Altered intestinal microbiota composition with epilepsy and concomitant diarrhea and potential indicator biomarkers in infants.
The diversity and dysregulation of intestinal microbiota is related to the pathology of epilepsy. Gut microbiota plays an important role in epilepsy, and regulating intestinal microbiota through exogenous intervention can alleviate symptoms. However, there are no studies about the effects of epilepsy-related diarrhea on gut microbiota. The diversity and dysregulation of intestinal microbiota is related to the pathology of epilepsy. Gut microbiota plays an important role in epilepsy, and regulating intestinal microbiota through exogenous intervention can alleviate symptoms. However, there are no studies about the effects of epilepsy-related diarrhea on gut microbiota. To evaluate changes in gut microbiota structure and composition in patients with epilepsy and associated diarrhea, the structure and composition of the fecal microbiota among patients with epilepsy (EP, 13 cases), epilepsy with diarrhea (ED, 13 cases), and probiotic treatments (PT, 13 cases), and healthy controls (CK, seven cases) were investigated and validated by utilizing high-throughput 16S rRNA sequencing. The results showed that the α-diversity indexes indicated that richness and phylogenetic diversity had no significant differences among groups. However, the variation of β-diversity indicated that the structure and composition of intestinal microbiota were significantly different among the CK, EP, ED, and PT groups (permutational multivariate analysis of variance, p-value = 0.001). Normalized stochasticity ratio and β-nearest taxon index indicated that stochastic mechanisms exerted increasing influence on community differences with epilepsy and associated diarrhea. ED microbiome alterations include increased Proteobacteria and decreased Actinobacteria and Firmicutes at the phylum level. Bifidobacterium was the core microbe in CK, EP, and PT, whereas it decreased significantly in ED. In contrast, Escherichia/Shigella was the core microbe in CK and ED, whereas it increased significantly in ED (Tukey's multiple comparisons test, adjusted p-value <0.05). The association network in CK has higher complexity and aggregation than in the other groups. The EP network indicated high connectivity density within each community and high sparsity among communities. The bacterial community network of the ED had a more compact local interconnection, which was in contrast to that of PT. The top 7 microbial amplicon sequence variant-based markers that were selected by machine learning to distinguish the groups of epilepsy, probiotic treatments, and healthy infants had stronger discrimination ability. In addition, ASVs_1 (Escherichia/Shigella) and ASVs_3 (Bifidobacterium) had the most importance in the recognition. Our research finally showed that infants with epilepsy, epilepsy with diarrhea, and probiotic treatments exhibit substantial alterations of intestinal microbiota structure and composition, and specific intestinal strains are altered according to different clinical phenotypes and can therefore be used as potential biomarkers for disease diagnosis.


Efficient capture of unique sequences from eukaryotic genomes.
Cot-based cloning and sequencing (CBCS), a synthesis of Cot analysis, DNA cloning and high-throughput sequencing, promises to accelerate the study of eukaryotic genomes. In particular, CBCS will (1) permit efficient gene discovery in species with substantial quantities of repetitive DNA, (2) allow the sequence complexity (i.e. all the unique sequence information) of large genomes to be elucidated at a fraction of the cost of shotgun sequencing, and (3) enhance genome sequencing efforts by facilitating capture of low-copy sequences not secured by EST sequencing. CBCS should accelerate comparative genomics research, especially in large genomes such as those of many crops.


Interaction of Temperature and Photoperiod Increases Growth and Oil Content in the Marine Microalgae Dunaliella viridis.
Eukaryotic marine microalgae like Dunaliella spp. have great potential as a feedstock for liquid transportation fuels because they grow fast and can accumulate high levels of triacylgycerides with little need for fresh water or land. Their growth rates vary between species and are dependent on environmental conditions. The cell cycle, starch and triacylglycerol accumulation are controlled by the diurnal light:dark cycle. Storage compounds like starch and triacylglycerol accumulate in the light when CO2 fixation rates exceed the need of assimilated carbon and energy for cell maintenance and division during the dark phase. To delineate environmental effects, we analyzed cell division rates, metabolism and transcriptional regulation in Dunaliella viridis in response to changes in light duration and growth temperatures. Its rate of cell division was increased under continuous light conditions, while a shift in temperature from 25 °C to 35 °C did not significantly affect the cell division rate, but increased the triacylglycerol content per cell several-fold under continuous light. The amount of saturated fatty acids in triacylglycerol fraction was more responsive to an increase in temperature than to a change in the light regime. Detailed fatty acid profiles showed that Dunaliella viridis incorporated lauric acid (C12:0) into triacylglycerol after 24 hours under continuous light. Transcriptome analysis identified potential regulators involved in the light and temperature-induced lipid accumulation in Dunaliella viridis.


The Evolutionary Game Analysis of Low Carbon Production Behaviour of Farmers, Government and Consumers in Food Safety Source Governance.
Whether the quality of agricultural products is safe or not is related to issues of food safety and low carbon production in agriculture. Based on evolutionary game theory, this paper establishes a game model among government, farmers and consumers and analyzes the dynamic evolutionary process and evolutionary stable strategies of the major stakeholders. The results show that: (i) government subsidy coefficient, farmers' penalty coefficient for not producing, consumer trust coefficient and willingness to pay carbon labelled agricultural products premium are positively related to farmers' adoption of low-carbon production behaviour, and fraud penalty coefficient and farmers' cost of adopting low-carbon production technology are negatively related; (ii) farmers' sensitivity to government regulation policies is: fraud penalty coefficient = farmers' cost of adopting low-carbon production technology > government subsidy The sensitivity of farmers to government regulation policies is: fraud penalty coefficient = cost of low-carbon production technology > government subsidy > penalty coefficient for non-production, and the sensitivity of farmers to direct market stimulation is: consumer trust coefficient > coefficient of willingness to pay premium for carbon labelled agricultural products, and the additional benefit coefficient has no significant effect on farmers' decision-making; (iii) In the early stage, the source control of food safety mainly depends on the government's policy intervention. In the later stage, the establishment of carbon label agricultural products market incentive mechanism can achieve long-term stable and effective source control of food safety.


Baia Mare accident--brief ecotoxicological report of Czech experts.
On 30 January 2000, following the breach in the tailing dam of the Aurul SA Baia Mare Co., a major spill of about 100,000 m(3) of cyanide and metal-rich liquid waste was released into the river system near Baia Mare in northwest Romania. The pollutants flowed via different tributaries into the Tizsa (Tisa) river and finally through the Danube river into the Black Sea. Along the way pollutants (especially cyanides) caused rapid death of aquatic organisms and animals living close to the poisoned rivers. Following request from the governments of Romania, Hungary, and the Federal Republic of Yugoslavia, United Nations sent international mission experts to the area of accident. The Czech team of four experts took very active part in this mission. Samples of surface water collected by this team 3 weeks after the accident showed high toxicity in the rivers on the Romanian territory. Due to this impact, water from the Szamos river and a large area of the Tisza river in Hungarian territory was still medially toxic. Improvement of this situation was detected only in downstream areas of the Tisza/Tisa river. The high toxicity of surface water from the locality of the Lapos river upstream of the accident indicated the possibility of toxic pollution from other sources in the area. Aquatic sediments were highly toxic only in the Aurul reservoir and its surrounding area. Rapid decline of their toxicity indicated more limited adverse impact of the "Aurul pollution" in comparison with surface water. From ecotoxicological results it is evident that there is an urgent need to start abatement activities in the Baia Mare area because the possibility of future accidents still exists (this hypothesis was proved by further accidents on 10.3.2000 and the beginning of May 2000).


Melanoma with cutaneous melanoma secondaries.
Mr HG presented in 2002 with a large black lesion on his left loin. It had been present for many years but had recently changed (Figure 1). Nearby, two similar lesions were apparently separated by normal skin. Histology confirmed these were malignant melanoma. The 'normal' skin between lesions also demonstrated melanoma beneath the surface. At its thickest, this melanoma was a (Breslow) 2.56 mm, Clark 4 lesion. The tumour was excised with a minimum 20 mm margin of normal skin. Given the depth of the tumour, Mr HG was co-managed with the Victoria Melanoma Unit. There are no radiotherapy or chemotherapy programs that have been demonstrated to improve survival in patients with an advanced primary melanoma such as this. Following discussion, Mr HG chose not have a sentinel lymph node biopsy (SLNB).


Shortcut to adiabaticity in the Lipkin-Meshkov-Glick model.
We study transitionless quantum driving in an infinite-range many-body system described by the Lipkin-Meshkov-Glick model. Despite the correlation length being always infinite the closing of the gap at the critical point makes the driving Hamiltonian of increasing complexity also in this case. To this aim we develop a hybrid strategy combining a shortcut to adiabaticity and optimal control that allows us to achieve remarkably good performance in suppressing the defect production across the phase transition.


[Health consequences of armed conflict in Guinea-Bissau].
The present paper reviews studies carried out by the Bandim Health Project during the armed conflict in Guinea-Bissau, 1998-1999. Common health interventions like vaccination and breastfeeding, as well as focused interventions such as nutrition interventions aimed at malnourished children are effective measures. Population-based studies of health status gives important information about health conditions for groups at special risk, and provides information about which interventions are the most effective in an emergency.


Predictability of the Achieved Lenticule Thickness in Small Incision Lenticule Extraction for Myopia Correction.
To investigate the predictability of the achieved lenticule thickness in small incision lenticule extraction (SMILE) for the correction of myopia. In this prospective study, a total of 80 eyes of 45 patients who underwent the SMILE procedure were included. A Scheimpflug camera was used to measure the preoperative and postoperative corneal topography. Achieved lenticule thicknesses at the pupil center and corneal vertex were calculated by subtracting the postoperative corneal thickness at the pupil center and corneal vertex from preoperative corresponding values. Predictability between the achieved and VisuMax readout at different locations (the pupil center and corneal vertex) and postoperative visits (postoperative day 1 and 6 months) were evaluated using a general linear model. Achieved lenticule thickness at the pupil center and corneal vertex showed good correlation at both postoperative day 1 (pupil center: r=0.914, corneal vertex: r=0.903) and 6 months (pupil center: r=0.886, corneal vertex: r=0.866). The achieved lenticule thickness at postoperative day 1 was 8.5-μm thinner at the pupil center and 9.6-μm thinner at the corneal vertex than the VisuMax readout. This study suggests that the predictability between the achieved and VisuMax readout is favorable. The lenticule thickness at the pupil center is closer to the VisuMax readout than corneal vertex.


