MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors.
Multi-modality image-guided radiotherapy is the standard of care in contemporary cancer management; however, it is not common in preclinical settings due to both hardware and software limitations. Soft tissue lesions, such as orthotopic prostate tumors, are difficult to identify using cone beam computed tomography (CBCT) imaging alone. In this study, we characterized a research magnetic resonance (MR) scanner for preclinical studies and created a protocol for combined MR-CBCT image-guided small animal radiotherapy. Two in-house dual-modality, MR and CBCT compatible, phantoms were designed and manufactured using 3D printing technology. The phantoms were used for quality assurance tests and to facilitate end-to-end testing for combined preclinical MR and CBCT based treatment planning. MR and CBCT images of the phantoms were acquired utilizing a Varian 4.7 T scanner and XRad-225Cx irradiator, respectively. The geometry distortion was assessed by comparing MR images to phantom blueprints and CBCT. The corrected MR scans were co-registered with CBCT and subsequently used for treatment planning. The fidelity of 3D printed phantoms compared to the blueprint design yielded favorable agreement as verified with the CBCT measurements. The geometric distortion, which varied between -5% and 11% throughout the scanning volume, was substantially reduced to within 0.4% after correction. The distortion free MR images were co-registered with the corresponding CBCT images and imported into a commercial treatment planning software SmART Plan. The planning target volume (PTV) was on average 19% smaller when contoured on the corrected MR-CBCT images relative to raw images without distortion correction. An MR-CBCT based preclinical workflow was successfully designed and implemented for small animal radiotherapy. Combined MR-CBCT image-guided radiotherapy for preclinical research potentially delivers enhanced relevance to human radiotherapy for various disease sites. This novel protocol is wide-ranging and not limited to the orthotopic prostate tumor study presented in the study.


Population size drives industrial Saccharomyces cerevisiae alcoholic fermentation and is under genetic control.
Alcoholic fermentation (AF) conducted by Saccharomyces cerevisiae has been exploited for millennia in three important human food processes: beer and wine production and bread leavening. Most of the efforts to understand and improve AF have been made separately for each process, with strains that are supposedly well adapted. In this work, we propose a first comparison of yeast AFs in three synthetic media mimicking the dough/wort/grape must found in baking, brewing, and wine making. The fermentative behaviors of nine food-processing strains were evaluated in these media, at the cellular, populational, and biotechnological levels. A large variation in the measured traits was observed, with medium effects usually being greater than the strain effects. The results suggest that human selection targeted the ability to complete fermentation for wine strains and trehalose content for beer strains. Apart from these features, the food origin of the strains did not significantly affect AF, suggesting that an improvement program for a specific food processing industry could exploit the variability of strains used in other industries. Glucose utilization was analyzed, revealing plastic but also genetic variation in fermentation products and indicating that artificial selection could be used to modify the production of glycerol, acetate, etc. The major result was that the overall maximum CO(2) production rate (V(max)) was not related to the maximum CO(2) production rate per cell. Instead, a highly significant correlation between V(max) and the maximum population size was observed in all three media, indicating that human selection targeted the efficiency of cellular reproduction rather than metabolic efficiency. This result opens the way to new strategies for yeast improvement.


Paclitaxel-based chemotherapy for advanced pancreatic cancer after gemcitabine-based therapy failure: a case series of 5 patients.
Gemcitabine (GEM) is a gold-standard chemotherapy agent for advanced pancreatic cancer. Because of the malignant character of the disease, nearly all patients show disease progression despite treatment with GEM-based chemotherapy; therefore, second-line chemotherapy may be beneficial for these patients. We report a retrospective analysis of 5 patients with advanced pancreatic cancer, treated with a paclitaxel-containing regimen as second-, third- or fourth-line chemotherapy after various therapies, such as a GEM-based regimen, S-1 regimen, and chemoradiation. We retrospectively analyzed the efficacy and adverse events, and evaluated the paclitaxel-containing regimens. A review of the literature is also discussed. The median overall survival from the start of salvage therapy was 10.7 months. The disease control rate of the paclitaxel-containing regimen according to RECIST criteria was 60%, including complete response in 0 patients, partial response in 3, and stable disease in 2. Two patients had malignant ascites at the start of this salvage therapy, and in both of them the ascites and clinical complaints improved. Grade 3 and 4 hematological adverse events were observed in 2 patients and 1 patient, respectively. Salvage paclitaxel-based therapy could be beneficial to advanced pancreatic cancer patients who maintain good performance status after several chemotherapy failures.


Memories of past episodes shape current intentions and decisions.
This research tested the hypothesis that people's decisions and future plans are influenced by recently activated autobiographical memories. University students rated the overall quality of their college experiences. They were also asked to describe a specific memory of being either satisfied or dissatisfied with the university. Control participants did not describe a memory. After statistically controlling for pre-existing attitudes towards the university, students who recounted a positive memory expressed the strongest intentions to donate money to the university, attend a class reunion, and recommend the university to others, and they were more likely than controls to specify that an actual donation be made to the university rather than to another charity. Emotional intensity of positive memories predicted future plans and donation decisions. Students who recounted a negative memory also tended to favour the university in their actual donation decisions compared to controls. Prompting the recall of emotional memories may be an effective way to influence intentions and decisions.


Feedback-linearization-based neural adaptive control for unknown nonaffine nonlinear discrete-time systems.
A new feedback-linearization-based neural network (NN) adaptive control is proposed for unknown nonaffine nonlinear discrete-time systems. An equivalent model in affine-like form is first derived for the original nonaffine discrete-time systems as feedback linearization methods cannot be implemented for such systems. Then, feedback linearization adaptive control is implemented based on the affine-like equivalent model identified with neural networks. Pretraining is not required and the weights of the neural networks used in adaptive control are directly updated online based on the input-output measurement. The dead-zone technique is used to remove the requirement of persistence excitation during the adaptation. With the proposed neural network adaptive control, stability and performance of the closed-loop system are rigorously established. Illustrated examples are provided to validate the theoretical findings.


Validity of 18F-fluorodeoxyglucose imaging with a dual-head coincidence gamma camera for detection of myocardial viability.
This study investigated the validity of myocardial 18F-fluorodeoxyglucose (FDG) imaging with a dual-head gamma camera operated in coincidence detection mode (DCD-I) by comparing this technique with conventional PET and SPECT with ultra-high-energy general-purpose collimators (UHGPs). The subjects included 5 healthy volunteers and 20 patients with a history of myocardial infarction. FDG (370 MBq) was injected intravenously after 75-g oral glucose loading, and PET, UHGP SPECT and DCD-I were performed 45, 60 and 210 min, respectively, after the injection. The target-to-background ratio of each imaging method was evaluated for the healthy volunteers by comparing myocardial uptake with uptake in the upper lungs or left ventricular cavity. Agreement between the results of the various imaging methods was investigated for the myocardial infarction patients, as was the validity of DCD-I for assessing myocardial viability as judged by comparison with myocardial perfusion SPECT. The left ventricular wall was divided into 18 regions, and uptake was evaluated using a five-grade defect score (0 = normal; 1-3 = low uptake; 4 = defect). The mean ratio of myocardial counts to lung counts was lower on the DCD images (2.77 +/- 1.12) than on the UHGP SPECT images (3.69 +/- 0.98) (P < 0.05). In contrast, the mean ratio of myocardial counts to left ventricular cavity counts was higher on the DCD images (2.76 +/- 1.36) than on the UHGP SPECT images (1.98 +/- 0.70) (P < 0.05). For the patients, only 30.6% of the defect scores obtained by DCD-I agreed with the scores obtained by PET, and the defect scores in the inferior and septal walls were higher for the DCD images than for the PET images. When DCD-I was compared with PET without attenuation correction (AC), agreement improved to 58.3%. When corrected by a modified AC method, DCD-I improved to 48.1%. Agreement between UHGP SPECT and PET was 55.0%. Of the segments (64) for which the defect score of the myocardial perfusion image was greater than that for the FDG PET image, DCD-I without AC, DCD-I with AC and UHGP SPECT allowed an accurate diagnosis in 12 (18.8%), 31 (48.4%) and 43 (67.2%), respectively. The image quality of DCD-I is superior to that of UHGP SPECT. However, because the effect of attenuation is marked, accurate AC, by the transmission method, for example, is required to equal the validity of PET.


Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors.
Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3) in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1α inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2α exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1α mutant behaviors. Using patch-clamp recordings in Nrxn2α knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. We also analyse at this cellular level a novel NRXN2 mouse model that carries a combined deletion of Nrxn2α and Nrxn2β. Electrophysiological analysis of this Nrxn2-mutant mouse shows surprisingly similar defects of excitatory release to Nrxn2α, indicating that the β-variant of Nrxn2 has no strong function in basic transmission at these synapses. Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. Furthermore, at Nrxn2α and Nrxn2-mutant excitatory synapses we find an altered facilitation and N-methyl-D-aspartate receptor (NMDAR) function because NMDAR-dependent decay time and NMDAR-mediated responses are reduced. As Nrxn can indirectly be linked to NMDAR via neuroligin and PSD-95, the trans-synaptic nature of this complex may help to explain occurrence of presynaptic and postsynaptic effects. Since excitatory/inhibitory imbalances and impairment of NMDAR function are alledged to have a role in autism and schizophrenia, our results support the idea of a related pathomechanism in these disorders.


