[177Lu-PSMA therapy : Current evidence for use in the treatment of patients with metastatic prostate cancer].
Despite significant progress in the treatment of metastatic castration-resistant prostate cancer (mCRPC) in recent years (including agents targeting androgen receptor signaling, chemotherapy, and 223Ra), most of these patients still succumb to prostate cancer. Recently, 177lutetium prostate-specific membrane antigen radioligand therapy (177Lu-PSMA-RLT) has been increasingly used within compassionate use provisions in these patients in Germany and showed promising efficacy. Establishment of the current position of 177Lu-PSMA-RLT in mCRPC in 2017. Presentation of the therapy landscape in mCRPC and the current challenges within treatment and survey of the available data on 177Lu-PSMA-RLT after PubMed-based research. In several larger retrospective studies, 177Lu-PSMA-RLT seems to be an encouraging new option with the potential to extend overall survival while displaying a favorable toxicity profile. Prospective trials are urgently needed to confirm these encouraging results found in retrospective analyses with 177Lu-PSMA-RLT in the treatment of mCRPC.


Social grooming among wild bonobos (Pan paniscus) at Wamba in the Luo Scientific Reserve, DR Congo, with special reference to the formation of grooming gatherings.
Chimpanzees (Pan troglodytes) groom in gatherings in which many individuals may be connected via multiple chains of grooming and they often exchange partners with each other. They sometimes groom another while receiving grooming; that is, one animal can play two roles (i.e., groomer and groomee) simultaneously. Although this feature of chimpanzees is notable from the viewpoint of the evolution of human sociality, information on our other closest living relative, the bonobo (Pan paniscus), is still lacking. In this study, I describe grooming interactions of bonobos at Wamba in the Luo Scientific Reserve, Democratic Republic of the Congo (DR Congo), with a particular focus on the formation of grooming gatherings. Like chimpanzees, the bonobos also performed mutual grooming (two individuals grooming each other simultaneously) and polyadic grooming (three or more individuals). However, unlike chimpanzees, these sessions lasted for only a short time. Bonobos rarely groomed another while receiving grooming. Because social grooming occurred not only in trees but also in open spaces, including treefall gaps, the conditions did not necessarily limit the opportunity to make multiple chains of grooming. However, bonobos also engaged in social grooming in different ways from chimpanzees; That is, many individuals were involved simultaneously at a site, in which they separated for dyadic grooming. Some cases clearly showed that bonobos preferred a third party not to join while grooming in a dyad, suggesting that bonobos have a preference for grooming in dyads and that immature individuals formed the preference that was shared among adults while growing up. Most members of the study group ranged together during the majority of the study period. Although bonobos show a fission-fusion grouping pattern, when group members frequently encounter one another on a daily basis, they may not be motivated to form multiple grooming chains at this site, as do chimpanzees.


Comparative Synthesis and Characterization of Nanostructured SAPO-34 Using TEA and Morpholine: Effect of Mono vs. Dual Template on Catalytic Properties and Performance toward Methanol to Light Olefins.
Production of light olefins from methanol was studied over SAPO-34 molecular sieves exploring the effect of mono and dual templates. Herein, the single templates of TEA, morpholine, and mixed templates of TEA/morpholine (equal molar ratio of TEA and morpholine) were used to synthesize SAPO-34 catalysts. The prepared samples were prepared via hydrothermal synthesis method and characterized with XRD, FESEM, PSD, EDX, BET, and FTIR techniques. It was found that the crystallinity decreased upon applying TEA as a template and it can also be noted that the intensity of the SAPO-34 phase peaks increased by increasing the morpholine in template mixture. Production of much smoother particles for the catalyst synthesized with a binary template mixture of TEA/morpholine can be dependent on the crystallinity increase. Si incorporation value was decreased for the catalyst with a major phase of SAPO-5 (topological structure of AFI). It is indicative that the TEA application would facilitate the formation of AFI structure, which is incapable of incorporating higher amounts of Si into the crystalline framework. The nature of the template determines the morphology of the final product due to the different rates of crystal growth obtained in accordance with XRD and FESEM results. Therefore, the catalyst synthesized with the TEA/morpholine mixture shows the best performance among synthesized samples in terms of lifetime in the MTO process, sustaining light olefins selectivity at higher values (about 90% after 630 min TOS).


Patient-Specific Dosimetry in Radioligand Therapy (RLT) for Metastatic Prostate Cancer Using 177Lu-DKFZ-PSMA-617.
177Lu-DKFZ-PSMA-617 is a promising treatment for patients with metastatic prostate cancer. Specific dosimetry for each patient is an important factor in planning the patient's treatment process. This study aimed to perform an image-based absorbed dose calculation for the treatment of metastatic prostate cancer with 177Lu-DKFZ-PSMA-617. The individualized patient dosimetry calculations were based on whole-body planar scintigraphy images acquired in 10 patients with a mean age of 71.4 ± 6.07 years (range 63-85 years) at approximately 0-2 h, 4-6 h, 18-24 h, and 36-48 h after administration of the mean 6253 ± 826.4 MBq (range 5500-7400 MBq) of 177Lu-DKFZ-PSMA-617. Time-activity curves were generated for various organs. For count conversion to activities, calibration factors were calculated. Finally, the absorbed dose for an individual cycle was calculated using IDIAC-DOSE 2.1 software. On average, the calculated absorbed dose for the kidneys and salivary glands were 0.46 ± 0.09 mGy/MBq and 0.62 ± 0.07 mGy/MBq, respectively. Based on the results, the177Lu-PSMA-617 therapy is a safe method for the treatment of castration-resistant prostate cancer patients. Large inter-individual variations in organ dose were found, demonstrating the need for patient-specific dosimetry and treatment planning.


Protocadherin-18a has a role in cell adhesion, behavior and migration in zebrafish development.
Protocadherin-18a (Pcdh18a) belongs to the delta 2-protocadherins, which constitute the largest subgroup within the cadherin superfamily. Here we present isolation of a full-length zebrafish cDNA that encodes a protein highly similar to human and mouse Pcdh18. Zebrafish pcdh18a is expressed in a complex and dynamic pattern in the nervous system from gastrula stages onward, with lesser expression in mesodermal derivatives. Pcdh18a-eGFP fusion protein is expressed in a punctate manner on the membranes between cells. Overexpression of pcdh18a in embryos caused cyclopia, mislocalization of hatching gland tissue, and duplication or splitting of the neural tube. Most neural markers tested were expressed in an approximately correct A-P pattern. By cell transplantation we showed that overexpression of pcdh18a causes diminished cell migration and reduced cell protrusions, resulting in a tendency of cells to stay more firmly aggregated, probably due to increased cell adhesion. In contrast, knockdown of pcdh18a by a morpholino oligonucleotide caused defects in epiboly, and led to reduced cell adhesion as shown by cell dissociation, sorting and transplantation experiments. These results suggest a role for Pcdh18a in cell adhesion, migration and behavior but not cell specification during gastrula and segmentation stages of development.


Evaluation of the impact of age and adiposity on a multi-biomarker disease activity score before and after adjustment.
We assessed the impact of adjustment of the multi-biomarker disease activity score (MBDA) for age, sex, and leptin, over the range of age and adiposity, and assessed relationships with clinical disease activity. Patients with RA, ages 18-75 years, were recruited from clinical practices and completed whole-body DXA to quantify fat mass indices (FMI, kg/m2). FMI Z-scores were calculated based on distributions in a reference population. Descriptive statistics described relationships between age, FMI Z-score, and the original MBDA and adjusted MBDA (aMBDA). Swollen joint counts (SJC) and the clinical disease activity index (CDAI) were assessed over MBDA categories. There were 104 participants (50% female) with mean (SD) age of 56.1 (12.5) and body mass index (BMI) of 28.8 (6.9). Older age was associated with higher MBDA scores in men. The aMBDA was not associated with age. The original MBDA score was associated with FMI Z-score among women (Rho = 0.42, p = 0.002) but not men. The aMBDA was not associated with FMI Z-score in either women or men. The aMBDA score was lower than the original MBDA in the highest quartile of FMI in women and was higher in the lowest FMI quartiles in women and men. CDAI, SJC, and radiographic scores were similar across activity categories for the original MBDA score and aMBDA. The aMBDA demonstrated reduced associations with adiposity, particularly among women. The aMBDA may be less likely to overestimate disease activity in women with greater adiposity and to underestimate disease activity in men and women with lesser adiposity. Key Points • Leptin adjustment of the MBDA score reduces the influence of adiposity, particularly among women. • Leptin adjustment results in significantly higher estimated disease activity in thin men and women. • The adjusted and unadjusted score correlate similarly with clinical disease activity measures.


Preoperative Dose-Escalated Intensity-Modulated Radiotherapy (IMRT) and Intraoperative Radiation Therapy (IORT) in Patients with Retroperitoneal Soft-Tissue Sarcoma: Final Results of a Clinical Phase I/II Trial.
To report the final results of a prospective, one-armed, single-center phase I/II trial (NCT01566123). Between 2007 and 2017, 37 patients with primary or recurrent (N = 6) retroperitoneal sarcomas were enrolled. Treatment included preoperative IMRT of 45-50 Gy with a simultaneous integrated boost of 50-56 Gy, surgery and IORT. The primary endpoint was local control (LC) at 5 years. The most common histology was dedifferentiated liposarcoma (51%), followed by leiomyosarcoma (24%) and well-differentiated liposarcoma (14%). The majority of lesions were high-grade (FNCLCC G1: 30%, G2: 38%, G3: 27%, two missing). Five patients were excluded from LC analysis per protocol. The minimum follow-up of the survivors was 62 months (median: 109; maximum 162). IORT was performed for 27 patients. Thirty-five patients underwent gross total resection; the pathological resection margin was mostly R+ (80%) and, less often, R0 (20%). We observed 10 local recurrences. The 5-year LC of the whole cohort was 59.6%. Eleven patients received a dose > 50 Gy plus IORT boost; LC was 64.8%; the difference, however, was not significant (p = 0.588). Of 37 patients, 15 were alive and 22 deceased at the time of final analysis. The 5-year OS was 59.5% (68.8% per protocol). The primary endpoint of a 5-year LC of 70% was not met. This might be explained by the inclusion of recurrent disease and the high rate of G3 lesions and leiomyosarcoma, which have been shown to profit less from radiotherapy. Stratification by grading and histology should be considered for future studies.


Time-resolved fluorescence biosensor for adenosine detection based on home-made europium complexes.
In this protocol, the authors report a time-resolved fluorescence biosensor based on home-made europium complexes for highly sensitive detection of small molecules using adenosine as a model analyte. The fluorophore that used is europium complexes. Its signal can be measured in a time-resolved manner that eliminates most of the unspecific fluorescent background. The amino modified aptamer probe, which is designed to specifically recognize adenosine, is combined to the aldehyde-group modified glass slide by covalent bond. Europium complex-labeled a short ssDNA, designed to segment hybridize with aptamer probe is immobilized on the glass slide by hybridization reaction. In the presence of adenosine, the aptamer part is more inclined to bounds with adenosine and triggers structure-switching of the aptamer from aptamer/ssDNA duplex to aptamer/target complex. As a result, europium complexes-labeled ssDNA is forced to dissociate from the sensor interface, resulting in time-resolved fluorescence intensity decrease. The decrement intensity is proportional to the amount of adenosine. Under optimized assay conditions, a linear range (1.0×10(-8)M to 1.0×10(-7)M) is got with low detection limit of 5.61nM. The biosensor exhibits excellent selectivity and can provide a promising potential for aptamer-based adenosine detection.


The role of steroid signals in the maturation of mammalian oocytes.
The resumption of meiosis in mammalian oocytes is associated with sequential changes in follicular steroidogenesis, the principal features of which are an initial stimulation and then suppression of the secretion of oestrogens and androgens, followed by a steady increase in the secretion of progesterone. The addition of steroid enzyme inhibitors to isolated follicles in vitro alters the normal profile of steroids secreted during maturation and induces intracellular changes in the oocytes which are expressed as nuclear abnormalities at fertilization. Different abnormalities are induced by selectively modifying steroid biosynthesis during maturation, the maturing oocyte being more sensitive to an imbalance in the steroid profile rather than the total inhibition of steroid secretion. The cause of the developmental aberrations may either result from or be associated with the abnormal patterns of proteins synthesized by oocytes denied the support of the correct balance or sequence of steroids during maturation.


Hypnosis, Part III: Uses in dentistry.
This article will discuss the uses of hypnosis in selected dental situations. In certain cases, the verbalization of the dentist during the procedural steps will be condensed or referenced in the literature.


Small intestinal strangulation caused by Meckel's diverticulum in a horse.
Necropsy of a 12-year-old Quarter Horse mare revealed a blind-end segment of intestine originating from the antimesenteric border of the ileum. The blind-end segment had looped around and strangulated the ileum and 3.5 m of the jejunum.


The therapeutic function of the chemokine RANTES on the H22 hepatoma ascites model.
This study aimed at analyzing the therapeutic function of the chemokine RANTES on the H22 hepatoma ascites model and preliminarily explore the mechanism of RANTES in malignant ascites to provide an important reference for applying chemokines in anti-tumor therapy. The murine H22 hepatoma ascites model was used. Three treatment groups were analyzed: a RANTES treatment group, an IL-2 control group, and an NS control group. Two regimens of early treatment and late treatment were designed, and the therapeutic effect of RANTES on malignant ascites was studied by measuring changes in mouse body weight and abdominal circumference and observing the survival time. The expression of TNF-α, IFN-γ, TGF-β1, and MCP-1 in mouse ascites was detected by ELISA, and the chemotactic function of RANTES on B lymphocytes and T lymphocytes was analyzed by flow cytometry. In the early and late treatment regimens, RANTES could effectively inhibit the increase in mouse body weight and abdominal circumference in the murine H22 hepatoma ascites model. The secretion of TNF-α and IFN-γ, which had anti-tumor effects, was higher in the RANTES treatment group than in the control groups (P < 0.05), whereas the secretion of TGF-β1 and MCP-1, which promoted tumor growth, invasion, and metastasis, was lower than in the control groups (P < 0.05). RANTES had chemotactic effects on CD4(+) and CD8(+) T lymphocytes; therefore, the percentage of CD3, CD4, and CD8 in the mouse ascites in the RANTES treatment group was significantly higher than in the NS control and IL-2 treatment groups, and the CD4/CD8 ratio was also significantly higher. RANTES can effectively inhibit the increase in body weight and abdominal circumference and significantly extend survival time in mice in the H22 hepatoma ascites model.


Widespread exposure to lead affects the body condition of free-living whooper swans Cygnus cygnus wintering in Britain.
Lead poisoning, through the ingestion of spent lead gunshot, is an established cause of morbidity and mortality in waterbirds globally, but the thresholds at which blood levels begin to affect the physiology of birds in the wild are less well known. Here we determine the prevalence of lead exposure in whooper swans and, for the first time, identify the level of blood lead associated with initial reductions in body condition. Blood lead elevated above background levels (i.e. >20 μg dL(-1)) was found in 41.7% (125/300) of swans tested. Blood lead was significantly negatively associated with winter body condition when levels were ≥44 μg dL(-1) (27/260 = 10%). Our findings indicating that sub-lethal impacts of lead on body condition occur at the lower end of previously established clinical thresholds and that a relatively high proportion of individuals in this population may be affected, reaffirm the importance of reducing contamination of the environment with lead shot.


DNA ultra-sensitive quantification, a technology for studying HIV unintegrated linear DNA.
Unintegrated HIV DNA represents between 20% and 35% of the total viral DNA in infected patients. Only the linear forms (unintegrated linear DNAs [ULDs]) can be substrates for integration and for the completion of a full viral cycle. In quiescent cells, these ULDs may be responsible for pre-integrative latency. However, their detection remains difficult due to the lack of specificity and sensitivity of existing techniques. We developed an ultra-sensitive, specific, and high-throughput technology for ULD quantification called DUSQ (DNA ultra-sensitive quantification) combining linker-mediated PCR and next-generation sequencing (NGS) using molecular barcodes. Studying cells with different activity levels, we determined that the ULD half-life goes up to 11 days in resting CD4+ T cells. Finally, we were able to quantify ULDs in samples from patients infected with HIV-1, providing a proof of concept for the use of DUSQ in vivo to track pre-integrative latency. DUSQ can be adapted to the detection of other rare DNA molecules.


Afterhyperpolarization time-course and minimal discharge rate in low threshold motor units in humans.
The alpha-motoneurone afterhyperpolarization (AHP) duration correlates with a number of its muscle unit properties in animal preparations. In humans, the interval death rate (IDR) analysis has been used to estimate the time course of human motoneurone AHP based on the pattern of motor unit firing. The purpose of this experiment was first, to examine the relationship between estimated AHP time course and the minimal firing rate of the motor unit and second, to examine the relationship between the AHP and motor unit contractile properties in the tibialis anterior (TA) muscle. Motor unit data were obtained from the TA muscle during low force isometric contractions lasting 600 s. Muscle unit twitch characteristics were determined using spike-triggered averaging (STA) and the motoneurone AHP time course was estimated using the IDR analysis. Minimal discharge rate and derecruitment threshold torque were determined for 2 s preceding motor unit derecruitment. The AHP time constant and minimal discharge rate were negatively correlated, whereas the derecruitment threshold torque was not associated with the AHP time constant. The estimated AHP duration, however, is considerably shorter than the mean ISI of the minimal discharge rate suggesting that synaptic noise and AHP duration are important factors in dictating the minimal discharge rate in low force voluntary contractions in humans. The AHP time constant did not vary significantly with motor unit twitch amplitude; however, significant positive relationships were found between the AHP time constant and the temporal properties of the motor unit twitch. The calculated AHP time course using the IDR analysis, therefore, is a reasonable estimate and coupled with motor unit properties attained with STA, it provides a powerful method to describe low-threshold motor units.


High specificity of a rare terrestrial orchid toward a rare fungus within the North American tallgrass prairie.
The Orchidaceae are globally distributed and represent a diverse lineage of obligate mycotrophic plants. Given their dependence on symbiotic fungi for germination and/or plant development, fungal community structure in substrates is expected to influence the distribution and persistence of orchid species. Yet, simultaneous characterization of orchid mycorrhizal fungal (OMF) communities in roots and in soil is rarely reported. To explain the co-distributions of OMF in roots, orchid-occupied, and bulk soil, we characterized mycorrhizal fungi associated with Platanthera praeclara over multiple years across its entire natural distribution within the North American tallgrass prairie. Root derived OMF communities included 24 Ceratobasidiaceae and 7 Tulasnellaceae operational taxonomic units (OTUs) though the orchid exhibited high spatio-temporal specificity toward a single Ceratobasidiaceae OTU, which was strongly stable across population sizes and phenological stages of the sampled individuals. The preferred OMF OTUs were primarily restricted to orchid-occupied locations while infrequent or absent in bulk soil. Variation in soil OMF assemblies was explained most by soil moisture, magnesium, manganese, and clay. In this first study of coupled root and soil OMF communities across a threatened grassland ecosystem, we report a strong relationship, further nuanced by soil chemistry, between a rare fungus and a rare orchid.


Sodium-pump injury and arrhythmogenic transient depolarizations in catecholamine-induced cardiac hypertrophy.
The pathogenesis of arrhythmogenic transient depolarizations (TDs) was studied by means of electrophysiological and cytochemical methods in normal and hypertrophied left ventricular myocardium of the rat. In hypertrophy induced by administration of 5 mg/kg isoprenaline once daily for 7 days, the myocardial membrane was depolarized, the action potential duration was prolonged and the Vmax was decreased, as compared with those of age-matched normal controls. TDs induced by a train of action potentials could be observed in hypertrophied myocardium, but not in normal control myocardium. Ryanodine completely abolished TDs, but the beta-adrenoceptor agonist noradrenaline and the adenylate cyclase activator forskolin were without effect. In cytochemical studies, the Na+,K(+)-ATPase activity was localized in the sarcolemma, and three times as much reaction product, which appeared on the inner side of the cell membrane, was found in the normal myocardium than in the hypertrophied myocardium. The results suggest that catecholamine-induced cardiac hypertrophy damages the membrane-bound Na+,K(+)-ATPase and causes a cAMP-independent intracellular Ca overload and TDs, thereby permitting abnormal impulse formation, which predisposes the diseased myocardium to develop arrhythmias.


Dry eye symptoms in children: can we reliably measure them?
Many dry eye questionnaires are available, but these may not be suitable for paediatric eye care. The feasibility of use and repeatability of symptom questionnaires administered to children was examined. Participants aged 6-15 years (n = 62; 25M:37F; 40% male) completed six questionnaires twice in random order at a single visit: Symptoms assessment in dry eye (SANDE), ocular surface disease index (OSDI), numerical rating scale (NRS), ocular comfort index (OCI, n = 30), dry eye questionnaire 5 (DEQ-5) and the instant ocular symptoms survey (IOSS). Completion time and need for assistance were recorded and relationships with age examined (Pearson correlation, independent t-test). The number of participants requiring assistance and with which items were compared (linear mixed model, pairwise test). Repeatability (coefficient of repeatability (CoR), limit of agreement, bias) and intraclass correlation coefficient (ICC) were examined. Completion time was ≤2 min for each individual questionnaire. Younger participants took longer to complete (r = -0.43 to -0.60, p ≤ 0.01), and required more assistance (p ≤ 0.001). Forty-eight participants required assistance with at least one questionnaire. Older children (13-15 years) only required assistance with OSDI (p ≤ 0.004) and NRS (p ≤ 0.003). Participants required more assistance with SANDE, OSDI and NRS than with DEQ-5 and IOSS (p ≤ 0.02) and with gritty (OSDI, 77% of participants; OCI, 100%) and foreign body sensation (NRS, 92%) items. CoR was similar for all questionnaires with no evidence of a learning effect (p > 0.05). ICC was moderate to excellent. Dry eye questionnaires can be used reliably in paediatric eye care; more time and assistance may be required for younger children. The DEQ-5 and IOSS are recommended for use in younger age children.


Repair of right aortic arch with aberrant left subclavian artery and left ligamentum arteriosum.
A case of right aortic arch with an aberrant left subclavian artery arising from a Kommerell's diverticulum of the descending thoracic aorta with a left ligamentum arteriosum completing a vascular ring about the trachea and esophagus is presented. A posterolateral left thoracotomy alone is sufficient to provide an excellent exposure for the division of the ligamentum arteriosum and the resection of the Kommerell's diverticulum. Furthermore, the development of a subclavian steal syndrome is prevented by the reimplantation of the divided left subclavian artery into the left common carotid artery through this same incision.


[Concentration and significance of s-ICAM-1, s-VCAM-1, and vWF in the plasma of patients with rheumatic heart disease].
To measure the concentrations of soluble intercellular adhesion molecule-1 (s-ICAM-1), soluble vascular cell adhesion molecule-1 (s-VCAM-1), and von Willebrand factor (vWF) in the plasma of patients with rheumatic heart disease (RHD), and to provide basic theory for the mechanism of valvular and myocardial damage. The consecutive patients with RHD (n=40) and healthy people (n=40) were chosen. All blood samples were taken from the peripheral veins. s-ICAM-1, s-VCAM-1 and vWF levels in all samples were measured by enzyme-linked immunosorbant assay. s-ICAM-1, s-VCAM-1 and vWF levels were significantly elevated in patients with RHD compared with healthy people (P < 0.01. The level of sICAM-1 was elevated in patients with atrial fibrillation compared with patients without atrial fibrillation. The concentrations of s-ICAM-1, s-VCAM-1 and vWF levels were significantly elevated in patients with static rheumatic fever, which might be one of the pathogenic mechanisms of valvular damage, endothelial dysfunction, and myocardial damage in rheumatic heart disease.


Clinicopathological correlation of parapapillary atrophy in monkeys with experimental glaucoma and temporary central retinal artery occlusion.
To investigate the clinicopathological correlation of parapapillary atrophy. The study included 16 eyes of rhesus monkeys (Macaca mulatta) - 4 eyes with experimental glaucoma, 11 eyes after experimental temporary occlusion of the central retinal artery, and 1 normal eye. On histological sections, we measured zones with different histological characteristics.On fundus photographs, alpha zone and beta zone of parapapillary atrophy were measured and correlated with the histological data. The size of the clinical alpha zone of parapapillary atrophy was significantly correlated with the size of the histological region with irregularities of the retinal pigment epithelium (P = 0.05; correlation coefficient r = 0.49) and with the size of the histological region with a decreased density of retinal photoreceptors (P = 0.01; r = 0.60). The size of clinical beta zone of parapapillary atrophy significantly correlated with the size of the histological region with complete loss of the retinal pigment epithelium (P <0.001; r = 0.91), with the size of the histological zone with a complete loss of photoreceptors (P <0.001; r = 0.81), and with the size of the histological zone with a closed choriocapillaris (P <0.001; r = 0.89). The clinically seen alpha zone of parapapillary atrophy correlates with histological parapapillary irregularities of the retinal pigment epithelium and decreased density of retinal photoreceptors. The clinically seen beta zone of parapapillary atrophy correlates with histological complete loss of the retinal pigment epithelium and of the photoreceptors, and a closure of the choriocapillaris.


Antibody subpopulation in antihorse cytochrome c serum.
A specific antibody subpopulation(s) in antihorse cytochrome c serum was detected for peptide fragment 81-104 of cyanogen bromide (CNBr) cleaved horse cytochrome c (HCytc). This antiserum was made in the rabbit against polymeric horse cytochrome c. The presence of the peptide-specific antibody subpopulation(s) was demonstrated utilizing HCytc, CNBr-peptide 81-104 and isolated chymotrypsin-digested HCytc fragments 60-67, 83-97 and 98-104 to compete with radio-labeled peptide 81-104 and antiHCytc serum in a competitive radioimmunoassay (RIA). This antibody subpopulation(s) in antiHCytc serum was demonstrated to be specific for peptide 81-104. At the 50% inhibition level in competitive RIA, 100- and 1000-fold molar excesses of HCytc and its peptide 1-65, respectively, were required to affect an equivalent binding to that of the HCytc peptide 81-104. Competitive RIAs have been performed utilizing three different kinds of antigen to compete with HCytc peptide 81-104 and antihorse cytochrome c sera. These three kinds of antigens are: endopeptidase digests of HCytc, cytochrome c peptides 81-104 of several species and several isolated chymotryptic peptide fragments of HCytc. The results have indicated that this peptide-specific antibody subpopulations(s) in antiHCytc serum is similar to antibodies made against peptide 81-104-BSA. Regions of antigenicity have been identified at positions 92, 100, 103 and 104 with both antisera.


Temporal Partitioning between Forest-Dwelling Small Rodents in a Mediterranean Deciduous Woodland.
Temporal partitioning is reported as one of the main strategies adopted by coexisting mammal species to limit interspecific competition and behavioural interference. In the last decades, camera-trapping surveys have provided valuable insights in assessing temporal niche and activity rhythms of medium and large-sized mammalian species. Conversely, this method has been poorly applied to small rodents. In this work we aimed at assessing temporal niche partitioning between two species of forest-dwelling small rodents-Apodemus flavicollis and Clethrionomys glareolus-by means of intensive camera-trapping. Camera traps were placed in areas where previous genetic analyses have confirmed the only presence of A. flavicollis amongst wood mice species, to prevent misinterpretation of records. We collected 124 independent records of A. flavicollis and 67 records of C. glareolus over three years. The former was mostly nocturnal, with activity peaking after midnight, whereas the latter was mostly active at dawn and dusk. Therefore, a limited temporal overlap was observed, confirming the potential for interspecific competition. Intraguild interference competition between A. flavicollis and C. glareolus may play a pivotal role forcing C. glareolus to be more active in daylight hours where, the more strictly nocturnal A. flavicollis is present. Nocturnal activity of C. glareolus was limited and not influenced by moon phases, whereas A. flavicollis was mostly active in the darkest nights, avoiding bright moonlight nights.


Optic neuropathy associated with dengue fever.
To report a case series of three patients of optic neuropathy associated with dengue fever. Observational case series. Three patients aged of 19, 31, and 40 years (cases 1, 2, and 3) complained of unilateral blurring of vision within a week of being diagnosed with dengue fever. Their presenting visual acuities were counting fingers in cases 1 and 2, and 6/6 in case 3, with features suggestive of optic neuropathy. Two of the three patients (cases 2 and 3) had bilateral ocular signs. The visual acuity recovered to 6/9 in case 1, worsened to no light perception in case 2, and remained unchanged in case 3. Although spontaneous visual recovery is possible, optic neuropathy associated with dengue fever may result in severe and permanent visual loss.


Effect of heat stress on performance and expression of selected amino acid and glucose transporters, HSP90, leptin and ghrelin in growing pigs.
Exposing animals to high ambient temperature provokes heat stress (HS) that may affect cellular function and reduced productive performance. The effect of chronic exposure (21d) of pigs to high ambient temperature on expression of amino acid (b(0,+)AT, CAT1) and glucose (SGLT1, GLUT4) transporters, ghrelin, leptin and HSP90 was evaluated. Eighteen pigs (32.6kg body weight) were distributed into 3 groups: (1) pigs housed under natural high ambient temperature conditions, and fed ad libitum (HS); (2) pigs housed in an air-conditioned room at 24°C (thermo-neutral) fed ad libitum (TNad); (3) pigs housed as in (2), but pair-fed with the HS pigs (TNpf). Body temperature, respiratory frequency, weight gain, feed intake, and feed conversion ratio were measured. At d-21 pigs were euthanized and samples from stomach, duodenum, jejunum, liver, longissimus and semitendinosus muscles, and white adipose tissue were collected for mRNA analysis. In the HS room ambient temperature fluctuated every day (23.6-37.6°C). Respiratory frequency and body temperature were higher in HS pigs (P<0.001). Weight gain and feed intake of TNad were higher (P<0.001) than TNpf and HS; gain: feed ratio was not affected by ambient temperature. Expression of HSP90 was higher in duodenum and longissimus (P≤0.038) of HS compared to TNpf. Expression of ghrelin, leptin and b(0,+)AT were not affected by ambient temperature (P>0.050). CAT1 expression in liver was higher (P=0.050) but in longissimus was lower (P=0.017) in HS than in TNpf pigs. Expression of SGLT1 was higher (P=0.045) in duodenum of HS than in TNpf but it was not different in jejunum (P=0.545); GLUT4 tended to be higher in liver and semitendinosus of HS pigs (P=0.063). In conclusion, feed intake remains low whereas respiratory frequency and body temperature remain higher; and expression of HSP90, CAT1, SGLT1 and GLUT4 increases in some tissues in pigs under chronic HS conditions.


Preparation of photo-cross-linked small molecule affinity matrices for affinity selection of protein targets for biologically active small molecules.
Small molecule-immobilized affinity matrices are indispensable tools in chemical genomics to screen and purify protein targets for biologically active small molecules. Usually, prior to immobilization, small -molecules have to be derivatized at a position that does not significantly abrogate the intrinsic biological activity, or chemically synthesized to have an appropriate functional group for the immobilization chemistry. Here, we describe a photo-cross-linking technique to immobilize biologically active small molecules for protein target screening, without the need for chemical derivatization.