[A woman with multiple masses on her left hand].
We describe a 66-year-old woman who presented with firm masses on her left hand, which had recently increased in size, and multiple haemangiomas. A diagnosis of Maffucci syndrome was established. Renewed growth of enchondromas during adulthood is suspicious for malignant transformation. Therefore, curettage with adjuvant fenolisation was performed in our patient. Clinical and radiological follow-up was required concerning local recurrence.


[Urinary malformations in synostoses of the cervical vertebrae (Klippel-Feil syndrome). Apropos of 35 cases].
A study of 35 cases of congenital fusion of the cervical vertebrae demonstrated the high incidence of its association with urinary anomalies (52 per cent). More than half of these cases concerned unilateral kidney defects. The urinary anomalies are normally asymptomatic, but there is always the risk of chronic renal failure, and preventive surgery may be necessary. It is therefore advisable to make a systematic practice of obtaining ultrasound examinations and intravenous urograms. There are many other possible associated anomalies, which are often the first to be noted and lead to the discovery of the vertebral and urinary malformations. The authors define Klippel-Feil syndrome as the synostosis of two or more cervical vertebrae.


Excess biglycan causes eyelid malformation by perturbing muscle development and TGF-alpha signaling.
Tissue morphogenesis during development is regulated by growth factors and cytokines, and is characterized by constant remodeling of extracellular matrix (ECM) in response to signaling molecules, for example, growth factors, cytokines, and so forth. Proteoglycans that bind growth factors are potential regulators of tissue morphogenesis during embryonic development. In this study, we showed that transgenic mice overexpressing biglycan under the keratocan promoter exhibited exposure keratitis and premature eye opening from noninfectious eyelid ulceration due to perturbation of eyelid muscle formation and the failure of meibomian gland formation. In addition, in vitro analysis revealed that biglycan binds to TGF-alpha, thus interrupting EGFR signaling pathways essential for mesenchymal cell migration induced by eyelid epithelium. The defects of TGF-alpha signaling by excess biglycan were further augmented by the interruption of the autocrine or paracrine loop of the EGFR signaling pathway of HB-EGF expression elicited by TGF-alpha. These results are consistent with the notion that under physiological conditions, biglycan secreted by mesenchymal cells serves as a regulatory molecule for the formation of a TGF-alpha gradient serving as a morphogen of eyelid morphogenesis.


Multiple thyroid ectopics in a single patient: a rare presentation.
A rare case of multiple thyroid ectopics has been presented. A 16 years old girl presented with swelling on the right side of neck and sense of lump in the throat. Oral examination confirmed presence of lingual thyroid. Examination of neck confirmed a 4 cm rounded soft mass on upper right side of patient's neck. Thyroid scan with I131 showed uptake of radio-iodine at the tongue base and also on right side of neck. Biopsy of mass from tongue dorsum and FNA from neck mass confirmed presence of thyroid tissue at both sites. Hormonal assay showed high TSH and low T3 and T4 level. Treatment with thyroxin for 3 months caused regression of thyroid tissue from both sites and improvement of patient's symptoms. Thyroid hormonal profile improved with thyroxin therapy and patient soon became euthyroid. The patient remained on long-term hormonal replacement with no recurrence of symptoms.


Critical phenomena in magnetic nanowires.
In this paper we report the first experimental study of critical phenomena in case of magnetic nanowires of nickel near the ferromagnetic-paramagnetic transition from the electrical transport properties. Nickel nanowire arrays, prepared by potentiostatic electrodeposition of nickel inside pores of nanoporous anodic alumina template were well characterized by X-ray Diffraction, Transmission electron microscopy and Energy dispersive Spectroscopy. Precise electrical resistance measurement of the nanowire arrays of wire diameter 20 nm have been done in the temperature range between 300 K to 700 K. We see a drop in the Curie temperature as observed from the resistivity anomaly. We analyzed the resistance data near the critical region and extracted the critical exponent alpha directly from the resistance. We observed a decrease in the critical part of the resistivity including a decrease in the magnitude of the critical exponent alpha and severe modification in the correction to scaling.


Effect of watermelon supplementation on exercise performance, muscle oxygenation, and vessel diameter in resistance-trained men.
Watermelon shows promise as an ergogenic aid due to its high concentration of L-citrulline, vitamins, minerals, and antioxidants. The purpose of this study was to examine the effect of watermelon supplementation on exercise performance, muscle oxygenation, and vessel diameter. In a crossover design fashion, 15 resistance-trained men (22.4 ± 2.9 years; 177.5 ± 7.1 cm; 82.7 ± 11.2 kg) were randomly assigned to supplement with either watermelon juice concentrate (WM; 2.2 g·day-1 L-citrulline) or placebo (PL) for 7 days prior to completing an experimental trial consisting of an isometric mid-thigh pull test and acute bench press protocol. Participants completed two sets of two repetitions at 75% 1 repetition maximum (1-RM) with maximum ballistic intent followed by five repetition-maximum (RM) sets at the same load. Barbell velocity and power were measured via linear position transducer during the first two sets, while volume load and muscle oxygenation were quantified during RM sets. Brachial artery diameter and subjective perception measures were assessed at baseline and immediately pre- and post-exercise. Except for a greater percent change in skeletal muscle oxygenation during WM compared to PL on average and across sets (mean difference = + 4.1%, p = 0.033, BF10 = 2.2-54.5), separate traditional and Bayesian analyses of variance with repeated measures, as well as paired-samples t tests for calculated summary measures, revealed no evidence favoring conditional differences in any measure of performance, perception, or muscle oxygenation. Short-term watermelon supplementation does not appear to enhance isometric force production, bench press performance, blood vessel diameter, or muscle oxygenation parameters compared to PL in resistance-trained men.


Verifying a vocal tract model with a closed side-branch.
In this article an implementation of a vocal tract model and its validation are described. The model uses a transmission line model to calculate pole and zero frequencies for a vocal tract with a closed side-branch such as a sublingual cavity. In the validation study calculated pole and zero frequencies from the model are compared with frequencies estimated using elementary acoustic formulas for a variety of vocal tract configurations.


Task-evoked fMRI changes in attention networks are associated with preclinical Alzheimer's disease biomarkers.
There is a growing emphasis on examining preclinical levels of Alzheimer's disease (AD)-related pathology in the absence of cognitive impairment. Previous work examining biomarkers has focused almost exclusively on memory, although there is mounting evidence that attention also declines early in disease progression. In the current experiment, 2 attentional control tasks were used to examine alterations in task-evoked functional magnetic resonance imaging data related to biomarkers of AD pathology. Seventy-one cognitively normal individuals (females = 44, mean age = 63.5 years) performed 2 attention-demanding cognitive tasks in a design that modeled both trial- and task-level functional magnetic resonance imaging changes. Biomarkers included amyloid β42, tau, and phosphorylated tau measured from cerebrospinal fluid and positron emission tomography measures of amyloid deposition. Both tasks elicited widespread patterns of activation and deactivation associated with large task-level manipulations of attention. Importantly, results from both tasks indicated that higher levels of tau and phosphorylated tau pathologies were associated with block-level overactivations of attentional control areas. This suggests early alteration in attentional control with rising levels of AD pathology.


Jejunal Diverticular Perforation due to Enterolith.
Jejunal diverticulosis is a rare entity with variable clinical and anatomical presentations. Although there is no consensus on the management of asymptomatic jejunal diverticular disease, some complications are potentially life-threatening and require early surgical treatment. Small bowel perforation secondary to jejunal diverticulitis by enteroliths is rare. The aim of this study was to report a case of small intestinal perforation caused by a large jejunal enterolith. An 86-year-old woman was admitted with signs of diffuse peritonitis. After initial fluid recovery the patient underwent emergency laparotomy. The surgery showed that she had small bowel diverticular disease, mainly localized in the proximal jejunum. The peritonitis was due to intestinal perforation caused by an enterolith 12 cm in length, localized inside one of these diverticula. The intestinal segment containing the perforated diverticulum with the enterolith was removed and an end-to-end anastomosis was done to reconstruct the intestinal transit. The patient recovered well and was discharged from hospital on the 5th postoperative day. There were no signs of abdominal pain 1 year after the surgical procedure. Although jejunal diverticular disease with its complications, such as formation of enteroliths, is difficult to suspect in patients with peritonitis, it should be considered as a possible source of abdominal infection in the elderly patient when more common diagnoses have been excluded.


Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas.
CD19CAR T cells facilitate a transformational treatment in various relapsed and refractory aggressive B-lineage cancers. In general, encouraging response rates have been observed in B-lineage-derived non-Hodgkin's lymphomas treated with CD19CAR T cells. The major cause of death in heavily pretreated NHL patients is lymphoma progression and lymphoma recurrence. Inefficient CAR T cell therapy is the result of the limited potency of the CAR T cell product or is due to loss of the targeted antigen. Target antigen loss has been identified as the key factor that can be addressed stringently by dual- or multitargeted CAR T cell approaches. We have developed a versatile adapter CAR T cell technology (AdCAR) that allows multitargeting. Screening of three different B-lineage lymphoma cell lines has revealed distinct immune target profiles. Cancer-specific adapter molecule combinations may be utilized to prevent antigen immune escape. In general, CD19CAR T cells become non-functional in CD19 negative lymphoma subsets; however, AdCAR T cells can be redirected to alternative target antigens beyond CD19, such as CD20, CD22, CD79B, and ROR-1. The capability to flexibly shift CAR specificity by exchanging the adapter molecule's specificity broadens the application and significantly increases the anti-leukemic and anti-lymphoma activity. The clinical evaluation of AdCAR T cells in lymphoma as a new concept of CAR T cell immunotherapy may overcome treatment failure due to antigen immune escape in monotargeted conventional CAR T cell therapies.