Management [corrected] of conversions to cardiopulmonary bypass in beating heart coronary surgery.
This study investigated outcomes in patients undergoing coronary artery bypass grafting (CABG) without cardiopulmonary bypass (CPB), who needed conversion to CPB. Between September, 1998 and September, 2003, 1000 CABG procedures were performed in a Cardiovascular Clinic, University Clinical Centre Tuzla. Multivessel CABG were selected arbitrarily for CABG without CPB (OPCAB) or CABG with CPB (ONCAB). Patients who required conversion due to technical difficulty with grafting were performed with ONCAB including cardioplegic arrest. Patients with severe hemodynamic instability and cardiac arrest were performed as ONCAB without crossclamping, while patients converted for mild to moderate hemodynamic instability were given cardioplegic arrest or not, depending on surgeon preference. 493 operations were scheduled and performed as ONCAB (49.3%), 468 as OPCAB (46.8%) and 39 originally scheduled OPCAB operations were converted to ONCAB (7.7% of originally scheduled OPCAB patients or 3.9% of total number of CABG). Reasons for conversions were: mild to severe hemodynamic instability--28 (71.8%); poor vessels or difficult graft revision--11 (28.2%). Patients converted because of technical difficulty or mild hemodynamic instability behaved as regular ONCAB patients. In the 9 patients who were emergently converted due to cardiac arrest or ventricular fibrillation, 3 patients had stroke and 3 severe myocardial ischemia requiring intraaortic balloon pump. It is of great importance to keep conversions to CPB due to cardiac arrest at a low level. The serious complications seen in such patients can significantly impede the overall benefits of a successful OPCAB program.


Modeling Retention Behavior on Analysis of Hallucinogenic Mushrooms Using Hydrophilic Interaction Liquid Chromatography.
The goal of this work was to investigate and compare the selectivity of three different hydrophilic interaction liquid chromatography (HILIC) charge modulated amide columns, iHILIC®-Fusion, iHILIC®-Fusion(+) and iHILIC®-Fusion(P), for analysis of compounds in hallucinogen mushrooms. An extract of a truffle-like fungus containing psilocin, psilocybin and baeocystin was chosen as test material. Three different modeling methods were applied to describe the retention times of constituents in isocratic separation mode as a function of mobile phase composition, pH and temperature. Two models using DryLab® 2010 assumed quadratic and exponential relationship between the retention time and solvent fraction of aqueous component of the mobile phase, respectively. These models also illustrate the van't Hoff like equation to describe the temperature-dependence of the retention factor and the theory of Snyder et al. to estimate the retention factor as a function of pH of the aqueous mobile phase component. The third model using STATISTICA® multivariate data analysis in a predefined experimental space was able to predict the retention times. All HILIC columns in this comparison were proved to be suitable for separation of the two hallucinogenic alkaloids from each other and from the matrix components. Majority of compounds were separated with satisfactory resolutions required by the comparative analysis despite some of them were not fully baseline separated. It was found the best modeling was obtained by using the quadratic approach to predict chromatograms for predefined chromatographic conditions (volumetric ratio of acetonitrile to buffer, pH of the buffer and temperature), while the exponential model proved to be the worst for prediction. The modeling with multivariate data analysis fell between the other two methods.


Hyperplasia or neoplasia. Macroscopic versus microscopic appearance of colorectal polyps.
Small light-red sessile colorectal polyps, 1-5 mm in diameter, are generally believed to be hyperplastic (non-neoplastic), whereas polyps that are dark-red in contrast to the surrounding mucosa are thought to be adenomas. This hypothesis was tested prospectively in a series of 209 polyps removed by one endoscopist in a 6-month period. A 'blinded' pathologist provided the histopathological diagnosis. Twenty-two per cent of polyps described as hyperplastic by the endoscopist were adenomas, whereas 40% of those believed to be adenomas, 1-5 mm in diameter, were hyperplastic. The diagnostic effectivity of the endoscopist increased with increasing size of the polyps. In conclusion, all colorectal polyps must be removed to prevent possible precancerous lesions from being left behind and to define a group of patients with increased risk of new adenomas, in whom follow-up examinations should be considered.


[Indications and results of preventive endoprosthezing of the abdominal wall during operations on organs of the abdominal cavity and retroperitoneal space].
Complex examination and treatment of 120 patients with anatomo-functional insufficiency of the abdominal wall was made after operations on organs of the abdominal cavity and retroperitoneal space. In the 1st group (60 patients) the abdominal wall was sutured by traditional methods. In the 2nd group (60 patients) laparotomy was followed by implantation of polypropylene endoprosthesis by over-aponeurotic method, and suturing of the lateral wall--by sub-aponeurotic method. At the long-term postoperative period the postoperative ventral hernias were formed in 21.6% of patients of the 1st group, in the 2nd group of patients hernias were not detected. Physical component of quality of life of the 2nd group was 1.5 times, and mental component 1.7 times higher than in the 1st group.


Liver abscess caused by Clostridium difficile.
We report the first case of an infected cyst and liver abscess caused by Clostridium difficile. It recurred 11 months later, despite therapy with vancomycin and percutaneous drainage. Administration of metronidazole following percutaneous drainage achieved a favorable outcome.


Differential distribution of gonadotropin-releasing hormone-immunoreactive neurons in the stingray brain: functional and evolutionary considerations.
Gonadotropin-releasing hormone (GnRH) is a neuropeptide that occurs in multiple structural forms among vertebrate species. Bony fishes, amphibians, reptiles, birds, and mammals express different forms of GnRH in the forebrain and endocrine regions of the hypothalamus which regulate the release of reproductive gonadotropins from the pituitary. In contrast, previous studies on bony fishes and tetrapods have localized the chicken GnRH-II (cGnRH-II) nucleus in the midbrain tegmentum and, combined with cladistic analyses, indicate that cGnRH-II is the most conserved form throughout vertebrate evolution. However, in elasmobranch fishes, the neuroanatomical distribution of cGnRH-II and dogfish GnRH (dfGnRH) cells and their relative projections in the brain are unknown. We used high-performance liquid chromatography and radioimmunoassay to test for differential distributions of various GnRH forms in tissues from the terminal nerve (TN) ganglia, preoptic area, and midbrain of the Atlantic stingray, Dasyatis sabina. These experiments identified major peaks that coelute with cGnRH-II and dfGnRH, minor peaks that coelute with lamprey GnRH-III (lGnRH-III), and unknown forms. Immunocytochemistry experiments on brain sections show that dfGnRH-immunoreactive (-ir) cell bodies are localized in the TN ganglia, the caudal ventral telencephalon, and the preoptic area. Axons of these cells project to regions of the hypothalamus and pituitary, diencephalic centers of sensory and behavioral integration, and the midbrain. A large, discrete, bilateral column of cGnRH-II-ir neurons in the midbrain tegmentum has sparse axonal projections to the hypothalamus and regions of the pituitary but numerous projections to sensory processing centers in the, midbrain and hindbrain. Immunocytochemical and chromatographic data are consistent with the presence of lGnRH-III and other GnRH forms in the TN that differ from dfGnRH and cGnRH-II. This is the first study that shows differential distribution of cGnRH-II and dfGnRH in the elasmobranch brain and supports the hypothesis of divergent function of GnRH variants related to gonadotropin control and neuromodulation of sensory function.


The effects of topical diazoxide on hair follicular growth and physiology of the stumptailed macaque.
Diazoxide, an anti-hypertensive agent, has diverse pharmacologic effects; hypertrichosis, hyperglycemia associated with suppression of insulin release, and elevation of serum levels of androgens. Taking advantage of the hypertrichotic side effects of diazoxide, we examined the effect of topical application of the drug on hair regrowth in the bald frontal scalp of stumptailed macaques (Macaca arctoides); we also monitored systemic side effects. Using 7 adult stumptails, we applied diazoxide (5% solution in a vehicle) topically on the bald frontal scalp, once a day, 5 days per week. Two of seven macaques had vehicle alone applied. Hair growth was monitored by photographic recording (once every month) and by sequential analysis of folliculograms from biopsied skin (once every 4 months). We also examined body weight, hematology, blood pressure, heart rate, serum levels of testosterone and dihydrotestosterone, and glucose tolerance for a 4-month period. All 5 diazoxide-treated animals showed thickening and maintenance of the frontal hair during the entire treatment period (16 months). Analysis of folliculograms showed progressive enlargement of hair follicular size and acceleration of its cyclic growth from telogen to anagen phase and prolongation of anagen phase in all treated animals. Controls showed no consistent progressive changes of follicular growth. None of the animals treated with diazoxide showed abnormal changes in physical growth, cardiovascular function, serum levels of androgens, glucose tolerance (including insulin levels), or hematology.


Multimorbidity and functional limitation: the role of social relationships.
To examine the relationship between multimorbidity and functional limitation, and how social relationships alter that association. This cross-sectional study used data collected by self-reported questionnaires from adults aged 65 years and older living in a rural area in Japan in 2017. This analysis included complete data from 570 residents. Multimorbidity status was defined as having two chronic diseases exist simultaneously in one individual, and the function status was measured by their long-term care needs. Social relationships were assessed by the Index of Social Interaction and divided into high and low levels. Multiple logistic regression analysis was used to examine the association between social relationships and functional limitation and to assess the role of social relationships in this association. The logistic regression model indicated that the risk of functional limitation was higher in multimorbidity participants than free-of-multimorbidity participants (OR = 2.55, 95% CI = 1.56-4.16). Compared with participants with no multimorbidity and a high level of social relationships, low level of social relationships increased the risk of functional limitation among participants both with and without multimorbidity, with the OR = 7.71, 95% CI = 3.03-19.69 and OR = 3.28, 95% CI = 1.30-8.27, respectively. However, no significant result was found in participants with multimorbidity and a high level of social relationships (P = 0.365). Multimorbidity was associated with functional limitations. However, this association could be increased by a low level of social relationships and decreased by a high level of social relationships.


Nucleic Acid Therapy for β-Thalassemia.
β-thalassemia is caused by mutations in the β-globin gene which diminishes or abolishes β-globin chain production. This reduction causes an imbalance of the α/β-globin chain ratio and contributes to the pathogenesis of the disease. Several approaches to reduce the imbalance of the α/β ratio using several nucleic acid-based technologies such as RNAi, lentiviral mediated gene therapy, splice switching oligonucleotides (SSOs) and gene editing technology have been investigated extensively. These approaches aim to reduce excess free α-globin, either by reducing the α-globin chain, restoring β-globin expression and reactivating γ-globin expression, leading a reduced disease severity, treatment necessity, treatment interval, and disease complications, thus, increasing the life quality of the patients and alleviating economic burden. Therefore, nucleic acid-based therapy might become a potential targeted therapy for β-thalassemia.


