum notti a new natural product, N2,N2,7-trimethylguanine (1) has been isolated. The structure of 1 was elucidated by analysis of spectroscopic data.


Inability of imipramine to protect against type A or type B monoamine oxidase inhibition by pargyline.
Imipramine (30 mg/kg i.p.) did not antagonize the inhibition of either type A or type B MAO by pargyline in brain, heart or liver of rats. Occupancy of active sites on mitochondrial MAO by imipramine probably does not occur at doses of imipramine adequate to inhibit monoamine uptake.


Biology of infection with Borrelia burgdorferi.
The spirochete Borrelia burgdorferi is a tick-borne obligate parasite whose normal reservoir is a variety of small mammals. Although infection of these natural hosts does not lead to disease, infection of humans can result in Lyme disease as a consequence of the human immunopathologic response to B burgdorferi. Consistent with the pathogenesis of Lyme disease, bacterial products that allow B burgdorferi to replicate and survive seem to be primarily what is required for the bacterium to cause disease in a susceptible host. This article describes the basic biology of B burgdorferi and reviews some of the bacterial components required for infection of and survival in the mammalian and tick hosts.


S100B, GFAP, UCH-L1 and NSE as predictors of abnormalities on CT imaging following mild traumatic brain injury: a systematic review and meta-analysis of diagnostic test accuracy.
Biomarkers such as calcium channel binding protein S100 subunit beta (S100B), glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1) and neuron-specific enolase (NSE) have been proposed to aid in screening patients presenting with mild traumatic brain injury (mTBI). As such, we aimed to characterise their accuracy at various thresholds. MEDLINE, SCOPUS and EMBASE were searched, and articles reporting the diagnostic performance of included biomarkers were eligible for inclusion. Risk of bias was assessed using the QUADAS-II criteria. A meta-analysis was performed to assess the predictive value of biomarkers for imaging abnormalities on CT. A total of 2939 citations were identified, and 38 studies were included. Thirty-two studies reported data for S100B. At its conventional threshold of 0.1 μg/L, S100B had a pooled sensitivity of 91% (95%CI 87-94) and a specificity of 30% (95%CI 26-34). The optimal threshold for S100B was 0.72 μg/L, with a sensitivity of 61% (95% CI 50-72) and a specificity of 69% (95% CI 64-74). Nine studies reported data for GFAP. The optimal threshold for GFAP was 626 pg/mL, at which the sensitivity was 71% (95%CI 41-91) and specificity was 71% (95%CI 43-90). Sensitivity of GFAP was maximised at a threshold of 22 pg/mL, which had a sensitivity of 93% (95%CI 73-99) and a specificity of 36% (95%CI 12-68%). Three studies reported data for NSE and two studies for UCH-L1, which precluded meta-analysis. There is evidence to support the use of S100B as a screening tool in mild TBI, and potential advantages to the use of GFAP, which requires further investigation.


Subclavian artery aneurysm secondary to a cervical supernumerary rib in a child.
A case of subclavian artery aneurysm secondary to a cervical supernumerary rib is reported in a 9-year-old boy. Such a complication in a cervical rib has never been reported in so young a child. The risk of inserting inextensible prosthetic material in a growing child led to regular supervision instead of an early surgical cure.


Determining risk factors for triple whammy acute kidney injury.
Concurrent use of a diuretic, a renin-angiotensin system (RAS) inhibitor, and a non-steroidal anti-inflammatory drug (NSAID) significantly increases the risk of acute kidney injury (AKI). This phenomenon is known as "triple whammy". Diuretics and RAS inhibitors, such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker, are often prescribed in tandem for the treatment of hypertension, whereas some NSAIDs, such as ibuprofen, are available over the counter. As such, concurrent treatment with all three drugs is common. The goals of this study are to better understand the mechanisms underlying the development of triple whammy AKI and to identify physiological factors that may increase an individual's susceptibility. To accomplish these goals, we utilize sex-specific computational models of long-term blood pressure regulation. These models include variables describing the heart and circulation, kidney function, sodium and water reabsorption in the nephron and the RAS and are parameterized separately for men and women. Hypertension is modeled as overactive renal sympathetic nervous activity. Model simulations suggest that low water intake, the myogenic response, and drug sensitivity may predispose patients with hypertension to develop triple whammy-induced AKI. Triple treatment involving an ACE inhibitor, furosemide, and NSAID results in blood pressure levels similar to double treatment with ACEI and furosemide. Additionally, the male and female hypertensive models act similarly in most situations, except for the ACE inhibitor and NSAID double treatment.


[Microdetermination of glucose using glucose dehydrogenase, with independent sample preparation in the routine laboratory (author's transl)].
A micromethod for the determination of glucose in 20 microliter of capillary blood using glucose dehydrogenase is described. After deproteinisation with uranyl acetate, the samples are analysed by an Autoanalyzer II method or by a manual procedure. Precision and accuracy are well correlated with the hexokinase-glucose-6-phosphate dehydrogenase method. Eleven months experience have shown the practicability and economic advantages of this method.