Changes in frequency content of inspiratory neuron and nerve activities in the course of inspiration.
In decerebrate paralyzed cats, the spectra and coherences of inspiratory (I) nerve activities and of medullary I neuron discharges were compared between different stages of I. The correlated high-frequency oscillations (HFOs) in the activities had common time courses of frequency and strength, which were influenced by lung afferent input; whereas the time courses for the uncorrelated medium-frequency oscillations (MFOs) depended on individual activity patterns. These results indicate that HFOs are characteristic of the common I pattern generator, whereas MFOs are specific to individual activities.


Molecularly bonded chitosan prepared as chiral stationary phases in open-tubular capillary electrochromatography: comparison with chitosan nanoparticles bonded to the polyacrylamide phase.
The chiral selector, chitosan (CS), was attached to the silanized capillary via a silane coupling agent, (3-glycidyloxypropyl)trimethoxysilane (GTS), to form the GTS-CS capillary, and results for this capillary were compared with those of a previous study on the copolymerization of CS with methacrylamide (MAA) (forming the MAA-CS capillary). The GTS-CS capillary did not exhibit enantioselectivity for d/l-tryptophan, whereas the GTS-BSA capillary, which was prepared by replacement of CS with bovine serum albumin (BSA), succeeded in the chiral separation with an Rs=2.4 in Tris buffer (50mM, pH 8.5). To increase CS attachment, the CS units were crosslinked by succinic acid, and the resulting GTS-CS-s capillary phase improved the resolution to 1.9. Alternatively, the SiH-CS-s capillary was constructed by CS attachment on the silicon hydride phase via stepwise silanization and hydrosilation reactions and crosslinking by succinic acid, but this approach could only achieve a resolution of 1.4 in Tris buffer (50mM, pH 9.5). Although the GTS-CS-s and SiH-CS-s capillaries were still inferior to the MAA-CS capillary (Rs=3.8), the enantioselectivities of the three capillaries were all in the range of 1.4-1.6. For the (±)-catechin sample, the plate heights of the GTS-CS-s and SiH-CS-s capillaries conditioned in pH 8.5 Tris buffer with 60% MeOH modifier were 0.9 cm ((-)-catechin) and 6.0 cm ((+)-catechin)) and 2.9 cm (-) and 3.2 cm (+), respectively, and these heights were comparable to the MAA-CS capillary (2.5 cm (-), 6.0 cm (+)) in pH 6.6 phosphate buffer with 80% MeOH. Finally, a racemate of ibuprofen, a weakly acidic anti-inflammatory drug, was successfully baseline resolved by the GTS-CS-s and SiH-CS-s capillaries in the borate buffers, which were 30 mM at pH 7.5 and 10mM at pH 8.0, respectively.


Derivation of hybrid ES cell lines from two different strains of mice.
Parental origin-dependent expression of the imprinted genes is essential for mammalian development. Zfp57 maintains genomic imprinting in mouse embryos and ES cells. To examine the allelic expression patterns of the imprinted genes in ES cells, we obtained multiple hybrid ES clones that were directly derived from the blastocysts generated from the cross between mice on two different genetic backgrounds. The blastocyst-derived ES clones displayed largely intact DNA methylation imprint at the tested imprinted regions. These hybrid ES clones will be useful for future studies to examine the allelic expression of the imprinted genes in ES cells and their differentiated progeny.


Footshock stress facilitates self-stimulation of the medial prefrontal cortex but not the lateral hypothalamus in the rat.
The effects of stress on self-stimulation were investigated by exposing rats to either controllable, uncontrollable or no footshock. Both controllable and uncontrollable footshock increased medial prefrontal cortex self-stimulation rates immediately as well as 24 h following treatment. Controllable footshock produced a greater enhancement than uncontrollable footshock. In contrast, self-stimulation of the lateral hypothalamus was unaffected by either footshock treatment. These results are interpreted with reference to the neurochemical response of the mesocortical dopaminergic system to acute stress.


Human immunodeficiency virus infection, Part II.
The acceptance of highly active antiretroviral therapy (HAART) among patients and health care providers has had a dramatic impact on the epidemiology and clinical characteristics of many opportunistic infections associated with human immunodeficiency virus (HIV). Previously intractable opportunistic infections and syndromes are now far less common. In addition, effective antibiotic prophylactic therapies have had a profound impact on the risk of patients developing particular infections and on the incidence of these infections overall. Most notable among these are Pneumocystis carinii, disseminated Mycobacterium avium complex, tuberculosis, and toxoplasmosis. Nevertheless, infections continue to cause significant morbidity and mortality among patients who are infected with HIV. The role of HAART in many clinical situations is unquestioned. Compelling data from clinical trials support the use of these therapies during pregnancy to prevent perinatal transmission of HIV. HAART is also recommended for health care workers who have had a "significant" exposure to the blood of an HIV-infected patient. Both of these situations are discussed in detail in this article. In addition, although more controversial, increasing evidence supports the use of HAART during the acute HIV seroconversion syndrome. An "immune reconstitution syndrome" has been newly described for patients in the early phases of treatment with HAART who develop tuberculosis, M avium complex, and cytomegalovirus disease. Accumulating data support the use of hydroxyurea, an agent with a long history in the field of myeloproliferative disorders, for the treatment of HIV. Newer agents, particularly abacavir and adefovir dipivoxil, are available through expanded access protocols, and their roles are being defined and clarified.


The sp3/sp2 carbon ratio as a modulator of in vivo and in vitro toxicity of the chemically purified detonation-synthesized nanodiamond via the reactive oxygen species generation.
Nanodiamonds have been suggested as biocompatible materials and are suitable for various biomedical applications, but little is known about how to synthesize safer nanodiamonds. Herein, seven different detonation-synthesized nanodiamonds (DNDs) with sequential sp3/sp2 carbon ratios were assembled by controlling the chemical purification parameters and the role of sp3/sp2 carbon ratio on the toxicity of DNDs was investigated. Carbon black and nickel oxide nanoparticles were used as reference particles. The intrinsic reactive oxygen species (ROS) generation potential of DNDs was estimated by a 2'7'-dichlorofluorescein diacetate (DCFH-DA) assay, and these values showed a good negative correlation with the sp3/sp2 carbon ratios, which implies that ROS generation increased as the sp3/sp2 carbon ratio decreased. As a model to investigate inflammogenic potential of DND samples, a rat intratracheal instillation model was used as the lung is very sensitive to nanoparticle exposures. The sp3/sp2 carbon ratios or the estimated values of ROS generation potential showed excellent linear correlations with the number of neutrophils and pro-inflammatory cytokines in bronchoalveolar lavage fluid at 24 h after instillation. Treatment of DND samples to THP-1 derived macrophages also showed that the sp3/sp2 carbon ratios or the estimated values of ROS generation potential were closely related with the toxicity endpoints such as cell viability and pro-inflammatory cytokines. Taken together, these data demonstrate that the sp3/sp2 carbon ratio is the key determinant for the toxicity of DNDs, which can be a useful tool for the safer-by-design approach of DNDs and the safety assessment of carbon nanoparticles.


Clinical characteristics and risk factors of intracranial hemorrhage after spinal surgery.
Intracranial hemorrhage after spinal surgery is a rare and devastating complication. To investigate the economic burden, clinical characteristics, risk factors, and mechanisms of intracranial hemorrhage after spinal surgery. A retrospective cohort study was conducted from January 1, 2015, to December 31, 2022. Patients aged ≥ 18 years, who had undergone spinal surgery were included. Intracranial hemorrhage patients were selected after spinal surgery during hospitalization. Based on the type of spinal surgery, patients with intracranial hemorrhage were randomly matched in a 1:5 ratio with control patients without intracranial hemorrhage. The patients' pre-, intra-, and post-operative data and clinical manifestations were recorded. A total of 24472 patients underwent spinal surgery. Six patients (3 males and 3 females, average age 71.3 years) developed intracranial hemorrhage after posterior spinal fusion procedures, with an incidence of 0.025% (6/24472). The prevailing type of intracranial hemorrhage was cerebellar hemorrhage. Two patients had a poor clinical outcome. Based on the type of surgery, 30 control patients were randomly matched in 1:5 ratio. The intracranial hemorrhage group showed significant differences compared with the control group with regard to age (71.33 ± 7.45 years vs 58.39 ± 8.07 years, P = 0.001), previous history of cerebrovascular disease (50% vs 6.7%, P = 0.024), spinal dura mater injury (50% vs 3.3%, P = 0.010), hospital expenses (RMB 242119.1 ± 87610.0 vs RMB 96290.7 ± 32029.9, P = 0.009), and discharge activity daily living score (40.00 ± 25.88 vs 75.40 ± 18.29, P = 0.019). The incidence of intracranial hemorrhage after spinal surgery was extremely low, with poor clinical outcomes. Patient age, previous stroke history, and dura mater damage were possible risk factors. It is suggested that spinal dura mater injury should be avoided during surgery in high-risk patients.


The dimerization of protochlorophyll pigments in non-polar solvents.
The infrared, visible and nuclear magnetic resonance spectra of protochlorophyll a and vinylprotochlorophyll a in dry non-polar solvents (carbon tetrachloride, chloroform, cyclohexane) are presented and interpreted in terms of dimer interaction. The infrared spectra in the 1600-1800 cm-1 region clearly show the existence of a coordination interaction between the C-9 ketone oxygen function of one molecule and the central magnesium atom of another molecule. Infrared spectra in the OH stretching region (3200-3800 cm-1) provide a valuable test of the water content in the samples. The analysis of the absorption and circular dichroism spectra of protochlorophyll a and vinylprotochlorophyll a in carbon tetrachloride demonstrates the existence of a monomer-dimer equilibrium in the concentration range from 10(-6) to 5.10(-4) M. The dimerization constants are (6 +/-2).10(5)1.M-1 for protochlorophyll a and (4.5 +/-21.10(5) 1.M-1 for vinylprotochlorophyll a at 20 degrees C. The deconvolution of visible spectra in the red region has been performed in order to obtain quantitative information on the dimer structure. Two models involving a parallel or a perpendicular arrangement of the associated molecules are considered. From 1H NMR spectra, it appears that the region of overlap occurs near ring V, in agreement with the interpretation of the infrared spectra.