A validated ultra high-pressure liquid chromatography method for separation of candesartan cilexetil impurities and its degradents in drug product.
A selective, specific, and sensitive "Ultra High-Pressure Liquid Chromatography" (UPLC) method was developed for determination of candesartan cilexetil impurities as well asits degradent in tablet formulation. The chromatographic separation was performed on Waters Acquity UPLC system and BEH Shield RP18 column using gradient elution of mobile phase A and B. 0.01 M phosphate buffer adjusted pH 3.0 with Orthophosphoric acid was used as mobile phase A and 95% acetonitrile with 5% Milli Q Water was used as mobile phase B. Ultraviolet (UV) detection was performed at 254 nm and 210 nm, where (CDS-6), (CDS-5), (CDS-7), (Ethyl Candesartan), (Desethyl CCX), (N-Ethyl), (CCX-1), (1 N Ethyl Oxo CCX), (2 N Ethyl Oxo CCX), (2 N Ethyl) and any unknown impurity were monitored at 254 nm wavelength, and two process-related impurities, trityl alcohol and MTE impurity, were estimated at 210 nm. Candesartan cilexetil andimpurities were chromatographed with a total run time of 20 min. Calibration showed that the response of impurity was a linear function of concentration over the range limit of quantification to 2 μg/mL (r2≥0.999) and the method was validated over this range for precision, intermediate precision, accuracy, linearity, and specificity. For the precision study, percentage relative standard deviation of each impurity was <15% (n=6). The method was found to be precise, accurate, linear, and specific. The proposed method was successfully employed for estimation of candesartan cilexetil impurities in pharmaceutical preparations.


Pig peripheral blood mononuclear leucocyte subsets are heritable and genetically correlated with performance.
Indicator traits used to select pigs for increased resistance to infection or improved health must be heritable and, preferably, be associated with improved performance. We estimated the heritability of a range of immune traits and their genetic and phenotypic correlations with growth performance. We measured immune traits on 589 pigs and performance on 1941 pigs from six farms, three of which were classified as 'high health status' (i.e. specific pathogen-free) and three were of lower health status. All pigs were apparently healthy. Immune traits were total white blood cells (WBC), and peripheral blood mononuclear leucocyte (PBML) subsets positive for CD4, CD8α, gamma delta (γδ) T cell receptor, CD11R1 (natural killer cell marker), B cell and monocyte markers at the start and the end of standard growth performance tests. At both time points, all immune traits were moderately to highly heritable except for CD8α+ cells. At end of test, heritability estimates (h2) (±s.e.) were 0.18 (±0.11) for total WBC count. For PBML subset proportions, the heritabilities were 0.52 (±0.14) for γδ TCR+ cells, 0.62 (±0.14) for CD4+ cells, 0.44 (±0.14) for CD11R1+ cells, 0.58 (±0.14) for B cells and 0.59 (±0.14) for monocytes. Farm health status affected the heritabilities for WBC, being substantially higher on lower health status farms, but did not have consistent effects on heritabilities for the PBML subsets. There were significant negative genetic correlations between numbers and proportions of various PBML subsets and performance, at both start and end of test. In particular, the proportion of PBML cells that were CD11R1+ cells, at end of test, was strongly correlated with daily gain (rg = -0.72; P < 0.01). There were also weaker but significant negative phenotypic correlations between PBML subsets measured at end of test and performance, for γδ+ T cells, CD8α+, CD11R1+ cells, B cells or monocytes. Phenotypic correlations with daily gain were generally lower at the start of test than at the end of test. These results show that most of the major pig PBML subsets are heritable, and that systemic levels of several of these PBML subsets are genetically negatively correlated with performance. This approach provides a basis for using immune trait markers when selecting boars that can produce higher-performing progeny.


Electroactive polyglycine coatings for nanobiosensing applications: Label-free DNA hybridization, DNA-Antitumor agent interaction and antitumor agent determination.
Bioinspired materials have attracted great attention due to their great functionality, bioactivity and biocompability. In particular, electroactive polyamino acid surfaces endow preparation of robust coatings for various applications. In this research article, preparation of carbon nanotubes doped polyglycine coated electrodes and their applications in the biomedical field such as DNA hybridization, DNA-antitumor agent interaction and antitumor agent determination were described. This biosensing platform was created using a simple, reproducible and fast in situ and one-pot electropolymerization procedure onto graphite surfaces by cyclic voltammetry. The coated electrodes were characterized with cyclic voltammetry and electrochemical impedance spectroscopy (EIS). After the characterization studies, bioapplications of the proposed electrode were demonstrated. The new electrode led to significant improvement for the investigation of the electrochemical behavior of double-stranded DNA (dsDNA). 6-fold and 5-fold improvements were obtained for oxidation of the electroactive DNA bases, guanine (G) and adenine (A), respectively over the bare electrode. For these steps, each electrode was characterized with scanning electron microscopy (SEM) and energy dispersive X-ray (EDX). Then, DNA hybridization studies were performed in the light of these results. The proposed electrode allowed the quantification of specific target DNA down to 11.2 fM in serum samples (n = 3). In addition, it constituted a sensitive biosensing platform for electrochemical monitoring of the interaction between dsDNA and a commonly used antitumor agent, Mitomycin C. Mitomycin C determination was also carried out using the inhibition effect occurred at the guanine oxidation signal. The detection limit of this antitumor agent was found as 1.78 mg L-1 in untreated serum samples (n = 3).


Recent advances in the control and function of the anterior pituitary.
Major advances in our understanding of the synthesis and release of anterior pituitary hormones have been made over the past several years. Neurons of the hypothalamus have been found to serve as "neuroendocrine transducers" in that they have both electrical and secretory functions. Peptidergic neurons respond to appropriate stimuli with a release of hypothalamic factors into the hypophyseal-portal system. These factors or hormones ultimately control the endocrine function of anterior pituitary cells. Three hormones, Thyrotropin Releasing Hormone (TRH), Gonadotropin Releasing Hormone (GnRH or LHRH) and somatostatin have been identified, synthesized and tested for clinical applications. The clinical assessment of pituitary function has been greatly improved by new and improved radioimmunoassays. One of the recent clinical advances in the area of pituitary disease has been the determination of the relatively high frequency of prolactinomas. Prolactin secreting microadenomas are an important and treatable cause of amenorrhea and infertility in young women. In addition, many pituitary tumors previously believed to be non-functional or "chromophobe adenomas" appear to be prolactinomas. Many new diagnostic and therapeutic techniques are continuing to be developed to improve our management of patients with hypothalamic-pituitary disease.


Effectiveness of adjunctive low-frequency repetitive transcranial magnetic stimulation therapy over the left dorsolateral prefrontal cortex in patients with obsessive-compulsive disorder refractory to medical treatment:A double-blind, randomized clinical trial.
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder. The Food and Drug Administration (FDA) approved repetitive transcranial magnetic stimulation (rTMS) to treat OCD in 2018. So far, various approaches to treat this disorder have been evaluated. We evaluated the effect of adjunctive low-frequency rtMS over the left dorsolateral prefrontal cortex in patients with OCD refractory to treatment. The present clinical trial was done on 37 patients with OCD referring from the psychiatry clinic, 22 Bahman Hospital, Qazvin province, between 2018 and 2020 and patients were randomly divided into two groups. The intervention group received rTMS treatment at 1 Hz for 20 min (1200 pulses/day) over the left DLPFC area as adjunctive to the medical treatment three times a week and for five weeks, whereas those in the control group were subjected to only the sham condition plus their medical treatment. The Yale-Brown Obsessive-Compulsive Scale (Y-BOC.S) was completed by patients before the study, following sessions 5 and 10 during the intervention, at the end of the intervention, and three to six months after the intervention under the direct supervision of a psychiatrist. SPSS software version 26 was used to compare the results between the two groups. The intervention group showed significantly lower mean Y-BOCS scores after the intervention and at follow-up (P < 0.05) and all patients of the intervention group showed significantly lower Y-BOCS scores than their own baseline scores (P < 0.05). Also, using antipsychotic agents along with the serotonergic agents yielded significantly lower scores in the intervention group at the end of the intervention (P < 0.05). All the patients were found with higher follow-up scores than their scores at the end of the intervention; however, this difference was not significant (p > 0.05). Adjunctive low-frequency (1 Hz) rTMS over the left DLPFC is able to effectively reduce Y-BOCS score in OCD patients refractory to treatment following 15 sessions, and the reduction was durable even after three to six months. Using antipsychotic agents as an adjuvant with serotonergic agents was identified as a possible predictor for response to adjunctive rTMS therapy.


High pressure modifies respiratory activity in isolated rat brain stem-spinal cord.
Exposure to hyperbaric pressure causes a constellation of motor disturbances and ventilatory difficulties in animals and humans. The present experiments were designed to examine the effects of hyperbaric pressure on the rhythmic activity of the respiratory center in the absence of peripheral sensory afferents by using the isolated brain stem-spinal cord preparation from newborn rats. In addition, we examined the effect of pressure on the response of the respiratory center to sensory input from the trigeminal and vagus cranial nerves. Hyperbaric pressure significantly depressed the mean inspiratory drive (frequency X time integral of single electrical bursts) in C5 but not in C1 ventral roots. Pressure also reduced the amount of inhibition on the respiratory activity normally exerted by trigeminal and vagal nerve stimulation and in some cases reversed it to excitation. It is concluded that in the absence of sensory input, exposure to hyperbaric pressure depresses central respiratory activity. However, in an intact system, it may alter the balance between excitation and inhibition and render the system hyperexcitable to the same sensory input.


