Detection of inflammatory bowel disease (IBD)-associated microRNAs by two color DNA-templated silver nanoclusters fluorescent probes.
Researches demonstrated that circulating miRNAs could be used as novel diagnostic and prognostic potential markers for patients with inflammatory bowel diseases (IBD). It is of great significance in clinical to develop rapid and specific detection methods for miRNAs. Herein, we established a fluorescent probe for ulcerative colitis (UC) activity-associated two serum biomarkers (miR-23a and miR-223) simultaneous detection, which used multi-color fluorescent DNA-stabilized silver nanoclusters (DNA-AgNC) illuminated by a close guanine (G)-rich sequence as a signal transducer and two split DNA probes as recognition units. In principle, the two DNA probe sequences containing AgNC nucleation sequence and G-rich sequence respectively, formed a ternary complex when in the presence of target miRNA through base pairing, so as to induce enhancement of fluorescence emission of AgNC by shortening the distance from G-rich sequence. The combined probes for miR-23a and miR-223 detection generated increased fluorescence signals at 460 nm ex/545 nm em and at 560 nm ex/630 nm em, respectively. With this technique, we successfully quantified the two target miRNAs with high selectivity. Furthermore, the potential clinic applicability of this method was verified by testing the spiked standard miRNAs in human serum. Thus, this one-step, low-cost, and homogenous method offers a great opportunity for disease-associated multiplex miRNAs simultaneous detection.


Site-specific incorporation of [125I]iododeoxyuridine into DNA.
A procedure for the incorporation of [125I]IdU into specific sites in DNA is described. The approach depends upon attachment of radioiododeoxyuridine to a controlled pore glass support which is then used for automated synthesis of an oligomer. The resulting oligomer, containing a terminal 3'[125I]iododeoxyuridine, is used as a primer during DNA synthesis catalyzed by the Taq polymerase employing thermal cycling. The product formed includes the radioiodonucleotide at a single internal site determined by the length of the oligomer.


Identifying Reasons for Nonmedical Delays in Fixation of Femur, Pelvis, and Acetabular Fractures at a Level 1 Trauma Center.
To identify reasons for nonmedical delays in femur, pelvis, and acetabular fracture fixation at an institution with a dedicated orthopaedic trauma room (DOTR) and an early appropriate care practice model. Retrospective review of a prospective registry. Urban Level 1 trauma center. