From initiation to cessation: Turning points and coping resources in the breastfeeding experience of first-time mothers.
While most mothers initiate breastfeeding, many do not continue for recommended durations. This study aimed to understand the gap between breastfeeding initiation and duration through an in-depth exploration of first-time mothers' breastfeeding experiences. Contextual factors that may facilitate or deter breastfeeding maintenance were explored by identifying common turning points (significant events or periods promoting a change in thoughts/behaviors or facilitating maintenance) described by mothers with varied breastfeeding durations. In semistructured interviews conducted from March to June 2015, twenty-eight first-time mothers in Iowa were asked to describe their breastfeeding experiences from initiation through cessation. Using thematic analysis, seven turning points, consistent across varied durations and experiences were identified: breastfeeding problems, the unknowns, recurring stressors, living new life with baby, reentering social roles, special occasions, and letting go. Turning points were usually associated with stressful situations, and mothers described intrapersonal (e.g., determination) and interpersonal (e.g., social support) coping resources as facilitators of breastfeeding maintenance. These findings highlight contextual factors that may trigger turning points, representing critical intervention periods, and the importance of enhancing support networks. Interventions to facilitate longer breastfeeding durations should consider key turning points and availability of coping resources to determine strategies that best fit the mother at each point.


The zebrafish heart regenerates after cryoinjury-induced myocardial infarction.
In humans, myocardial infarction is characterized by irreversible loss of heart tissue, which becomes replaced with a fibrous scar. By contrast, teleost fish and urodele amphibians are capable of heart regeneration after a partial amputation. However, due to the lack of a suitable infarct model, it is not known how these animals respond to myocardial infarction. Here, we have established a heart infarct model in zebrafish using cryoinjury. In contrast to the common method of partial resection, cryoinjury results in massive cell death within 20% of the ventricular wall, similar to that observed in mammalian infarcts. As in mammals, the initial stages of the injury response include thrombosis, accumulation of fibroblasts and collagen deposition. However, at later stages, cardiac cells can enter the cell cycle and invade the infarct area in zebrafish. In the subsequent two months, fibrotic scar tissue is progressively eliminated by cell apoptosis and becomes replaced with a new myocardium, resulting in scarless regeneration. We show that tissue remodeling at the myocardial-infarct border zone is associated with accumulation of Vimentin-positive fibroblasts and with expression of an extracellular matrix protein Tenascin-C. Electrocardiogram analysis demonstrated that the reconstitution of the cardiac muscle leads to the restoration of the heart function. We developed a new cryoinjury model to induce myocardial infarction in zebrafish. Although the initial stages following cryoinjury resemble typical healing in mammals, the zebrafish heart is capable of structural and functional regeneration. Understanding the key healing processes after myocardial infarction in zebrafish may result in identification of the barriers to efficient cardiac regeneration in mammals.


Dietary bioactive compounds and their health implications.
There is strong scientific evidence suggesting that regular consumption of fruits and vegetables is negatively associated with risk of developing chronic diseases. The 2010 Dietary Guidelines for Americans recommend at least 9 servings of fruits and vegetables a day based on a 2000 kcal diet. However, the average person in the United States consumes 3.6 servings of fruits and vegetables per day. In order to achieve the goal of at least 9 servings, we should continue educating Americans about the health benefits of fruits and vegetables and recommend consumers to eat a wide variety of fruits and vegetables. The key is to increase the amount up to 9 to 13 servings of fruits and vegetables a day in all forms. Fresh, cooked, and processed fruits and vegetables including frozen and canned, 100% fruit juices, 100% vegetable juices, and dried fruits are all considered as servings of fruits and vegetables. A wide variety of fruits and vegetables provide a range of nutrients and different bioactive compounds including phytochemicals (phenolics, flavonoids, and carotenoids), vitamins (vitamin C, folate, and provitamin A), minerals (potassium, calcium, and magnesium), and fibers. More and more evidence suggests that the health benefits of fruits and vegetables are attributed to the additive and synergistic interactions of the phytochemicals present in whole foods by targeting multiple signal transduction pathways. Therefore, consumers should obtain nutrients and bioactive compounds from a wide variety of whole foods for optimal nutrition and health well-being, not from expensive dietary supplements.


Ethnic and familial factors in early child development.
A sample (1,031 individuals) of infants born at varying gestational ages (26-42 weeks) and birth weights (860-4,750 g) was used in a study of 5 developmental traits appearing during the first 2 years of life: the ages at which a child could turn over, sit up, stand up, walk without support, and eruption of the first tooth. The mean age of attaining each developmental milestone was not significantly different among the Jewish ethnic groups represented in the sample. In addition, the following potential predictor variables were evaluated: the infant's weight, length, and head circumference at birth and at 1.5 years of age; maternal body weight, height at the infant's birth, and number of miscarriages; family size and parental occupation. Only few variables showed significant effects with developmental milestone; birth weight made the greatest contribution. Highly significant intraclass and Pearson correlations were observed between siblings in the ages of appearance of each of the 5 developmental milestones. The correlations ranged between 0.30 and 0.53 for the total group, after adjusting for all significant covariates. © 1992 Wiley-Liss, Inc.


[Future trends in the development of endoscopic studies of digestive tract organs].
Presented in the paper are new promising endoscopic devices for examinations of the digestive tract organs. Special attention is paid to one of the important directions, the development of endoscopes for peroral examinations of hepatic passages, the intraoperation choledochoscopy. In order to improve the diagnostic capabilities of the small intestine endoscopy the development of a long controllable endoscope is advisable. A new trend in endoscopy, the endoscopic microscopy, is noted to be of great research importance. This trend calls for creation of not only new methodologic basis but of new types of endoscopes as well. They should be capable of detecting changes in both structural formations and cell structures.


Transanterior perforating substance approach to the thalamomesencephalic junction.
Lesions in the thalamomesencephalic junction can be reached via an anterolateral approach, interhemispheric approach, transcortical (parieto-occipital lobule) approach, subtemporal approach, supracerebellar approaches, or transsylvian-insular approach. We now describe a new approach, a transanterior perforating substance approach, to this territory. A 33-year-old man with progressive right arm tremors, mild hemiparesis, and a cavernous malformation of the thalamomesencephalic junction was followed for 5 years. Because of clinical progression, he underwent a left orbitozygomatic approach to the cavernous malformation, which could not be accessed because of a high-riding basilar artery. Hence, a new transsylvian corridor of exposure was developed using frameless neuronavigation. The trajectory, which was dorsal to M1, led through the perforating branches of M1. Care was taken to avoid violating any arterial perforators. To reach the lesion, a small opening into the brain was created near the optic tract. The cavernous malformation was resected totally. Postoperatively, the patient's tremors were cured. No visual deficits were encountered. Imaging showed a small ischemic stroke in the basal ganglia likely related to manipulation of a perforator. Initially, his hemiparesis worsened, but it improved significantly within 10 months with only a moderate decrease in strength. The transanterior perforating substance approach effectively allowed access to the thalamomesencephalic junction and was associated with significant morbidity. However, the safety of the approach needs further validation. Neuronavigation is indicated to choose the most direct trajectory through the M1 perforators. Tractography may help protect the optic tract.


Adeno-associated virus infection and cervical neoplasia: is there a protective role against human papillomavirus-related carcinogenesis?
The aim of this study was to investigate whether adeno-associated virus (AAV) infection can be associated with a reduced risk for human papillomavirus (HPV)-related cervical neoplasia. The study was a prospective descriptive analysis of the prevalence of AAV and HPV DNA sequences in women with and without neoplastic cervical lesions. The study population consisted of 373 women aged 19-65 years old who attended the outpatient colposcopy clinic of a tertiary university center. Cytologic and colposcopic examination, as well as AAV-DNA and HPV-DNA detection and typing were performed in all individuals; biopsies (histological verification) and treatment were performed as appropriate. Women with normal Papanicolaou smear test and normal colposcopic findings served as the control group (n=280). Those with histologically proven cervical pathology were categorized into three groups: (a) women with grade 1 cervical intraepithelial neoplasia (CIN 1) (n=31), (b) women with grades 2 and 3 cervical intraepithelial neoplasia (CIN 2, 3) (n=45), and (c) women with invasive cervical cancer (n=17). AAV infection was confirmed in 63 (16.80%) women. AAV detection was not statistically different between HPV (-) and HPV (+) controls (P=0.06). In the disease groups, however, the prevalence of AAV was statistically significantly lower in the HPV (+) relative to the HPV (-) patients (P=0.0009, P=0.00001, and P=0.0225, for women with low-grade cervical lesions, for women with high-grade cervical lesions, and for women with cervical cancer, respectively). No difference in the prevalence of AAV DNA between HPV-positive and HPV-negative unaffected (control) women is observed. Nevertheless, our results indicate that HPV-infected individuals are less likely to develop cervical neoplasia if AAV is present, and that AAV probably demonstrates a protective role against the pathogenic consequences of HPV infection.


Multiplicity: discussion points from the Statisticians in the Pharmaceutical Industry multiplicity expert group.
In May 2012, the Committee of Health and Medicinal Products issued a concept paper on the need to review the points to consider document on multiplicity issues in clinical trials. In preparation for the release of the updated guidance document, Statisticians in the Pharmaceutical Industry held a one-day expert group meeting in January 2013. Topics debated included multiplicity and the drug development process, the usefulness and limitations of newly developed strategies to deal with multiplicity, multiplicity issues arising from interim decisions and multiregional development, and the need for simultaneous confidence intervals (CIs) corresponding to multiple test procedures. A clear message from the meeting was that multiplicity adjustments need to be considered when the intention is to make a formal statement about efficacy or safety based on hypothesis tests. Statisticians have a key role when designing studies to assess what adjustment really means in the context of the research being conducted. More thought during the planning phase needs to be given to multiplicity adjustments for secondary endpoints given these are increasing in importance in differentiating products in the market place. No consensus was reached on the role of simultaneous CIs in the context of superiority trials. It was argued that unadjusted intervals should be employed as the primary purpose of the intervals is estimation, while the purpose of hypothesis testing is to formally establish an effect. The opposing view was that CIs should correspond to the test decision whenever possible.


Lumbar Radiofrequency Ablation Interfering With S1 Dorsal Root Ganglion Stimulation Systems: Experience From Two Cases.
Dorsal root ganglion stimulation (DRG-S) has emerged as a treatment for complex regional pain syndrome (CRPS) of the lower extremities, and recent small studies are demonstrating its potential efficacy in pain syndromes that are traditionally considered nociceptive in nature, such as axial low back pain. While improvements in neuromodulation technology have been substantial over the past decade, with DRG-S systems patients occasionally require additional interventional pain treatments for treatment of pain from other sources. Radiofrequency ablation (RFA) of medial branch nerves innervating the facet joints is an accepted therapy for pain arising from the facet joints. We describe 2 cases from the same practice where we observed similar phenomena while performing a 2-needle monopolar lumbar RFA in patients with a DRG-S system implanted with leads positioned bilaterally at the S1 DRGs. Initiation of RFA resulted in motor activation and discomfort in an S1 distribution in the legs in both individual cases. RFA can interfere with implanted DRG-S systems, resulting in overstimulation with motor recruitment. Specific anatomical considerations and device settings that may prevent interference are discussed.


Stathmin expression in pheochromocytomas, paragangliomas, and in other endocrine tumors.
Pheochromocytomas are neuroendocrine tumors confined to the adrenal glands, and malignant pheochromocytomas can spread to various sites including the liver, lung, and bones. Paragangliomas occur in numerous locations in the body, so assessment of metastatic disease is more challenging, as patients with familial syndromes often have multiple, possibly independent paragangliomas. The most reliable criterion for malignancy in pheochromocytomas and paragangliomas is metastatic disease. Because there are few immunohistochemical markers that are useful in the diagnosis of malignancy in pheochromocytomas and paragangliomas before they metastasize, more markers are needed to characterize these tumors. Stathmin is a widely expressed 17-kDa cytoplasmic, microtubule destabilizing and sequestering phosphoprotein that is important in cell motility and cancer cell metastasis. It is upregulated in various malignancies. We examined stathmin expression in tissues from patients with pheochromocytomas (n = 48), malignant pheochromocytomas (n = 28), paragangliomas (n = 42), and malignant paragangliomas (n = 21) by immunohistochemistry using tissue microarrays (TMA) with a polyclonal antibody against stathmin. A series of other endocrine tissues and tumors (n = 70) were also examined for stathmin expression. Stathmin was more highly expressed in pheochromocytomas compared to normal adrenals, a finding confirmed by Western blot. There was higher expression of stathmin by immunohistochemical staining in malignant pheochromocytomas compared to pheochromocytomas without metastasis when analyzed by maximal staining (p = 0.012). Stathmin was present in a wide variety of endocrine tumors and was most highly expressed in rapidly proliferating tumors including anaplastic thyroid carcinomas, Merkel cell carcinomas of the skin and small cell carcinomas of the lung. These results show that stathmin is expressed at higher levels in more rapidly proliferating endocrine tumors. However, it is probably not useful as a stand-alone marker to determine malignancy in pheochromocytomas for individual tumors.


SE-ResNet-ViT Hybrid Model for Noise Classification in Adhesive Patch-type Wearable Electrocardiographs.
In purpose of screening arrhythmia, wearable adhesive patch-type electrocardiographs that can measure electrocardiogram continuously for 14 days have been replacing the 24-hour Holter monitor. The reason for that is the patch-type electrocardiograph being smaller and lighter than the Holter monitor, making it more convenient for patients to coexist with in their daily lives. However, this type of electrocardiograph generates a lot of noise signals due to movements during various physical activities and extended wear time.While analyzing electrocardiograms automatically using software, noise signals make the analysis difficult and they may be misclassified as arrhythmia signals. These misclassified signals require a lot of effort and time from clinical technicians to reclassify them as noise. To resolve this problem, this study hypothesized that a deep learning algorithm could be used to screen noise signals. We used 7,467 noise signals and 15,638 ECG signals collected from arrhythmia patients and healthy people. The signals were divided into 10 seconds segments and labeled by cardiologists. We split the data into training and test datasets, ensuring no patient overlap.A hybrid noise classification model, Squeeze and Excitation - Residual Network - Vision Transformer (SE-ResNet-ViT) was developed using the training and validation datasets with an 8:2 ratio. We evaluated the performance of the model using a test dataset. The best F1 score was 0.964. The proposed model can effectively screen for noise signals and potentially reducing the time and effort required by clinical technicians.


Using the Blood Coagulation Factors as a Predictor Component of the Occupational Vibration Exposure.
Exposure to hand-arm vibrations higher than permissible standard rates can have destructing effects on workers' health. Pneumatic hammers are among the tools that are used in civil and industrial projects, transferring high vibration acceleration to the workers. This study has considered the probable effects of hand-arm vibrations on the performance of blood coagulation factors in the workers using this tool and exposed to high vibration acceleration. Five new workers without any experience in exposure with hand-arm vibrations were selected for this interventional study. Blood sample was taken from each worker before they started working for the required analysis. Sampling was repeated in two other stages in 2-month intervals from the first sampling, whereas the workers were then experienced in working with pneumatic hammers. Measuring the vibration of the pneumatic hammer was done according to ISO 28927-10 standard. The point of measuring the vibration acceleration was selected close to the hand, in accordance with the standard. Regarding the exposure time of the workers, the amount of vibration acceleration was obtained 15.54 m/s2. Activated partial thromboplastin times of four samples in the second and third stages have shown increases in comparison to the first stage in that respect. On the other hand, a number of red blood cells, white blood cells, and platelets did not show a consistent trend in the three stages. The considered samples showed longer time for blood coagulation as compared to the reference time. Thus, it can be concluded that the main reason is the acceleration in three different coordinate axes of x, y, and z. Hence, the values beyond permissible standard rate of hand-arm vibration in 8 h shifts affect the blood parameters, among which the considered coagulation parameters in this study showed more tangible changes in that respect.


Intracranial Squamous Cell Carcinoma Arising From a Cerebellopontine Angle Epidermoid Cyst Remnant Four Decades After Partial Resection.
Intracranial epidermoid cysts are benign lesions that typically remain asymptomatic; however, although histopathologically benign, these cysts can rarely undergo malignant transformation into squamous cell carcinoma. Primary intracranial squamous cell carcinoma carries a poor prognosis as optimal treatment modalities remain unclear due to their low incidence. Here, we present a case of a cerebellopontine angle epidermoid cyst remnant that underwent malignant transformation into squamous cell carcinoma 40 years after partial resection. To our knowledge, this case establishes the longest time interval to date for an intracranial epidermoid cyst to undergo malignant transformation. We also review the relevant literature and discuss recent retrospective clinical studies that have analyzed the effect of multimodal treatment approaches on survival outcomes in patients with these lesions.


Taurine acts on a subclass of GABAA receptors in mammalian brain in vitro.
Taurine, an inhibitory amino acid, potently acts on a subclass of gamma-aminobutyric acid type A (GABAA) receptors. Taurine competitively inhibits [3H]muscimol binding to purified GABAA receptors with an average IC50 value of 50 microM, and enhances [3H]flunitrazepam binding to GABAA-linked benzodiazepine receptors with an EC50 of about 10 microM and with maximal extent lower than that for GABA. Taurine shows variable affinities (low micromolar to near millimolar) for muscimol binding sites in different brain regions as measured by autoradiography. The taurine-sensitive GABA sites are enriched in dentate gyrus, substantia nigra, cerebellum molecular layer, median thalamic nuclei, and hippocampal field CA3; these areas are also enriched in mRNA for the GABA-binding beta 2 subunit subtype. Taurine shows differential affinities for the multiple muscimol-GABA binding polypeptides present in purified GABAA receptors, notably a higher affinity for a beta 55 than a beta 58 polypeptide; these probably represent beta 2 and beta 3 clones, respectively. This work defines a significant target of taurine's inhibitory activity as some GABAA receptor GABA sites, lending support to the hypothesis that this endogenous substance may have a physiological action.


Glycosaminoglycan origin and structure revealed by multivariate analysis of NMR and CD spectra.
Principal component analysis (PCA) is a method of simplifying complex datasets to generate a lower number of parameters, while retaining the essential differences and allowing objective comparison of large numbers of datasets. Glycosaminoglycans (GAGs) are a class of linear sulfated carbohydrates with diverse sequences and consequent complex conformation and structure. Here, PCA is applied to three problems in GAG research: (i) distinguishing origins of heparin preparations, (ii) structural analysis of heparin derivatives, and (iii) classification of chondroitin sulfates (CS). The results revealed the following. (i) PCA of heparin (13)C NMR spectra allowed their origins to be distinguished and structural differences were identified. (ii) Analysis of the information-rich (1)H and (13)C NMR spectra of a series of systematically modified heparin derivatives uncovered underlying properties. These included the presence of interactions between residues, providing evidence that a degree of degeneracy exists in linkage geometry and that a different degree of variability exists for the two types of glycosidic linkage. The relative sensitivity of each position (C or H nucleus) in the disaccharide repeating unit to changes in O-, N-sulfation and N-acetylation was also revealed. (iii) Analysis of the (1)H NMR and CD spectra of a series of CS samples from different origins allowed their structural classification and highlighted the power of employing complementary spectroscopic methods in concert with PCA.


The Active Segmentation Platform for Microscopic Image Classification and Segmentation.
Image segmentation still represents an active area of research since no universal solution can be identified. Traditional image segmentation algorithms are problem-specific and limited in scope. On the other hand, machine learning offers an alternative paradigm where predefined features are combined into different classifiers, providing pixel-level classification and segmentation. However, machine learning only can not address the question as to which features are appropriate for a certain classification problem. The article presents an automated image segmentation and classification platform, called Active Segmentation, which is based on ImageJ. The platform integrates expert domain knowledge, providing partial ground truth, with geometrical feature extraction based on multi-scale signal processing combined with machine learning. The approach in image segmentation is exemplified on the ISBI 2012 image segmentation challenge data set. As a second application we demonstrate whole image classification functionality based on the same principles. The approach is exemplified using the HeLa and HEp-2 data sets. Obtained results indicate that feature space enrichment properly balanced with feature selection functionality can achieve performance comparable to deep learning approaches. In summary, differential geometry can substantially improve the outcome of machine learning since it can enrich the underlying feature space with new geometrical invariant objects.