Osteolytic lesions (brown tumors) of primary hyperparathyroidism misdiagnosed as multifocal giant cell tumor of the distal ulna and radius: a case report.
Brown tumors represent a rare clinical manifestation reported in approximately 3% of patients with primary hyperparathyroidism and correspond to radiologically osteolytic lesions with well-defined borders in different parts of the skeleton. We report the case of a 53-year-old white man who presented to our hospital with osteolytic lesions of his distal ulna and radius, causing pain and swelling of 2-month duration. A subsequent biopsy revealed histological features consistent with giant cell tumor and a complete resection of his distal ulna was followed, along with curettage and cementoplasty of the distal radial metaphysis. Two weeks later, he was re-admitted with diffuse musculoskeletal soreness, anorexia, constipation, nausea, and localized abdominal pain and multiple osteolytic lesions on plain radiographs. A histopathological examination of the ulna and radius specimens showed similar findings and, given the multifocality, brown tumors related to primary or secondary hyperparathyroidism was included in the differential diagnosis. A laboratory examination showed high total serum calcium (14.5 mg/dl) and low serum phosphorus and 25-hydroxyvitamin D levels. Primary hyperparathyroidism was suspected and confirmed by the elevated parathyroid hormone levels of 1453 pg/mL. At radiological work-up, using computed tomography, ultrasonography, and parathyroid subtraction technetium-99m sestamibi scintigraphy, a 4.5 × 2.5 × 3.2 cm mass emanating from the right lobe of his thyroid gland was detected, displaying extensive uptake in the right lower parathyroid gland. After appropriate medical support including hyperhydration and high doses of diuretics and diphosphonates, his laboratory profile normalized and he underwent total thyroidectomy with removal of the parathyroid glands. Our patient is now recovering 12 months after surgery, with normal values of serum parathyroid hormone and calcium levels. The lytic bone lesions have almost disappeared and no other additional orthopedic intervention was necessary. The present case report emphasizes the need of inclusion of brown tumors in the differential diagnosis of multifocal osteolytic bone lesions, in order to avoid harmful surgical interventions. Laboratory testing of serum phosphate, calcium levels, and parathyroid hormone levels should always be included in the routine survey of patients with multifocal osteolytic lesions.


Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats.
Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippocampal deficits seen in schizophrenia.


Hierarchical structure and the prediction of missing links in networks.
Networks have in recent years emerged as an invaluable tool for describing and quantifying complex systems in many branches of science. Recent studies suggest that networks often exhibit hierarchical organization, in which vertices divide into groups that further subdivide into groups of groups, and so forth over multiple scales. In many cases the groups are found to correspond to known functional units, such as ecological niches in food webs, modules in biochemical networks (protein interaction networks, metabolic networks or genetic regulatory networks) or communities in social networks. Here we present a general technique for inferring hierarchical structure from network data and show that the existence of hierarchy can simultaneously explain and quantitatively reproduce many commonly observed topological properties of networks, such as right-skewed degree distributions, high clustering coefficients and short path lengths. We further show that knowledge of hierarchical structure can be used to predict missing connections in partly known networks with high accuracy, and for more general network structures than competing techniques. Taken together, our results suggest that hierarchy is a central organizing principle of complex networks, capable of offering insight into many network phenomena.


Conversion of quinoa and lupin agro-residues into biochar in the Andes: An experimental study in a pilot-scale auger-type reactor.
In the last decades, the cultivation of quinoa and lupin became an important source of income for Andean farmers due to the demand for high nutrient-density foods from the Global North. The increase in the cultivation intensity caused by this exogenous demand led to the overexploitation of local ecosystems and a decrease in soil fertility. As an alternative to recover and improve soil quality, this work uses a pilot-scale auger pyrolysis reactor, implemented in the Andes, to assess the conversion of the agro residues generated in the post-harvesting processes of quinoa and lupin into biochar for soil amendment. Following the European Biochar Certificate guidelines, the pyrolyzed quinoa stems can be classified as biochar while the pyrolyzed quinoa husks can be classified as pyrogenic carbonaceous material. Both can be used for soil amendment considering their molar ratios (H/Corg, O/Corg) and carbon content. It was not possible to carbonize lupin stems and seedcases. Despite the altitude (2,632 m.a.s.l), the CO concentration during the carbonization of quinoa stems and husks were 1,024.4 and 559 mg/Nm3, this last, near the European eco-design standard of 500 mg/Nm3. A subsequent SWOT analysis showed the need to explore low-cost and low-complexity pyrolysis reactors that allow the decentralized conversion of agro residues at the farm-scale. The development of local standards to regulate the production and use of biochar is also essential to grant the safety of the processes, the quality of the products, and mobilize funds that allow implementation at relevant scales.


The interaction of the chaperonin tailless complex polypeptide 1 (TCP1) ring complex (TRiC) with ribosome-bound nascent chains examined using photo-cross-linking.
The eukaryotic chaperonin tailless complex polypeptide 1 (TCP1) ring complex (TRiC) (also called chaperonin containing TCP1 [CCT]) is a hetero-oligomeric complex that facilitates the proper folding of many cellular proteins. To better understand the manner in which TRiC interacts with newly translated polypeptides, we examined its association with nascent chains using a photo-cross-linking approach. To this end, a series of ribosome-bound nascent chains of defined lengths was prepared using truncated mRNAs. Photoactivatable probes were incorporated into these (35)S- labeled nascent chains during translation. Upon photolysis, TRiC was cross-linked to ribosome-bound polypeptides exposing at least 50-90 amino acids outside the ribosomal exit channel, indicating that the chaperonin associates with much shorter nascent chains than indicated by previous studies. Cross-links were observed for nascent chains of the cytosolic proteins actin, luciferase, and enolase, but not to ribosome-bound preprolactin. The pattern of cross-links became more complex as the nascent chain increased in length. These results suggest a chain length-dependent increase in the number of TRiC subunits involved in the interaction that is consistent with the idea that the substrate participates in subunit-specific contacts with the chaperonin. Both ribosome isolation by centrifugation through sucrose cushions and immunoprecipitation with anti-puromycin antibodies demonstrated that the photoadducts form on ribosome-bound polypeptides. Our results indicate that TRiC/CCT associates with the translating polypeptide shortly after it emerges from the ribosome and suggest a close association between the chaperonin and the translational apparatus.


Relations between inhibitory control and the development of academic skills in preschool and kindergarten: a meta-analysis.
Although there is evidence that young children's inhibitory control (IC) is related to their academic skills, the nature of this relation and the role of potential moderators of it are not well understood. In this meta-analytic study, we summarized results from 75 peer-reviewed studies of preschool and kindergarten children (14,424 children; 32-80 months old [M = 54.71 months; SD = 9.70]) across a wide range of socioeconomic status. The mean effect size (r) across studies was .27 (95% confidence interval [.24, .29]), indicating a moderate and statistically significant association between self-regulation and academic skills. The association between IC and academic skills was moderated by type of IC behavior task (i.e., hot vs. cool behavior task), by method of assessing IC (i.e., behavior task vs. parent report), and by academic subject (i.e., literacy vs. math), but not by other methods of assessing IC (i.e., behavior task vs. teacher report, parent report vs. teacher report) or by grade (i.e., preschool vs. kindergarten). The results of this meta-analysis suggest that there are preferred methods for assessing IC (i.e., cool behavior tasks, teacher reports) that should be considered when examining the relations between IC and academic skills in young children. (PsycINFO Database Record (c) 2014 APA, all rights reserved).


Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential as a marker of GH abuse in sports: a double blind, placebo-controlled study. The GH-2000 Study Group.
The effects of GH on bone remodeling in healthy adults have not been systematically investigated. An analysis of these effects might provide insights into GH physiology and might yield data useful for the detection of GH doping in sports. The aim of this study was to evaluate the effects of GH administration on biochemical markers of bone and collagen turnover in healthy volunteers. Ninety-nine healthy volunteers of both sexes were enrolled in a multicenter, randomized, double blind, placebo-controlled study and assigned to receive either placebo (40 subjects) or recombinant human GH (0.1 IU/kg day in 29 subjects and 0.2 IU/kg x day in 30 subjects). The treatment duration was 28 days, followed by a 56-day wash-out period. The biochemical markers evaluated were the bone formation markers osteocalcin and C-terminal propeptide of type I procollagen, the resorption marker type I collagen telopeptide, and the soft tissue marker procollagen type III. All variables increased on days 21 and 28 in the two active treatment groups vs. levels in both the baseline (P < 0.01) and placebo (P < 0.01) groups. The increment was more pronounced in the 0.2 IU/kg-day group and remained significant on day 84 for procollagen type III (from 0.53 +/- 0.13 to 0.61 +/- 0.14 kU/L; P < 0.02) and osteocalcin (from 12.2 + 2.9 to 14.6 +/- 3.6 UG/L; P < 0.02), whereas levels of C-terminal propeptide of type I procollagen and type I collagen telopeptide declined after day 42 and were no longer significantly above baseline on day 84 (from 3.9 +/- 1.2 to 5.1 +/-1.5 microg/L and from 174 +/- 60 to 173 +/- 53 microg/L, respectively). Gender-related differences were observed in the study; females were less responsive than males to GH administration with respect to procollagen type III and type I collagen telopeptide (P < 0.001). In conclusion, exogenous GH administration affects the biochemical parameters of bone and collagen turnover in a dose- and gender-dependent manner. As GH-induced modifications of most markers, in particular procollagen type III and osteocalcin, persist after GH withdrawal, they may be suitable markers for detecting GH abuse.