Myco-engineered gold nanoparticles from Jahnula aquatica coated with ampicillin/amoxicillin and their antibacterial and anticancer activity against cancer cells.
Antibiotics play an important role in medical treatments. However, the multidrug resistance (MDR) bacteria impairs their functionality. Therefore, drug delivery represents the solution for this problem. Many techniques and methods are used in drug delivery, however nanoparticles conjugated drug is one of the most effective and promising techniques. The current work investigates a one-step method of extracellular biosynthesis of gold nanoparticles (AuNPs) and their biocompatibility in antibiotic delivery, where the synthesized AuNPs were loaded with Ampicillin/Amoxicillin. Both ampicillin and amoxicillin antibiotics are successfully conjugated with the Au NPs surface (the potential efficiency), especially, at the smaller particle size. Where, the Au NPs with particle size of 8 m size reveals a promising activity against cancer cells with 48 µg/mL inhibitory concentration (IC50) after 24 h of their exposure to HeLa cells, and induction of apoptosis was also noticed on HeLa treated cells. The bio-synthesised Au NPs using Jahnula. aquatica fungi show a promising nanocarrier biocompatibility drug delivery system in cancer clinical treatments, in particular for antibiotics delivery antibiotics in pharmaceutical applications with large-scale commercial production. To the best of our knowledge, freshwater fungi have never been exploited for AuNPs synthesis.


Near-infrared light is neuroprotective in a monkey model of Parkinson disease.
To examine whether near-infrared light (NIr) treatment reduces clinical signs and/or offers neuroprotection in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson disease. We implanted an optical fiber device that delivered NIr (670 nm) to the midbrain of macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.5-2.1mg/kg) were made over a 5- to 7-day period, during which time the NIr device was turned on. This was then followed by a 3-week survival period. Monkeys were evaluated clinically (eg, posture, bradykinesia) and behaviorally (open field test), and their brains were processed for immunohistochemistry and stereology. All monkeys in the MPTP group developed severe clinical and behavioral impairment (mean clinical scores = 21-34; n = 11). By contrast, the MPTP-NIr group developed much less clinical and behavioral impairment (n = 9); some monkeys developed moderate clinical signs (mean scores = 11-15; n = 3), whereas the majority--quite remarkably--developed few clinical signs (mean scores = 1-6; n = 6). The monkeys that developed moderate clinical signs had hematic fluid in their optical fibers at postmortem, presumably limiting NIr exposure and overall clinical improvement. NIr was not toxic to brain tissue and offered neuroprotection to dopaminergic cells and their terminations against MPTP insult, particularly in animals that developed few clinical signs. Our findings indicate NIr to be an effective therapeutic agent in a primate model of the disease and create the template for translation into clinical trials.


von Willebrand activation factor as a marker of mortality, cardiovascular events, and bleeding complications in patients treated with oral anticoagulants.
Serious bleeding is a frequent and feared treatment complication in patients treated with oral anticoagulants (OACs). Levels of von Willebrand factor (VWF) antigen have been linked to the risk of bleeding complications, mortality, and cardiovascular events. In this longitudinal cohort study of evaluating patients treated with OACs, we aimed to evaluate the relationship between VWF displaying a glycoprotein Ib binding conformation (VWF activation factor) and the risk of cardiovascular events, bleeding complications, or all-cause mortality. Blood samples were collected at baseline in 356 patients on OACs. Patients were followed for an average of 48 months and bleeding complications leading to admission to hospital or death, cardiovascular events (myocardial infarction, ischemic stroke, and peripheral arterial emboli), and all-cause mortality were recorded and classified. During the study period, 47 bleeding complications, 84 cardiovascular events, and 97 deaths occurred. In multivariate Cox regression analyses, VWF activation factor was significantly associated with all-cause mortality (HR 1.62; 95% CI: 1.25-2.08) and cardiovascular events (HR 1.28; 95% CI: 1.01-1.63). There was no association observed between VWF activation factor and bleeding complications. Patients with high levels of VWF activation factor had an increased risk of cardiovascular events and all-cause mortality during OAC treatment. The selectivity for thrombotic complications adds to the potential value of VWF activation factor as a biomarker or pharmacological target.


Synovial accumulation of technetium labelled liposomes in rheumatoid arthritis.
Technetium labelled, negatively charged, unilamellar liposomes were given by intravenous injection to patients with rheumatoid arthritis and the joints scanned 20-22 hours later. Positive scintigraphy was obtained in all six patients with active disease, and, with the exception of the small interphalangeal joints, all clinically involved joints could be visualised.


Anxiety: its role in the history of psychiatric epidemiology.
The role played by anxiety in the history of psychiatric epidemiology has not been well recognized. Such lack of understanding retarded the incremental growth of psychiatric research in general populations. It seems useful to look back on this history while deliberations are being carried out about how anxiety will be presented in DSM-V. Drawing on the literature and our own research, we examined work that was carried out during and after the Second World War by a Research Branch of the United States War Department, by the Stirling County Study, and by the Midtown Manhattan Study. The differential influences of Meyerian psychobiology and Freudian psychoanalysis are noted. The instruments developed in the early epidemiologic endeavors used questions about nervousness, palpitations, sweating, trembling, shortness of breath, upset stomach, etc. These symptoms are important features of what the clinical literature called 'manifest', 'free-floating' or 'chronic anxiety'. A useful descriptive name is 'autonomic anxiety'. Although not focusing on specific circumstances as in Panic and Phobic disorders, a non-specific form of autonomic anxiety is a common, disabling and usually chronic disorder that received empirical verification in studies of several community populations. It is suggested that two types of general anxiety may need to be recognized, one dominated by excessive worry and feelings of stress, as in the current DSM-IV definition of Generalized Anxiety Disorder (GAD), and another emphasizing frequent unexplainable autonomic fearfulness, as in the early epidemiologic studies.