Secretion of plasminogen activator and its inhibitor by glomerular epithelial cells.
The effects of thrombin, interleukin-1 (IL-1), tumor necrosis factor (TNF) and gamma-interferon (gamma-IFN) on the release of plasminogen activator (PA) and inhibitor (PAI) were studied using cultivated human glomerular epithelial cells (GECs). Species of PAs and PAI secreted from the GECs were urokinase-type PA (u-PA) and tissue-type PA (t-PA), while the major species was a single chain u-PA in the amount of 28.6 +/- 2.34 ng/10(5) cells for 24 hours (N = 4, mean +/- SD), and PAI-1. The addition of increased concentrations of thrombin (0.1 to 31.6 U/ml) into confluent cultures enhanced the GECs to release u-PA, t-PA and PAI-1 in a dose- and time-dependent manner. The incubation of the GECs with 10 U/ml thrombin resulted in about a fourfold increase in the concentration of u-PA, threefold in t-PA and twofold in PAI-1. All thrombin effects, however, were suppressed by the simultaneous addition of cycloheximide, indicating that the enhancing effects of thrombin were due to an increase in the production of PAs and PAI-1, via protein synthesis. These thrombin effects appeared to be dependent upon the enzymatically active site of thrombin because DFP-thrombin had no effect. In the conditioned medium which was under continuous thrombin stimulation for 24 hours, no u-PA activity was detectable, even after the plasmin treatment, because a single chain u-PA was degraded by the thrombin. The stimulation of cultured GECs with thrombin only for the first three hours in 24 hour cultivation showed an apparent increase in the antigenic amount of u-PA. IL-1 enhanced the release of t-PA and PAI-1, and TNF did that of u-PA and t-PA, while gamma-IFN showed no significant effects. These findings indicate that the GECs participate in the regulation of extracapillary fibrinolysis in the glomerular microenvironment, as being modulated by thrombin and two cytokines, IL-1 and TNF.


The experience of two practice education models: collaborative learning unit and preceptorship.
Twenty-two Bachelor of Science in Nursing (BSN) graduates shared their perceptions one year after graduation on two practice education models they experienced during years three and four of their nursing education. The two models evaluated were collaborative learning units (CLU) and preceptorship. The participants described what was most important about each of these models in preparing them for graduate practice. While the preceptorship model has been researched for decades, the CLU data are previously unexplored information. The CLU data revealed the themes of working with many and making practice their own, while the themes of working with one and consolidation of nursing practice emerged from the preceptorship data. The participants suggest that both models offer different yet complementary paths for learning and enhanced professional development and practice. There is also confirmation that both are relevant and perhaps necessary to accomplish the complexities of preparing students for professional nursing practice.


Wavelet gated multiformer for groundwater time series forecasting.
Developing accurate models for groundwater control is paramount for planning and managing life-sustaining resources (water) from aquifer reservoirs. Significant progress has been made toward designing and employing deep-forecasting models to tackle the challenge of multivariate time-series forecasting. However, most models were initially taught only to optimize natural language processing and computer vision tasks. We propose the Wavelet Gated Multiformer, which combines the strength of a vanilla Transformer with the Wavelet Crossformer that employs inner wavelet cross-correlation blocks. The self-attention mechanism (Transformer) computes the relationship between inner time-series points, while the cross-correlation finds trending periodicity patterns. The multi-headed encoder is channeled through a mixing gate (linear combination) of sub-encoders (Transformer and Wavelet Crossformer) that output trending signatures to the decoder. This process improved the model's predictive capabilities, reducing Mean Absolute Error by 31.26 % compared to the second-best performing transformer-like models evaluated. We have also used the Multifractal Detrended Cross-Correlation Heatmaps (MF-DCCHM) to extract cyclical trends from pairs of stations across multifractal regimes by denoising the pair of signals with Daubechies wavelets. Our dataset was obtained from a network of eight wells for groundwater monitoring in Brazilian aquifers, six rainfall stations, eleven river flow stations, and three weather stations with atmospheric pressure, temperature, and humidity sensors.


[Bovine chromosome mapping with the cell hybridization technic. Localization on the x chromosome of glucose-6-phosphate dehydrogenase, phosphoglycerate kinase, alpha-galactosidase A and hypoxanthine phosphoribosyltransferase].
Twelve hamster x cattle (Bos taurus) cell hybrids showed loss of cattle chromosomes, which allows their use for chromosome mapping of cattle. Genes coding for G6PD, alpha-GAL A, PGK, and (indirectly) HGPRT are synteneic and localized on the X chromosome.


The encircling mesh in abdominal wall surgery: rationale and technical details of a dorso-ventral physiological restoration.
We describe a new, functional surgical technique, known as 'encircling mesh', designed to address abdominal wall problems. The rationale of the procedure is to connect the anterior and posterior trunk muscle compartments by means of a purpose built polypropylene mesh that encloses a belt shifted posteriorly across the spine subcutaneously, through use of a disposable introducer. The technical details and a case presentation, with specific references to the cosmetic and functional outcomes are described.


N-acetyltransferase activity as a possible criterion in prognosing the anti-tumor effect of cyclophosphamide.
The results obtained in the present study indicated that a reduction in the activity of N-acetyltransferase (EC 126.96.36.199) occurs in cyclophosphamide-treated mice with sarcoma 37. A difference in variations of the level of N-acetyltransferase activity in outbred mice with and without tumors was observed in cyclophosphamide-treated animals. It was established that the effect of cyclophosphamide on the activity of N-acetyltransferase depends on the initial level of the enzyme activity (phenotype of acetylation) as well as on the genotype which determines the N-acetyltransferase activity.


Risk factors for asthma among schoolchildren who participated in a case-control study in urban Uganda.
Data on asthma aetiology in Africa are scarce. We investigated the risk factors for asthma among schoolchildren (5-17 years) in urban Uganda. We conducted a case-control study, among 555 cases and 1115 controls. Asthma was diagnosed by study clinicians. The main risk factors for asthma were tertiary education for fathers (adjusted OR (95% CI); 2.32 (1.71-3.16)) and mothers (1.85 (1.38-2.48)); area of residence at birth, with children born in a small town or in the city having an increased asthma risk compared to schoolchildren born in rural areas (2.16 (1.60-2.92)) and (2.79 (1.79-4.35)), respectively; father's and mother's history of asthma; children's own allergic conditions; atopy; and cooking on gas/electricity. In conclusion, asthma was associated with a strong rural-town-city risk gradient, higher parental socio-economic status and urbanicity. This work provides the basis for future studies to identify specific environmental/lifestyle factors responsible for increasing asthma risk among children in urban areas in LMICs.


Heme content of normal and porphyric cultured skin fibroblasts.
Partial deficiencies in enzyme activities of the heme biosynthetic pathway have been demonstrated in cultured skin fibroblasts and other tissues from patients with protoporphyria (PP) and acute intermittent porphyria (AIP). We have quantitatively and qualitatively assessed the heme and free porphyrin content in cultured PP, AIP, VP (variegate porphyria, in which an enzymatic deficiency has not been identified), and normal skin fibroblasts during routine culture conditions in order to assess the overall metabolism of heme in these cells. The total heme concentration was not significantly different between control and porphyric lines; 189 +/- 15 pmoles/mg protein (mean +/- SEM) in controls, 154 +/- 17 in PP, 175 +/- 20 in AIP, and 181 +/- 81 in VP. The hemoprotein difference spectra were similar in all lines. Free porphyrins were not detected in any of the disorders. Despite partial deficiencies in enzyme activities of the heme pathway, porphyric fibroblasts thus maintain normal heme content during routine culture conditions without detectable porphyrin accumulation.


Association of large for gestational age with cardiovascular metabolic risks: a systematic review and meta-analysis.
The aim of this study was to clarify the relationships among large for gestational age (LGA) and cardiometabolic risk factors. PubMed, Web of Science, and the Cochrane Library databases were searched to identify studies on LGA and outcomes of interest, including BMI, blood pressure, glucose metabolism, and lipid profiles. Data were independently extracted by two reviewers. A meta-analysis was performed using a random-effects model. The Newcastle-Ottawa Scale and funnel graph were used to assess the quality and publication bias, respectively. Overall, 42 studies involving 841,325 individuals were included. Compared with individuals born appropriate for gestational age, individuals born LGA had higher odds of overweight and obesity (odds ratios [OR] = 1.44, 95% CI: 1.31-1.59), type 1 diabetes (OR = 1.28, 95% CI: 1.15-1.43), hypertension (OR = 1.23, 95% CI: 1.01-1.51), and metabolic syndrome (OR = 1.43, 95%; CI: 1.05-1.96). No significant difference was found in hypertriglyceridemia and hypercholesterolemia. Stratified analyses showed that, compared with individuals born appropriate for gestational age, individuals born LGA had higher odds for overweight and obesity from toddler age to puberty age (toddler age: OR = 2.12, 95% CI: 1.22-3.70; preschool: OR = 1.81, 95% CI: 1.55-2.12; school age: OR = 1.53, 95% CI: 1.09-2.14; puberty: OR = 1.40, 95% CI: 1.11-1.77). LGA is associated with increased odds of obesity and metabolic syndrome later in life. Future studies should focus on elucidating the potential mechanisms and identifying risk factors.


Therapeutic plasma exchange as adjunct therapy in 3 dogs with myasthenia gravis and myasthenia-like syndrome.
To describe the use of therapeutic membrane-based plasma exchange (TPE) for treatment of clinical signs associated with suspected acquired myasthenia gravis (MG) in 3 dogs. Three dogs presented with clinical signs consistent with acquired MG. All 3 dogs were medically managed prior to being treated with TPE. Two of the 3 dogs had increased acetylcholine receptor antibody titers that decreased after TPE. One dog diagnosed with primary MG became clinically normal after 2 sessions of TPE and continued to do well with medical management several months later. The second dog was diagnosed with a suspect thymoma, and TPE was performed as a bridge to surgery, with marked improvement of clinical signs after TPE. The dog was ultimately diagnosed with a thymic carcinoma. The third dog had a positive acetylcholine antibody titer and was ultimately diagnosed with hemangiosarcoma (spleen and liver) and invasive mediastinal thymoma. This dog developed severe pneumonia, was ventilator dependent, and died of multiple organ dysfunction. No immediate complications were observed secondary to TPE. All 3 dogs were concurrently treated with either immunosuppressive agents, anticholinesterase drugs, or both. The use of TPE in dogs with MG appears to be well tolerated and safe. It may be a reasonable adjunct therapy to acetylcholinesterase drugs in cases that are not responding to medical management alone. Therapeutic plasma exchange might also be considered preoperatively to prevent postoperative complications in dogs with severe MG, although further studies should be performed.


Murine model of triosephosphate isomerase deficiency with anemia and severe neuromuscular dysfunction.
Triosephosphate isomerase deficiency (TPI Df) is a rare, aggressive genetic disease that typically affects young children and currently has no established treatment. TPI Df is characterized by hemolytic anemia, progressive neuromuscular degeneration, and a markedly reduced lifespan. The disease has predominately been studied using invertebrate and in vitro models, which lack key aspects of the human disease. While other groups have generated mammalian Tpi1 mutant strains, specifically with the mouse mus musculus, these do not recapitulate key characteristic phenotypes of the human disease. Reported here is the generation of a novel murine model of TPI Df. CRISPR-Cas9 was utilized to engineer the most common human disease-causing mutation, Tpi1 E105D , and Tpi1 null mice were also isolated as a frame-shifting deletion. Tpi1 E105D/null mice experience a markedly shortened lifespan, postural abnormalities consistent with extensive neuromuscular dysfunction, hemolytic anemia, pathological changes in spleen, and decreased body weight. There is a ∼95% reduction in TPI protein levels in Tpi1 E105D/null animals compared to wild-type littermates, consistent with decreased TPI protein stability, a known cause of TPI Df. This work illustrates the capability of Tpi1 E105D/null mice to serve as a mammalian model of human TPI Df. This work will allow for advancement in the study of TPI Df within a model with physiology similar to humans. The development of the model reported here will enable mechanistic studies of disease pathogenesis and, importantly, efficacy testing in a mammalian system for emerging TPI Df treatments.


Tetrazole-biarylpyrazole derivatives as cannabinoid CB1 receptor antagonists.
Cannabinoid CB1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed a new series of tetrazole-biarylpyrazoles. The various analogues were efficiently prepared and bio-assayed for binding to cannabinoid CB1 receptor. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor. Noticeably, cyclopentyl-tetrazole (9a) demonstrated good binding affinity and selectivity for CB1 receptor (IC(50)=11.6nM and CB2/CB1=366).


Neural response to emotional stimuli associated with successful antidepressant treatment and behavioral activation.
Major Depressive Disorder (MDD) is a leading cause of disability globally. Currently available treatments have limited efficacy and combination strategies are frequently used. Several lines of research have demonstrated that MDD patients experience impairments in various components of affective processing, including regulation of affective states. To identify baseline and 1-week neuroimaging predictors of response to a 6-week trial of fluoxetine/olanzapine combination treatment during an affective processing task. Twenty-one MDD patients and 18 healthy controls were enrolled in the study. MDD patients were treated for 6 weeks with fluoxetine (40-60 mg/day) and olanzapine (5-12.5mg/day). All participants viewed images from the International Affective Picture Rating System during a functional magnetic resonance (fMRI) scan at baseline and 1 week. There was a 57% response rate (defined as a 50% decrease in Hamilton Rating Scale for Depression-17 item) at 6 weeks. At baseline, responders had increased premotor activity while viewing negative images compared to non-responders and healthy controls. Higher baseline premotor activity was also predictive of greater percent change on the HAMD-17 and improvement in negative disposition and behavioral drive. Non-responders exhibited increased insular activity at baseline compared to responders. Higher activity in the posterior cingulate cortex was also predictive of greater percent change on the HAMD-17. Change from baseline to 1 week did not produce any significant predictive findings. Treatment with fluoxetine/olanzapine demonstrated similar biomarkers of response to monotherapeutic strategies. In particular, posterior cingulate cortex, anterior insula, and premotor cortex may show predictive differences in their response to affective images prior to treatment. Further research needs to be conducted to determine the utility of early changes in emotion circuitry in predicting antidepressant response.


Stochastic models for X chromosome inactivation.
A multivariate Gaussian model for mammalian development is presented with the associated biological and mathematical assumptions. Many biological investigations use the female mammal X chromosome to test hypotheses and to estimate parameters of the developmental system. In particular, Lyon's (1961) hypotheses are used as a basis of the mathematical model. Experimental mouse data and three sets of human experimental data are analyzed using the hypothesized Gaussian model. The estimated biological parameters are consistent with some current biological theories.


Transgene transmission to progeny by oMt1a-oGH transgenic mice.
Most studies utilizing transgenic technology focus on the impact to traits of interest, rather than propagation of the transgene to offspring. In animals containing growth hormone constructs, transgene transmission to progeny follows a Mendelian pattern of inheritance in the first few generations following generation of a founder animal, but decreases in subsequent generations. In the present study, the ovine metallothionein 1a-ovine growth hormone (oMt1a-oGH) transgenic mouse was used to determine whether transgene transmission rate to progeny was affected by overexpression of ovine growth hormone in the transgenic parent. The oMt1a-oGH mouse is a useful model for assessing transgene transmission, as the construct is easily regulatable and transgene inactivation results in a return of plasma GH to basal levels. Male and female hemizygous oMt1a-oGH mice were assigned to 1 of 3 treatment groups: (1) mice never actively expressing the transgene, (2) mice actively expressing the transgene from 3 weeks of age, and (3) mice actively expressing the transgene from 3 to 11 (males) or 3 to 8 (females) weeks of age. Transgenic mice were mated to wild type animals and the resulting progeny were genotyped. Males never actively expressing the transgene passed on the transgene to progeny in a Mendelian fashion, while males actively expressing the transgene transmitted the transgene to a smaller than expected number of progeny. However, following inactivation of the oMt1a-oGH construct in transgenic males, subsequent offspring demonstrated Mendelian inheritance of the transgene. In contrast, females expressing the transgene from 3 to 8 weeks of age were able to pass on the oMt1a-oGH construct in a Mendelian fashion, but females from other treatment groups were not. In oMt1a-oGH males, reduced transgene transmission appears to be due to selection against transgenic gametes. In females, however, selection against the transgenic genotype likely occurs at the embryonic level.


Phylogeny of the major tetrapod groups: morphological data and divergence dates.
The phylogeny of the major groups of tetrapods (amphibians, reptiles, birds, and mammals) has until recently been poorly understood. Cladistic analyses of morphological data are producing new hypotheses concerning the relationships of the major groups, with a focus on the identification of monophyletic groups. Molecular phylogenies support some of these views and dispute others. Geological dates of the major evolutionary branching points are recalculated on the basis of the cladograms and new fossil finds.


Surgical approach to gallbladder disease in rural Guatemala.
In this article, we report the current surgical approach to gallbladder disease at a major referral hospital in rural Guatemala. Complications in a cohort of patients undergoing open versus laparoscopic cholecystectomy were catalogued. We reviewed cholecystectomies performed by surgeons at the Hospital Nacional de San Benito in El Peten, Guatemala, after the adoption of the laparoscopic approach. Laparoscopic cholecystectomies (LCs) between 2014 and 2015 (n = 42) were reviewed and matched by 58 randomly selected open cholecystectomies (OCs) during the same period. Patient demographics were similar in the LC and OC groups. Of the 63 patients who had elective surgery, 43 (68%) underwent OC. Conversion rate, hospital length of stay, and readmission rate were 4%, 4.8 days, and 5%, respectively. Complications were similar between groups. Despite the low number of LCs, their complications were not different from that of OCs. During the study period, a large number of cholecystectomies continued to be open, even in the elective setting.


Concentration of endogenous oestradiol as related to oestradiol receptor sites in breast tumor cytosol.
Biopsies or mastectomy specimens from 69 malignant and 17 non-malignant human breast tumours have been examined with respect to cytoplasmic oestradiol receptors and endogenous oestradiol concentration. Of the malignant tumours, 45 (65%) had significant oestradiol receptor concentrations (136.7 fmol/mg protein +/- 38.3 S.E.M.). Oestradiol values in the cytosol were not correlated to receptor levels. Cytosol oestradiol concentrations in the receptor-negative tumours were normally distributed about a mean value of 7.4 fmol/mg protein +/- 0.9 (S.E.M.). Oestradiol levels were similar to the median concentration of receptor found in tumours from younger women, and consequently may influence receptor measurements in such tumours. In receptor-positive cytosols a much wider range (less than 1 to 69.7 fmol/mg protein) and a non-symmetrical distribution of oestradiol values were found which closely corresponded to the range of occupied receptor concentrations previously measured in tumour cytosol. When tumours having undetectable oestradiol values were excluded, receptor-positive cytosols had significantly higher oestradiol concentrations than those found in receptor-negative tumours (P less than 0.01). No significant difference in cytosol oestradiol concentration was found in receptor-positive and negative pre- and postmenopausal women. This would indicate that factors other than plasma levels influence tissue availability of oestradiol.


Injuries due to deliberate violence in areas of Denmark. IV. Alcohol intoxication in victims of violence. The Copenhagen Study Group.
A material of 1316 victims of deliberate violence was collected prospectively during a one year period in three Danish emergency wards covering a provincial/rural area and two metropolitan areas. The frequency of alcohol intoxication was determined. Forty-one percent of the patients were intoxicated. The highest frequency was found in male victims, in the provincial/rural area, in restaurants or their vicinity, in the age group 35-49, during evenings and nights and in May. It is difficult to indicate specific preventive measures. However, a more restrictive attitude is suggested with regard to serving alcohol to intoxicated persons in restaurants.


Neogenin interacts with RGMa and netrin-1 to guide axons within the embryonic vertebrate forebrain.
In the embryonic forebrain, pioneer axons establish a simple topography of dorsoventral and longitudinal tracts. The cues used by these axons during the initial formation of the axon scaffold remain largely unknown. We have investigated the axon guidance role of Neogenin, a member of the immunoglobulin (Ig) superfamily that binds to the chemoattractive ligand Netrin-1, as well as to the chemorepulsive ligand repulsive guidance molecule (RGMa). Here, we show strong expression of Neogenin and both of its putative ligands in the developing Xenopus forebrain. Neogenin loss-of-function mutants revealed that this receptor was essential for axon guidance in an early forming dorsoventral brain pathway. Similar mutant phenotypes were also observed following loss of either RGMa or Netrin-1. Simultaneous partial knock downs of these molecules revealed dosage-sensitive interactions and confirmed that these receptors and ligands were acting in the same pathway. The results provide the first evidence that Neogenin acts as an axon guidance molecule in vivo and support a model whereby Neogenin-expressing axons respond to a combination of attractive and repulsive cues as they navigate their ventral trajectory.


Surgical strategy for suspected early gallbladder carcinoma including incidental gallbladder carcinoma diagnosed during or after cholecystectomy.
This paper presents an overview of the surgical strategy for patients with suspected gallbladder carcinoma (GBC), including incidental GBC cases, preoperatively or intraoperatively, as well as their outcomes. Between April 2009 and December 2017, 529 patients underwent cholecystectomy for gallbladder disease at our hospital. Both intraoperative and postoperative histological examinations of the excised gallbladder facilitated the diagnosis of GBC. Surgery-related variables and surgical approaches were evaluated according to the extent of tumor invasion. Of 529 patients, eight were diagnosed with GBC during/after cholecystectomy, including four women and four men. Mean age was 75.4 (range, 59-89) years. Five patients had gallbladder stones and three had cholecystitis. Three patients with stages T1b and T2 underwent additional liver bed wedge resections with or without prophylactic common bile duct excision. Five of the eight patients are still alive and two of the remaining three died from other diseases; one patient with pT3 died of recurrent GBC (peritonitis carcinomatosa). Because of the ability to obtain full-thickness frozen biopsies during laparoscopic cholecystectomy, we could diagnose GBC intraoperatively, allowing for rapid diagnosis and tumor resection. We recommend developing a surgical treatment strategy for suspected early GBC in advance of cholecystectomy.


Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells.
Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. It is well known that Aurora kinase A (AKA) over-expression promotes tumorigenesis, but its role in the pathogenesis of systemic mastocytosis (SM) has not yet been investigated. Evidence from the literature suggests that AKA may confer cancer cell chemo-resistance, inhibit p53, and enhance Polo-like kinase 1 (Plk1), CDK1, and cyclin B1 to promote cell cycle progression. In this study, we aimed to investigate the pathogenetic role of AKA and Plk1 in the advanced forms of SM. We demonstrate here, for the first time, that SM cell lines display hyper-phosphorylated AKA and Plk1. Danusertib (Aurora kinase inhibitor) and volasertib (Plk1 inhibitor) inhibited growth and induced apoptotic cell death in HMC-1.1 and -1.2 cells. Their growth-inhibitory effects were associated with cell cycle arrest and the activation of apoptosis. Cell cycle arrest was associated with increased levels of phospho-Wee1. Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA ± Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM.


Myofascial trigger point development from visual and postural stressors during computer work.
The mechanism of musculoskeletal pain underlying low level static exertions, such as those experienced during computer work, is poorly understood. It was hypothesized that static postural and visual stress experienced during computer work might contribute to trigger point development in the trapezius muscles, resulting in myofascial pain. A study was conducted to observe the development of myofascial trigger points while 16 female subjects used a computer under conditions of high and low postural and visual stress. Trigger point development was monitored via expert opinion, subject self-report, and electromyographic activity. Only the high visual stress conditions resulted in greater trigger point sensitivity as reported by subjects and the myofascial specialist. Cyclic trends in median frequency of the EMG signal were assessed for the trapezius muscle. When high visual stress was combined with low postural stress condition there were significantly fewer cycles (1.6 cycles) as compared to the condition of low visual and low postural stress (2.8 cycles), and the condition of high visual and high postural stress (3.5 cycles). These significant differences between conditions were found for the right trapezius but not for the left. The findings suggest that high visual stress may be involved in the development of the myofascial pain response.


The antioxidant and antihyperlipidemic activities of phosphorylated polysaccharide from Ulva pertusa.
Ulvan was the polysaccharide (U) from a large edible green algae Ulva pertusa. In this study, phosphorylated ulvan (PU) was prepared by the sodium trimetaphosphate -sodium tripolyphosphate method. Antioxidant and antihyperlipidemic effects of U and PU were investigated employing in vivo systems. The PU was confirmed by IR, 31P NMR and 13C NMR spectra. And in addition, we found that the PU3 group at the dose of 500 mg/kg showed stronger antioxidant activity. Compared with hyperlipidemia group, it significantly increased GSH-Px (34.29%; P < 0.01), SOD (20.04%; P < 0.01) and CAT (37.49%; P < 0.01). Treatment of hyperlipidemia mice with PU resulted in a significant decrease in TC, TG and LDL-C, and significant increase in HDL-C. The PU3 significantly increased HDL-C (33.70%; P < 0.01), decreased LDL-C (52.73%; P < 0.01) and TG (33.58%; P < 0.01) compared with hyperlipidemia group. The result showed that phosphorylation could improve hypolipidaemic and antioxidant activities in vivo. PU may be used as a drug for hyperlipidaemia treatment.


Mutations of the APC, beta-catenin, and axin 1 genes and cytoplasmic accumulation of beta-catenin in oral squamous cell carcinoma.
The Wnt pathway is involved in carcinogenesis and three regulatory genes of the Wnt pathway, APC, beta-catenin and Axin are mutated in some primary human cancers. Mutations in these genes can impair the down regulation of beta-catenin, which results in the stabilization of beta-catenin, accumulation of free beta-catenin and subsequent activation of the Wnt pathway. To clarify the genetic alterations of components of the Wnt pathway in oral squamous cell carcinoma (SCC), we examined mutations in the APC, beta-catenin and Axin genes and subcellular localization of beta-catenin. 20 oral SCC tissues and four cell lines derived from oral SCC were used. Mutational analysis was performed by a single-strand conformation polymorphism (SSCP) method and direct sequencing analysis. The samples were also examined by immunohistochemical staining and immunoblot analysis. In 3 of 4 cell lines, mutations were observed in the APC and Axin1 genes without amino acid substitutions. In a clinical sample, a mutation in the Axin1 gene was detected; a T insertion at codon 250 resulted in the formation of a stop codon at codon 259. In addition, cytoplasmic accumulation of beta-catenin was observed in 3 (75%) of 4 cell lines and 18 (90%) of 20 cancer tissue samples. The Axin1 gene may be one of the mutational target in oral SCC. In addition, the cytoplasmic accumulation of beta-catenin is a common characteristic of oral SCC, but is not closely associated with mutational alterations in the APC, beta-catenin and Axin1 genes.


IBDV particles packaged with only segment A dsRNA.
Multi-segmented dsRNA viruses have been suggested to utilize cis-acting elements in the plus-strand RNA to accomplish genomic RNA assortment during viral packaging. It is not clear if bi-segmented dsRNA birnavirus uses the same strategy. By applying a reverse genetic technique, we generated IBDV particles packaged with only segment A by co-transfection DF-1 cells of cDNA from segment A and VP1 (without 5' and 3' noncoding region of segment B) supporting random assortment mechanism and indicating the packaging elements of segment B include sequences in the 5' and 3' NCR. However, gfp-containing IBDV could not be generated in the presence of gfp cDNA constructs flanked by 5' and 3' NCR from segment A or segment B. The data suggest additional packaging signals are required for IBDV genomic packaging. The presence of VP1 protein in the IBDV-A particles also suggests the formation of ribonucleoprotein (RNP) complexes might be involved in the assembly of viral particles.


Occurrence of sulfonamide and tetracycline-resistant bacteria and resistance genes in aquaculture environment.
The occurrence of sulfonamide and tetracycline resistance and their pollution profile in the aquaculture environment of Tianjin, northern China, were investigated. The presence of antibiotic-resistant bacteria was identified and the corresponding antibiotic resistance genes (ARGs) were quantified at 6 aquaculture farms in Tianjin. Sulfonamide-resistance genes were prevalent and their concentrations were the highest detected (3.0 × 10(-5) to 3.3 × 10(-4) for sul1/16S rDNA, 2.0 × 10(-4) to 1.8 × 10(-3) for sul2/16S rDNA) among the various ARGs, most likely because the use of sulfonamides is more prevalent than tetracyclines in this area. Bacillus was the most dominant bacterial genus in both sulfamethoxazole resistant bacteria (63.27% of the total resistant bacteria) and tetracycline-resistant bacteria (57.14% of the total resistant bacteria). At least two of those genes (tetM, tetO, tetT, tetW, sul1 and sul2) were detected in the isolates of Bacillus cereus, Bacillus subtilis, Bacillus megaterium and Acinetobacter lwofii, and all of the above genes were detected in B. cereus, suggesting the occurrence of multi-resistance in the studied area. The genetic transfer of sul1 between intestinal bacteria (e.g., Enterococcus spp.) and indigenous bacteria (e.g., Bacillus spp.) was implied by phylogenetic analysis. Several strains of resistant opportunistic pathogens (e.g., Acinetobacter spp.) were found in indigenous bacteria, which increase the risk of ARGs to public health. Overall, this is the first study to comprehensively investigate the antibiotic resistance profile by analyzing the species of antibiotic-resistant bacteria and adopting qualitative and quantitative methods to investigate ARGs at a typical aquaculture area in northern China.


[RNAse activity as an indirect index of the enterotoxigenicity of staphylococci].
On the basis of investigations carried out there was revealed a direct relationship between the capacity of staphylococci to produce enterotoxin and the extent of their RNA-ase activity. The activity of RNA-ase can serve as a significant indirect sign pointing to the enterotoxigenicity of staphylococcus.


[The role of feedback in the dynamics of functional asymmetry of brain hemispheres in man].
Reaction time, number of correct evaluations of time microintervals, and P300 wave were studied in healthy adult subjects. The role is shown of feedback stimuli in training of a subject to discriminate short intervals and in changes of interhemispheric functional relations. These relations change in the course of training as a result of lateralized activation of the left hemisphere. Training with informative feedback is more efficient in the left hemisphere. The right hemisphere in lesser extent than the left one is subject to correcting influence of the feedback. In this sense the former is more autonomous.


Sustained upregulation of glial fibrillary acidic protein in Müller cells in pigeon retina following disruption of the parasympathetic control of choroidal blood flow.
Choroidal blood flow in pigeon eyes is light driven and controlled by a parasympathetic input from ciliary ganglion (CG) neurons that receive input from the medial subdivision of the ipsilateral nucleus of Edinger-Westphal (EWM). EWM lesions diminish basal ChBF and irreversibly prevent ipsilateral light-evoked increases in ChBF, presumably rendering the retina mildly ischemic. To characterize the location, severity, and time course of the retinal abnormality caused by an EWM lesion, we quantitatively analyzed the cellular and regional extent of Müller cell glial fibrillary acidic protein (GFAP) immunolabeling up to nearly a year after an EWM lesion. We found that unilateral EWM lesions greatly increased Müller cell GFAP throughout the entire retinal depth and topographic extent of the affected eye, up to nearly a year post lesion. By contrast, destruction of the pupilloconstrictive pretectum or of the pupilloconstrictive part of lateral EW (EWL) did not appreciably increase Müller cell GFAP. Thus, the large increase in Müller cell GFAP following an EW lesion is attributable to an ongoing defect in choroidal vasodilatory function rather than to chronic pupil dilation. The Müller cell GFAP increase was greater ipsilateral than contralateral to the EWM destruction for the retinal territory deep to the heavily CG-innervated superior and temporal choroid, but not for the retinal territory deep to the poorly CG-innervated inferior and nasal choroid. The GFAP increase was light-dependent, since it did not occur in EW-lesioned birds housed in dim illumination. Our results show that the chronic vascular insufficiency caused by the loss of the EWM-mediated parasympathetic control of choroidal blood flow leads to a significant and sustained increase in retinal Müller cell GFAP. This increase could be a sign of a disturbance in retinal homeostasis that eventually leads to retinal injury and impaired visual function.