Uncontrolled asthma predicts severe COVID-19: a report from the Swedish National Airway Register.
Severe asthma increases the risk of severe COVID-19 outcomes such as hospitalization and death. However, more studies are needed to understand the association between asthma and severe COVID-19. A cohort of 150,430 adult asthma patients were identified in the Swedish National Airway Register (SNAR) from 2013 to December 2020. Data on body mass index, smoking habits, lung function, and asthma control test (ACT) were obtained from SNAR, and uncontrolled asthma was defined as ACT ⩽19. Patients with severe COVID-19 were identified following hospitalization or in death certificates based on ICD-10 codes U07.1 and U07.2. The Swedish Prescribed Drug register was used to identify comorbidities and data from Statistics Sweden for educational level. Multivariate logistic regression analyses were used to estimate associations with severe COVID-19. Severe COVID-19 was identified in 1067 patients (0.7%). Older age (OR = 1.04, 95% CI = 1.03-1.04), male sex (1.42, 1.25-1.61), overweight (1.56, 1.27-1.91), obesity (2.12, 1.73-2.60), high-dose inhaled corticosteroids in combination with long-acting β-agonists (1.40, 1.22-1.60), dispensed oral corticosteroids ⩾2 (1.48, 1.25-1.75), uncontrolled asthma (1.64, 1.35-2.00), cardiovascular disease (1.20, 1.03-1.40), depression (1.47, 1.28-1.68), and diabetes (1.52, 1.29-1.78) were associated with severe COVID-19, while current smoking was inversely associated (0.63, 0.47-0.85). When comparing patients who died from COVID-19 with those discharged alive from hospital until 31 December 2020, older age, male sex, and current smoking were associated with COVID-19 death. Patients with uncontrolled asthma and high disease burden, including increased asthma medication intensity, should be identified as risk patients for severe COVID-19. Furthermore, current smoking is strongly associated with COVID-19 death in asthma.


The steady-state kinetics of isotope exchange for one substrate-one product enzymic reactions.
Steady-state kinetic equations for isotope exchange are derived for a number of one substrate-one product enzymic mechanisms in which two molecules of substrate or product can be combined with an enzyme molecule at the one time (e.g. allosteric mechanisms). The usual assumption, that the radioactive material is distributed among the substrate and product components according to a first-order law, is not valid. One can recognize whether isotope-exchange kinetics of an enzyme reaction follows first-order behaviour by using various initial concentrations of the labelled substance added to a mixture.


A novel, radiolabel-free pulse chase strategy to study Kir3 channel ontogeny.
Kir3 channels are essential regulators of cellular excitability, maintaining cells at resting membrane potentials. While much research has been dedicated to elucidating the mechanisms regulating Kir3 channel gating, little is known regarding the channel's early associations with signaling partners, its stability at the plasma membrane or mechanisms regulating its internalization and degradation. To address these issues we have established an inducible Kir3.1 cell line that allows monitoring of a discrete "pulse" of channel as it progresses along the biosynthetic pathway. Using this system, we have been able to track Kir3 maturation and the influence of partner subunits on Kir3 lifetime and stability. Of note, we show that Kir3.1, in the absence of trafficking partner subunits, can exit the endoplasmic reticulum (ER) and reach the Golgi (though not the plasma membrane), and that expression of Kir3.3 subunits drastically reduced levels of Kir3.1 in the cell. We also show that interfering with trafficking from the ER to Golgi has a pronounced inhibitory effect on Kir3.1-Kir3.2 interactions, suggesting that this complex is stabilized either en route to the Golgi or in the Golgi itself. Finally, we showed that the Kir3 channel can reach the cell surface as early as 6 h post-induction and that removal of cell surface-localized channel occurs within 48 h. This system can be adapted to study the life cycle of any cellular protein without the confounds associated with radioactive labeling or the complications noted with expressing supraphysiological levels of proteins.


[Inhibitory and excitatory effects of methionine-enkephalin in the isolated rabbit ileum].
Methionine-enkephalin first inhibited and then stimulated the spontaneous rhythmic activity of the rabbit isolated ileum. The inhibitory effect of methionine-enkephalin was antagonized by naloxone. On the contrary, atropine did not change significantly either the inhibitory or the stimulatory action of this peptide. Furthermore, methionine-enkephalin inhibited the peristaltic reflex of the rabbit isolated ileum as well. Naloxone completely antagonized the inhibition of peristalsis produced by methionine-enkephalin. On the other hand, acetylcholine reversed only the propulsive activity and the back pressure, but not the peristaltic movements of the longitudinal muscle previously abolished by methionine-enkephalin. It appears, therefore, that only the inhibitory effects of methionine-enkephalin are mediated through opioid receptors in the intestine.


Does pea lectin expressed transgenically in oilseed rape (Brassica napus) influence honey bee (Apis mellifera) larvae?
The European honey bee (Apis mellifera) is important both for pollination and for honey production. Pollen is the major protein source for bees, which exposes them directly to changes in pollen quality e.g. through genetic engineering. In order to create a worst case scenario regarding pea lectin (PSL) expressed transgenically in oilseed rape anthers and pollen, the maximum amount of dried pollen that could be mixed in an artificial diet without negatively affecting larval performance (1.5% w/w) was fed to bee larvae. Pollen from two transgenic plant lines expressing PSL up to 1.2% of total soluble protein and pollen from one non-transgenic line was added to the same diet and used as a pollen control. When these three pollen diets and the control diet (without added pollen) were compared, no negative effect from the pollen of the transgenic plants could be detected on larval mortality, weight, or development time. An increased weight and a reduced developmental time were recorded for larvae on all diets containing pollen when compared to the diet without pollen.


Effects of surface friction on a two-dimensional granular system: cooling bound system.
Experiments performed by Phys. Rev. E 62, 2380 (2000)] on two-particle collisions and dynamics emphasized the importance of the role played by substrate friction, in particular kinetic friction, on the particle dynamics after collisions on a substrate. We present a numerical model which accounts for collisional and surface frictional dissipation and their influence on particle dynamics for a quasi-two-dimensional cooling initially dilute granular material. This model makes the simplifying assumption that the collision dynamics is determined solely by the incoming velocity and angular velocities of the colliding particles. We apply this model to a numerical simulation of a monolayer of monodisperse particles moving on a substrate, enclosed between inelastic walls. We find that surface friction-in particular, kinetic friction-plays a dominant role in determining the dynamics of quasi-two-dimensional multiparticle systems where the particles are in continuous contact with a substrate. Results from simulations performed for different system sizes indicate that surface friction and the inelastic walls lead to clustering of the particles in and near the vicinity of the walls. We find that the rate of decrease of average total kinetic energy is the highest when the majority of the particles have just collided and are experiencing kinetic frictional forces and torques. We also find from our calculations that, on average, particle-wall collisions lead to more dissipation than particle-particle collisions for a single particle for fixed restitutional parameters.


Oral dysbacteriosis in type 2 diabetes and its role in the progression to cardiovascular disease.
Salivary changes and proliferation of specific bacterial communities are known to result in oral disease which may adversely impact on systemic conditions like diabetes and cardiovascular diseases. This study reports on the changes in oral ecology of healthy and diseased adults and the possible role in disease causation. The study comprised 150 participants divided into control (healthy), diabetic and cardiac groups. After dental examination for (Decayed Missing Filled Teeth (DMFT) and Oral Rating Index (ORI), stimulated saliva was sampled to determine flow rate and buffering capacity. Salivary microbial load of Streptococcus mutans and Lactobacilli were subsequently quantified. DMFT, ORI, buffering capacity and flow rate were inferior for both diabetic and cardiac patients, who had higher bacterial counts (p<0.05). Long standing diabetics harboured a higher load of Streptococcus mutans. The microbial load of Streptococcus mutans in cardiac patients was double that of diabetics. Disruption in the salivary environment and changes in microbial ecology with increased load of cariogenic bacteria were found in diabetic and cardiac patients. This study brings forward new evidence of a markedly higher load of Streptococcus mutans in cardiac patients which may underlie the progression of diabetes to cardiovascular disease in this population.


Observation of the first excited transverse mode in guided matter waves.
In direct analogy to the textbook example of light guided in a few-mode fiber (FMF), we report the observation of the first excited mode of an optically guided atomic beam. We selectively excite the atomic analog of the LP₀₁ optical mode by controlling the energy distribution of ultracold atoms loaded into the guide, resulting in a modal structure dominated by a 47(2)% population in the first excited transverse mode. The ability to guide lower-order modes has been essential to demonstrating optical effects such as multimode interferometry, slow light, and entanglement, and an atomic analog to a FMF may lead to similarly useful applications.


Immunohistochemistry in the evaluation of spermatogenesis and Sertoli cell's maturation status.
An increasing incidence of male infertility has been noted over the past few decades. This adds urgency to the need to develop immunohistochemical markers for better evaluation of testicular biopsies. We provide evidence that a histopathological evaluation performed according to morphological criteria and assisted by immunohistochemical staining on consecutive sections enhances the sensitivity and accuracy of the diagnosis based on testicular biopsies from infertile men.


Auditory experience modulates fronto-parietal theta activity serving fluid intelligence.
Children who are hard of hearing are at risk for developmental language and academic delays compared with children with normal hearing. Some work suggests that high-order cognitive function, including fluid intelligence, may relate to language and academic outcomes in children with hearing loss, but findings in these studies have been mixed and to date, there have been no studies of the whole-brain neural dynamics serving fluid intelligence in the context of hearing loss. To this end, this study sought to identify the impact of hearing loss and subsequent hearing aid use on the neural dynamics serving abstract reasoning in children who are hard of hearing relative to children with normal hearing using magnetoencephalography. We found significant elevations in occipital and parietal theta activity during early stimulus evaluation in children who are hard of hearing relative to normal-hearing peers. In addition, we found that greater hearing aid use was significantly related to reduced activity throughout the fronto-parietal network. Notably, there were no differences in alpha dynamics between groups during later-stage processing nor did alpha activity correlate with hearing aid use. These cross-sectional data suggest that differences in auditory experience lead to widespread alterations in the neural dynamics serving initial stimulus processing in fluid intelligence in children.