Sorafenib as a potential strategy for refractory pulmonary arterial hypertension.
Sorafenib is an inhibitor of multi-kinases including tyrosine and serine/threonine kinases. We investigated the efficacy and safety of sorafenib for the treatment of patients with refractory pulmonary arterial hypertension (PAH). Sorafenib was started in 9 patients (7 with idiopathic PAH, 2 with pulmonary veno-occlusive disease) who had severe PAH and right heart failure, in spite of treatment with vasodilators specific for PAH. Sorafenib was started as an add-on therapy at a dose of 50 or 100 mg/day, and increased to 100-400 mg/day. New York Heart Association functional class improved in 8 patients and did not change in 1. Mean pulmonary arterial pressure improved in 6 patients (14-28% decrease) and did not apparently change in 2 (follow-up catheterization was not performed in 1 patient). The main adverse effects of sorafenib were skin reactions on the hands and feet, which appeared in 5 patients. They were tolerable in 4 patients, but discontinuation of sorafenib was needed in only 1 patient. In conclusion, sorafenib had favorable effects to improve symptoms and objective variables in patients with refractory PAH, with tolerable adverse events. Sorafenib is an alternative strategy for patients with refractory PAH.


TonB is essential for virulence in avian pathogenic Escherichia coli.
Avian pathogenic Escherichia coli (APEC) strains have multiple iron-uptake systems that facilitate adaptation to iron-restricted environments and are believed to assist in colonisation of the host. These systems include several TonB-dependent transporters of ferri-siderophores encoded by the chromosome and the large virulence plasmid common to APECs. The tonB gene of the virulent APEC strain E956 was replaced with a selectable antibiotic resistance marker using Lambda Red recombinase mutagenesis. The phenotype of the ΔtonB E956 mutant was compared to the parent strain under various culture conditions and in chickens experimentally infected via the respiratory route. The mutant was resistant to streptonigrin, impaired in its ability to adapt to growth in iron-depleted medium and had greater tolerance of oxidative stress than the parental strain. The mutant was avirulent in chickens, did not affect the growth of chicks and colonisation was mostly limited to the trachea. This study has demonstrated that TonB is essential for virulence in APEC.


Applicability of HIN-1, MGMT and RASSF1A promoter methylation as biomarkers for detecting field cancerization in breast cancer.
It has been shown in some articles that genetic and epigenetic abnormalities cannot only be found in tumor tissues but also in adjacent regions that appear histologically normal. This phenomenon is metaphorically called field cancerization or field defect. Field cancerization is regarded as clinically significant because it is assumed to be an important factor in local recurrence of cancer. As the field showing these molecular abnormalities may not be removed completely by surgery, these changes might lead to neoplasms and subsequent transformation to a tumor. We aimed to investigate the applicability of the methylation status of six tumor suppressor genes as biomarkers for detecting field cancerization in breast cancer. The promoter methylation status of CCND2, DAPK1, GSTP1, HIN-1, MGMT and RASSF1A was determined by methylation-sensitive high-resolution melting (MS-HRM) analysis. MS-HRM methods for CCND2, MGMT and RASSF1A were developed in-house, primer sequences for DAPK1, GSTP1 and HIN-1 have already been published. Biopsy samples were taken from tumor, tumor-adjacent and tumor-distant tissue from 17 breast cancer patients. Normal breast tissues of four healthy women served as controls. All MS-HRM methods proved to be very sensitive. LODs were in the range from 0.1 to 1.5 %, LOQs ranged from 0.3 to 5.3 %. A total of 94 %, 82 % and 65 % of the tumors showed methylation of RASSF1A, HIN-1 and MGMT promoters, respectively. The methylation status of these promoters was significantly lower in tumor-distant tissues than in tumor tissues. Tumor-adjacent tissues showed higher methylation status of RASSF1A, HIN-1 and MGMT promoters than tumor-distant tissues, indicating field cancerization. The methylation status of the HIN-1 promoter in tumor-adjacent tissues was found to correlate strongly with that in the corresponding tumors (r = 0.785, p < 0.001), but not with that in the corresponding tumor-distant tissues (r = 0.312, p = 0.239). Among the gene promoters investigated, the methylation status of the HIN-1 promoter can be considered the best suitable biomarker for detecting field cancerization. Further investigation is needed to test whether it can be used for defining surgical margins in order to prevent future recurrence of breast cancer.


Structure of a low-population binding intermediate in protein-RNA recognition.
The interaction of the HIV-1 protein transactivator of transcription (Tat) and its cognate transactivation response element (TAR) RNA transactivates viral transcription and represents a paradigm for the widespread occurrence of conformational rearrangements in protein-RNA recognition. Although the structures of free and bound forms of TAR are well characterized, the conformations of the intermediates in the binding process are still unknown. By determining the free energy landscape of the complex using NMR residual dipolar couplings in replica-averaged metadynamics simulations, we observe two low-population intermediates. We then rationally design two mutants, one in the protein and another in the RNA, that weaken specific nonnative interactions that stabilize one of the intermediates. By using surface plasmon resonance, we show that these mutations lower the release rate of Tat, as predicted. These results identify the structure of an intermediate for RNA-protein binding and illustrate a general strategy to achieve this goal with high resolution.