Endoplasmic Reticulum Stress-Activated Neuronal and Microglial Autophagy Contributes to Postoperative Cognitive Dysfunction in Neonatal rats.
Surgery and anesthesia in neonates may lead to cognitive impairment or abnormal behaviors. It has been shown that autophagy plays a critical role in neuropsychiatric disorders, while the role of autophagy in postoperative cognitive impairment in neonates is not known. Here, we determined this role and the involvement of endoplasmic reticulum (ER) stress in regulating brain cell autophagy after surgery. Seven-day old neonatal rats (P7) had right common carotid artery exposure under anesthesia with 3% sevoflurane for 2 h. Learning and memory were tested using Barnes maze (BM) and fear conditioning (FC) on P31-42 and P42-44, respectively. In another experiment, rat brains were harvested for biochemical studies. The ratio of microtubule-associated protein 1 light chain 3 (LC3) BII/I was increased and sequestosome 1 (P62/SQSTM1) levels were decreased in the brain 24 h after surgery and anesthesia in neonatal rats. Immunofluorescent staining of LC3B was co-localized with a neuronal or a microglial marker but was not co-localized with a marker for astrocytes in rats with surgery. These rats had a poorer performance in the BM and FC tests than control rats when they were adolescent. Pretreatment with an autophagy inhibitor, 3-methyladenine, attenuated the poor performance. Surgery and anesthesia increased the expression of 78 kDa glucose-regulated protein (BIP/GRP78), an indicator of ER stress, 6 h after surgery and anesthesia. The ER stress activator tunicamycin and inhibitor tauroursodeoxycholic acid increased the markers for autophagy in control rats and decreased the autophagy markers in rats with surgery, respectively. Our results suggest that surgery in neonatal rats induces ER stress that then activates neuronal and microglial autophagy, which contributes to learning and memory impairment later in life.


Non-alcoholic fatty liver disease--a common and benign finding in octogenarian patients.
Non-alcoholic fatty liver disease (NAFLD), a common entity in the general population, has been shown to be linked with insulin resistance and metabolic syndrome. Several of the components of the metabolic syndrome are more common in the aged population. The aims of the current study were to determine in the aged, the prevalence and the clinical presentation of NAFLD, as well as the relation to the underlying metabolic abnormalities. In this prospective study, we evaluated 91 octogenarians with a mean age of 85.56+/-3.76 years, who were admitted to the rehabilitation departments of a geriatric hospital. Clinical evaluation included: abdominal ultrasound (US), fasting glucose and lipid levels, serum liver enzymes, ferritin, iron and transferrin saturation. Elderly patients with NAFLD were compared with 46 young patients with NAFLD. NAFLD diagnosed by US was a common finding in this aged population, is present in 42/91 patients (46.2%). No significant differences were observed between the patients with or without NAFLD in the following: age, gender, chronic illnesses, anthropometric parameters, lipid profile, fasting glucose levels, metabolic syndrome prevalence, serum levels of transaminases, ferritin and iron. Young patients with NAFLD had significantly higher serum levels of triglycerides and a significantly higher prevalence of glucose intolerance, obesity and the metabolic syndrome compared with the elderly patients with NAFLD. NAFLD was a common finding in our group of elderly patients and the prevalence was higher than reported in the general population. In contrast to the well-described association between the metabolic syndrome and NAFLD in the general population, we did not find this association in the aged group. In addition, none of the patients had stigmata of advanced liver disease. These data suggest that NAFLD is a common and benign finding in the elderly population, but is not associated with the metabolic syndrome.


Multi-level chirality in liquid crystals formed by achiral molecules.
Complex materials often exhibit a hierarchical structure with an intriguing mechanism responsible for the 'propagation' of order from the molecular to the nano- or micro-scale level. In particular, the chirality of biological molecules such as nucleic acids and amino acids is responsible for the helical structure of DNA and proteins, which in turn leads to the lack of mirror symmetry of macro-bio-objects. To fully understand mechanisms of cross-level order transfer there is an intensive search for simpler artificial structures exhibiting hierarchical arrangement. Here we present complex systems built of achiral molecules that show four levels of structural chirality: layer chirality, helicity of a basic repeating unit, mesoscopic helix and helical filaments. The structures are identified by a combination of hard and soft x-ray diffraction measurements, optical studies and theoretical modelling. Similarly to many biological systems, the studied materials exhibit a coupling between chirality at different levels.


[Reconstruction of circumferential defect of cervical esophagus with platysma myocutaneous flaps after resection of hypopharyngeal carcinoma].
To show the results of reconstruction of circumferential defect of cervical esophagus with platysma myocutaneous flaps after resection of hypopharyngeal carcinoma in 11 cases. Total larynx, pharynx and cervical esophagus were resected and a permanent tracheostomy was made in the patients, because the cancer had invaded the larynx and cervical esophagus. Two platysma myocutaneous flaps were designed and dissected at both anteror-lateral neck, which was about 3.5-4 cm x 7-10 cm respectively. The flaps were made into a skin tube. The upper edge of the skin tube was sutured to the cut end of the pharynx and the lower sutured to the end of the esophagus. All of the flaps survived and there was no death after operation. There was fistula in 2 cases. The fistula healed after 14 days and 18 days respectively. All cases were normal in swallowing food. The operative methods, advantages and experiences are also descussed.


A new complex polymorphic repeat close to the HLA-A and HLA-E loci.
We describe a complex polymorphic repeat discovered analyzing YAC 225B1, which spans the region between the HLA-A and HLA-E loci. The repeat consists of a variable number of the nucleotide A followed by a variable number of the trinucleotide AAG [(A)n(AAG)n]. Three different alleles were detected with an observed heterozygosity of 0.30.


At Long Last: Olefin Metathesis Macrocyclization at High Concentration.
Macrocyclic lactones, ketones, and ethers can be obtained in the High-Concentration Ring-Closing Metathesis (HC-RCM) reaction in high yield and selectivity at concentrations 40 to 380 times higher than those typically used by organic chemists for similar macrocyclizations. The new method consists of using tailored ruthenium catalysts together with applying vacuum to distill off the macrocyclic product as it is formed by the metathetical backbiting of oligomers. Unlike classical RCM, no large quantities of organic solvents are used, but rather inexpensive nonvolatile diluents, such as natural or synthetic paraffin oils. Moreover, use of a protecting atmosphere or a glovebox is not needed, as the new catalysts are perfectly moisture and air stable. In addition, some other cyclic compounds previously reported as unobtainable by RCM in neat conditions, or in high dilutions even, can be formed with the help of the HC-RCM method.


Particle image correlation spectroscopy (PICS): retrieving nanometer-scale correlations from high-density single-molecule position data.
A new data analysis tool that resolves correlations on the nanometer length and millisecond timescale is derived. This tool, adapted from methods of spatiotemporal image correlation spectroscopy, exploits the high positional accuracy of single-particle tracking. While conventional tracking methods break down if multiple particle trajectories intersect, our method works in principle for arbitrarily large molecule densities and diffusion coefficients as long as individual molecules can be identified. The method is computationally cheap and robust and requires no a priori knowledge about the dynamical coefficients, as opposed to other methods. We demonstrate the validity of the method by Monte Carlo simulations and by application to single-molecule tracking data of membrane-anchored proteins in live cells. The results faithfully reproduce those obtained by conventional tracking. Upon activation, a fraction of the small GTPase H-Ras is confined to domains of <200 nm diameter, which further substantiates the prediction that membrane organization is a determinant in cellular signaling.


Prodigiosin Promotes Nrf2 Activation to Inhibit Oxidative Stress Induced by Microcystin-LR in HepG2 Cells.
Microcystin-LR (MC-LR), a cyanotoxin produced by cyanobacteria, induces oxidative stress in various types of cells. Prodigiosin, a red linear tripyrrole pigment, has been recently reported to have antimicrobial, antioxidative, and anticancer properties. How prodigiosin reacts to reactive oxygen species (ROS) induced by MC-LR is still undetermined. This study aimed to examine the effect of prodigiosin against oxidative stress induced by MC-LR in HepG2 cells. Ros was generated after cells were treated with MC-LR and was significantly inhibited with treatment of prodigiosin. In prodigiosin-treated cells, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2-related phase II enzyme heme oxygenase-1 (HO-1) were increased. Besides, prodigiosin contributed to enhance nuclear Nrf2 level and repressed ubiquitination. Furthermore, prodigiosin promoted Nrf2 protein level and inhibited ROS in Nrf2 knocked down HepG2 cells. Results indicated that prodigiosin reduced ROS induced by MC-LR by enhancing Nrf2 translocation into the nucleus in HepG2 cells. The finding presents new clues for the potential clinical applications of prodigiosin for inhibiting MC-LR-induced oxidative injury in the future.


EEG-Based Person Identification during Escalating Cognitive Load.
With the development of human society, there is an increasing importance for reliable person identification and authentication to protect a person's material and intellectual property. Person identification based on brain signals has captured substantial attention in recent years. These signals are characterized by original patterns for a specific person and are capable of providing security and privacy of an individual in biometric identification. This study presents a biometric identification method based on a novel paradigm with accrual cognitive brain load from relaxing with eyes closed to the end of a serious game, which includes three levels with increasing difficulty. The used database contains EEG data from 21 different subjects. Specific patterns of EEG signals are recognized in the time domain and classified using a 1D Convolutional Neural Network proposed in the MATLAB environment. The ability of person identification based on individual tasks corresponding to a given degree of load and their fusion are examined by 5-fold cross-validation. Final accuracies of more than 99% and 98% were achieved for individual tasks and task fusion, respectively. The reduction of EEG channels is also investigated. The results imply that this approach is suitable to real applications.


[Functional somatic symptoms - a large patient group in need of biopsychosocial competencies].
Functional somatic symptoms are symptoms that cannot be attributed to any known, well-defined physical disease, but may be very disabling for the patient. Functional symptoms may arise from almost any part of the body and they are common in practically all areas of medicine. Arranging the care for these patients poses a substantial challenge for many professionals, with a great degree of distress for the patients and costs for the health care system. A biopsychosocial approach is needed to understand the complex mechanisms involved. There are several evidence-based treatment methods for these disorders, but in Sweden, they have not yet been put into practice on a larger scale. The TERM model, as well as other models, has been developed for practitioners to help the patient to change focus, and engage in treatment options better suited for their condition. Consultation-liaison psychiatry is considered an important part of the health care provided for these patients.