Prescriber Attitudes, Experiences, and Proclivities Toward Digital Medicine and How They Influence Adoption of Digital Medicine Platforms.
Psychiatric prescribers (prescribers) typically assess medication adherence by patient or caregiver self-report. Despite likely clinical benefit of a new digital medicine technology, the role of specific prescriber attitudes, behaviors, and experiences in the likelihood of adoption is unclear. To identify prescriber characteristics that may affect adoption of the ingestible event marker (IEM) platform. A survey of prescribers treating seriously mentally ill patients was conducted. Factor analysis was performed on 11 items representing prescriber characteristics believed to be related to endorsement of the IEM platform. Four factors were extracted. Regression analysis was used to test the strength of the relationships between the factors and likelihood of adoption of the IEM platform. A total of 131 prescribers completed the survey. Most (84%) agreed that visits allow enough time to monitor adherence. Factor analysis revealed four underlying dimensions: 1) perspectives on the value of adherence; 2) concerns about measuring adherence; 3) views toward digital health technologies; and 4) views on payer role/reimbursement. Factors 1 and 3 were related to gender, the belief that computerization benefits prescribers, the presence of office support staff, and the belief that new digital medicine (DM) technology will be cost prohibitive. Willingness to adopt the IEM platform was related to gender (p < 0.05) and perspectives on the value of adherence (p < 0.05), with those scoring higher on that measure also being more likely to adopt. Psychiatric prescribers are concerned about medication adherence, perceive current monitoring tools to be problematic, and are open to using digital technologies to improve accuracy of adherence assessment. Relationships among prescriber characteristics, beliefs, and experiences should be considered when developing educational materials, particularly when the goal is to encourage adoption and use of the IEM platform.


Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia.
The aim of this study was to ascertain prevalence and natural history of hepatitis C virus (HCV) infection in a large cohort of patients cured of childhood leukemia who had been followed prospectively for liver disease for at least 10 years since chemotherapy withdrawal: 114 consecutive patients entered the study. Liver function tests and ultrasonography were used to assess presence of liver disease. Patients were tested for antibody to HCV and for serum HCV-RNA at the end of chemotherapy and at the end of follow-up. At chemotherapy withdrawal, 56 patients (49%) were HCV-RNA positive, often without detectable anti-HCV, and in these cases, transaminase levels were more elevated during (P = .08) and after (P = .04) chemotherapy compared with HCV-RNA negative cases. Patients were then followed-up 13 to 27 years (mean, 17) after chemotherapy withdrawal. During this period, 38 initially anti-HCV negative patients seroconverted to anti-HCV and 17 initially anti-HCV positive cases lost reactivity. Forty patients were persistently HCV-RNA positive in serum, while 16 initially viremic patients became HCV-RNA negative during follow-up. At the end of the observation period, a persistent transaminase elevation was detected only in four HCV-RNA positive and anti-HCV positive cases, while no patient developed signs or symptoms of decompensated liver disease. Thus, hepatitis C was a frequent finding in long-term survivors after chemotherapy. It was associated with an atypical serologic profile and did not cause severe liver impairment over a period of 13 to 27 years.


Deciphering the microbiome shift during fermentation of medicinal plants.
The importance of the human-microbiome relationship for positive health outcomes has become more apparent over the last decade. Influencing the gut microbiome via modification of diet represents a possibility of maintaining a healthy gut flora. Fermented food and lactic acid bacteria (LAB) display a preventive way to inhibit microbial dysbioses and diseases, but their ecology on plants is poorly understood. We characterized the microbiome of medicinal plants (Matricaria chamomilla L. and Calendula officinalis L.) using 16S rRNA gene profiling from leaves that were fermented over a six-week time course. The unfermented samples were characterized by a distinct phyllosphere microbiome, while the endosphere revealed a high similarity. During fermentation, significant microbial shifts were observed, whereby LAB were enhanced in all approaches but never numerically dominated. Among the LAB, Enterococcaceae were identified as the most dominant family in both plants. M. chamomilla community had higher relative abundances of Lactobacillaceae and Carnobacteriaceae, while C. officinalis showed a higher presence of Leuconostocaceae and Streptococcaceae. The natural leaf microbiome and the indigenous LAB communities of field-grown Asteraceae medicinal plants are plant-specific and habitat-specific and are subjected to significant shifts during fermentation. Leaf surfaces as well as leaf endospheres were identified as sources for biopreservative LAB.


Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease.
To compare the temporal and spatial expression patterns of amyloid precursor protein (APP), amyloid-beta deposits, inflammatory chemokines, and apoptosis in the retina of a mouse model of Alzheimer disease (AD). Retinas of transgenic mice harboring a mutant presenilin (PS1) and a mutant APP gene were processed for TUNEL and immunohistochemistry with antibodies against APP, amyloid-beta, monocyte chemotactic protein (MCP)-1, and F4/80. Comparisons were made between age groups and between transgenic and wild-type congeners. The neuroretina demonstrated age-dependent increases in APP in the ganglion cells (RGCs) and in neurons of the inner nuclear layer (INL). Amyloid-beta demonstrated significant age-dependent deposition in the nerve fiber layer (NFL). TUNEL-positive RGC increased in an age-dependent fashion and in transgenic compared with wild-type congeners. Concomitant overexpression of MCP-1 and intense immunoreactivity for F4/80 suggested that RGCs upregulate MCP-1 in response to amyloid-beta. Activated microglia proliferated in response to MCP-1. In the outer retina, retinal pigment epithelium (RPE) demonstrated moderate age-dependent APP immunoreactivity, but nearby drusenlike deposits were not present. Amyloid-beta was observed in the choriocapillaris of the older animals. Amyloid-beta deposits accumulate with age in the retina of a transgenic mouse model of AD. The amyloid-beta loads are accompanied by increased immunoreactivity for MCP-1, F4/80, and TUNEL-positive profiles in the RGC layer. The results suggest that amyloid-beta causes neurodegeneration in the retina of the doubly mutant transgenic mouse model of AD.


Diminished cerebral inhibition in neonates associated with risk factors for schizophrenia: parental psychosis, maternal depression, and nicotine use.
Diminished inhibitory gating of cerebral auditory evoked responses is transmitted in families with psychoses as an endophenotype related to the genetic risk for these illnesses. To assess whether the endophenotype is already expressed in infants of parents with psychotic illness and to assess effects of other known risk factors for schizophrenia, ie, maternal cigarette smoking and depression, inhibitory gating of cerebral auditory evoked responses was evaluated by comparing the P1 evoked responses to the first and second of paired auditory stimuli. Cerebral evoked responses were recorded during active sleep from 22 infants with a parent diagnosed with a psychotic illness and 129 infants with parents with no such history. Of these infants, 25 were prenatally exposed to nicotine (16 from the comparison group and 9 from the group with parental psychosis). Mothers of 35 infants had diagnoses of major depressive disorder. Parental psychosis (P = .032) and exposure to maternal smoking (P = .012) both resulted in diminished inhibitory gating in infant offspring. Compared to infants of mothers who did not smoke and who had neither parental psychosis nor maternal depression, diminished inhibitory gating was observed in infants with parental psychosis (P = .027) and in infants with maternal depression (P = .049). Diminished inhibitory gating of auditory evoked response in infants who have risk factors for schizophrenia mirrors reports of its familial transmission in adults. The results further indicate that the phenotypic expression of familial genetic and environmental risks for psychosis is already manifest very early in development.


The Use of Alcohol Among NCAA Division I Female College Basketball, Softball, and Volleyball Athletes.
To identify and describe alcohol use among NCAA Division I female college basketball, softball, and volleyball players and to determine to what extent the players have been exposed to alcohol or other drug education programs. Mailed self-reporting questionnaire, sample of convenience. The study was conducted in the Department of Physical Education at the University of South Carolina. NCAA Division I athletic trainers of ten female basketball teams, ten female softball teams, and eleven female volleyball teams received questionnaires. A total of 371 participants returned questionnaires: 106 basketball players, 138 softball players, and 127 volleyball players. After reviewing the related literature, I developed a questionnaire and pilot tested it with a group of female swimmers and track and field athletes. The questionnaire consisted of three sections: demographic information, alcohol use, and alcohol education. I analyzed the questionnaires descriptively (frequencies, percentages, and means) and collectively, on the total population, and separately, on all teams. To validate and further understand information gained from the questionnaires, I conducted multiple face-to-face interviews with forty (11%) of the participants. Almost 79% of the subjects consumed alcohol, with light beers being the most popular beverage. Most started using alcohol before 18 years of age. More softball (89.1%) and volleyball (88.9%) athletes reported drinking than did basketball (63.2%) athletes. Quantity and frequency of alcohol use decreased during the competitive sport season but increased out of season. Almost 60% (55.9%) of the participants engaged in binge drinking (defined as four or more drinks per drinking episode) out of season and 35% in season. Female athletes who lived off campus drank more frequently than those who lived in residence halls, but athletes living in residence halls reported drinking in larger quantities. The most common reasons subjects chose not to use alcohol included the effects alcohol has on health and sports performance, coaches' rules, dislike of the taste of alcohol, and concerns about weight gain. Those who chose to use alcohol did so mostly for social purposes. Most subjects received 4 to 8 hours of alcohol education in lecture sessions during their college careers. The majority wanted additional education, especially with regard to the effects of alcohol on sports performance. Based upon the results of this study, alcohol education has little impact on alcohol use among NCAA Division I female basketball, softball, and volleyball players, particularly out of season. Most choose to use alcohol simply to have fun. Because alcohol affects athletic performance, female athletes tend to use less alcohol in season. Future studies should address the types of alcohol prevention and intervention methods used during out-of-season and in-season periods. Correlation studies should investigate relationships between these programs and alcohol use among female athletes. A broader population of athletes from various sports (eg, field hockey, golf, gymnastics, tennis, soccer, and swimming) should also be investigated.


Classification of Balance Assessment Technology: A Scoping Review of Systematic Reviews.
Accurate assessment of postural balance is necessary to identify and measure falls risk, inform clinical practice, determine efficacy of treatment and ultimately falls prevention. The aim of this scoping review was to identify gaps and inform practice, research and policy. There are a multitude of technologies available for assessing balance and no one that meets the requirements of every situation. Force plates had provided the gold standard technology for measuring centre of pressure variables as the cornerstone of balance assessment. Inertial measurements units are now considered as valid and reliable, however inertial sensors in smartphone require further refinement to measure with the same degree of accuracy. Fusion systems combine wearable and non-wearable technology in formal gait labs but also gaming. The flexibility provided choice of wearable, non-wearable and fusion systems meets most clinical and research requirements.