Impressive Enrichment of Semiempirical Quantum Mechanics-Based Scoring Function: HSP90 Protein with 4541 Inhibitors and Decoys.
The image shows the ability of SQM-based frame to separate the actives (background: green spheres) from inactives (red spheres) while maintaining a powerful sampling (front: HSP90 crystal complex). Read the full text of the Article at 10.1002/cphc.201900628.


Testosterone-induced meiotic maturation of Xenopus laevis oocytes: evidence for an early effect in the synergistic action of insulin.
Meiosis reinitiation in oocytes (stage 5-6 of Dumont) isolated free of follicle cells by collagenase treatment from ovarian pieces of Xenopus laevis, was studied in observing the germinal vesicle breakdown (GVBD) provoked by progesterone and testosterone (0.1 nM-1 microM), alone or in association with insulin (30 micrograms/ml). Testosterone, was more active than progesterone to elicit GVBD in vitro, raising the question of the relative roles of both steroids in the physiological maturation process in vivo. The potentiating effect of insulin, already observed on progesterone action, was also demonstrated upon testosterone effect; the results suggested that it occurs during the early phase of hormone-induced meiosis reinitiation.


The emergence of overweight as a disease entity: measuring up normality.
As Charles Rosenberg [(2002). The tyranny of diagnosis. The Milbank Quarterly, 80, 237-260] has recently written, clinical diagnosis contributes to imposing structure on cultural reality in a manner which is not unproblematic. A social power resides in the process of naming diseases-one, which legitimises concerns, explains reality, naturalises deviance and imposes status. But clinical entities are not static, as both the concerns of society, and the technological ability of practitioners change (what Rosenberg refers to as the "iatrogenesis of nosology"), so too do the range of labels available for identifying disease. In this paper, I argue that being "overweight," once predominantly an adjectival descriptor of corpulence, a physical sign or a symptom, and even, in some cultures, a sign of wealth and status, is undergoing the transformation to disease entity. I suggest that evidence of this is present in both the frequency and the way in which the term is being used by the media, the medical establishment and the laity. I argue that this change stems from the convergence of two particular phenomena. The first is the belief in the neutrality of quantification, and the objectivity that measurement brings to qualitative description. The second is the importance attributed to normative appearance in health. I discuss some of the implications of this evolution and its impact on health practices, including the exploitation of this purported disease state for commercial benefit.


Susceptibility of Culiseta longiareolata to insecticides in West Azerbaijan province, northwestern Iran.
Mosquitoes are involved in the transmission of a wide range of diseases and among them, Culiseta longiareolata, acts as a vector of avian malaria, tularemia and several arboviruses like West Nile fever. The current study was conducted to determine the susceptibility of C. longiareolata against deltamethrin 0.05% (pyrethroids), fenitrothion 1.00% (organophosphate) and bendiocarb 0.10% (carbamate). Mosquitoes were collected from different parts of Urmia county, the capital of West Azerbaijan. In the current study, 443 empty 3 - 5 days old adult female C. longiareolata were used for susceptibility tests. The susceptibility status of C. longiareolata was determined using WHO's recommended procedure. The results indicated higher mortality rates of Culiseta longiareolata against studied insecticides. Culiseta longiareolata, was resistant to all studied insecticides (deltamethrin, mortality rate: 62.50%, fenitrothion, mortality rate: 35.96% and bendiocarb, mortality rate: 20.16%). The current study represents the first report of susceptibility status of C. longiareolata to fenitrothion and bendicarb in Iran. Considering the climatic diversity and geographical conditions of northwestern Iran, reports of resistance of other mosquitoes' of this region, the susceptibility status of medically and veterinary important mosquitoes should be given serious attention.


Radiosurgery fractionation and post-treatment hemorrhage development for intact melanoma brain metastases.
To assess, for intact melanoma brain metastases (MBM), whether single-fraction stereotactic radiosurgery (SRS) versus fractionated stereotactic radiotherapy (fSRT) is associated with a differential risk of post-treatment lesion hemorrhage (HA) development. A single institution retrospective database review identified consecutive patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 and 2021. The presence of lesion HA was determined by multi-disciplinary imaging review. Dosimetric variables were reported as biologically effective doses using an α/β ratio of 2.5 (BED2.5). Statistical analysis was performed using mixed effect logistic regression for post-treatment HA and Cox frailty modeling for local control (LC). The cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Of lesions without prior HA, 63 of 133 lesions (47.4%) receiving SRS demonstrated evidence of post-treatment HA versus 2 of 24 lesions (8.3%) treated with fSRT (p = 0.01). A larger maximum BED2.5 was observed in lesions developing HA compared to no HA (238.3 Gy vs. 211.4 Gy; p = 0.022). 12-month LC was 65.7% (95% CI 37.2-87.3%) and 77.5% (95% CI 58.5-91.2%) for lesions demonstrating pre-treatment and post-treatment HA, respectively, with no local failure events observed within 12 months for non-hemorrhagic lesions (p < 0.001). We found an increased incidence of post-treatment HA for intact MBM receiving a larger maximum BED2.5, which was significantly higher for single fraction treatments within our cohort. The presence of lesion HA, either pre- or post-treatment, was indicative of inferior LC. Further investigations of optimal dose and fractionation schedules for treatment of MBM in the era of immunotherapy are warranted.