Establishment of a line of human fetal glial cells that supports JC virus multiplication.
Primary cultures of human fetal brain cells were transfected with plasmid DNA pMK16, containing an origin-defective mutant of simian virus 40 (SV40). Several weeks after DNA treatment, proliferation of glial cells was evident in the culture, allowing passage of the cells at low split ratios. Initially, only 10% of the cells demonstrated nuclear fluorescence staining using a hamster tumor antibody to the SV40 T protein. By the sixth passage, however, 100% of the cells reacted positively to the same antibody. During these early passages, the cells designated SVG began growing very rapidly and acquired a homogeneous morphology. Cell division required only low serum concentrations, was not contact-inhibited, and remained anchorage dependent. These characteristics of the SVG cells have been stable through 25 passages or approximately equal to 80 cell generations. The SV40 T protein is continuously produced in the cells and can direct the replication of DNA inserts in the pSV2 vector, determined by in situ hybridization using biotin-labeled DNA probes, which contains the SV40 replication origin. More importantly, SVG cells support the multiplication of the human papovavirus JCV at levels comparable to primary cultures of human fetal glial cells, producing infectious virus as early as 1 week after viral adsorption. Their brain-cell derivation has been established as astroglial, based on their reactivity with a monoclonal antibody to glial fibrillary acid protein and lack of activity with an anti-galactocerebroside antibody, which identifies oligodendroglial cells. The SVG cells represent a unique line of continuous rapidly growing human fetal astroglial cells that synthesizes a replication-proficient SV40 T protein. Their susceptibility to JC virus (JCV) infection obviates a host restriction barrier that limited JCV studies to primary cultures of human fetal brain and thus should allow for more detailed molecular studies of human brain cells and JCV that infects them.


[Clinical efficacy of Bushen Huoxue Anshen therapy in treating perimenopausal sleep disorder with kidney deficiency and blood stasis].
The efficacy and safety of traditional Chinese medicine and acupuncture in the treatment of kidney-deficiency and bloodstasis perimenopausal sleep disorders were evaluated. A total of 67 subjects who completed the study were randomly divided into two groups. The traditional Chinese medicine group was orally given Bushen Huoxue Anshen Fang,and the acupuncture group was given acupuncture treatment. Both groups were treated for three consecutive courses of treatment,with a course of treatment of 30 days. The changes of PSQI score,improved Kupperman score,TCM syndromes,serum sex hormone,coagulation,routine blood and urine,liver and kidney function and electrocardiogram were observed before and after treatment. After treatment,the total effective rates of Chinese medicine group and acupuncture group were similar or respectively 91. 43% and 87. 50%. The scores of PSQI,improved Kupperman and TCM syndromes in both groups decreased significantly( P<0. 05). The effect of improving Kupperman score in TCM group was better than that in acupuncture group( P< 0. 01). The effect of improving PSQI and TCM syndromes was similar to that in acupuncture group. The levels of serum FSH and LH were decreased in both groups( P<0. 05),but with no significant difference between the two groups; the level of serum E2 was increased in both groups,but with no significant difference. Compared with before treatment,PT was increased in traditional Chinese medicine group( P<0. 05),but with no significant difference in APTT,TT and FIB before and after treatment; PT and TT were prolonged in acupuncture group( P<0. 05),but with no significant difference in APTT and FIB before and after treatment. The effect of improving PT and TT in the acupuncture group was better than that in the traditional Chinese medicine group( P<0. 05). The results showed that TCM and acupuncture had similar therapeutic effects on perimenopausal sleep disorder of kidney deficiency and blood stasis type,and were safe and reliable. The mechanism was related to the improvement of serum FSH and E2 levels.


Skin involvement in invasive breast carcinoma: safety of skin-sparing mastectomy.
There is concern about the oncological safety of preserving most of the breast skin in skin-sparing mastectomy (SSM). Most supportive evidence for SSM evaluates the local recurrence rate on clinical follow-up. The skin and 10 mm of the subcutaneous tissue of 30 total mastectomy specimens were studied with a step-serial sectioning technique. The incidence and mode of involvement of the skin and subcutaneous tissue were recorded in detail. This was correlated with other clinical and pathologic parameters. The incidence of skin involvement outside the nipple-areola complex was 20% (6 of 30). This was significantly related to the clinical T stage, site of the tumor, skin tethering, pathologic tumor size, and perineural infiltration. When the effects of both skin and subcutaneous tissue involvement were considered, the incidence of skin-flap involvement outside the nipple-areola complex was 23% (7 of 30). The significant parameters related to skin-flap involvement were skin tethering (75% vs. 15%; P <.05), pathologic tumor size (P <.03), and perineural infiltration (63% vs. 9%; P <.01). It would be oncologically safe to perform SSM in T1 and T2 tumors, because the chance of skin involvement is small. It is safe to preserve the skin overlying the tumor if there is no skin tethering.


Dynamic T-cell changes in peripheral blood and bronchoalveolar lavage after antigen bronchoprovocation in asthmatics.
We previously demonstrated decrease of peripheral blood CD4+ cells 48 to 72 h after antigen-induced bronchoprovocation in asthmatic subjects. To determine if this was accompanied by reciprocal changes in bronchoalveolar lavage (BAL) fluid, we sampled BAL before and 48 h after antigen administration. Peripheral blood lymphocytes (PBL) and BAL T-cell subset composition were examined in eight extrinsic asthmatics during three different weeks. During control week (CW) BAL was preformed at baseline, and PBL subsets were followed for 3 days. During placebo week (PW) a placebo inhalation was followed by a BAL at 48 h and daily PBL for 3 days. Asthmatic attacks were induced by inhalation of a relevant antigen at the start of antigen week (AW) and followed by examining the BAL at 48 h and PBL daily for 72 h. We found that BAL as a stimulus had no effect on T-cell composition of the PBL after the procedure. After induction of an asthmatic attack there was a reduction of PBL CD4+ cells from a baseline mean of 52.6% to 38.8% at 48 h (p less than 0.05). At the same time BAL CD4+ cells increased from 35.6% at PW to 47.3% in AW (p less than 0.05). These data are compatible with specific recruitment of PBL CD4+ cells into the respiratory system in atopic subjects undergoing antigenic bronchoprovocation.


Fluoxetine Modulates the Activity of Hypothalamic POMC Neurons via mTOR Signaling.
Hypothalamic proopiomelanocortin (POMC) neurons are important players in the regulation of energy homeostasis; we previously demonstrated that environmental stimulation excites arcuate nucleus circuits to undergo plastic remodeling, leading to altered ratio between excitatory and inhibitory synaptic contacts on these neurons. The widely used selective serotonin reuptake inhibitor fluoxetine (FLX) is known to affect body weight. On the other hand, FLX administration mimics the effects of environmental stimulation on synaptic plasticity in the hippocampus and cortex. The mammalian target of rapamycin (mTOR) pathway is instrumental in these phenomena. Thus, we aimed at investigating whether and how FLX affects POMC neurons activity and hypothalamic mTOR function. Adult mice expressing green fluorescent protein (GFP) under the POMC promoter were treated with FLX for 3 weeks resulting in diminished body weight. Patch clamp recordings performed on POMC neurons indicate that FLX increases their firing rate and the excitatory AMPA-mediated transmission, and reduces the inhibitory GABAergic currents at presynaptic level. Immunofluorescence studies indicate that FLX increases the ratio between excitatory and inhibitory synaptic contacts on POMC neurons. These changes are associated with an increased activity of the hypothalamic mTOR pathway. Use of the mTOR inhibitor rapamycin blunts the effects of FLX on body weight and on functional and structural plasticity of POMC neurons. Our findings indicate that FLX is able to remodel POMC neurons, and that this may be partly mediated by the mTOR signaling pathway.


Cytokines and adhesion molecules in multiple sclerosis patients treated with interferon-beta1b.
Multiple sclerosis (MS), an inflammatory, demyelinating disease of the central nervous system (CNS), is thought to be caused by a T cell-mediated attack on CNS myelin and axons. Recombinant interferon (IFN)-beta is an established treatment of multiple sclerosis, and is known to reduce the number of disease relapses and the development of irreversible symptoms and signs of disease. The mechanism of action of IFN-beta treatment is, however, not completely understood. Previous studies have suggested major effects on mononuclear cell cytokine production and T cell migration, but results have been inconsistent. We found decreases in CD4 and CD8 T cell expression of the CD49d/VLA-4 molecule, increases in plasma concentrations of soluble vascular cell adhesion molecule (sVCAM-1), and increases in plasma concentrations of tumor necrosis factor and interleukin (IL)-12 p40 chain in patients with MS who were initiated on de novo treatment with IFN-beta1b. We found only minor associations between the different changes induced by IFN-beta1b-treatment. Our findings are consistent with changes in T cell expression of CD49d/VLA-4 and induction of sVCAM-1 as important effects of treatment with IFN-beta1b in multiple sclerosis, whereas the role of changes in TNF and IL-12 p40 chain concentrations is more difficult to interpret.


Treatment of textile effluents with Pistia stratiotes, Eichhornia crassipes and Oedogonium sp.
Phytoremediation by aquatic macrophytes is a promising technology with higher efficiency and no energy consumption. For this purpose, two macrophytes (Pistia stratiotes, Eichhornia crassipes), and an alga (Oedogonium sp.) were used to treat textile effluents rich in COD, BOD, dyes, and heavy metals (Pb, Fe, Cd, Cu). The aim of the study was to focus on comparative phytoremediation potential of these species by their metal removal capability. During 7 days experiment (day 0-day 6), the results showed that Oedogonium sp. was the best for COD removal and decolorization. Eichhornia crassipes was the best for BOD and heavy metal removal and proves more efficient than Pistia stratiotes and Oedogonium sp. However, Pistia stratiotes was found to accumulate more concentrations of Pb and Fe than Eichhornia stratiotes.


Estimation of ambient PM2.5 concentrations in Maryland and verification by measured values.
In 1997, Maryland had no available ambient Federal Reference Method data on particulate matter less than 2.5 microm in aerodynamic diameter (PM23), but did have annual ambient data for PM smaller than 10 microm (PM10) at 24 sites. The PM10 data were analyzed in conjunction with local annual and seasonal zip-code-level emission inventories and with speciated PM2.5 data from four nearby monitors in the IMPROVE network (located in the national parks, wildlife refuges, and wilderness areas) in an effort to estimate annual average and seasonal high PM2.5 concentrations at the 24 PM10 monitor sites operating from 1992 to 1996. All seasonal high concentrations were estimated to be below the 24-hr PM2.5 National Ambient Air Quality Standards (NAAQS) at the sites operating in Maryland between 1992 and 1996. The estimates also indicated that 12 monitor sites might exceed the 3-year annual average PM2.5 NAAQS of 15 microg/m3, but Maryland's air quality shows signs that it has been improving since 1992. The estimates also were compared with actual measurements after the PM2.5 monitor network was installed. The estimates were adequate for describing the chemical composition of the PM2.5, forecasting compliance status with the 24-hr and annual standards, and determining the spatial variations in PM2.5 across central Maryland.