Changing illness perceptions and adherence to dual antiplatelet therapy in patients with stable coronary disease.
Platelet inhibition with dual antiplatelet therapy (DAPT) is an important component of medical management in patients with stable coronary artery disease (CAD). Dual antiplatelet therapy nonadherence is associated with increased mortality. Little is known about illness perceptions (IPs) surrounding the use of antiplatelet medications and whether they differ in stable CAD patients treated with medical and/or interventional approaches. The aim of this study was to examine temporal changes in IP scores for patients with stable CAD and examine the influence of clinical and demographic variables, IP, and depressive symptoms on adherence to DAPT. Patients (n = 180, 71.7% men; mean [SD] age, 65.1 [8.3] years) were recruited after coronary angiography and optimal medical therapy (OMT) (n = 90) or after percutaneous coronary intervention with initiation of OMT (n = 90). The Illness Perception Questionnaire-Revised and Patient Health Questionnaire-9 were administered at baseline and 30 days after treatment, with a response rate of 52.8% (n = 95) at 30 days. Adherence to DAPT (aspirin and thienopyridine) at 30 days was collected using a health history update. Patients with stable CAD experienced shifts in IP within the first 30 days after treatment. Patients treated with OMT demonstrated increased symptoms after treatment (timeline cyclical) and reduced beliefs in the level of control provided by their prescribed regimen (treatment control, t = 3.26, P = .002). Both groups demonstrated an increase in perceived understanding of illness (illness coherence subscale) from baseline to 30 days (percutaneous coronary intervention/OMT, t = -4.43, P < .001; OMT, t = -3.74, P = .001). Chronic IPs were associated with 5.7% increased odds for improved adherence to thienopyridine agents (B = 0.509, P = .009, Exp(B) = 1.66) and 5.6% increased odds for aspirin use (B = 0.265, P = .031, Exp(B) = 1.30). Depressive symptoms were predictive of adherence for thienopyridine medications (B = 0.509, P = .009, Exp(B) = 1.66). Illness perceptions influence adherence to DAPT in patients with stable CAD. Understanding patterns in IP after treatment may help identify the best strategies to promote a tailored approach for improving adherence to DAPT.


IoMT based smart healthcare system to control outbreaks of the COVID-19 pandemic.
The COVID-19 pandemic caused millions of infections and deaths globally requiring effective solutions to fight the pandemic. The Internet of Things (IoT) provides data transmission without human intervention and thus mitigates infection chances. A road map is discussed in this study regarding the role of IoT applications to combat COVID-19. In addition, a real-time solution is provided to identify and monitor COVID-19 patients. The proposed framework comprises data collection using IoT-based devices, a health or quarantine center, a data warehouse for artificial intelligence (AI)-based analysis, and healthcare professionals to provide treatment. The efficacy of several machine learning models is also analyzed for the prediction of the severity level of COVID-19 patients using real-time IoT data and a dataset named 'COVID Symptoms Checker'. The proposed ensemble model combines random forest and extra tree classifiers using a soft voting criterion and achieves superior results with a 0.922 accuracy score. The use of IoT applications is found to support medical professionals in investigating the features of the contagious disease and support managing the COVID pandemic more efficiently.


Long-term tumor-free survival in a metastatic pancreatic carcinoma patient with FOLFIRINOX/Mitomycin, high-dose, fever inducing Viscum album extracts and subsequent R0 resection: A case report.
Metastatic pancreatic cancer has a dismal prognosis. Many patients seek integrative care as an add-on to their conventional cancer treatment. Viscum album extracts (VAE)-widely used as an adjunct to cancer treatment-have cytotoxic, apoptogenic, and immune stimulatory properties. A statistically significant survival benefit has been demonstrated for VAE in advanced pancreatic cancer. A 28-year old patient presented with painless jaundice and was subsequently diagnosed as pancreatic adenocarcinoma with liver metastases. He was treated with FOLFIRINOX/Mitomycin, hyperthermia and fever-inducing VAE. Subsequently, the liver metastases regressed. Surgical intervention involved successful R0-resection of the primary tumor, as well as an atypical liver resection. A relapse was again treated with FOLFIRINOX/Mitomycin and hyperthermia. As of publication of this report, 49 months after initial diagnosis, the patient exhibits good condition, and is unrestricted in quality of life (till publication). This case demonstrates the favorable outcome of a patient with metastatic pancreatic cancer following treatment with chemotherapy, integrative medicine, and surgical excision. As other positive outcomes in pancreatic cancer patients are related to inflammatory events, we presume the immunologic effects of VAE to have contributed to the favorable outcome here. Based on this case, and the other positive results of VAE use in pancreatic cancer, further investigations seem highly worthwhile.


Understanding the dementia diagnosis gap in Norfolk and Suffolk: a survey of general practitioners.
The National Health Service (NHS) has announced its new target to increase the 'shockingly low dementia diagnosis rate' in England from the current level of 45% to 66% by end of March 2015. Clinical commissioning groups (CCGs) in England have committed to meeting this target. The Norfolk and Suffolk dementia diagnosis rate (DDR) is below the rate for England in some areas; across the CCGs included in this study, the average DDR was 39.9% with a standard deviation of 5.3. This study aimed to explore and understand the low DDR in Norfolk and Suffolk and to learn what might be needed to support general practitioners (GPs) to meet the targets set by the UK Department of Health. An online survey was developed including questions from the National GP Audit 2009. The link to the online survey was sent via email to all GPs in four participating CCGs in Norfolk and Suffolk. SPSS was used for descriptive analysis. Chi-square tests were conducted to identify significant differences in response rates between groups of GPs. The survey was completed by 28% (N = 113) of 400 GPs in 108 practices across three CCGs receiving the survey link. There was a significant difference in response rates from GPs in each CCG, but there were no significant differences in terms of their answers to the questions in the survey. GP respondents expressed confidence in their ability to identify cases of dementia for onward referral to memory services. Participating GPs also acknowledged the benefits to patients and their carers of a timely dementia diagnosis at an early stage of the disease. However, they reported concerns about the quality and availability of post-diagnostic support services for people with dementia and their carers. In this survey, GPs' attitudes were more positive about diagnosing dementia than those responding to the National Audit 2009. Despite GPs' attitudes being more positive than in 2009 about diagnosing dementia, the Norfolk and Suffolk DDR remains low. This may reflect lack of GP confidence in the quality and availability of post-diagnostic support services. This study has identified a need to map the existing post-diagnostic support services for people with dementia and to identify gaps in services. This could lead to the development of a resource which might enable GPs to provide relevant advice to newly diagnosed patients and their carers, facilitate signposting to support services, and give GPs confidence to increase the DDR in their area.


Practice Variation in Skin Cancer Treatment and Follow-Up Care: A Dutch Claims Database Analysis.
Quality indicators are used to benchmark and subsequently improve quality of healthcare. However, defining good quality indicators and applying them to high-volume care such as skin cancer is not always feasible. To determine whether claims data could be used to benchmark high-volume skin cancer care and to assess clinical practice variation. All skin cancer care-related claims in dermatology in 2016 were extracted from a nationwide claims database (Vektis) in the Netherlands. For over 220,000 patients, a skin cancer diagnosis-related group was reimbursed in 124 healthcare centres. Conventional excision reflected 75% of treatments for skin cancer but showed large variation between practices. Large practice variation was also found for 5-fluorouracil and imiquimod creams. The practice variation of Mohs micrographic surgery and photodynamic therapy was low under the 75th percentile, but outliers at the 100th percentile were detected, which indicates that few centres performed these therapies far more often than average. On average, patients received 1.8 follow-up visits in 2016. Claims data demonstrated large practice variation in treatments and follow-up visits of skin cancer and may be a valid and feasible data set to extract quality indicators. The next step is to investigate whether detected practice variation is unwarranted and if a reduction improves quality and efficiency of care.


Rapid Resistance of FGFR-driven Gastric Cancers to Regorafenib and Targeted FGFR Inhibitors can be Overcome by Parallel Inhibition of MEK.
Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of FGFR family members. These four cell lines were also sensitive to the FGFR-specific inhibitors, BGJ398, erdafitinib, and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFRs 1-4 was detected in 8%-19% of cases, however, this was not associated with improved progression-free survival and no objective responses were observed in these cases. Further preclinical analyses revealed FGFR-driven gastric cancer cell lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response to regorafenib. Importantly, combination treatment with an FGFR and MEK inhibitor delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven gastric cancer cell lines. These findings suggest that upfront combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for FGFR-driven gastric cancers.


Androgens and spermatogenesis.
Male infertility contributes to 50% of all cases of infertility. The main cause is low quality and quantity of sperm. In humans, spermatogenesis starts at the beginning of puberty and lasts lifelong. It is under the control of FSH and testicular androgens, and mainly testosterone (T), and therefore requires a normal gonadotroph axis, intratesticular T production by Leydig cells and functional androgen receptors (ARs) within testicular Sertoli cells. Various clinical cases illustrate the roles of T in human spermatogenesis. Men with complete congenital hypogonadotropic hypogonadism (HH) are usually azoospermic. Treatment by exogenous testosterone injection and FSH is not able to produce sperm. However, combined treatment with FSH and hCG is effective. This example shows that intratesticular T plays a major role in spermatogenesis. Furthermore, testicular histology of men with LH receptor mutations shows Leydig cell hypoplasia/agenesis/dysplasia with conserved Sertoli cell count. The sperm count is reduced, as in males with partial inactivating mutation of the androgen receptor. Some protocols of hormonal male contraception or exogenous androgen abuse induce negative feedback in the hypothalamic pituitary axis, decreasing FSH, LH and T levels and inducing sperm defects and testicular atrophy. The time to recovery after cessation of drug abuse is around 14 months for sperm output and 38 months for sperm motility. In summary, abnormal androgen production and/or AR signaling impairs spermatogenesis in humans. The minimal level of intratesticular T for normal sperm production is a matter of debate. Interestingly, some animal models showed that completely T-independent spermatogenesis is possible, potentially through strong FSH activation. Finally, recent data suggest important roles of prenatal life and minipuberty in adult spermatogenesis.