Advanced imaging of tuberculosis arthritis.
Musculoskeletal manifestations are seen in approximately 3% of tuberculosis (MTb) cases, more commonly in the spine. Extra-axial bone and joint MTb is infrequently encountered in the West. In the last decade, public health strategies for control of MTb have been so successful in industrialized countries that many clinicians are unfamiliar with the range of extrapulmonary manifestations of MTb and therefore hold a low index of suspicion for MTb in the diagnosis of bone and joint infection. MTb, however, persists as a serious and significant cause of musculoskeletal pathology in many parts of the world and for specific patient cohorts in industrialized countries. Knowledge of the patient groups at risk and awareness of the varied osteoarticular manifestations of MTb are essential for timely diagnosis and intervention and potential cure.


Current and future directions in medical therapy for breast carcinoma: endocrine treatment.
Endocrine therapy remains a mainstay of treatment for breast carcinoma in both adjuvant and metastatic settings. The choice of endocrine therapy is guided by the presence and degree of expression of estrogen receptor (ER) and progesterone receptor (PgR) as well as by clinical parameters. Adjuvant tamoxifen (TAM) given for 5 years is accepted standard therapy for postmenopausal ER and/or PgR positive (+ve) women. In premenopausal women, 5 years of TAM given alone has similar effects, but is used less frequently because chemotherapy has been regarded as a standard even in ER and PgR +ve women. Recent literature has demonstrated the equivalence or superiority of (Zoladex [ZOL], Zeneca Pharmaceuticals, Wilmington, DE) goserelin acetate plus TAM to cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy in premenopausal ER and PgR +ve women. This, together with older data showing equivalence or superiority of ovarian ablation (OA) to CMF chemotherapy in the same setting, as well as accumulating data suggesting benefit from the addition of ZOL, OA, and/or TAM to chemotherapy in the premenopausal adjuvant setting, has raised issues regarding whether ZOL, OA, and/or TAM can substitute for chemotherapy or should always be added to it for premenopausal receptor +ve women. In the metastatic setting, the second-generation aromatase inhibitors (AI) clearly have moved into position as second-line therapy after TAM. Recent data have shown equivalence and perhaps some superiority to TAM by at least one AI (anastrazole [AN]) in first-line metastatic treatment. The results of adjuvant studies comparing TAM, AN, and TAM + AN in the adjuvant setting will be awaited with great interest. In the interim, the development of other SERMS (raloxifene, EM 850) and of pure antiestrogens may provide new and exciting approaches in the metastatic, adjuvant, and preventive settings.


Evaluation of cosmetic results of a randomized trial comparing surgery and radiotherapy in the treatment of basal cell carcinoma of the face.
Basal cell carcinoma is the most frequent cutaneous carcinoma, and it is characterized by its local spreading and an exceptional tendency to metastasize. Radical excision or destruction ensures the highest chance of cure. The most frequent site of this tumor is the face, where radical excision is limited by the proximity of essential anatomic structures. The main difficulty is to avoid mutilation and to provide good cosmetic results despite the vicinity of the eyes, the nose, and the mouth. Surgery and radiotherapy are known to provide similar chances of cure, but results concerning cosmetic sequelae are controversial, depending sometimes on the specialty of the physician in charge of the treatment. A randomized trial was performed at the Gustave-Roussy Institute to compare basal cell carcinomas of the face treated either by surgery or by radiotherapy. In summary, a significant advantage was observed in favor of surgery, as has been published elsewhere. Looking at the details of the cosmetic results, we analyzed the specific methodology of the cosmetic evaluation set up to eradicate the usual bias owing to subjective judgments. We looked also to the evolution of the cosmetic results with time. A panel of five judges performed repeated evaluations during the follow-up, and standardized photographs were taken at each visit and rated later by three nonmedical judges. In total, 174 patients were treated by surgery and 173 by radiotherapy; the choice of the treatment was allocated by randomization. Postoperative complications were higher in the radiotherapy group. The final cosmetic results after 4 years of follow-up were rated significantly better with surgery than with radiotherapy (good in 87 percent versus 69 percent according to the patient, 79 percent versus 40 percent according to the dermatologist, and respectively for each of the observers). Evolution of the ratings during the follow-up demonstrated an improvement of the cosmesis after surgery and stable or deteriorated results after radiotherapy. The same trend was observed regardless of the site of the tumor on the face, except for the nose, where the difference--still in favor of the surgery--was not significant. Concordance of all assessments in our study was the main guarantee of reliability of our methodology for cosmetic evaluation.


A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta.
To get a better understanding of mutagenic mechanisms in humans, we have cloned and sequenced the human homolog of the Saccharomyces cerevisiae REV3 gene. The yeast gene encodes the catalytic subunit of DNA polymerase zeta, a nonessential enzyme that is thought to carry out translesion replication and is responsible for virtually all DNA damage-induced mutagenesis and the majority of spontaneous mutagenesis. The human gene encodes an expected protein of 3,130 residues, about twice the size of the yeast protein (1,504 aa). The two proteins are 29% identical in an amino-terminal region of approximately 340 residues, 39% identical in a carboxyl-terminal region of approximately 850 residues, and 29% identical in a 55-residue region in the middle of the two genes. The sequence of the expected protein strongly predicts that it is the catalytic subunit of a DNA polymerase of the pol zeta type; the carboxyl-terminal domain possesses, in the right order, the six motifs characteristic of eukaryotic DNA polymerases, most closely resembles yeast pol zeta among all polymerases in the GenBank database, and is different from the human alpha, delta, and epsilon enzymes. Human cells expressing high levels of an hsREV3 antisense RNA fragment grow normally, but show little or no UV-induced mutagenesis and are slightly more sensitive to killing by UV. The human gene therefore appears to carry out a function similar to that of its yeast counterpart.


Manganese intoxication during intermittent parenteral nutrition: report of two cases.
The administration of trace elements is thought to be needed in patients receiving long-term parenteral nutrition. Recently, manganese intoxication or deposition was documented in such patients. We report two cases of manganese intoxication during intermittent parenteral nutrition including manganese. Manganese had been administered for 4 years at a frequency of one or two times per week in one case and for 5 years at a frequency of one or two times per month in the other case. Both cases showed mild symptoms with headache and dizziness. One case had mild hepatic dysfunction and the other did not. The whole-blood manganese level increased in one case, but not in the other case. T1-weighted magnetic resonance images revealed symmetrical high-intensity areas in basal ganglia and thalamus in both cases. After the administration of manganese was stopped, these symptoms all disappeared and the magnetic resonance images abnormalities gradually improved in both patients. Mild long-term manganese intoxication is thus considered to occur regardless of the frequency of using a manganese supplement. Patients should be carefully monitored when receiving long-term parenteral nutrition including manganese, even when the manganese dose is small and the frequency of receiving a manganese supplement is low.


Extracellular Vesicle Biogenesis and Functions in Gram-Positive Bacteria.
Extracellular vesicles (EVs) are membrane-derived lipid bilayers secreted by bacteria and eukaryotic cells. Bacterial membrane vesicles were discovered over 60 years ago and have been extensively studied in Gram-negative bacteria. During their production, EVs are loaded with proteins, nucleic acids, and various compounds that are subsequently released into the environment. Depending on the packaged cargo, EVs have a broad spectrum of action and are involved in pathogenesis, antibiotic resistance, nutrient uptake, and nucleic acid transfer. Due to differences in cell wall structure, EVs in Gram-positive bacteria have been disregarded for decades, and our understanding of their biogenesis and host cell interaction is incomplete. Recently, studies on bacteria such as Staphylococcus aureus, Streptococcus spp., Bacillus subtilis, and Mycobacterium spp. have demonstrated EV production in Gram-positive bacteria and shown the great importance EVs have in Gram-positive bacterial physiology and disease progression. Here, we review the latest findings on the biogenesis and functions of EVs from Gram-positive bacteria and identify key areas for future research.


Changes in naming and semantic abilities with aging from 50 to 90 years.
The aim of this study was to determine whether naming difficulties arise in individuals as young as their 50s. Participants of 25-35, 50-59, 60-69, and above 70 years of age were given a picture naming task. To uncover subtle naming difficulties, latencies were analyzed in addition to accuracy. To control whether the expected slower naming latencies could be due to a general slowing affecting all cognitive tasks, participants were also given an odd/even judgment task to assess cognitive processing speed. The results confirmed that participants in their 50s presented decline in naming performance, reflected by an increase in naming latencies, whereas adults in their 60s and their 70s showed both a decrease in accuracy and an increase in latency. Moreover, the increase in naming latencies remained significant even after controlling for odd/even judgment latencies, suggesting a degradation specific to the picture naming task. We assumed that these slower latencies may result from a language-specific impairment. As a further test for language-specific degradation, participants' semantic capacities were also assessed with a synonym judgment task and the Pyramids and Palm Trees test. The above-70 group showed semantic degradation. The contributions of multiple factors to naming difficulties in aging are discussed.


Divergence in regulation of nitric-oxide synthase and its cofactor tetrahydrobiopterin by tumor necrosis factor-alpha. Ceramide potentiates nitric oxide synthesis without affecting GTP cyclohydrolase I activity.
Synthesis of 6(R)-5,6,7,8-tetrahydrobiopterin (BH(4)), a required cofactor for inducible nitric-oxide synthase (iNOS) activity, is usually coordinately regulated with iNOS expression. In C6 glioma cells, tumor necrosis factor-alpha (TNF-alpha) concomitantly potentiated the stimulation of nitric oxide (NO) and BH(4) production induced by IFN-gamma and interleukin-1beta. Expression of both iNOS and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in the BH(4) biosynthetic pathway, was also markedly increased, as were their activities and protein levels. Ceramide, a sphingolipid metabolite, may mediate some of the actions of TNF-alpha. Indeed, we found that bacterial sphingomyelinase, which hydrolyzes sphingomyelin and increases endogenous ceramide, or the cell permeable ceramide analogue, C(2)-ceramide, but not C(2)-dihydroceramide (N-acetylsphinganine), significantly mimicked the effects of TNF-alpha on NO production and iNOS expression and activity in C6 cells. Surprisingly, although TNF-alpha increased BH(4) synthesis and GTPCH activity, neither BH(4) nor GTPCH expression was affected by C(2)-ceramide or sphingomyelinase in IFN-gamma- and interleukin-1beta-stimulated cells. It is likely that increased BH(4) levels results from increased GTPCH protein and activity in vivo rather than from reduced turnover of BH(4), because the GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, blocked cytokine-stimulated BH(4) accumulation. Moreover, expression of the GTPCH feedback regulatory protein, which if decreased might increase GTPCH activity, was not affected by TNF-alpha or ceramide. Treatment with the antioxidant pyrrolidine dithiocarbamate, which is known to inhibit NF-kappaB and sphingomyelinase in C6 cells, or with the peptide SN-50, which blocks translocation of NF-kappaB to the nucleus, inhibited TNF-alpha-dependent iNOS mRNA expression without affecting GTPCH mRNA levels. This is the first demonstration that cytokine-stimulated iNOS and GTPCH expression, and therefore NO and BH(4) biosynthesis, may be regulated by discrete pathways. As BH(4) is also a cofactor for the aromatic amino acid hydroxylases, discovery of distinct mechanisms for regulation of BH(4) and NO has important implications for its specific functions.