(De)constructing 'basic' benefits: citizens define the limits of coverage.
Many initiatives for covering the uninsured call for "basic" health care coverage, yet few define that term. The Just Coverage project used a computer-based simulation exercise to learn how nearly 800 community members in northern California identified the inclusions and exclusions that would constitute basic coverage. Working with a limited budget, participants distinguished essential from nonessential health care needs, resisted high patient cost sharing, and tolerated tight restrictions on provider choice. They also supported practice guidelines and standards of effectiveness, and they excluded high-cost, low-value interventions. These results reinforce the importance of community input to policymakers.


A 72-Year-Old Female With Bow Hunter Syndrome: A Rare Surgical Approach to C4-5 Vertebral Artery Decompression: 2-Dimensional Operative Video.
Bow hunter syndrome is defined as vertebrobasilar insufficiency due to mechanical occlusion of the vertebral artery during head and neck rotation. In many cases, this is due to osteophyte formation, disc herniation, cervical spondylosis, tendinous bands, or tumors. Symptomatic disease may vary from inducing transient vertigo to posterior circulation stroke. Although digital subtraction angiography is the gold standard in diagnosis, the underlying pathology in bow hunter syndrome may be detected with doppler ultrasound, computed tomography (CT) angiogram, magnetic resonance imaging and angiogram, and diagnostic angiography with dynamic testing. In this case, a 72-yr-old female with a recent right-sided cerebellar stroke underwent operative intervention to decompress the right vertebral artery at C4-C5 in order to relieve symptomatic bow hunter syndrome. Preoperative CT angiogram revealed bilateral significant stenosis of the vertebral arteries at the C4-C5 level with follow-up diagnostic angiogram revealing complete occlusion of the right vertebral artery with the head rotated right (compared to 80% occlusion observed when the patient's head was rotated left). Prior to the procedure, the patient experienced lightheadedness, diaphoresis, dizziness, and a sensation of facial flushing exacerbated by rotating her head to the right. To relieve her symptoms, operative intervention was undertaken. To access the lateral osteophytes originating from the uncovertebral joint, a C4-5 discectomy is utilized. The vertebral artery was decompressed, and a standard anterior cervical fusion was performed. Postoperatively, the patient was stable and was discharged 1 d after surgery. Postoperative imaging showed adequate decompression of the right vertebral artery at the level of C4-5. The authors confirm that they have obtained, prior to submission, a written release from the patient authorizing use of this surgical video to be submitted and published in the journal Operative Neurosurgery, as well as consent to perform the procedure.


[Reliability of the Neuropsychiatric Inventory-Nursing Homes Polish version].
The present study evaluated the reliability of the Neuropsychiatric Inventory-Nursing Homes) (NPI-NH) Polish version. 43 nursing home residents fulfilling the ICD-10 criteria for dementia were assessed with NPI-NH. For analysis of data we used Cronbach's alpha and Spearman's rank correlation coefficients. The internal consistency of the NPI-NH was satisfactory (Cronbach's alpha for the total was 0.25 and only 0.881 for the frequency and severity of symptoms). Spearman's rank correlation coefficients for the test-retest reliability was 0.75 for the total scale results and ranged from 0.40 to 0.85 for each symptom assessed. Interrater reliabilities were 0.86 for the total and from 0.71 to 1.00 for each symptom reported. The preliminary results of the Neuropsychiatric Inventory-Nursing Homes Polish version reliability were all satisfactory.


Relationship among selected neuroendocrine and sleep measures in patients with recurrent depression.
Relationships among cortisol, TSH, and EEG sleep variables were examined in a group of 23 outpatients with recurrent unipolar depression at initial assessment prior to treatment for an acute major depressive episode. Blunted TSH responses were found in 39% of the sample (criteria of less than or equal to 7 microU/ml); cortisol nadir of greater than 2.5 micrograms% was rated in 41% of the group; and a reduced REM latency (less than or equal to 60 min) was measured in 57% of the group. Although almost all patients demonstrated abnormalities in at least one major neuroendocrine or sleep category, this preliminary analysis failed to find significant associations among these multiple biologic variables. Further studies on this so-called lack of association in a larger group of recurrent depressives is indicated. At this point caution is urged in assuming that biologic measures will identify a homogeneous group of severely depressed patients.


A Study of Interaction Effects and Quantum Berezinskii- Kosterlitz-Thouless Transition in the Kitaev Chain.
The physics of the topological state of matter is the second revolution in quantum mechanics. We study the effect of interactions on the topological quantum phase transition and the quantum Berezinskii-Kosterlitz-Thouless (QBKT) transition in topological state of a quantum many-body condensed matter system. We predict a topological quantum phase transition from topological superconducting phase to an insulating phase for the interacting Kitaev chain. We observe interesting behaviour from the results of renormalization group study on the topological superconducting phase. We derive the renormalization group (RG) equation for QBKT through different routes with a few exact solutions along with the physical explanations, wherein we find the existence of two new important emergent phases apart from the two conventional phases of this model Hamiltonian. We also present results of a length-scale dependent study to predict asymptotic freedom like behaviour of the system. We do rigorous quantum field theoretical renormalization group calculations to solve this problem.


Form and function in the acquisition of Korean wh-questions.
In this paper the order in which wh-questions are acquired in the production and comprehension of two Korean children, aged 1;8-2;8 and 1;10-2;10, is analysed and compared with the available cross-linguistic data. Consistencies in acquisition order are hypothesized to be based on universals of cognitive development, which constrain the comprehension and production of wh-forms and influence the order in which mothers introduce them, and on functionally based similarities in the input of form/function pairs across children and languages. Discrepancies in acquisition order are attributed to differences in interactive style across caregivers and children, leading to different input frequencies of particular forms and individual children's selection of different forms for use.


Tritiated photoactivatable analogs of the native human thrombin receptor (PAR-1) agonist peptide, SFLLRN-NH2.
Six photoactivatable analogs of the human thrombin receptor activating peptide (TRAP), SFLLRN-NH2, were synthesized by substituting the photoactive amino acid, p-benzoylphenylalanine (Bpa), into each position of the peptide sequence. Platelet aggregation assays indicated that the peptides with Bpa substitutions at positions 3 to 6 retained agonist activity. These peptides were prepared in tritiated form as potential thrombin receptor photoaffinity labels. The [3H]Bpa-containing analogs were constructed by resynthesizing the peptides with the amino acid, 4-benzoyl-2',5'-dibromophenylalanine (Br2Bpa), and subjecting the purified peptides to Pd-catalyzed tritiodebromination. The radiochemical yields for the reductive tritiation were < 2% for peptides with [3H]Bpa in the third and fourth positions, and between 7 and 16% for the peptides with substitutions at the fifth and sixth positions. The low yields were due to over-reduction of the Bpa carbonyl group and nonspecific degradation during reductive tritiation. This report describes the first use of Br2Bpa for the preparation of tritiated photoactivatable peptides.


Fronto-limbic functioning in children and adolescents with and without autism.
We used neuropsychological tasks to investigate integrity of brain circuits linking orbitofrontal cortex and amygdala (orbitofrontal-amygdala), and dorsolateral prefrontal cortex and hippocampus (dorsolateral prefrontal-hippocampus), in 138 individuals aged 7-18 years, with and without autism. We predicted that performance on orbitofrontal-amygdala tasks would be poorer in the Autism group compared to the Non-Autism group regardless of intellectual level (verbal mental age, VMA) and that performance on dorsolateral prefrontal-hippocampus tasks would be associated primarily with intellectual level. Predicted differences between Autism and Non-Autism groups on orbitofrontal-amygdala tasks were present but greater in individuals with higher VMA. On dorsolateral prefrontal-hippocampus tasks, poorer performance by the Autism compared to the Non-Autism group was found at all VMA levels. Group differences suggest both brain circuits are impaired in autism, but performance on all tasks is also associated with intellectual level.


Laparoscopic-assisted total colectomy with pouch reconstruction.
Whether in adults or children, benign diseases of the colon are ideally suited for laparoscopic-assisted resection. In children, the most frequent diseases leading to colectomy and pull-through include Hirschsprung's disease, ulcerative colitis, and familial polyposis. Laparoscopic proctocolectomy with J-pouch reconstruction is an ideal approach for children and adolescents who are generally stable but suffer from unremitting symptoms of ulcerative colitis. An early experience with this technique at the Children's Hospital in Alabama is described for children with ulcerative colitis.


The Irvingtonian Avifauna of Cumberland Bone Cave, Maryland.
The early and mid-Pleistocene avian communities of North America are best known from the Rocky Mountain region and peninsular Florida. In the Appalachian Mountain region, only a small number of avian bones from mid-latitude cave deposits have been attributed to this time period. Here, I enlarge this record by reporting on bird bones from Cumberland Bone Cave in western Maryland, a well-known locality for large and small Irvingtonian mammals and other vertebrates. The taxa identified encompass ground birds, waterfowl, a hawk, two eagles, a vulture, an owl, a jay, a flycatcher, a junco or sparrow, and a finch. No purely boreal elements are confirmed as part of the avian assemblage, and all of the extant species that are positively or tentatively identified in the assemblage still occur in the region today. An immature bone referred to the Black Vulture (Coragyps atratus (Bechstein)) represents an Irvingtonian breeding record for the species in Maryland. This record occurs at the northern limit of the current breeding range for the genus. Extinct species in the assemblage include the Passenger Pigeon (Ectopistes migratorius (Linnaeus)), a large screech owl (Megascops guildayi (Brodkorb Mourer-Chauviré 1984)), and the large goose, Branta dickeyi Miller 1924. It can be argued that none of these represent the extinction of a phyletic lineage during the Irvingtonian. Based on the broad habitat preferences of modern counterparts of the birds in the assemblage, we can expect that Irvingtonian habitats near the site included mixed forest with mast-producing hardwoods and both early and later successional stages represented. There must have been fluvial, wetland, or lacustrine habitat suitable for waterbirds nearby, and probably also open woodland or grassy savannah areas, suitable for vulture foraging, turkey nesting, and booming by Ruffed Grouse.