Evidence for the release of endogenous substance P from intestinal nerves.
The desensitization of receptors for substance P in the longitudinal muscle of the guinea-pig ileum has been studied. Receptors for substance P in the muscle became desensitized in the presence of relatively large concentrations of synthetic substance P; a desensitizing concentration of substance P of 7.5 x 10(-9) M shifted the concentration-response curve for substance P about 20-fold to the right, while a desensitizing concentration of 7.5 x 10(-8) M shifted the curve about 300-fold to the right. This desensitization appeared specific; concentration-response curves for carbachol, DMPP, 5-HT and bradykinin were not significantly affected by substance P, 7.5 x 10(-8) M. Furthermore, substance P in concentrations up to 7.5 x 10(-8) M did not modify transmission from either cholinergic nerves or enteric inhibitory nerves when these were stimulated electrically. However, hyoscine-resistant contractions produced by stimulation of nerves in the ileum at 10 Hz were abolished by exposure to concentrations of substance P of 7.5 x 10(-9) M or greater, suggesting that these nerves release a substance similar to or identical with substance P. DMPP evoked small hyoscine-resistant contractions of the ileum. These contractions were also antagonised by desensitization of receptors for substance P. Immunohistochemical studies showed substance P-like immunoreactivity in nerve terminals of both the myenteric and submucous plexuses.


Independent contribution of catecholamines to arrhythmogenesis during evolving infarction in the isolated rat heart.
Ventricular fibrillation (VF) in conscious rats with coronary artery ligation occurs in two phases, before (phase 1) and after (phase 2) 90 min of ischaemia respectively. The mechanisms of phase 2 VF are not established. Interestingly, phase 2 VF is absent in isolated (denervated) buffer-perfused rat hearts. We investigated whether catecholamine supplementation (to mimic sympathetic drive) was sufficient to restore phase 2 VF in such hearts. Isolated rat hearts (n=10 per group) underwent coronary ligation for 240 min. At 90 min, during a period of relative electrical stability, the perfusion solution was switched from standard (Krebs) to identical solution or Krebs containing catecholamines (313 nM noradrenaline and 75 nM adrenaline) with or without 10 microM trimazosin (an alpha(1)-adrenoceptor antagonist) or 10 microM atenolol (a beta(1)-adrenoceptor antagonist). Although in all groups the incidence of phase 1 VF was high (80 - 100%), the temporal distribution of VF was monophasic, i.e. only one heart in one group developed phase 2 VF (P=NS). Other ventricular arrhythmias (e.g., tachycardia; VT) exhibited a similar temporal distribution. Nevertheless, haemodynamic changes confirmed sympathomimetic effects of catecholamines, e.g., heart rate was increased from 278+/-7 beats min(-1) in controls to 335+/-8 beats min(-1) (P<0.05) by catecholamines, an effect that could be blocked by atenolol (285+/-7 beats min(-1)) but not by trimazosin (342+/-12 beats min(-1)). Coronary flow was correspondingly increased from 7.7+/-0.7 ml min(-1) g(-1) to 16.5+/-1.3 ml min(-1) g(-1) (P<0.05); this effect could be blocked by atenolol (8.1+/-0.6 ml min(-1) g(-1)) and was enhanced by trimazosin (20.7+/-2.4 ml min(-1) g(-1)). In conclusion, despite evidence of adequate alpha- and beta-adrenoceptor activation, catecholamine supplementation to isolated buffer-perfused rat hearts was insufficient to restore phase 2 VF. It therefore appears unlikely that catecholamines alone mediate phase 2 VF.


Diabetes: the cost of illness in Sweden.
To estimate the total cost of diabetes mellitus in Sweden in 1994 and to compare the cost structure with a former Swedish study and with American studies. The study also aims to investigate how the total cost is distributed between control of and complications of the disease. In order to estimate the economic burden of diabetes mellitus in Sweden in 1994, the cost-of-illness method, based on the human capital theory, has been used. Both direct and indirect costs have been estimated using a prevalence approach and a 'top-down' method. The economic burden of diabetes mellitus is estimated at 5746 MSEK (1US$ = 7.50 SEK) in Sweden in 1994. The direct costs are estimated at 2455 MSEK and constitute about 43% of the total cost. The indirect costs (production loss due to morbidity and premature mortality) were the dominant costs and amounted to 3291 MSEK, or 57% of total cost. Comparisons with a previous Swedish study from 1978 show some interesting results. Firstly, the distribution of direct and indirect costs is identical between the two studies. Secondly, the distribution of costs between management/control of the disease and complications was about the same, comparing the situation 16 years apart. Four American studies show a cost structure similar to the cost structure presented in this study. The overall conclusion must be that very little has changed in the cost structure of diabetes in Sweden between 1978 and 1994.