The ensemble approach to neural-network learning and generalization.
In this paper a new method is suggested for learning and generalization with a general one-hidden layer feedforward neural network. This scheme encompasses the use of a linear combination of heterogeneous nodes having randomly prescribed parameter values. The learning of the parameters is realized through adaptive stochastic optimization using a generalization data set. The learning of the linear coefficients in the linear combination of nodes is achieved with a linear regression method using data from the training set. One node is learned at a time. The method allows for choosing the proper number of net nodes, and is computationally efficient. The method was tested on mathematical examples and real problems from materials science and technology.


Adaptive threshold modulation for error diffusion halftoning.
Grayscale digital image halftoning quantizes each pixel to one bit. In error diffusion halftoning, the quantization error at each pixel is filtered and fed back to the input in order to diffuse the quantization error among the neighboring grayscale pixels. Error diffusion introduces nonlinear distortion (directional artifacts), linear distortion (sharpening), and additive noise. Threshold modulation, which alters the quantizer input, has been previously used to reduce either directional artifacts or linear distortion. This paper presents an adaptive threshold modulation framework to improve halftone quality by optimizing error diffusion parameters in the least squares sense. The framework models the quantizer implicitly, so a wide variety of quantizers may be used. Based on the framework, we derive adaptive algorithms to optimize 1) edge enhancement halftoning and 2) green noise halftoning. In edge enhancement halftoning, we minimize linear distortion by controlling the sharpening control parameter. We may also break up directional artifacts by replacing the thresholding quantizer with a deterministic bit flipping (DBF) quantizer. For green noise halftoning, we optimize the hysteresis coefficients.


Inflammasome activation by cystine crystals: implications for the pathogenesis of cystinosis.
Intralysosomal cystine crystal accumulation, due to mutations in the CTNS gene, is a hallmark of nephropathic cystinosis, but the role of these crystals in disease pathogenesis remains unclear. We hypothesized that, similar to other host-derived crystalline moieties, cystine crystals can induce IL-1β production through inflammasome activation. Thus, we investigated the proinflammatory effects of cystine crystals in primary human PBMCs. LPS-primed PBMCs stimulated with cystine crystals secreted IL-1β in a dose-dependent manner. Similarly to IL-1β secretion induced by other crystalline inflammasome activators, cystine crystal-induced IL-1β secretion required activation of caspase-1. Additionally, exogenous cystine crystals were internalized by monocytes, and inhibition of phagocytosis, cathepsin B leakage, generation of reactive oxygen species, and potassium efflux reduced cystine crystal-induced IL-1β secretion. Patients with cystinosis had higher levels of circulating IL-1β and IL-18 compared with controls. Analysis of inflammasome-related gene expression in PBMCs from patients with cystinosis revealed a significant increase in IL-1β and CASP-1 transcript levels compared with controls. Moreover, knockout of cystinosin in mice led to significant increases in serum IL-18 levels and kidney expression of inflammasome-related genes (Casp-1, Pycard, Il-18, Il18r1, Il1r1, and Il1rl2). Taken together, these data demonstrate that cystine crystals are endogenous inflammasome-activating stimuli, suggesting a novel role for cystine crystals in the pathogenesis of nephropathic cystinosis.


Evaluation of a microcolony detection method and phage assay for rapid detection of Mycobacterium tuberculosis in sputum samples.
Early and rapid diagnosis of tuberculosis is necessary for both treatment and control of the disease. This study evaluated two microcolony observation techniques based on liquid and solid media and a mycobacteriophage assay, to evaluate their effectiveness in the diagnosis of pulmonary TB compared with a standard culture (BACTEC 460 and LJ medium). Middlebrook7H9 (M7H9) broth based on microcolony determination detected 57/61 positives cultures (n = 200) with a sensitivity of 93.4% and a specificity of 87.1%. M7H11 agar detected 57/62 positive cultures (n = 198) with a sensitivity of 91.9% and a specificity of 89.7%. The mycobacteriophage assay detected 98/143 (68.5%) of positive samples. The time to positivity was 48 hours in the mycobacteriophage assay versus 7 days in both the M7H9 broth and M7H11 agar. The costs in comparison with the culture (BACTEC 460 and LJ) were 33% and 48% for the microcolony and mycobacteriophage methods, respectively. Microcolony methods were rapid and cost effective compared to standard cultures. The mycobacteriophage assay, despite its lower sensitivity, has a short turn around time, and may be recommended as a screening test in countries with a low prevalence of tuberculosis.


Engineering Stem Cell Self-organization to Build Better Organoids.
Organoids form through self-organization processes in which initially homogeneous populations of stem cells spontaneously break symmetry and undergo in-vivo-like pattern formation and morphogenesis, though the processes controlling this are poorly characterized. While these in vitro self-organized tissues far exceed the microscopic and functional complexity obtained by current tissue engineering technologies, they are non-physiological in shape and size and have limited function and lifespan. Here, we discuss how engineering efforts for guiding stem-cell-based development at multiple stages can form the basis for the assembly of highly complex and rationally designed self-organizing multicellular systems with increased robustness and physiological relevance.


Systematic review of the comparative effectiveness of antiepileptic drugs for fibromyalgia.
Fibromyalgia is a difficult-to-treat chronic pain syndrome that affects 2% of the US population. Pregabalin is an antiepileptic recently FDA approved for fibromyalgia treatment. Other antiepileptics have been suggested for treatment. This systematic review examines the relative benefits and harms of antiepileptic drugs in the treatment of fibromyalgia. A literature search was conducted and 8 studies matched criteria (7 studies of pregabalin, 1 of gabapentin). Both drugs reduced mean pain scores more than placebo at a modest rate (pregabalin, 38% to 50%; gabapentin, 51%). In a 6-month trial of pregabalin responders, 32% continued to have response at 6 months, with a mean time to loss of response of 34 days. Compared to placebo, the drugs had similarly high rates of adverse events and withdrawals. Without a head-to-head trial it is not possible to conclude if 1 antiepileptic is more effective or harmful than the other, although limited evidence suggests potential differences. Future studies must directly compare the drugs, include a more broadly defined population, examine long term benefits and harms, and include cointerventions. We conclude that pregabalin and gabapentin are modestly effective for the treatment of fibromyalgia but that their long-term safety and efficacy remain unknown. This systematic review evaluates the benefits and harms of using the antiepileptic drugs gabapentin and pregabalin for the treatment of fibromyalgia. Conclusions from this paper can help clinicians to more effectively treat the pain associated with fibromyalgia.


Genetic structure among continental and island populations of gyrfalcons.
Little is known about the possible influence that past glacial events have had on the phylogeography and population structure of avian predators in the Arctic and sub-Arctic. In this study, we use microsatellite and mitochondrial control region DNA variation to investigate the population genetic structure of gyrfalcons (Falco rusticolus) throughout a large portion of their circumpolar distribution. In most locations sampled, the mtDNA data revealed little geographic structure; however, five out of eight mtDNA haplotypes were unique to a particular geographic area (Greenland, Iceland, or Alaska) and the Iceland population differed from others based on haplotype frequency differences (F(ST)). With the microsatellite results, significant population structure (F(ST), principal components analysis, and cluster analysis) was observed identifying Greenland and Iceland as separate populations, while Norway, Alaska and Canada were identified as a single population consistent with contemporary gene flow across Russia. Within Greenland, differing levels of gene flow between western and eastern sampling locations was indicated with apparent asymmetric dispersal in western Greenland from north to south. This dispersal bias is in agreement with the distribution of plumage colour variants with white gyrfalcons in much higher proportion in northern Greenland. Lastly, because the mtDNA control region sequence differed by only one to four nucleotides from a common haplotype among all gyrfalcons, we infer that the observed microsatellite population genetic structure has developed since the last glacial maximum. This conclusion is further supported by our finding that a closely related species, the saker falcon (Falco cherrug), has greater genetic heterogeneity, including mtDNA haplotypes differing by 1-16 nucleotide substitutions from a common gyrfalcon haplotype. This is consistent with gyrfalcons having expanded rapidly from a single glacial-age refugium to their current circumpolar distribution. Additional sampling of gyrfalcons from Fennoscandia and Russia throughout Siberia is necessary to test putative gene flow between Norway and Alaska and Canada as suggested by this study.


Marine natural products from the deep Pacific as potential non-linear optical chromophores.
Theoretical analysis using quadratic response theory within the time-dependent density functional theory (TDDFT) formalism shows that the dermacozines, a group of phenazine-based compounds isolated from cultures of Dermacoccus abyssi found in the Mariana Trench, possess large first hyperpolarisability (β) values at common incident laser wavelengths that are highly sensitive to the degree and type of substitution of the core structure. The phenazine moiety is a versatile and tunable chromophore for non-linear optics and this work serves to highlight the potential that (marine) natural products, even those found in the darkest places on the planet, may have for aiding developments in optical materials design.


Rapid onset of blindness due to meningeal carcinomatosis from an oesophageal adenocarcinoma.
We report a 49 year old man who presented with left leg weakness, frontal headache, impaired concentration and dysphagia. He was thought to have a benign oesophageal stricture on barium swallow and oesophagoscopy though this was not initially biopsied. During admission his vision deteriorated so that he could only recognize bright light. Repeat oesophagoscopy demonstrated an oesophageal adenocarcinoma. The diagnosis of meningeal carcinomatosis was confirmed at post-mortem. Sudden bilateral blindness is a common feature of meningeal carcinomatosis but, as this is rare, it is not commonly considered in the differential diagnosis of visual loss. The visual loss can be explained by vascular insufficiency in association with tumour cuffing of the subarachnoid space of the optic nerve sheath, by neuronal toxins, or other, as yet unknown, mechanisms.