First-Principles Study of the Optical Dipole Trap for Two-Dimensional Excitons in Graphane.
Recent studies on excitons in two-dimensional materials have been widely conducted for their potential usages for novel electronic and optical devices. Especially, sophisticated manipulation techniques of quantum degrees of freedom of excitons are in demand. In this Letter we propose a technique of forming an optical dipole trap for excitons in graphane, a two-dimensional wide gap semiconductor, based on first-principles calculations. We develop a first-principles method to evaluate the transition dipole matrix between excitonic states and combine it with the density functional theory and GW+BSE calculations. We reveal that in graphane the huge exciton binding energy and the large dipole moments of Wannier-like excitons enable us to induce the dipole trap of the order of meV depth and μm width. This Letter opens a new way to control light-exciton interacting systems based on newly developed numerically robust ab initio calculations.


Using a Taxonomy to Systematically Identify and Describe Self-Management Interventions Components in Randomized Trials for COPD.
Self-management interventions (SMIs) may improve outcomes in Chronic Obstructive Pulmonary Disease (COPD). However, accurate comparisons of their relative effectiveness are challenging, partly due to a lack of clarity and detail regarding the intervention content being evaluated. This study systematically describes intervention components and characteristics in randomized controlled trials (RCTs) related to COPD self-management using the COMPAR-EU taxonomy as a framework, identifying components that are insufficiently incorporated into the design of the intervention or insufficiently reported. Overall, 235 RCTs published between 2010 and 2018, from a systematic review were coded using the taxonomy, which includes 132 components across four domains: intervention characteristics, expected patient (or caregiver) self-management behaviours, patient relevant outcomes, and target population characteristics. Risk of bias was also assessed. Interventions mainly focused on physical activity (67.4%), and condition-specific behaviours like breathing exercise (63.5%), self-monitoring (50.8%), and medication use (33.9%). Support techniques like education and skills-training, self-monitoring, and goal setting (over 35% of the RCTs) were mostly used for this. Emotional-based techniques, problem-solving, and shared decision-making were less frequently reported (less than 15% of the studies). Numerous SMIs components were insufficiently incorporated into the design of COPD SMIs or insufficiently reported. Characteristics like mode of delivery, intensity, location, and providers involved were often not described. Only 8% of the interventions were tailored to the target population's characteristics. Outcomes that are considered important by patients were hardly taken into account. There is still a lot to improve in both the design and description of SMIs for COPD. Using a framework such as the COMPAR-EU SMI taxonomy may contribute to better reporting and to better informing of replication efforts. In addition, prospective use of the taxonomy for developing and reporting intervention content would further aid in building a cumulative science of effective SMIs in COPD.


Linear Dimensional Changes of Five Interocclusal Recording Materials When Immersed in Two Disinfectants for Different Time Intervals.
In this study, we intend to compare the linear dimensional changes of interocclusal recording media by immersing them in disinfectant solutions at different time intervals. Five interocclusal recording materials were used for this study and were grouped according to material types, namely wax, zinc oxide eugenol impression paste, polyether, polyvinyl siloxane, and bisacryl bite registration material. Each material was manipulated and injected into a stainless steel die. The materials were divided into 5 groups with 5 subgroups of 10 samples with a total of 250 samples. The samples were subjected to immersion in 2% glutaraldehyde and 0.5% sodium hypochlorite each for 30 and 60 minutes. Linear dimensional changes of the samples were tested by measuring the distance between points A and B at different time intervals by means of a stereomicroscope and compared with the control group. Bisacryl showed the least linear dimensional change when immersed in both the solutions. Bisacryl (Luxabite) presented no linear dimensional change at both time intervals as opposed to the other materials, hence, it is most accurate.


Persistent clubfoot deformity following treatment by the Ponseti method.
The Ponseti method of clubfoot correction is now widely practiced worldwide. Initial correction rates are nearly 100%, but subsequent relapses may occur in up to one-third of patients. Very little has been written by anyone other than Dr Ponseti about the characterization and treatment of recurrent clubfoot deformity following use of the Ponseti method. This review paper is the first one which draws together the current literature on the topic.


[Effects of an educational program for the reduction of physical restraint use by caregivers in geriatric hospitals].
The purposes of this study were to develop an educational program to reduce the use of physical restraints for caregivers in geriatric hospitals and to evaluate the effects of the program on caregivers' knowledge, attitude and nursing practice related to the use of physical restraints. A quasi experimental study with a non-equivalent control group pretest-posttest design was used. Participants were recruited from two geriatric hospitals. Eighteen caregivers were assigned to the experimental group and 20 to the control group. The data were collected prior to the intervention and at 6 weeks after the intervention through the use of self-administered questionnaires. Descriptive statistics, X(2) test, Fisher's exact probability test, and Mann-Whitney U test were used to analyze the data. After the intervention, knowledge about physical restraints increased significantly in experimental group compared to the control group. However, there were no statistically significant differences between the groups for attitude and nursing practice involving physical restraints. Findings indicate that it is necessary to apply knowledge acquired through educational programs to nursing practice to reduce the use of physical restraints. User friendly guidelines for physical restraints, administrative support of institutions, and multidisciplinary approaches are required to achieve this goal.


The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors.
Anticancer drugs gain access to solid tumors via the circulatory system and must penetrate the tissue to kill cancer cells. Here, we study the distribution of doxorubicin in relation to blood vessels and regions of hypoxia in solid tumors of mice. The distribution of doxorubicin was quantified by immunofluorescence in relation to blood vessels (recognized by CD31) of murine 16C and EMT6 tumors and human prostate cancer PC-3 xenografts. Hypoxic regions were identified by injection of EF5. The concentration of doxorubicin decreases exponentially with distance from tumor blood vessels, decreasing to half its perivascular concentration at a distance of about 40 to 50 mum, The mean distance from blood vessels to regions of hypoxia is 90 to 140 microm in these tumors. Many viable tumor cells are not exposed to detectable concentrations of drug following a single injection. Limited distribution of doxorubicin in solid tumors is an important and neglected cause of clinical resistance that is amenable to modification. The technique described here can be adapted to studying the distribution of other drugs within solid tumors and the effect of strategies to modify their distribution.


A method for UV-bonding in the fabrication of glass electrophoretic microchips.
This paper presents an approach for the development of methodologies amenable to simple and inexpensive microchip fabrication, potentially applicable to dissimilar materials bonding and chip integration. The method involves a UV-curable glue that can be used for glass microchip fabrication bonding at room temperature. This involves nothing more than fabrication of glue "guide channels" into the microchip architecture that upon exposure to the appropriate UV light source, bonds the etched plate and cover plate together. The microchip performance was verified by capillary zone electrophoresis (CZE) of small fluorescent molecules with no microchannel surface modification carried out, as well as with a DNA fragment separation following surface modification. The performance of these UV-bonded electrophoretic microchips indicates that this method may provide an alternative to high temperature bonding.


Coordinated expression of caspase 8, 3 and 7 mRNA in temporal cortex of Alzheimer disease: relationship to formic acid extractable abeta42 levels.
Recent studies support the hypothesis that Alzheimer disease (AD)-associated amyloid-beta protein (Abeta) may induce apoptosis mediated by a caspase cascade. To assess whether mRNA levels of caspase-3, 7, 8 and 9 change in AD brain, and whether these changes correlate with neurofibrillary tangles, Abeta40 or Abeta42 protein levels or senile plaques, 25 AD and 21 non-demented control brains were examined. Elevated mRNA levels of caspases-7 and 8 measured by a quantitative PCR method were observed in the AD temporal neocortex as compared to the control brains. No significant differences were noticed in levels of caspases-3 or 9 between AD and control brains. Multiple regression analysis demonstrated that, within subjects, the mRNA levels of caspase-8 strongly correlated with both caspse-3 and caspase-7 independently of postmortem interval. Further, there was a strong positive correlation of caspase-8 levels with formic acid extractable Abeta42 levels. Our results suggest that the transcriptional activation of key components of the apoptotic cascade correlates with accumulation of Abeta 42. Thus, a principal caspase pathway from caspase-8 to caspase-3 and/or 7 may contribute to neuron loss in AD brain.


Erotomania variants in dementia.
Erotomania is a delusional syndrome in which an affected individual is convinced that another person loves him or her. Erotomania usually occurs in middle-aged female patients. Only 3 cases have been described in dementia so far. The authors report 2 cases, in Alzheimer's disease and vascular dementia, in which erotomania emerged in the early stage of the underlying disorder. In both cases, erotomania partially responded to antipsychotic treatment. Erotomania may be understood in evolutionary terms as a pathologic deviation of an evolved psychological mechanism relating to mate selection and may therefore account for the typical sex distribution of the syndrome in favor of women and the onset of the disorder, usually during the late reproductive phase. The association of erotomania with dementing disorders may tentatively be interpreted to suggest that such complex psychological mechanisms and behaviors as involved here in "organic" delusions may have distinct, "hard-wired" representations in the human brain.


The genes encoding the type II gonadotropin-releasing hormone receptor and the ribonucleoprotein RBM8A in humans overlap in two genomic loci.
We have cloned and characterized two genomic loci encoding the human type II gonadotropin-releasing hormone (GnRH) receptor and RNA-binding motif protein-8 (RBM8A). In both loci the genes overlap and are in antisense orientation to each other. The locus on chromosome 1 encompasses the type II GnRH receptor gene (GNRHR2), which is composed of three exons. We found transcripts from this gene in a wide range of tissues, but they lacked a methionine initiation codon and had a stop codon in exon 2. In the antisense orientation, this locus contains RBM8A, which consists of six exons and directs the synthesis of an RBM8A protein of 173 or 174 amino acids by alternative splicing. A second locus on chromosome 14 contains pseudogenes of RBM8A and the type II GnRH receptor and probably originated from the chromosome 1 locus by retrotransposition.


Speech perception scores in cochlear implant recipients: An analysis of ceiling effects in the CUNY sentence test (Quiet) in post-lingually deafened cochlear implant recipients.
To evaluate the clinical utility of the City University of New York sentence test in a cohort of post-lingually deafened cochlear implants recipients over time. 117 post-lingually deafened, Australian English-speaking CI recipients aged between 23 and 98 years (M = 66 years; SD = 15.09) were recruited. CUNY sentence test scores in quiet were collated and analysed at two cut-offs, 95% and 100%, as ceiling scores. CUNY sentence scores ranged from 4% to 100% (M = 86.75; SD = 20.65), with 38.8% of participants scoring 95% and 16.5% of participants reaching the 100% scores. The percentage of participants reaching the 95% and 100% ceiling scores increased over time (6 and 12 months post-implantation). The distribution of all post-operative CUNY test scores skewed to the right with 82% of test scores reaching above 90%. This study demonstrates that the CUNY test cannot be used as a valid tool to measure the speech perception skills of post-lingually deafened CI recipients over time. This may be overcome by using adaptive test protocols or linguistically, cognitively or contextually demanding test materials. The high percentage of CI recipients achieving ceiling scores for the CUNY sentence test in quiet at 3 months post-implantation, questions the validity of using CUNY in CI assessment test battery and limits its application for use in longitudinal studies evaluating CI outcomes. Further studies are required to examine different methods to overcome this problem.