Pelvic reconstruction after abdominoperineal resection: a pilot study using an absorbable synthetic prosthesis.
Abdominoperineal resection (APR) is not free of complications, in particular complications due to the occupation of the pelvis by the small bowel after surgery. A number of surgical techniques have been described to prevent the small bowel from entering and adhering to the pelvis (pelvic partition), but there is no agreement concerning their use. The aim of this study was to evaluate the feasibility, effectiveness and safety of using an absorbable synthetic prosthetic material for pelvic partitioning after APR. A prospective non-randomised longitudinal pilot study was carried out on a series of 10 patients who underwent APR due to lower-third rectal cancer, in order to evaluate the feasibility, safety and efficacy of pelvic partitioning with an absorbable synthetic prosthetic material. In all the patients, it was possible to perform a radical resection and to install the prosthesis. After a mean follow-up of 9 months (range: 4-18 months), no abdominal or perineal complications were detected. One patient (10%) suffered chronic pelvic pain. Pelvic partition after APR of the rectum with an absorbable synthetic prosthesis is feasible, effective and safe.


Superoxide involvement in the bactericidal effects of negative air ions on Staphylococcus albus.
The physical nature of small air ions is well established and it is recognized that they can produce a variety of biological effects. However, in only a few instances have any underlying biochemical changes been detected. Theoretically, one can consider the hydrated superoxide radical anion (O2) (H2O)n with n congruent to 4-8 as a likely candidate for a biologically active species of negative air ion. The chemical and biological reactivity of superoxide is high and includes a leading role in bacterial killing caused by radiation, in which superoxide dismutase (SOD), an enzyme that catalyses the reaction: O2 + O2 +2H leads to H2O2 +O2 protected markedly. Other studies have also demonstrated the bactericidal effect of O2 (refs 9-11). Inasmuch as the bactericidal action of small negative air ions has been repeatedly confirmed, we decided to test for the involvement of O2 in this phenomenon by evaluating the protective effect of SOD. Our results show strong O2 involvement in negative air ion bacterial kill.


A case of intoxication with a new cathinone derivative α-PiHP - A presentation of concentrations in biological specimens.
Cathinones are currently the second largest and the second most frequently seized group of new psychoactive substances (NPS). One of the most recent synthetic cathinones that has appeared on the 'legal highs' market is alpha-pyrrolidinoisohexanophenone (α-PiHP). An 18-year-old man was found dead in an apartment. The autopsy materials were collected for toxicological analyses. The quantitative analyses were carried out by LC-MS/MS. α-PiHP was detected and quantified in all post-mortem materials except the hair. The determined concentrations of the compound in the blood, urine and bile were 69 ng/mL, 2072 ng/mL, and 341 ng/mL respectively. The concentrations of α-PiHP in solid tissues were in the range of 7-478 ng/g. 4-Chloromethcathinone (4-CMC), N-ethylhexedrone, benzoylecgonine and 3,4-methylenedioxymethamphetamine (MDMA) were also detected in some materials. No cases presenting concentrations of α-PiHP in biological materials have been reported so far. Due to the similarity of structures and the reported dosages, an attempt to compare the concentrations of α-PVP and α-PHP has been made. In the described case, functional death through intoxication of α-PiHP was accepted as the final cause of death. The other detected substances did not contribute to death due to their very likely distant administration. α-PiHP is another new synthetic cathinone that is a danger to the life of users. The described fatal intoxication case presents the concentrations of α-PiHP in post-mortem materials. This data could be valuable for further interpretation of other results from toxicological analyses in cases where the use of α-PiHP is suspected.


Biomarker Reproducibility Challenge: A Review of Non-Nucleotide Biomarker Discovery Protocols from Body Fluids in Breast Cancer Diagnosis.
Breast cancer has now become the most commonly diagnosed cancer, accounting for one in eight cancer diagnoses worldwide. Non-invasive diagnostic biomarkers and associated tests are superlative candidates to complement or improve current approaches for screening, early diagnosis, or prognosis of breast cancer. Biomarkers detected from body fluids such as blood (serum/plasma), urine, saliva, nipple aspiration fluid, and tears can detect breast cancer at its early stages in a minimally invasive way. The advancements in high-throughput molecular profiling (omics) technologies have opened an unprecedented opportunity for unbiased biomarker detection. However, the irreproducibility of biomarkers and discrepancies of reported markers have remained a major roadblock to clinical implementation, demanding the investigation of contributing factors and the development of standardised biomarker discovery pipelines. A typical biomarker discovery workflow includes pre-analytical, analytical, and post-analytical phases, from sample collection to model development. Variations introduced during these steps impact the data quality and the reproducibility of the findings. Here, we present a comprehensive review of methodological variations in biomarker discovery studies in breast cancer, with a focus on non-nucleotide biomarkers (i.e., proteins, lipids, and metabolites), highlighting the pre-analytical to post-analytical variables, which may affect the accurate identification of biomarkers from body fluids.


Hydrocortisone enhancement of insulin's action on macromolecular synthesis in MCF-7 cells.
In MCF-7 human breast cancer cells, insulin stimulated the rate of [3H]uridine incorporation into RNA, [3H]thymidine incorporation into DNA, and [3H]leucine incorporation into protein. In addition, hydrocortisone appeared to augment the effect of insulin, by further increasing the rate of [3H]uridine incorporation into RNA and [3H]thymidine incorporation into DNA. A significant increase in the total amount of DNA and protein was present in cultures treated with insulin compared to untreated controls. Hydrocortisone was shown to augment the insulin effect on total protein accumulation and total RNA accumulation in MCF-7 cells.


Comparing the performance of two gamma cameras under high counting rates: principles and practice.
The performance of two large Anger cameras at high counting rates was compared, and the principles for measuring the relevant parameters, especially deadtime loss and coincidence artifacts, are discussed. The results demonstrate the importance of the following factors: modern pulse-shaping circuitry with short paralyzable deadtime, and anti-pileup circuit, and uniform energy information within the field of view, which requires separate summing matrices for energy and position. Elaborate testing of the specifications should be carried out before purchase of a gamma camera.