Structural analysis of oligosaccharide-alditols released by reductive beta-elimination from oviducal mucins of Bufo bufo: characterization of the carbohydrate sequence Gal(alpha1-3)GalNAc(alpha1-3)[Fuc(alpha1-2)]Gal.
Several tri- to hexasaccharide-alditols of the jelly coat surrounding the eggs of Bufo bufo were studied by methylation analysis, MALDI-TOF mass spectrometry, and 1H-NMR spectroscopy. As observed for six other amphibian species, these carbohydrate chains are highly species-specific. The main characteristics of the species Bufo bufo consists in the presence of the new carbohydrate sequence Gal(alpha1-3)GalNAc(alpha1-3)[Fuc(alpha1-2)]Gal, in which a blood group A determinant is substituted with an external alpha1-3 linked galactose unit. Since the role of carbohydrates appears more and more apparent during the fertilization processes, the species-specificity of these carbohydrate moieties should be relevant to the species-specific gamete recognition which characterizes most amphibians.


Spontaneous excision of BAC vector sequences from bacmid-derived baculovirus expression vectors upon passage in insect cells.
Repeated baculovirus infections in cultured insect cells lead to the generation of defective interfering viruses (DIs), which accumulate at the expense of the intact helper virus and compromise heterologous protein expression. In particular, Autographa californica multicapsid nucleopolyhedovirus (AcMNPV) DIs are enriched in an origin of viral DNA replication (ori) not associated with the homologous regions (hrs). This non-hr ori is located within the coding sequence of the non-essential p94 gene. We investigated the effect of a deletion of the AcMNPV non-hr ori on the heterologous protein expression levels following serial passage in Sf21 insect cells. Using homologous ET recombination in E. coli, deletions within the p94 gene were made in a bacterial artificial chromosome (BAC) containing the entire AcMNPV genome (bacmid). All bacmids were equipped with an expression cassette containing the green fluorescent protein gene and a gene encoding the classical swine fever virus E2 glycoprotein (CSFV-E2). For the parental (intact) bacmid only, a strong accumulation of DIs with reiterated non-hr oris was observed. This was not observed for the mutants, indicating that removal of the non-hr ori enhanced the genetic stability of the viral genome upon passaging. However, for all passaged viruses it was found that the entire BAC vector including the expression cassette was spontaneously deleted from the viral genome, leading to a rapid decrease in GFP and CSFV-E2 production. The rationale for the (intrinsic) genetic instability of the BAC vector in insect cells and the implications with respect to large-scale production of proteins with bacmid-derived baculoviruses are discussed.


Mutism after posterior fossa tumour resection in children: incomplete recovery on long-term follow-up.
Mutism after posterior fossa tumour resection is generally said to be transient. Our experience suggested that speech did not usually normalise, and that mutism was associated with neurologic deficits that did not recover fully. Children with mutism after posterior fossa tumour resection, and alive more than 2 years post-operatively, were reviewed retrospectively. Charts were reviewed and parents contacted to ascertain details about mutism, associated neurologic deficits, and the most recent speech and neurologic status. There were 7 children, with follow-up ranging from 2.5 to 13.1 years (mean 6.8 years). Tumours were midline, with 4 astrocytomas and 3 medulloblastomas. Mutism was noted immediately after post-operative extubation in all patients. Speech reappeared 1-15 weeks post-operatively, except for 1 patient, who remained mute at 2.5 years. Speech returned to normal in only 1 patient. Mutism was always accompanied by new or worsened cerebellar ataxia, which resolved incompletely in the long term. Sixth nerve palsies occurred in 3 and recovered incompletely. Seventh nerve paresis occurred in 2 and recovered completely. Mutism after posterior fossa tumour resection is associated with other neurologic deficits, particularly ataxia. Whereas speech usually returns, contrary to general opinion, speech rarely normalises. Other associated deficits rarely resolve completely. These findings have significant implications for counselling of family and patients.


Low and high ψ ways from post-transcriptional RNA regulation to drought tolerance.
Plants withstand adverse environmental effects by stress responses governed by a complex multilayer regulatory network. Besides well established transcriptional cascades posttranscriptional modifications give more plasticity to the plant's behavior under unfavorable circumstances. These modifications include various RNA alterations typically interlaced with transcriptional or translational regulation. Recent examples have been described in RNA splicing, processing, translation and degradation, some of which operate through effects of small non-coding RNAs. So far details of physiological output mechanisms affected by RNA regulation have been uncovered in a few cases only, some of those will be detailed in this review. In the well documented example of the nuclear cap binding complex (nCBC) mutants, molecular mechanisms of the regulatory switch and downstream events have been established in detail. New results directly link nCBC function to splicing, RNA processing and abscisic acid (ABA). Potential output mechanisms of this control point have also been implicated, both in fast stress responses and in developmental regulation. This latter aspect provides a new insight into how RNA regulation may contribute to acclimation by facilitating drought tolerant morphology. Recent results pinpoint the importance of cuticular structure in acclimation to drought stress at high water potential (ψ).


Ventricular pacing threshold variations in the young.
Ventricular Capture Management (VCM) is a Medtronic Kappa pacemakers (PM) feature that automatically measures pacing threshold through detection of the evoked response after a pacing stimulus. The aim of this study was to evaluate the range of variation of ventricular pacing threshold in pediatric patients with endocardial and epicardial pacing leads. Thirty-one patients (median age 6.5 years) were implanted with a Kappa 901 PM for atrioventricular block or sinus node dysfunction. Congenital heart defects (CHD) were present in 58% of patients. Ventricular leads were epicardial in 52% of patients. VCM was programmed to automatically measure threshold every 2 hours. In a median follow-up of 12 months, 27,110 threshold measurements, 72% of which were successful, have been taken in 94% of patients. Measurement success was 99% in the endocardial leads group (age at implantation 12 +/- 6 years) and 31% in epicardial leads (age 4 +/- 5 years) (P < 0.05). Main reasons for unsuccessful measurements were high heart rate and, in a patient with an endocardial lead, competition with intrinsic rhythm. Undersensing or oversensing of the evoked responses was not detected. In all successful VCM measurements, epicardial pacing and CHD contributed to stability of thresholds (multivariate analysis). Pacing threshold showed specific circadian patterns: higher thresholds were found between 00.00 and 06.00 a.m., but the variation was low, 0.03 +/- 0.01 V. In conclusion, children and young patients show stable ventricular thresholds, especially in presence of CHD, and epicardial leads are at least as stable as endocardial leads. Ventricular pacing threshold showed a circadian variability similar to that described in adults, that does not seem to influence VCM functioning and PM programming.


Innate immune signaling in the pathogenesis of necrotizing enterocolitis.
Necrotizing enterocolitis (NEC) is a challenging disease to treat, and caring for patients afflicted by it remains both frustrating and difficult. While NEC may develop quickly and without warning, it may also develop slowly, insidiously, and appear to take the caregiver by surprise. In seeking to understand the molecular and cellular processes that lead to NEC development, we have identified a critical role for the receptor for bacterial lipopolysaccharide (LPS) toll like receptor 4 (TLR4) in the pathogenesis of NEC, as its activation within the intestinal epithelium of the premature infant leads to mucosal injury and reduced epithelial repair. The expression and function of TLR4 were found to be particularly elevated within the intestinal mucosa of the premature as compared with the full-term infant, predisposing to NEC development. Importantly, factors within both the enterocyte itself, such as heat shock protein 70 (Hsp70), and in the extracellular environment, such as amniotic fluid, can curtail the extent of TLR4 signaling and reduce the propensity for NEC development. This review will highlight the critical TLR4-mediated steps that lead to NEC development, with a focus on the proinflammatory responses of TLR4 signaling that have such devastating consequences in the premature host.


Single Molecule Upconversion-Linked Immunosorbent Assay with Extended Dynamic Range for the Sensitive Detection of Diagnostic Biomarkers.
The ability to detect disease markers at the single molecule level promises the ultimate sensitivity in clinical diagnosis. Fluorescence-based single-molecule analysis, however, is limited by matrix interference and can only probe a very small detection volume, which is typically not suitable for real world analytical applications. We have developed a microtiter plate immunoassay for counting single molecules of the cancer marker prostate specific antigen (PSA) using photon-upconversion nanoparticles (UCNPs) as labels that can be detected without background fluorescence. Individual sandwich immunocomplexes consisting of (1) an anti-PSA antibody immobilized to the surface of a microtiter well, (2) PSA, and (3) an anti-PSA antibody-UCNP conjugate were counted under a wide-field epifluorescence microscope equipped with a 980 nm laser excitation source. The single-molecule (digital) upconversion-linked immunosorbent assay (ULISA) reaches a limit of detection of 1.2 pg mL-1 (42 fM) PSA in 25% blood serum, which is about ten times more sensitive than commercial ELISAs, and covers a dynamic range of three orders of magnitude. This upconversion detection mode has the potential to pave the way for a new generation of digital immunoassays.


Impact of menopause and diabetes on atherogenic lipid profile: is it worth to analyse lipoprotein subfractions to assess cardiovascular risk in women?
Cardiovascular disease is the leading cause of death in women at advanced age, who are affected a decade later compared to men. Cardiovascular risk factors in women are not properly investigated nor treated and events are frequently lethal. Both menopause and type 2 diabetes substantially increase cardiovascular risk in the female sex, promoting modifications on lipid metabolism and circulating lipoproteins. Lipoprotein subfractions suffer a shift after menopause towards a more atherogenic lipid profile, consisted of hypertriglyceridemia, lower levels of both total high density lipoprotein (HDL) and its subfraction HDL2, but also higher levels of HDL3 and small low-density lipoprotein particles. This review discusses the impact of diabetes and menopause to the lipid profile, challenges in lipoprotein subfractions determination and their potential contribution to the cardiovascular risk assessment in women. It is still unclear whether lipoprotein subfraction changes are a major driver of cardiometabolic risk and which modifications are predominant. Prospective trials with larger samples, methodological standardizations and pharmacological approaches are needed to clarify the role of lipoprotein subfractions determination on cardiovascular risk prediction and intervention planning in postmenopausal women, with or without DM.