Medicago truncatula NIN is essential for rhizobial-independent nodule organogenesis induced by autoactive calcium/calmodulin-dependent protein kinase.
The symbiotic association between legumes and nitrogen-fixing bacteria collectively known as rhizobia results in the formation of a unique plant root organ called the nodule. This process is initiated following the perception of rhizobial nodulation factors by the host plant. Nod factor (NF)-stimulated plant responses, including nodulation-specific gene expression, is mediated by the NF signaling pathway. Plant mutants in this pathway are unable to nodulate. We describe here the cloning and characterization of two mutant alleles of the Medicago truncatula ortholog of the Lotus japonicus and pea (Pisum sativum) NIN gene. The Mtnin mutants undergo excessive root hair curling but are impaired in infection and fail to form nodules following inoculation with Sinorhizobium meliloti. Our investigation of early NF-induced gene expression using the reporter fusion ENOD11::GUS in the Mtnin-1 mutant demonstrates that MtNIN is not essential for early NF signaling but may negatively regulate the spatial pattern of ENOD11 expression. It was recently shown that an autoactive form of a nodulation-specific calcium/calmodulin-dependent protein kinase is sufficient to induce nodule organogenesis in the absence of rhizobia. We show here that MtNIN is essential for autoactive calcium/calmodulin-dependent protein kinase-induced nodule organogenesis. The non-nodulating hcl mutant has a similar phenotype to Mtnin, but we demonstrate that HCL is not required in this process. Based on our data, we suggest that MtNIN functions downstream of the early NF signaling pathway to coordinate and regulate the correct temporal and spatial formation of root nodules.


An Amplifying Cascade of Contact Lens-Related End-of-Day Hyperaemia and Dryness Symptoms.
End-of-day (EOD) symptoms of dryness are too often the cause of poor soft contact lens (SCL) tolerance and abandonment of wear. This review examines an amplifying cascade model for these symptoms, which involve thin tear layers on contact lens (CL) front surfaces being susceptible to evaporation-related short tear breakup (TBU) times. Susceptibility to faster tear loss by evaporation may be exacerbated by other forms of tear instability, such as lipid and mucin deficiencies as well as lens surface soiling. Bulbar and palpebral conjunctival hyperaemia and associated faster evaporation of warmer pre-conjunctival tears could also contribute to evaporative dry eye EOD symptoms. In CL wearers, a cascade of increasing hyperaemia toward the end of day, associated increasing tear temperature and evaporative loss, shortened TBU times (TBUTs) and increased osmolarity, all elevate the risk of higher symptom levels according to progressive amplification of this cascade. Chronic wound healing responses to SCL wear, perhaps related to limbal conjunctival trauma, stem cell deficiency and persistent epitheliopathy, as well as one or more immune responses, may contribute directly or indirectly to inflammation and the amplifying evaporative dryness cascade. A diurnal cycle that culminates in EOD symptoms appears to involve a process of recovery from causal mechanisms after lens removal, which allows lenses to be worn comfortably, at least initially the next day. Possible recovery processes are discussed in this review as are procedures that may help de-amplify an inflammatory, evaporative dryness cascade and alleviate EOD symptoms. Evidence of an accrual of adverse responses over long periods of more or less successful lens wear indicate an incremental failure to recover from EOD hyperaemia. Such incremental failure could help explain how SCL wear too often needs to be abandoned after many years of comfortable wear.


A comparative study of chromosome morphology among the nine annual species of Cicer L.
Thirty-six accessions, representing the full complement of all the nine annual Cicer L. species, viz C. arietinum, C. reticulatum, C. echinospermum, C. pinnatifidum, C. judaicum, C. bijugum, C. chorassanicum, C. yamashitae and C. cuneatum, were subjected to karyotype analysis for the first time in a single comprehensive study. The detailed karyotype of C. chorassanicum was also investigated for the first time. A 12 h cold water pretreatment and 13 min 60 degrees C 1 N HCl hydrolysis confirmed a somatic chromosome number of 2n = 16 in all the species. Within species interchromosomal size variation was observed to be quite large in C. arietinum, C. reticulatum and C. echinospermum, but not in the remaining six species. Individual chromosome size ranged from 3.77 microns in C. echinospermum to 1.32 microns in C. arietinum while the haploid genome length ranged from 20.65 microns in C. echinospermum to 14.92 microns in C. cuneatum. Ample rearrangement of chromatin among chromosomes within a species was implied to have played a role in Cicer genome evolution. The nine species were classified in two groups based on karyotypic similarity, with the first group comprising the inter-crossable species C. arietinum, C. reticulatum and C. echinospermum, while the remaining species forming the second group. The first group species are also genetically close to each other as deduced by other morphological, biochemical and DNA based studies. Circumstantial evidence has lead to the speculation that perhaps karyotypic similarity and interspecific crossability are positively related to each other.


Fluctuating noise drives Brownian transport.
The transport properties of Brownian ratchet were studied in the presence of stochastic intensity noise in both overdamped and underdamped regimes. In the overdamped case, an analytical solution using the matrix-continued fraction method revealed the existence of a maximum current when the noise intensity fluctuates on intermediate timescale regions. Similar effects were observed for the underdamped case by Monte Carlo simulations. The optimal time-correlation for Brownian transport coincided with the experimentally observed time-correlation of the extrinsic noise in Escherichia coli gene expression and implied the importance of environmental noise for molecular mechanisms.


Meeting existential needs in palliative care--who, when, and why?
Existential concerns are of great importance to those who are terminally ill. However, these matters are seldom brought into focus in the care of the patients. One crucial question is: who should take care of the patient's existential needs? The present study focuses on possible alternatives for dealing with such concerns, including the staff or significant others. A focus group was set up to gather and examine reflections from people having first-hand experience with this problem. The results of this study indicate that, with regard to existential needs, there are no general solutions. On the other hand, under specific conditions, several solutions can be satisfactory. Possible ways of handling the problem are suggested. Moreover, staff should pay attention to constraints operating in care settings, such as continuity and time, competent organization, and personal prerequisites.


Control of adipocyte differentiation in different fat depots; implications for pathophysiology or therapy.
Adipocyte differentiation and its impact on restriction or expansion of particular adipose tissue depots have physiological and pathophysiological significance in view of the different functions of these depots. Brown or "beige" fat [brown adipose tissue (BAT)] expansion can enhance thermogenesis, lipid oxidation, insulin sensitivity, and glucose tolerance; conversely expanded visceral fat [visceral white adipose tissue (VAT)] is associated with insulin resistance, low grade inflammation, dyslipidemia, and cardiometabolic risk. The largest depot, subcutaneous white fat [subcutaneous white adipose tissue (SAT)], has important beneficial characteristics including storage of lipid "out of harms way" and secretion of adipokines, especially leptin and adiponectin, with positive metabolic effects including lipid oxidation, energy utilization, enhanced insulin action, and an anti-inflammatory role. The absence of these functions in lipodystrophies leads to major metabolic disturbances. An ability to expand white adipose tissue adipocyte differentiation would seem an important defense mechanism against the detrimental effects of energy excess and limit harmful accumulation of lipid in "ectopic" sites, such as liver and muscle. Adipocyte differentiation involves a transcriptional cascade with PPARγ being most important in SAT but less so in VAT, with increased angiogenesis also critical. The transcription factor, Islet1, is fairly specific to VAT and in vitro inhibits adipocyte differentiation. The physiological importance of Islet1 requires further study. Basic control of differentiation is similar in BAT but important differences include the effect of PGC-1α on mitochondrial biosynthesis and upregulation of UCP1; also PRDM16 plays a pivotal role in expression of the BAT phenotype. Modulation of the capacity or function of these different adipose tissue depots, by altering adipocyte differentiation or other means, holds promise for interventions that can be helpful in human disease, particularly cardiometabolic disorders associated with the world wide explosion of obesity.


Age, creatinine, and ejection fraction (ACEF) score as predictive values for late non-valvular atrial fibrillation recurrence after radiofrequency ablation.
The clinical risk factors associated with late recurrence in patients with non-valvular atrial fibrillation (AF) (NVAF) undergoing radiofrequency catheter ablation (RFCA) remain unknown. Furthermore, the current prognostic risk score system is commonly used in such patients as a noninvasive method to assess late AF recurrence. According to recent research, the Age, creatinine, and ejection fraction (ACEF) score is a useful risk score for cardiovascular morbidity and mortality. As a result, we hypothesized that pre-ablation ACEF score could be used to assess late recurrence in patients with NVAF. We included 325 NVAF patients undergoing RFCA. During a median follow-up period of 12 months, patients with late AF recurrence had higher ACEF scores (P < .001). The pre-ablation ACEF score was a risk factor for late AF recurrence after RFCA (P = .027). The ACEF score was a predictor of late AF recurrence after RFCA, with an AUC of 0.624 (P = .001). Moreover, the AUC of left atrial diameter (LAD) was 0.7 (P < .001), which was higher than the ACEF score, but no significant difference was found (P = .104). The ACEF score was positively correlated with LAD, advanced age, and B-type natriuretic peptide. In patients with NVAF, the pre-ablation ACEF score is a valuable risk score for assessing late AF recurrence after RFCA, as with LAD.


Competencies for quality spiritual care in palliative care in Latin America: from the Spirituality Commission of the Latin American Association for Palliative Care.
Spiritual care is an essential part of quality palliative care. However, the literature regarding spiritual care competencies in Latin America is limited. Herein we propose the basic quality standards for spiritual care in palliative care according to best professional practices and provide a common vocabulary and required competencies for quality clinical spiritual care. Both elements, quality standards and a common vocabulary, are part of an essential step implementing continuous educational initiatives among interdisciplinary palliative care teams in Latin America. Members of the Spirituality Commission of the Latin American Association for Palliative Care and three members of independent professional palliative care organizations identified and reviewed our proposed spiritual care competencies and created a consensus document describing the competencies for general spiritual care. In the context of palliative care in Latin America, general spiritual care is provided by members of interdisciplinary teams. We proposed six competencies for high-quality general spiritual care and their observable behaviors that every member of an interdisciplinary palliative care team should have to provide quality clinical spiritual care in their daily practice: (I) personal, spiritual, and professional development; (II) ethics of spiritual care; (III) assessment of spiritual needs and spiritual care interventions; (IV) empathic and compassionate communication; (V) supportive and collaborative relationships among the interdisciplinary team; and (VI) inclusivity and diversity.