Linking landscape structure and vegetation productivity with nut consumption by the Cantabrian brown bear during hyperphagia.
In bears, reproduction is dependent on the body reserves accumulated during hyperphagia. The Cantabrian brown bear mainly feeds on nuts during the hyperphagia period. Understanding how landscape heterogeneity and vegetation productivity in human-dominated landscapes influence the feeding habits of bears may therefore be important for disentangling species-habitat relationships of conservation interest. We determined the spatial patterns of nut consumption by brown bears during the hyperphagia period in relation to landscape structure, characteristics of fruit-producing patches and vegetation productivity. For this purpose, we constructed foraging models based on nut consumption data (obtained by scat analysis), by combining vegetation productivity data, topographical variables and landscape metrics to identify nut foraging patterns during this critical period for bears. The average wooded area of patches where scats were collected and where the nuts that the bears had consumed were produced was larger than that of the corresponding patches where nuts were not produced. For scats collected outside of nut-producing patches, the distance between the scats and the patches was greatest for chestnut-producing patches. Elevation, Gross Primary Production (GPP) and the Aggregation Index (AI) were good predictors of acorn consumption in the models. Good model fits were not obtained for data on chestnut consumption in bears. The findings confirm that brown bears feeding on nuts show a preference for relatively large, highly aggregated patches with a high degree of diversity in the landscape pattern, which may help the bears to remain undetected. The nut prediction model highlights areas of particular importance for brown bears during hyperphagia. The human presence associated with sweet chestnut forest stands or orchards may make bears feel more vulnerable when feeding.


Age and Gender Moderate the Impact of Early Palliative Care in Metastatic Non-Small Cell Lung Cancer.
Studies demonstrate that early palliative care (EPC) improves advanced cancer patients' quality of life (QOL) and mood. However, it remains unclear whether the role of palliative care differs based upon patients' demographic characteristics. We explored whether age and gender moderate the improvements in QOL and mood seen with EPC. We performed a secondary analysis of data from a randomized controlled trial of patients with metastatic non-small cell lung cancer. Patients received either EPC integrated with oncology care or oncology care alone. We assessed the degree to which QOL (Trial Outcome Index [TOI]) and mood (Hospital Anxiety and Depression Scale [HADS] and Patient Health Questionnaire 9 [PHQ-9]) outcomes at week 12 varied by patient age (<65) and gender. The week 12 data of 107 patients are included in this analysis. At 12 weeks, younger patients receiving EPC reported better QOL (TOI mean = 62.04 vs. 49.43, p = .001) and lower rates of depression (HADS-Depression = 4.0% vs. 52.4%, p < .001; PHQ-9 = 0.0% vs. 28.6%, p = .006) than younger patients receiving oncology care alone. Males receiving EPC reported better QOL (TOI mean = 58.81 vs. 48.30, p = .001) and lower rates of depression (HADS-Depression = 18.5% vs. 60.9%, p = .002; PHQ-9 = 3.8% vs. 34.8%, p = .008) than males receiving oncology care alone. At 12 weeks, QOL and mood did not differ between study groups for females and older patients. Males and younger patients who received EPC had better QOL and mood than those who received oncology care alone. However, these outcomes did not differ significantly between treatment groups for females or older patients. This study found that early palliative care improves patients' quality of life and mood differentially based on their age and gender. Specifically, males and younger patients receiving early palliative care experienced better quality of life and mood than those receiving oncology care alone. Conversely, females and older patients did not experience this treatment effect. Thus, palliative care interventions may need to be tailored to patients' age- and gender-specific care needs. Studying how patients' demographic characteristics affect their experience with palliative care will enable the development of interventions targeted to the distinct supportive care needs of patients with cancer.


Risk factors for postpartum depression: An evidence-based systematic review of systematic reviews and meta-analyses.
Postpartum depression (PPD) is the most common psychiatric condition after childbirth which not only effects the mother's health, but also might have impact on child's development and parenting behaviors. Because the etiology of PPD has not been fully cleared, the efforts towards identification of risk factors are crucial for both the children and mother's health. PubMed, EMBASE and PsycINFO databases were searched since inception until July 2019 to collect data about the risk factors of PPD and only systematic review and meta-analysis can be included. To identify the real risk factors, protective factors and controversial factors, nineteen parts of the interpretation were adopted. The risk factors are mainly concentrated in the following aspects: violence and abuse, immigration status, gestational diabetes, cesarean section, depressive history, vitamin D deficiency, obese and overweight, postpartum sleep disruption and poor postpartum sleep, lack of social support, traditional dietary pattern (Japanese, Indian, United Kingdom, and Brazilian dietary pattern), multiple births, preterm and low-birth-weight infants, postpartum anemia, negative birth experience. The controversial factors are serum level of cortisol, thyroid peroxidase autoantibodies status, acculturation, traditional confinement practices. Skin-to-skin care, higher concentrations of DHA in mothers' milk, greater seafood consumption, healthy dietary patterns, multivitamin supplementation, fish and PUFA intake, calcium, Vitamin D, zinc and possibly selenium are protective factors. Thirteen risk factors were identified, but five factors still controversial due to the insufficient of the evidence. What's more, skin-to-skin care and some nutrition related factors are protective factors against PPD.