[Prevalence of congenital dislocation of hip diffusion among the population of Lenkoran and Massaly region in Azerbaijan].
The occurrence of congenital hip dislocation in Lenkoran and Massaly areas of Azerbaijan Republic was studied. The population-genetic assessment in Lenkoran and Massaly regions was conducted. The phenotypic frequency of hip congenital dislocation according to Medical- Labor Expert Commission data are 0,065% and 0,035% respectively. According to present survey congenital hip dislocation data are: 0, 7% and 0, 4% respectively. The results of the study demonstrate strong demand of accurate data on the occurrence of congenital and genetic diseases in Azerbaijan Republic. The highest prevalence of multiple-factor type of heredity indicates the necessity to control teratogen factors of the environment.


Global-Scale Structure of the Eelgrass Microbiome.
Plant-associated microorganisms are essential for their hosts' survival and performance. Yet, most plant microbiome studies to date have focused on terrestrial species sampled across relatively small spatial scales. Here, we report the results of a global-scale analysis of microbial communities associated with leaf and root surfaces of the marine eelgrass Zostera marina throughout its range in the Northern Hemisphere. By contrasting host microbiomes with those of surrounding seawater and sediment, we uncovered the structure, composition, and variability of microbial communities associated with eelgrass. We also investigated hypotheses about the assembly of the eelgrass microbiome using a metabolic modeling approach. Our results reveal leaf communities displaying high variability and spatial turnover that mirror their adjacent coastal seawater microbiomes. By contrast, roots showed relatively low compositional turnover and were distinct from surrounding sediment communities, a result driven by the enrichment of predicted sulfur-oxidizing bacterial taxa on root surfaces. Predictions from metabolic modeling of enriched taxa were consistent with a habitat-filtering community assembly mechanism whereby similarity in resource use drives taxonomic cooccurrence patterns on belowground, but not aboveground, host tissues. Our work provides evidence for a core eelgrass root microbiome with putative functional roles and highlights potentially disparate processes influencing microbial community assembly on different plant compartments.IMPORTANCE Plants depend critically on their associated microbiome, yet the structure of microbial communities found on marine plants remains poorly understood in comparison to that for terrestrial species. Seagrasses are the only flowering plants that live entirely in marine environments. The return of terrestrial seagrass ancestors to oceans is among the most extreme habitat shifts documented in plants, making them an ideal testbed for the study of microbial symbioses with plants that experience relatively harsh abiotic conditions. In this study, we report the results of a global sampling effort to extensively characterize the structure of microbial communities associated with the widespread seagrass species Zostera marina, or eelgrass, across its geographic range. Our results reveal major differences in the structure and composition of above- versus belowground microbial communities on eelgrass surfaces, as well as their relationships with the environment and host.


Identification of 7-carboxymethylguanine in DNA from pancreatic acinar cells exposed to azaserine.
Studies were undertaken to determine the identity of an azaserine:DNA adduct. The most probable adduct, 7-carboxymethylguanine, was synthesized. DNA isolated from pancreatic acinar cells treated in culture with [14C]azaserine was hydrolyzed under neutral conditions to liberate N-alkylated purines. The neutral hydrolysate was subjected to high-performance liquid chromatography along with the synthetic standard. One of the radioactive peaks from the treated DNA was found to cochromatograph with 7-carboxymethylguanine in three systems: reverse phase; anion exchange; and ion pair reverse phase. These results suggest that azaserine metabolism in acinar cells results in carboxymethylation of DNA, supporting previously proposed models of azaserine degradation.


Occurrence and patterns of antibiotic resistance in vertebrates off the Northeastern United States coast.
The prevalence of antibiotic-resistant bacteria in the marine environment is a growing concern, but the degree to which marine mammals, seabirds and fish harbor these organisms is not well documented. This project sought to identify the occurrence and patterns of antibiotic resistance in bacteria isolated from vertebrates of coastal waters in the northeastern United States. Four hundred and seventy-two isolates of clinical interest were tested for resistance to a suite of 16 antibiotics. Fifty-eight percent were resistant to at least one antibiotic, while 43% were resistant to multiple antibiotics. A multiple antibiotic resistance index value >or=0.2 was observed in 38% of the resistant pathogens, suggesting exposure of the animals to bacteria from significantly contaminated sites. Groups of antibiotics were identified for which bacterial resistance commonly co-occurred. Antibiotic resistance was more widespread in bacteria isolated from seabirds than marine mammals, and was more widespread in stranded or bycaught marine mammals than live marine mammals. Structuring of resistance patterns based on sample type (live/stranded/bycaught) but not animal group (mammal/bird/fish) was observed. These data indicate that antibiotic resistance is widespread in marine vertebrates, and they may be important reservoirs of antibiotic-resistant bacteria in the marine environment.


Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice.
Young female patients who receive chemotherapy frequently face premature ovarian failure (POF). The therapeutic potential of stem cells in these patients has been explored in stem cells derived from different sources. However, many of these types of stem cells are either difficult to obtain or obtaining them involves invasive procedures. Here, we show that menstrual-derived stem cells (MenSCs) are easy to access and exhibit mesenchymal stem cell-like properties. MenSCs are therefore a novel source of stem cells that can be used for tissue repair. The aim of this study was to explore the reparative capacity and the mechanism underlying the activities of MenSCs. POF mouse models were established by 7 consecutive days of intraperitoneal injection of cisplatin, and then MenSCs or MenSC-derived conditioned media (CM) were infused via the tail vein. The ovaries were excised after either 7 or 21 days of treatment and the follicles were counted and categorized. Apoptosis of granulosa cells was observed by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling staining. Ovarian function was evaluated by monitoring serum sex hormone levels. Furthermore, MenSC tracking, Q-PCR, and small interfering RNA transfection were used to reveal the inner mechanism of repair. MenSC transplantation could improve the ovarian microenvironment by reducing apoptosis in granulosa cells and the fibrosis of ovarian interstitium, which contributes to increase the follicular numbers and return sex hormone levels to normal values. Meanwhile, the transplanted MenSCs directively migrate to ovarian interstitium to play a role in repair rather than differentiate to oocytes directly. Additionally, MenSCs and CM derived from these cells exerted protective effects on damaged ovaries partially by secreting FGF2. MenSCs repair ovarian injury, improve ovarian function, and stimulate regeneration, suggesting that transplantation of MenSCs may provide an effective and novel method for treating POF.


GWAS Central: a comprehensive resource for the discovery and comparison of genotype and phenotype data from genome-wide association studies.
The GWAS Central resource provides a toolkit for integrative access and visualization of a uniquely extensive collection of genome-wide association study data, while ensuring safe open access to prevent research participant identification. GWAS Central is the world's most comprehensive openly accessible repository of summary-level GWAS association information, providing over 70 million P-values for over 3800 studies investigating over 1400 unique phenotypes. The database content comprises direct submissions received from GWAS authors and consortia, in addition to actively gathered data sets from various public sources. GWAS data are discoverable from the perspective of genetic markers, genes, genome regions or phenotypes, via graphical visualizations and detailed downloadable data reports. Tested genetic markers and relevant genomic features can be visually interrogated across up to sixteen multiple association data sets in a single view using the integrated genome browser. The semantic standardization of phenotype descriptions with Medical Subject Headings and the Human Phenotype Ontology allows the precise identification of genetic variants associated with diseases, phenotypes and traits of interest. Harmonization of the phenotype descriptions used across several GWAS-related resources has extended the phenotype search capabilities to enable cross-database study discovery using a range of ontologies. GWAS Central is updated regularly and available at https://www.gwascentral.org.


Acute joint injuries of the hand.
The joints of the hand are stabilized by articular contours, tough ligamentous structures, and dynamically by a system of flexor and extensor tendons. Disruption of a joint seriously reduces the ability of the hand to function properly. The history and especially a detailed description of the mechanism of injury is invaluable information for the diagnosis and for the ability to anticipate complications. Radiographic evaluation is required for virtually all potential injuries. Multiple views and especially a true lateral view of the digit, when appropriate, are usually sufficient. The clinical examination includes the evaluation of (1) deformity, (2) swelling, (3) tendon and neurovascular status, (4) tests for stability, and (5) active and gentle passive range of motion. The most important aspect of treatment is the ability to distinguish between injuries that require surgery and those that can be splinted and referred for follow-up. In general a near full range of active motion indicates joint congruity, and the injury can be treated by splinting and referral to a hand surgeon.


Advanced Lung Adenocarcinoma with Nivolumab-associated Dermatomyositis.
We herein report a 42-year-old man with advanced lung adenocarcinoma and nivolumab-associated dermatomyositis. Nivolumab, an anticancer drug that is classified as an immune checkpoint inhibitor, often induces immune-related adverse events (irAEs). However, there have so far been no reports regarding nivolumab-associated dermatomyositis. This patient was diagnosed with dermatomyositis due to the presence of proximal muscle weakness with abnormal electromyography and magnetic resonance imaging findings; skin lesions, such as heliotrope rash, shawl sign, and periungual erythema; and an elevated serum aldolase level after nivolumab administration. It is important to consider drug-associated dermatomyositis in the differential diagnosis of patients presenting with skin lesions and muscle weakness after nivolumab treatment.


Therapeutic efficacy of unilateral subthalamotomy in Parkinson's disease: results in 89 patients followed for up to 36 months.
Stereotactic thermocoagulative lesions of the subthalamic nucleus (STN) have been shown to induce significant motor improvement in patients with Parkinson's disease (PD). 89 patients with PD were treated with unilateral subthalamotomy. 68 patients were available for evaluations after 12 months, 36 at 24 months and 25 at 36 months. The Unified Parkinson's Disease Rating Scale (UPDRS) motor scores improved significantly contralaterally to the lesion in the "off" and "on" states throughout the follow-up, except for the "on" state at the last evaluation. Axial features and signs ipsilateral to the lesion progressed steadily throughout the study. Levodopa daily doses were significantly reduced by 45%, 36% and 28% at 12, 24 and 36 months post-surgery. 14 patients (15%) developed postoperative hemichorea-ballism which required pallidotomy in eight. These 14 patients had significantly higher dyskinesia scores (levodopa induced) preoperatively than the entire cohort. Unilateral subthalamotomy was associated with significant and sustained motor benefit contralateral to the lesion. Further work is needed to ascertain what factors led to severe, persistent chorea-ballism in a subset of patients. Subthalamotomy may be considered an option in circumstances when deep brain stimulation is not viable.