Middle cerebral artery blood flow velocities and pulsatility index and the cerebroplacental pulsatility ratio: longitudinal reference ranges and terms for serial measurements.
To establish reference ranges suitable for serial assessments of the fetal middle cerebral (MCA) and umbilical (UA) artery blood flow velocities, pulsatility index (PI) and cerebroplacental pulsatility ratio and to provide terms for calculating conditional reference intervals suitable for individual serial measurements. This was a longitudinal study of 161 singleton pregnancies. Using Doppler ultrasound, MCA and UA blood velocities and PI were determined three to five times at 3-5-week intervals over a gestational age range of 19-41 weeks. Polynomial regression lines for the 95th, 50th and 5th percentiles were calculated for the peak systolic velocity (PSV), time-averaged maximum velocity (TAMXV), PI and cerebroplacental ratio. Terms for calculating conditional reference intervals were established. Based on 566 observations our new longitudinal reference ranges for fetal middle cerebral PSV, TAMXV and PI provided terms for calculating conditional reference intervals (i.e. predicting expected 95% confidence limits based on a previous measurement), and correspondingly for the cerebroplacental ratio (n = 550). The reference ranges were at some variance with those of previous cross-sectional studies. The narrow 95% confidence limits for the 5(th) and 95(th) percentiles ensured reliable ranges. We have established longitudinal reference ranges appropriate for the serial assessment of MCA blood velocities and PI and cerebroplacental ratio. Particularly the terms for calculating conditional ranges based on a previous observation make this system more appropriate for longitudinal monitoring than are cross-sectional data.


Modelling the relationship between poverty, environment, and institutions: a panel data study.
The paper examines the relationship between poverty and CO2 emission. We contribute by using a global panel data of 146 countries over the period 1996-2014 and by focusing on the role of institution in poverty and environmental degradation nexus. The main findings are that the non-linearity relationship between poverty and CO2 emission could prompt a further increase in the poverty and environmental degradation. However, an increase in the institutional quality leads to a reduction in poverty and more protection to the environment. The main policy recommendation is that all countries need to improve their institutional framework so that reduction of poverty and environmental degradation can occur.


Recognition of the activated states of Galpha13 by the rgRGS domain of PDZRhoGEF.
G12 class heterotrimeric G proteins stimulate RhoA activation by RGS-RhoGEFs. However, p115RhoGEF is a GTPase Activating Protein (GAP) toward Galpha13, whereas PDZRhoGEF is not. We have characterized the interaction between the PDZRhoGEF rgRGS domain (PRG-rgRGS) and the alpha subunit of G13 and have determined crystal structures of their complexes in both the inactive state bound to GDP and the active states bound to GDP*AlF (transition state) and GTPgammaS (Michaelis complex). PRG-rgRGS interacts extensively with the helical domain and the effector-binding sites on Galpha13 through contacts that are largely conserved in all three nucleotide-bound states, although PRG-rgRGS has highest affinity to the Michaelis complex. An acidic motif in the N terminus of PRG-rgRGS occupies the GAP binding site of Galpha13 and is flexible in the GDP*AlF complex but well ordered in the GTPgammaS complex. Replacement of key residues in this motif with their counterparts in p115RhoGEF confers GAP activity.


Effects of Heart Rate Variability Biofeedback on EEG Alpha Asymmetry and Anxiety Symptoms in Male Athletes: A Pilot Study.
Heart rate variability biofeedback (HRV-BFB) has been shown as useful tool to manage stress in various populations. The present study was designed to investigate whether the biofeedback-based stress management tool consisting of rhythmic breathing, actively self-generated positive emotions and a portable biofeedback device induce changes in athletes' HRV, EEG patterns, and self-reported anxiety and self-esteem. The study involved 41 healthy male athletes, aged 16-21 (mean 18.34 ± 1.36) years. Participants were randomly divided into two groups: biofeedback and control. Athletes in the biofeedback group received HRV biofeedback training, athletes in the control group didn't receive any intervention. During the randomized controlled trial (days 0-21), the mean anxiety score declined significantly for the intervention group (change-4 p < 0.001) but not for the control group (p = 0.817). In addition, as compared to the control, athletes in biofeedback group showed substantial and statistically significant improvement in heart rate variability indices and changes in power spectra of both theta and alpha brain waves, and alpha asymmetry. These changes suggest better self-control in the central nervous system and better flexibility of the autonomic nervous system in the group that received biofeedback training. A HRV biofeedback-based stress management tool may be beneficial for stress reduction for young male athletes.


Data-driven curvilinear reconstructions of 3D MR images: application to cryptogenic extratemporal epilepsy.
This paper presents a data-driven method for the reconstruction and visualisation of curvilinear slices from three-dimensional (3D) magnetic resonance (MR) scans of the head. Visualisation of curvilinear slices, rather than standard planar slices, produces symmetrical views of the cortex and allows small abnormalities to be detected by comparing the two hemispheres of the brain. In our method, the surface defined by the upper half of the brain is used as a reference shape for curvilinear reconstructions. The brain is first segmented from the 3D scan using a 3D region growing method associated to an unsupervised threshold selection technique. The upper half of the segmented brain is then extracted and fitted by a deformable surface model. This surface is finally interactively moved by the operator in the 3D scan, to visualise the desired curvilinear slice, which is projected on the screen as a two-dimensional image. We show an application of this visualisation technique to the localisation of cerebral epileptogenic lesions. The procedure has proven efficient and handy in clinical use.


Seasonal variation in emergent hemodialysis initiation in the late elderly: A single-center study.
The number of new dialysis patients, particularly among the elderly population, has been globally increasing. In Japan, patients aged ≥65 years and ≥75 years comprised 72% and 45% of patients on dialysis in 2018, respectively. Few studies have reported seasonal variations in the initiation of dialysis. We investigated the seasonal prevalence of the emergent hemodialysis initiation in the elderly. We reviewed 479 elderly patients who initiated hemodialysis between January 2006 and December 2018. Early elderly patients were defined as patients aged between 65 and 74 years, and late elderly patients were defined as those aged ≥75 years. Emergent hemodialysis initiation was defined as initiation with a temporary vascular catheter without elective permanent vascular access or unplanned hemodialysis initiation due to patients requiring critical care regardless of elective permanent vascular access. The information collected included age, sex, and details of the initiation of hemodialysis. The early elderly group consisted of 199 patients, and the late elderly group consisted of 279 patients. In the late elderly group, hemodialysis initiation was most frequent in winter, followed by spring, autumn, and summer (p = 0.018). Moreover, emergent hemodialysis initiation was most frequent in winter, followed by spring, autumn, and summer (p = 0.009). Emergent hemodialysis initiation due to fluid overload was most frequent in winter, followed by autumn, spring, and summer (p < 0.001). Among late elderly patients who initiated hemodialysis, 78% did not have permanent hemodialysis access at the time of the initiation of hemodialysis. In the late elderly group, hemodialysis initiation and emergent hemodialysis initiation were significantly more frequent in the winter than in the remaining seasons. In addition, emergent hemodialysis initiation due to fluid overload was most frequent in winter in the late elderly group.


Optical, structural and morphological properties of silver nanoparticles and its influence on the photocatalytic activity of TiO2.
Silver nanoparticles (Ag NPs) were synthesized by solution combustion method using glycine and citric acid as fuels. The prepared Ag NPs were characterized by optical absorption spectroscopy, X-Ray Diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM), Fourier Transform Infrared spectroscopy (FTIR) and Energy Dispersion Spectroscopic (EDS) techniques. Surface plasmon resonance peak was appeared at 410 and 418 nm for glycine (GAg) and citric acid (CAg) assisted silver nanoparticles respectively. The silver NPs are fcc in crystal structure. The calculated average particle size from XRD was found around 29 nm for GAg and 41 nm for CAg. HRTEM image shows that the silver nanoparticles have strain and fivefold symmetry formed by twinning in the crystal structure. The photocatalytic activity of TiO2 nanoparticles with Ag NPs were also elucidated and were found that the Ag NPs enhance the photocatalytic activity of TiO2.


Interferon-λ treatment accelerates SARS-CoV-2 clearance despite age-related delays in the induction of T cell immunity.
Interferons induced early after SARS-CoV-2 infection are crucial for shaping immunity and preventing severe COVID-19. We previously demonstrated that injection of pegylated interferon-lambda accelerated viral clearance in COVID-19 patients (NCT04354259). To determine if the viral decline is mediated by enhanced immunity, we assess in vivo responses to interferon-lambda by single cell RNA sequencing and measure SARS-CoV-2-specific T cell and antibody responses between placebo and interferon-lambda-treated patients. Here we show that interferon-lambda treatment induces interferon stimulated genes in peripheral immune cells expressing IFNLR1, including plasmacytoid dendritic cells and B cells. Interferon-lambda does not affect SARS-CoV-2-specific antibody levels or the magnitude of virus-specific T cells. However, we identify delayed T cell responses in older adults, suggesting that interferon-lambda can overcome delays in adaptive immunity to accelerate viral clearance in high-risk patients. Altogether, interferon-lambda offers an early COVID-19 treatment option for outpatients to boost innate antiviral defenses without dampening peripheral adaptive immunity.


Validation of a novel functional test for assessing metamorphopsia using epiretinal membranes as a model.
Current tests for assessing metamorphopsia do not account for confounders such as perceptual filling-in and spatial redundancy, which affect its sensitivity and repeatability. This proof-of-concept study aimed to assess the performance of a novel laboratory-based psychophysical test (Line Sag Test, LST) which addresses these issues for quantification of metamorphopsia in idiopathic epiretinal membranes. The LST quantifies perpendicular metamorphopsia at three eccentricities (3°, 6°, and 9°) along eight meridians (45° steps). Metamorphopsia was assessed using the LST and Amsler grid and the hit rates of both tests for detecting metamorphopsia were compared. Normal metamorphopsia scores using the LST did not differ significantly from 0 and fell within one step-size (p = 0.500). The LST detected significantly more cases of metamorphopsia than the Amsler grid (14/21 versus 3/21) (p = 0.003). Similarly, significantly more cases of visual distortions in asymptomatic iERMs were detected using the LST than the Amsler grid (11/18 versus 0/18) (p = 0.008). The LST has a higher hit rate compared to the Amsler grid (67% versus 14%). This work demonstrates a psychophysically-robust functional test addressing perceptual confounders is more sensitive for quantifying and localising metamorphopsia in macular disease, particularly in asymptomatic disease.