ICD-10-CM-Based Definitions for Emergency Department Opioid Poisoning Surveillance: Electronic Health Record Case Confirmation Study.
Valid opioid poisoning morbidity definitions are essential to the accuracy of national surveillance. The goal of our study was to estimate the positive predictive value (PPV) of case definitions identifying emergency department (ED) visits for heroin or other opioid poisonings, using billing records with International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. We examined billing records for ED visits from 4 health care networks (12 EDs) from October 2015 through December 2016. We conducted medical record reviews of representative samples to estimate the PPVs and 95% confidence intervals (CIs) of (1) first-listed heroin poisoning diagnoses (n = 398), (2) secondary heroin poisoning diagnoses (n = 102), (3) first-listed other opioid poisoning diagnoses (n = 452), and (4) secondary other opioid poisoning diagnoses (n = 103). First-listed heroin poisoning diagnoses had an estimated PPV of 93.2% (95% CI, 90.0%-96.3%), higher than secondary heroin poisoning diagnoses (76.5%; 95% CI, 68.1%-84.8%). Among other opioid poisoning diagnoses, the estimated PPV was 79.4% (95% CI, 75.7%-83.1%) for first-listed diagnoses and 67.0% (95% CI, 57.8%-76.2%) for secondary diagnoses. Naloxone was administered in 867 of 1055 (82.2%) cases; 254 patients received multiple doses. One-third of all patients had a previous drug poisoning. Drug testing was ordered in only 354 cases. The study findings suggest that heroin or other opioid poisoning surveillance definitions that include multiple diagnoses (first-listed and secondary) would identify a high percentage of true-positive cases.


Spatially resolved protein hydrogen exchange measured by matrix-assisted laser desorption ionization in-source decay.
Mass spectrometry has become a powerful tool for measuring protein hydrogen exchange and thereby reveal the structural dynamics of proteins in solution. Here we describe the successful application of a matrix-assisted laser desorption ionization (MALDI) mass spectrometry approach based on in-source decay (ISD) to measure spatially resolved amide backbone hydrogen exchange. By irradiating deuterated protein molecules in a crystalline matrix with a high laser fluence, they undergo prompt fragmentation. Spatially resolved deuteration levels are readily obtained by mass analysis of consecutive fragment ions. MALDI ISD analysis of deuterated cytochrome c yielded an extensive series of c-fragment ions which originate from cleavage of nearly all N-C(α) bonds (Cys17 to Glu104) allowing for a detailed analysis of the deuterium content of the backbone amides. While hydrogen scrambling can be major concern when using mass spectrometric fragmentation to obtain detailed information on protein hydrogen exchange, we show that the level of hydrogen scrambling in our MALDI ISD measurements is negligible and that the known dynamic behavior of cytochrome c in solution is accurately reflected in the deuterium contents of the fragment ions. The developed method combines several attractive features from a practical point of view as it is simple to perform and it readily provides a detailed mapping of the dynamic structure of a protein in solution.


An uncommon case of synchronous gastric and colonic metastases from breast cancer.
Invasive lobular carcinoma is the second-most-common subtype of breast cancer. It is characterized by a different metastatic pattern with a propensity to metastasize to pleura, peritoneum, gastrointestinal tract, and ovary. We report a woman with known metastatic disease outside the gastrointestinal tract who had endoscopy and colonoscopy for gastrointestinal symptoms. Extensive metastases were found in the stomach and colon with a diffuse infiltration of signet ring-like cells at histology and immunohistochemical findings consistent with breast carcinoma. To the best of our knowledge, this is the first report of such a case from Africa.


Tumor Immune Microenvironment Components and Checkpoint Molecules in Anaplastic Variant of Diffuse Large B-Cell Lymphoma.
Anaplastic diffuse large B-cell lymphoma(A-DLBCL) is a rare morphological subtype characterized by the presence of polygonal, bizarre-shaped tumor cells. Our previous research found that A-DLBCL displays many genetic alterations and biological features that differ greatly from those of ordinary DLBCL. However, the status of tumor immune microenvironment components and checkpoint molecules in A-DLBCL remains unclear. Thirty A-DLBCL patients were enrolled to study tumor immune microenvironment components and checkpoint molecules and their associations with clinicopathological features and prognosis. Patients with A-DLBCL presented higher expression of PD-L1 (40% vs 10%, P=0.004) than patients with ordinary DLBCL. FISH analysis showed that extra copies of PD-L1 were more frequent in A-DLBCL cases than in ordinary DLBCL cases (23.3% vs 4.0%, P=0.001). The numbers of PD-1+ TILs (tumor infiltrating lymphocytes) and CD8+T cells were significantly lower in A-DLBCL versus ordinary DLBCL. In contrast, the numbers of GATA3+ Th2 cells, FOXP3+ Tregs and CD33+ myeloid-derived suppressor cells (MDSCs) were significantly higher in A-DLBCL than in ordinary DLBCL. The associations between clinicopathological features and tumor immune microenvironment cell frequency were analyzed in A-DLBCL patients. Briefly, the number of PD-1+ TILs was lower and the number of CD33+ MDSCs was higher in patients with mutated TP53 compared to those with wild-type TP53. The number of FOXP3+ Tregs was much lower in patients with a noncomplete response (CR) to chemotherapy than in those with a complete response. The number of CD8+ T cells showed a decreasing trend in patients with high International Prognostic Index (IPI) scores and in those with concurrent MYC and BCL2 and/or BCL6 abnormalities. Univariate survival analysis showed that patients with PD-L1+, mPD-L1+(PD-L1+ nonmalignant stromal cells) or mPD-L1+ status had a significantly poorer overall survival (OS) than those with PD-L1- status. An increase in the number of CD3+ T cells, FOXP3+ Treg cells and T-bet+ Th1 cells was significantly associated with prolonged OS in patients with A-DLBCL. Our study suggests that A-DLBCL displays a distinct pattern of tumor immune microenvironment components and checkpoint molecules that distinguish it from ordinary DLBCL. The analysis of tumor immune microenvironment components and checkpoint molecules could help in predicting the prognosis of A-DLBCL patients and determining therapeutic strategies targeting the tumor immune microenvironment.


microRNA-203 functions as a natural Ras inhibitor in hepatocellular carcinoma.
microRNA-203 (miR203) plays an important role in the formation and development of multiple types of cancers. However, its role in hepatic carcinogenesis has not been well studied. Mitogen-activated protein kinase signaling is known to be activated in hepatocellular carcinoma (HCC), but there is a lack of effective drugs targeting this pathway for HCC treatment. In this study, we investigated the role of miR203 in HCC and the underlying mechanism. We found that miR203 was significantly downregulated in HCC cell lines and patient tissues compared with a hepatocyte cell line (L02) or normal liver tissues. Restoration of miR203 inhibited HCC cell growth and induced cell cycle arrest and apoptosis. In primary and xenograft HCC mouse models, miR203 also significantly blocked HCC growth. Bioinformatic analysis indicated that miR203 directly binds to the 3'UTR of NRas mRNA, resulting in decreased expression of NRas and inactivation of mitogen-activated protein kinase (MAPK) signaling. Activation of MAPK signaling by ectopic NRas expression rescued the cell proliferation blocked by miR203. Together, our findings illustrate the fundamental role of miR203 as a natural inhibitor of RAS/MAPK signaling in hepatic carcinogenesis in vitro and in vivo. In light of the critical and universal activation of the MAPK pathway in HCC, miR203 has the potential to serve as a nucleotide drug for the treatment of HCC with activated MAPK signaling.


[Rescue helicopter services for emergency treatment at the scene of the accident (author's transl)].
During the last three years 3639 emergencies were dealt with using the rescue helicopter "Christoph 4" in Hannover. Of these, 89.3% were primary flights to the scene of the accident to give qualified first aid by a medical team. The average distance to the scene of the accident was 20.8 km with an average flight time of 8.5 min. 2688 patients were treated by the helicopter crew. 89.8% of the patients had injuries of a severity of NACA (National Commitee for Aeronautics) 3 and more. Intubation and artificial respiration was carried out on 293 occasions. Shock treatment with blood substitute was given in 1593 cases. 30 resuscitations at the scene of the accident were successful.


Effects of a program to strengthen general practice care on hospitalisation rates: a comparative observational study.
To determine the effect of a large-scale program to strengthen general practice on hospitalisation rates. This observational study compared enrolled patients in the program and a sample of non-participating patients from non-participating GPs in the same geographic area in Germany. Key components of the program are: prompt access to care, comprehensiveness, continuity, empanelment, data-driven quality improvement, computerized decision support, and additional reimbursement of general practices. The outcomes in this study were hospitalisation, rehospitalisation, and avoidable hospital admission up to four years after patient inclusion. Poisson regression models and generalized estimating equations were used to estimate intervention effects. In the baseline year, 19.1% were hospitalised and 13.6% had a potentially avoidable hospitalisation, 14.5% were rehospitalised within 4 weeks. Across the four observed years, yearly hospitalisations were 9.8 to 14.9% lower in enrolled patients, yearly re-hospitalisations were 5.3 to 11.5% lower, and yearly avoidable hospitalisations were 6.8 to 8.6% lower compared to the control cohort (all differences were statistically significant). The trend in the between-group difference for hospitalisations and re-hospitalisations increased, while it remained stable for avoidable hospitalisations. This study provides strong indications for the positive impact of strong general practice care on population outcomes. Key points A program to strengthen general practice in Germany comprised of prompt access to care, comprehensiveness, continuity, empanelment, data-driven quality improvement, computerized decision support, and additional reimbursement of general practices. Patients who remained in the program during 4 years had increasingly lowered rates of hospitalisation and rehospitalisation compared to a control group of patients. Avoidable hospitalisations were also lower, but no trend of further lowering was found. This might suggest a ceiling effect to impact of strong general practice on hospitalisations.