[Limb-length measurements using wooden boards: an accurate and experience-independent method].
To determine the precision and reliability of the indirect limb-length measurement, and the inter-observer variance between doctors differing in level of experience. Descriptive. Indirect limb-length measurement by placing 0.5 cm-thick wooden boards under the foot of the shorter leg until the difference in length was corrected, was performed by 3 observers differing in experience (medical student, resident and orthopaedic surgeon) on 66 patients with unilateral femoral-shaft fractures treated with a femoral nail. The group of patients consisted of 51 men and 15 women with a median age of 30 years (range: 18-90). In total 17 observers participated and 177 limb-length measurements were performed. The measurements obtained were compared with limb-length measurements obtained by orthoradiograms of the entire leg. Of the 177 indirect limb-length measurements, 144 (81%) differed by 0-1.0 cm compared with the limb length obtained by orthoradiogram. There was no statistically significant difference in the limb-length measurements obtained by the three groups of observers with different experience levels. There was a certain degree of correlation between values measured by medical students and residents (r = 0.7). When comparing the measurements carried out by staff members with those of residents and medical students, respectively, a lower degree of correlation was found (r = 0.6 and 0.5, respectively). Indirect limb-length measurement with wooden boards was accurate. Experience did not play an essential role.


Mediterranean diet trajectories and 20-year incidence of cardiovascular disease: The ATTICA cohort study (2002-2022).
Only few studies have assessed longitudinal dietary trends in relation to cardiovascular disease (CVD) risk. We aimed to evaluate the association between adherence to the Mediterranean diet, both baseline and longitudinal, and 20-year CVD incidence. This was a prospective study among 1988 Greek adults (50% men, age: 45 ± 14years). Adherence to the Mediterranean diet was evaluated at baseline and 10 years through the MedDietScore, based on which longitudinal Mediterranean diet trajectories were identified. CVD incidence was recorded at 20 years. Each one-unit increase in baseline MedDietScore was associated with an 8% reduction in 20-year CVD incidence. Compared to subjects in the lowest tertile of baseline MedDietScore, those in the highest exhibited a 44% lower 20-year CVD risk (relative risk: 0.56, 95% confidence interval: 0.32, 0.97) adjusted for age, sex, baseline body mass index, smoking, physical activity, presence of hypercholesterolemia, hypertension and diabetes mellitus, and family history of CVD; further adjustment for high-sensitivity C-reactive protein, uric acid and estimated glomerular filtration rate attenuated this association. Results were similar in models adjusted for longitudinal changes in body weight, physical activity and smoking, and 10-year medical status. Mediterranean diet trajectory analysis revealed that 24.7%, 8.6%, 45.8% and 20.9% of participants longitudinally sustained a low adherence, moved closer, moved away or sustained a high adherence, respectively; among those, the corresponding CVD incidence was 63.3%, 65.5%, 28.1% and 9.4% (p-value<0.001). The Mediterranean diet offers long-term protection against CVD, part of which is mediated by inflammation, uricemia and renal function.


Teaching program for the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale: (MDS-UPDRS).
To accompany the newly developed Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), we developed a teaching program. The DVD-based program covers the four parts of the scale with visual and verbal instructions for uniform application. For the motor section (Part III), all items except rigidity are shown with an example of each rating option (0-4) as agreed upon by a panel of experts. The rate of agreement for the selected samples was always significant, with Kendall's coefficient of concordance W ranging between 0.99 and 0.72. The teaching program also provides a full patient examination with rating answers provided and four full MDS-UPDRS cases for a Certificate Program exercise of Part III. This training program is in English, but as non-English official translations of the MDS-UPDRS are developed, the program can be potentially modified into different languages.


Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current.
A human cDNA for the voltage-sensitive potassium channel subunit Kv4.2 has been cloned and functionally characterized. The human Kv4.2 (KCND2) gene was mapped at 7q31-32. Kv4.2 mRNA is prominently expressed in human brain. Relatively high concentrations of Kv4.2 mRNA occurred in mRNA preparations of amygdala, caudate nucleus, cerebellum, hippocampus, substantia nigra, and thalamus. Kv4.2 mRNA was not detected in human heart, kidney, liver, lung, pancreas, and skeletal muscle. The derived Kv4.2 open reading frame consists of 630 amino acids. In comparison to rat Kv4.2, the human Kv4.2 sequence is highly conserved showing amino acid sequence differences at five positions only. The Kv4.2 subunits were expressed heterologously in human embryonic kidney (293) cells and mediated a rapidly inactivating, A-type outward K+ current. The gating kinetics of the Kv4.2-mediated currents were very similar to those of rat Kv4.2-mediated currents. Both the Kv4.2 and Kv4.3 subunits have been implicated in mediating the transient outward K+ current Ito in rodent cardiac myocytes. In contrast we did not detect Kv4.2. but solely Kv4.3 mRNA in human heart RNA preparations. This may suggest that Kv4.2 subunits do not contribute to the rapid transient outward K+ current of atrial and ventricular myocytes in humans.


Characterization of human chorionic gonadotropin peptide variants with a radio-receptor assay using recombinant human luteinizing hormone/chorionic gonadotropin receptors.
There are potential interactions between various human chorionic gonadotropin (hCG) isoforms at the level of luteinizing hormone/chorionic gonadotropin (LH/CG) receptor. The objective of this study was to characterize the receptor-binding activities of the primary peptide variants of hCG including intact hCG, free beta subunit, beta-core fragment and nicked hCG, and to test the effects of these hCG variants on the binding of intact hCG. A radio-receptor assay based on cell membranes expressing recombinant human LH/CG receptors was validated and used in this study to avoid species differences in the receptor-binding specificity. The results showed that none of the hCG variants that we studied had sufficient binding affinity to compete with binding of intact hCG, nor were they able to antagonize the binding of intact hCG. These results suggest that hCG variants with either abbreviated polypeptide structures or incomplete peptide linkage are products or metabolites which do not have the tropic biological activity of the whole hormone, the intact heterodimeric hCG.


Identification of TRIM56 as a Potential Biomarker for Lung Adenocarcinoma.
Lung adenocarcinoma (LUAD) is the primary subtype of human lung cancer. The effectiveness of treatment and long-term survival of patients with LUAD are current suboptimal. Tripartite motif containing 56 (TRIM56) is a member of the TRIM protein family that have functions predominantly in immunity and cancer. To investigate the expression of TRIM56 in LUAD, and explore the potential regulatory role of TRIM56 in the invasion and migration of LUAD cells. The Gene Expression Omnibus datasets and The Cancer Genome Atlas-LUAD cohort were used to analyze the mRNA expression of TRIM56 in LUAD. The differential expression profiles of miRNAs associated with TRIM56 were obtained from The Cancer Genome Atlas-LUAD cohort. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to determine the principal functions of miRNAs and interacting proteins. Transwell and wound healing were used to detect the effect of overexpression of TRIM56 on the invasion and migration of LUAD cells. The expression of TRIM56 was decreased in LUAD and associated with poor prognosis. We determined the genome copy number, negatively correlated miRNA and potential transcription factors of TRIM56, and conducted enrichment analysis. Among them, hsa-mir-542 and hsa-mir-627 were the most likely to inhibit the expression of TRIM56. We also predicted the interacting proteins and potential ubiquitination substrate of TRIM56. Finally, we demonstrated that overexpression of TRIM56 inhibits the invasion and migration of LUAD cells. This study is the first to analyze the expression of TRIM56 and its inhibitory effect on the invasion and migration of LUAD. This evidence provides a new direction for further study of the reasons for the low expression of TRIM56 in LUAD and its regulatory mechanism.


Pediatric acute leukemia presenting as bilateral renal enlargement. Report of a case with fine needle aspiration cytologic features suggestive of megakaryocytic differentiation.
Fine needle aspiration (FNA) cytologic diagnosis of acute myeloid leukemia involving the kidney has rarely been reported, but acute leukemia with cytologic features suggestive of megakaryocytic differentiation has not been described before. An 8-month-old male presented with an abdominal swelling, bilateral cervical and inguinal lymphadenopathy and enlarged left epididymis. Ultrasonography of the abdomen revealed a space-occupying lesion in the liver and bilateral enlargement of the kidneys. FNA smears from the right kidney and right submandibular lymph node showed numerous blast cells. Since rare blast cells were positive for myeloperoxidase, a cytodiagnosis of involvement by acute myeloid leukemia (AML) was made. However, following the hematologic diagnosis of acute megakaryoblastic leukemia (M7) from peripheral blood and bone marrow smear examination, FNA smears were reviewed. There were cytoplasmic blebs or protrusions in the blast cells and cytologic features suggestive of their differentiation toward micro-megakaryocytes and megakaryocytes. There was also evidence of shedding of platelets, including numerous giant platelets. The reviewed FNA cytodiagnosis was suggestive of AML (M7). Extramedullary involvement by acute megakaryoblastic leukemia (M7) can be suspected based on cytomorphologic features in FNA smears.


Interaction of a G protein with an activated receptor opens the interdomain interface in the alpha subunit.
In G-protein signaling, an activated receptor catalyzes GDP/GTP exchange on the G(α) subunit of a heterotrimeric G protein. In an initial step, receptor interaction with G(α) acts to allosterically trigger GDP release from a binding site located between the nucleotide binding domain and a helical domain, but the molecular mechanism is unknown. In this study, site-directed spin labeling and double electron-electron resonance spectroscopy are employed to reveal a large-scale separation of the domains that provides a direct pathway for nucleotide escape. Cross-linking studies show that the domain separation is required for receptor enhancement of nucleotide exchange rates. The interdomain opening is coupled to receptor binding via the C-terminal helix of G(α), the extension of which is a high-affinity receptor binding element.