Percutaneous ethanol injection into parathyroid adenomas: mid- and long-term results.
The aim of this study was to evaluate mid- and long-term results of ultrasonically guided ethanol injection into parathyroid adenomas. From 1988 to 1996, 27 patients (mean age 77 +/- 13 years) were treated for parathyroid adenomas by percutaneous ethanol injection. The survey included clinical information, plasma calcium, phosphorus and PTH (1-84) evaluation. Follow-up lasted 22.6 +/- 10 months. No major complications were observed for 63 ethanol injections. Biochemical recovery was 58%, biochemical improvement at 3 months was 33%, and failure was 7%. Four of 15 cured patients presented a recurrence of the disease 1 or 2 years after the first treatment. Ultrasonically guided ethanol injection can be useful in the treatment of parathyroid adenomas when surgery is not possible. The immediate results are interesting but not as good as those obtained with surgery. A regular biochemical survey is necessary so that recurrences can be recognized and treated at an early stage.


T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia.
Acquired T-cell dysfunction is common in chronic B-cell malignancies. Given the strong connection between T-cell metabolism and function, we investigated metabolic alterations as the basis of T-cell dysfunction induced by malignant cells. Using B-cell malignant cell lines and human peripheral blood mononuclear cells, we first established a model that recapitulates major aspects of cancer-induced T-cell dysfunction. Cell lines derived from chronic lymphocytic leukemia (CLL) (PGA-1, CII, and Mec-1), but not from other B-cell malignancies, altered the T-cell metabolome by generating a pseudohypoxic state. T cells were retained in aerobic glycolysis and were not able to switch to oxidative phosphorylation (OXPHOS). Moreover, T cells produced immunosuppressive adenosine that negatively affected function by dampening the activation, which could be restored by the blocking of adenosine receptors. Subsequently, we uncovered a similar hypoxic-like signature in autologous T cells from primary CLL samples. Pseudohypoxia was reversible upon depletion of CLL cells ex vivo and, importantly, after the in vivo reduction of the leukemic burden with combination therapy (venetoclax and obinutuzumab), restoring T-cell function. In conclusion, we uncovered a pseudohypoxic program connected with T-cell dysfunction in CLL. Modulation of hypoxia and the purinergic pathway might contribute to therapeutic restoration of T-cell function.


A 3-year longitudinal study of the association of physical activity and sedentary behaviours with childhood obesity in China: The childhood obesity study in China mega-cities.
Examine school children's physical activity (PA) and sedentary behaviours (SB) during 2015 to 2017 in China, and study their associations with children's weight status and relevant gender differences. This open cohort study included students from five major cities (Beijing, Shanghai, Xi'an, Nanjing, and Chengdu) across China. Data were collected from students in 2015, 2016, and 2017 (n = 5535) and from their parents and school personnel. Children's weight, height, and waist circumference were measured. SB and PA factors were evaluated using questionnaires. Mixed-effects models examined the relationship between weight status and PA-/SB-associated factors using this longitudinal data. These children had high rates of obesity (12.4%, 95% CI 11.6%-13.3%) and central obesity (28.1%, 95% CI 26.9%-29.3%) during 2015 to 2017. Boys were more likely to have obesity than girls (16.5% vs 8.4%, respectively) as well as centrally obesity (36.3% vs 19.8%, respectively) and spent more time in screen viewing than girls (hours/week ± SD: 2015, 1.8 ± 2.5 vs 1.5 ± 2.0; 2016, 2.0 ± 2.4 vs 1.8 ± 2.5; 2017, 1.7 ± 2.3 vs 1.4 ± 2.1 hours/week). Those who walked <5 minutes on their average daily walk to school were more likely to have obesity (OR: 1.96, 95% CI 1.03-3.73) than those who spent ≥15 minutes on walking to school. When stratified by gender, this higher risk was only observed in girls (OR: 3.01, 95% CI 1.09-8.35). Children who spent more time in screen viewing were more likely to have obesity (OR: 1.13, 95% CI 1.06-1.21) and have central obesity (OR: 1.05, 95% CI 1.02-1.09). The association for obesity was consistent in boys and girls (boys, OR: 1.15, 95% CI 1.05-1.25; girls, OR: 1.12, 95% CI 1.00-1.24). More screen time and less walking time were risk factors for developing obesity in urban Chinese children. The associations varied by gender.


[Teredoika aspectabilis sp. n., a new endoparasitic copepod from the gastropod mollusc, Clinopegma unicum, in the Sea of Okhotsk].
A new species of the genus Teredoika Stock, 1959 is described. T. aspectabilis sp. n., the second species of the genus, was found in the kidney of Clinopegma unicum in the Okhotsk Sea while the type species is known from the stomach of the shipworm Teredo utriculus caught in the Gulf of Naples.


Two new ellagic acid rhamnosides from Punica granatum heartwood.
From Punica granatum heartwood two new ellagic acid rhamnosides, 3- O-methylellagic acid 4-O-alpha-L-rhamnopyranoside (1) and 3,4'-O-dimethylellagic acid 4-O-alpha-L-rhamnopyranoside (2) were isolated together with brevifolincarboxylic acid, 3-O-methylellagic acid and 4,4'-O-dimethylellagic acid.