Impact of 8 lifestyle factors on mortality and life expectancy among United States veterans: The Million Veteran Program.
Lifestyle medicine has been proposed as a way to address the root causes of chronic disease and their associated health care costs. This study aimed to estimate mortality risk and longevity associated with individual lifestyle factors and comprehensive lifestyle therapy. Age- and sex-specific mortality rates were calculated on the basis of 719,147 veterans aged 40-99 y enrolled in the Veteran Affairs Million Veteran Program (2011-2019). Hazard ratios and estimated increase in life expectancy were examined among a subgroup of 276,132 veterans with complete data on 8 lifestyle factors at baseline. The 8 lifestyle factors included never smoking, physical activity, no excessive alcohol consumption, restorative sleep, nutrition, stress management, social connections, and no opioid use disorder. On the basis of 1.12 million person-years of follow-up, 34,247 deaths were recorded. Among veterans who adopted 1, 2, 3, 4, 5, 6, 7, and 8 lifestyle factors, the adjusted hazard ratios for mortality were 0.74 (0.60-0.90), 0.60 (95% CI: 0.49, 0.73), 0.50 (95% CI: 0.41, 0.61), 0.43 (95% CI: 0.35, 0.52), 0.35 (95% CI: 0.29, 0.43), 0.27 (95% CI: 0.22, 0.33), 0.21 (95% CI: 0.17, 0.26), and 0.13 (95% CI: 0.10, 0.16), respectively, as compared with veterans with no adopted lifestyle factors. The estimated life expectancy at age 40 y was 23.0, 26.5, 28.8, 30.8, 32.7, 35.1, 38.3, 41.3, and 47.0 y among males and 27.0, 28.8, 33.1, 38.0, 39.2, 41.4, 43.8, 46.3, and 47.5 y for females who adopted 0, 1, 2, 3, 4, 5, 6, 7, and 8 lifestyle factors, respectively. The difference in life expectancy at age 40 y was 24.0 y for male veterans and 20.5 y for female veterans when comparing adoption of 8-9 lifestyle factors. A combination of 8 lifestyle factors is associated with a significantly lower risk of premature mortality and an estimated prolonged life expectancy.


Protein-based electrochemical biosensor for detection of silver(I) ions.
Silver(I) ions are extremely toxic to aquatic animals. Hence, monitoring of these ions in the environment is needed. The aim of the present study was to suggest a simple biosensor for silver(I) ions detection. The suggested biosensor is based on the modification of a hanging mercury drop electrode (HMDE) by the heavy metal binding protein metallothionein (MT) for silver(I) ions detection. Metallothionein accumulated for 120 s onto the HMDE surface. After rinsing the electrode, the biosensor (MT modified HMDE) was prepared prior to detection of silver(I) ions. The biosensor was immersed in a solution containing silver(I) ions. These ions were bound to the MT structure. Furthermore, the electrode was rinsed and transferred to a pure supporting electrolyte solution, in which no interference was present. Under these experimental conditions, other signals relating to heavy metals naturally occurring in MT were not detected. This phenomenon confirms the strong affinity of silver(I) ions for MT. The suggested biosensor responded well to higher silver(I) ion concentrations. The relative standard deviation for measurements of concentrations higher than 50 microM was approximately 2% (n = 8). In the case of concentrations lower than 10 microM, the relative standard deviation increased to 10% (n = 8). The detection limit (3 signal/noise) for silver(I) ions was estimated as 500 nM.


Studies on hematopoietic growth factor receptors using human recombinant IL-3, GM-CSF, G-CSF, M-CSF, IL-1 and IL-4.
An increasing number of cytokines including GM-CSF, G-SCF, M-CSF, IL-3, IL-1 and IL-4, have been implicated in the control of the growth and differentiation of hematopoietic cells. The characterization of the cell surface receptors for these proteins is described. The binding of rh IL-3 to human monocytes is described in some detail, and the binding parameters measured for this cytokine are compared with those determined for the other cytokines. The range of cells to which rh IL-3, rh GM-CSF and rh G-CSF bind is more restricted than that observed for the cytokines IL-1 and IL-4, which bind to a diverse spectrum of cell types. Practical applications of receptor studies include the determination of receptor affinity as a measure of recombinant cytokine potency and the use of the receptor ligand interaction to establish sensitive radioreceptor assays for the detection of cytokines in solution. Finally, methods used for the molecular characterization of cytokine receptors are described and summarized for the CSF receptors, IL-4 and IL-1.


Epidemic of influenza A(H1N1)pdm09 analyzed by full genome sequences and the first case of oseltamivir-resistant strain in Myanmar 2017.
A community outbreak of human influenza A(H1N1)pdm09 virus strains was observed in Myanmar in 2017. We investigated the circulation patterns, antigenicity, and drug resistance of 2017 influenza A(H1N1)pdm09 viruses from Myanmar and characterized the full genome of influenza virus strains in Myanmar from in-patients and out-patients to assess the pathogenicity of the viruses. Nasopharyngeal swabs were collected from out-patients and in-patients with acute respiratory tract infections in Yangon and Pyinmana City in Myanmar during January-December 2017. A total of 215 out-patients and 18 in-patients infected with A(H1N1)pdm09 were detected by virus isolation and real-time RT-PCR. Among the positive patients, 90.6% were less than 14 years old. Hemagglutination inhibition (HI) antibody titers against A(H1N1)pdm09 viruses in Myanmar were similar to the recommended Japanese influenza vaccine strain for 2017-2018 seasons (A/Singapore/GP1908/2015) and WHO recommended 2017 southern hemisphere vaccine component (A/Michigan/45/2015). Phylogenetic analysis of the hemagglutinin sequence showed that the Myanmar strains belonged to the genetic subclade 6B.1, possessing mutations of S162N and S164T at potential antigenic sites. However, the amino acid mutation at position 222, which may enhance the severity of disease and mortality, was not found. One case with no prior history of oseltamivir treatment possessed H275Y mutated virus in neuraminidase (NA), which confers resistance to oseltamivir and peramivir with elevated IC50 values. The full genome sequence of Myanmar strains showed no difference between samples from in-patients and out-patients, suggesting no additional viral mutations associated with patient severity. Several amino acid changes were observed in PB2, PB1, and M2 of Myanmar strains when compared to the vaccine strain and other Asian strains. However, no mutations associated with pathogenicity were found in the Myanmar strains, suggesting that viral factors cannot explain the underlying reasons of the massive outbreak in Myanmar. This study reported the first detection of an oseltamivir-resistant influenza virus in Myanmar, highlighting the importance of continuous antiviral monitoring and genetic characterization of the influenza virus in Myanmar.


Action of calcium ions on spinach (Spinacia oleracea) chloroplast fructose bisphosphatase and other enzymes of the Calvin cycle.
Thiol-treated spinach (Spinacia oleracea) chloroplast fructose bisphosphatase is powerfully inhibited by Ca2+ non-competitively with respect to its substrate, fructose 1,6-bisphosphate. 500 microM-Ca2+ causes virtually complete inhibition and the Ki is 40 microM. Severe inhibition of sedoheptulose bisphosphatase is also caused by Ca2+. A role for Ca2+ in regulation of the Calvin cycle in spinach chloroplasts is proposed.


How communicating a diagnosis of polycystic ovarian syndrome (PCOS) impacts wellbeing: a retrospective community survey.
Polycystic ovary syndrome (PCOS) is associated with wellbeing. Many women report dissatisfaction with the diagnostic process. This study assessed the impact of aspects of the diagnostic consultation on subsequent wellbeing. A retrospective community survey. Females with PCOS (n = 147) completed measures of aspects of the diagnostic consultation (consultation satisfaction, language used in terms of framing and focus) and current wellbeing (body esteem, quality of life). Most diagnoses took place in primary care. The majority showed a medium degree of satisfaction with the consultation. Most diagnoses were framed using a neutral term 'raised' but many used the more judgemental term 'abnormal'. The majority focused on taking oral contraception and weight management. Poorer body esteem (body dissatisfaction and dieting behaviour) and poorer quality of life (self-identity, concerns about fertility, physical health, hirsutism, and overall quality of life) were predicted by lower communication comfort during the diagnostic consultation and greater use of the word 'raised'. Greater use of the word 'irregular' predicted greater concerns about fertility, greater focus on fertility predicted greater concerns about physical health, and greater focus on appearance predicted greater concerns about hirsutism. How a diagnosis of PCOS is delivered can impact subsequent wellbeing. The diagnostic consultation may take a few minutes, yet how these minutes are managed, what words are used, and how this makes the patient feel may change how the patient makes sense of their condition and influence the impact of the condition on their wellbeing for the longer term.


Understanding the Mechanics of the Temporomandibular Joint Osteochondral Interface from Micro- and Nanoscopic Perspectives.
The condylar cartilage of the temporomandibular joint (TMJ) is connected to the subchondral bone by an osteochondral interface that transmits loads without causing fatigue damage. However, the microstructure, composition, and mechanical properties of this interface remain elusive. In this study, we found that structurally, a spatial gradient assembly of hydroxyapatite (HAP) particles exists in the osteochondral interface, with increasing volume of apatite crystals with depth and a tendency to form denser and stacked structures. Combined with nanoindentation, this complex assembly of nanoscale structures and components enhanced energy dissipation at the osteochondral interface, achieving a smooth stress transition between soft and hard tissues. This study comprehensively demonstrates the elemental composition and complex nanogradient spatial assembly of the osteochondral interface at the ultramicroscopic scale, providing a basis for exploring the construction of complex mechanical models of the interfacial region.