Getting a grip: cats respond negatively to scruffing and clips.
Use of scruffing and scruffing tools (eg, clipnosis clips) to immobilise cats is contentious, and cat handling guidelines vary in recommendations regarding these techniques. The current study examined whether cats show negative responses to the following restraint methods: (1) scruff (n=17), (2) clip application to the dorsal neck skin (n=16) and (3) full body (a known negative; n=19). Each cat was also handled with passive restraint (control) for comparison. During handling, cats were examined for behavioural (side/back ear positions, vocalisations, lip licking) and physiological (pupil dilation ratio, respiratory rate) responses. Full-body restrained cats showed more negative responses than passively restrained cats (respiratory rate: p=0.006, F3,37=4.31, p=0.01; ear p=0.002, F3,49=6.70, p=0.0007; pupil: p=0.007, F3,95=14.24, p=0.004; vocalisations: p=0.009, F3,49=4.85, p=0.005) and scruff-restrained cats (pupil: p=0.009; vocalisations: p=0.04). Clip restraint resulted in more negative responses than passive (pupil: p=0.01; vocalisations: p=0.007, ear p=0.02) and scruff restraint (pupil p=0.01; vocalisations: p=0.02). No differences were detected between full-body restraint, known to be aversive, and clip restraint. Full-body restraint and clip restraint resulted in the greatest number of negative responses, scruffing resulted in fewer negative responses and passive restraint showed the least number of responses. We therefore recommend against the use of full-body and clip restraint, and suggest that scruff restraint should be avoided when possible.


Problem-Solving Phase Transitions During Team Collaboration.
Multiple theories of problem-solving hypothesize that there are distinct qualitative phases exhibited during effective problem-solving. However, limited research has attempted to identify when transitions between phases occur. We integrate theory on collaborative problem-solving (CPS) with dynamical systems theory suggesting that when a system is undergoing a phase transition it should exhibit a peak in entropy and that entropy levels should also relate to team performance. Communications from 40 teams that collaborated on a complex problem were coded for occurrence of problem-solving processes. We applied a sliding window entropy technique to each team's communications and specified criteria for (a) identifying data points that qualify as peaks and (b) determining which peaks were robust. We used multilevel modeling, and provide a qualitative example, to evaluate whether phases exhibit distinct distributions of communication processes. We also tested whether there was a relationship between entropy values at transition points and CPS performance. We found that a proportion of entropy peaks was robust and that the relative occurrence of communication codes varied significantly across phases. Peaks in entropy thus corresponded to qualitative shifts in teams' CPS communications, providing empirical evidence that teams exhibit phase transitions during CPS. Also, lower average levels of entropy at the phase transition points predicted better CPS performance. We specify future directions to improve understanding of phase transitions during CPS, and collaborative cognition, more broadly.


Fatal neonatal parechovirus encephalitis.
Two infants developed encephalitis in the late neonatal period due to human parechovirus type 3 (HPeV-3). This finally resulted in intractable seizures leading to death. Both presented with classical signs and symptoms. HPeV-3 was detected in nasopharyngeal and rectal swabs, cerebrospinal fluid, serum and postmortem samples (for one infant). Ultrasound and magnetic resonance imaging findings showed severe white matter injury in one infant, and limited hippocampal injury in the other. Parents consented to autopsy in the latter, showing diffuse gliotic oedema of cerebral white matter, bilateral bronchopneumonia, and inflammation in spleen. We emphasise that polymerase chain reaction (PCR) testing for parechovirus in neonates with severe sepsis-like syndrome and meningoencephalitis is mandatory.


Development and Validation of a New Measurement Scale for Existential Loneliness.
This article deals with the development and initial validation of the Existential Loneliness Scale (ELS). An initial pool of 40 items, generated based on literature review, qualitative studies, and previously developed scales, was evaluated by the experts' judgment, so 30 items were retained and then administered to an Iranian sample of 433 youth and adult participants aged 20 to 85 years. Participants also completed other measures relevant for construct validity: Existential Loneliness Questionnaire (ELQ), De Jong Gierveld Loneliness Scale (DJGLS-6), Existential Anxiety Questionnaire (EAQ), Meaning in Life Questionnaire (MLQ), Beck Depression Inventory (BDI-13), and Satisfaction with Life Scale (SWLS). Exploratory factor analysis and parallel analysis showed strong evidence of unidimensionality. This result was also supported by confirmatory factor analysis test. Finally, 19 items were kept, which were free from DIF by gender and by marital status. The scale had high internal consistency (α = .95 and ω = .95) and adequate test-retest reliability with a 1-month interval (r = .74). Examination of the ELS' correlation with criterion measures indicated that the scale has good concurrent, discriminant, and convergent validity. Findings revealed the ELS as a reliable, valid, and suitable instrument to measure existential loneliness in the Iranian adult population.


Cytotoxic constituents and a new hydroxycinnamic acid derivative from Leontodon saxatilis (Asteraceae, Cichorieae).
In our ongoing research for the discovery of new constituents with antimyeloma activity, we investigated 15 compounds present in the aerial parts of Leontodon saxatilis for their cytotoxic potential against NCI-H929, U266, and OPM2 cell lines. One of the isolated compounds displayed a new natural product and was identified as 5-feruloyl-2α-hydroxyquinic acid after LC-MS and NMR experiments. Of the remaining compounds, cichoric acid and three flavone glycosides, apigenin 4'-O-β-d-glucoside, luteolin 7-O-β-d-glucoside and luteolin 4'-O-β-d-glucoside, showed moderate cytotoxic activity, whereas the effects of two aglyones apigenin and luteolin were more pronounced. Though the cytotoxic potential of the two aglycones (against other cell lines) was reported in various studies, our work moreover showed that cooccurrence of these two compounds with similar components of lower activity led to comparable results and at the same time minimized the damage of healthy fibroblast cells. Thus, our work could be a starting point for additional studies on the synergistic effect of similar components against myeloma cell lines.


Recommendations for acquisition and interpretation of MRI of the spine and sacroiliac joints in the diagnosis of axial spondyloarthritis in the UK.
To develop evidence-based recommendations on the use of MRI in the diagnosis of axial SpA (axSpA). A working group comprising nine rheumatologists and nine musculoskeletal radiologists with an interest in axSpA was established, with support from the British Society of Spondyloarthritis (BRITSpA). Two meetings were held. In the first meeting, research questions were formulated. In the second meeting, the results of a systematic literature review designed to inform the recommendations were reviewed. An anonymized Delphi process was used to formulate the final set of recommendations. For each recommendation, the level of evidence and strength of recommendation was determined. The level of agreement was assessed using a 0-10 numerical rating scale. Two overarching principles were formulated, as follows: The diagnosis of axSpA is based on clinical, laboratory and imaging features (overarching principle 1), and patients with axSpA can have isolated inflammation of either the sacroiliac joints or the spine (overarching principle 2). Seven recommendations addressing the use of MRI in the assessment of patients with suspected axSpA were formulated, covering topics including recommended sequences, anatomical coverage, acquisition parameters and interpretation of active and structural MRI lesions. The level of agreement for each recommendation was very high (range 8.8-9.8). A joint rheumatology and radiology consensus on the acquisition and interpretation of MRI in axSpA diagnosis was achieved, and a research agenda formulated. This consensus should help standardize practice around MRI and ensure a more informed, consistent approach to the diagnosis of axSpA.


Factors Associated With Survival in Patients With Synovial Cell Sarcoma of the Head and Neck: An Analysis of 167 Cases Using the SEER (Surveillance, Epidemiology, and End Results) Database.
Synovial cell sarcoma of the head and neck (SCSHN) is a rare tumor associated with significant morbidity and mortality. The literature regarding these tumors is limited to case series and case reports. We used data from the population-based US Surveillance, Epidemiology, and End Results (SEER) cancer registry to determine factors affecting both overall survival and disease-specific survival of patients with SCSHN. To determine the clinicopathologic and therapeutic factors determining survival in patients with SCSHN. The SEER registry was reviewed for patients with primary SCSHN from January 1, 1973, to January 1, 2011. Overall survival (OS) and disease-specific survival. A total of 167 cases of SCSHN were identified. The mean (SD) age at diagnosis was 37.9 (17.3) years, and 100 (59.9%) of the patients were males. The monophasic spindle cell and biphasic variants were the most common histologic subtypes. Surgical resection and radiotherapy were performed in 150 (89.8%) and 108 (64.7%) of the cases, respectively. The median OS at 2, 5, and 10 years was 77%, 66%, and 53%, respectively. Univariate Kaplan-Meier survival analysis revealed that age, race, and tumor stage and size were associated with improved survival. Histologic subtype was not associated with significant differences in survival. Radiotherapy was associated with improved disease-specific survival (hazard ratio [HR], 0.29 [95% CI, 0.12-0.68]; P = .003), but surgical management was not associated with improved survival (HR, 0.52 [95% CI, 0.19-1.46]; P = .21). Multivariate Cox regression analysis revealed that size greater than 5 cm (adjusted HR, 3.60 [95% CI, 1.43-9.08]; P = .007) and stage at presentation (adjusted HR, 3.86 [95% CI, 2.01-7.44]; P < .001) were independent determinants of OS. In separate analysis of cohorts with tumors 5 cm or less and larger than 5 cm, stage at presentation was found to be a significant indicator of the probability of survival in both cohorts (adjusted HR, 3.10 [95% CI, 1.46-6.60]; P = .003 and 5.32 [95% CI, 1.49-18.98]; P = .01, respectively); surgical resection and radiotherapy were not associated with differential survival outcomes using this model. Synovial cell sarcoma of the head and neck is rare. Independent significant determinants of survival include size (>5 cm) and stage at presentation. Histologic subtype of the tumor is not a significant indicator of the probability of survival. Surgical resection and radiotherapy were not independent determinants of survival.


Cultural diffusion of Indo-Aryan languages into Bangladesh: A perspective from mitochondrial DNA.
Although both linguistic and historical studies indicated only a small group of Aryans had been involved into the diffusion of Indo-Aryan languages into Bangladesh, no genetic studies had been carried out to prove this notion. By studying mitochondrial DNA variants of 240 Bengali speakers in Bangladesh, among which 23 mitogenomes are completely sequenced, we found a high proportion of South Asian components in this group. By contrast, only a small proportion of lineages can be traced back to western Eurasia, which could be attributed to recent gene flow. Our results implied a cultural diffusion of the Indo-Aryan languages into Bangladesh.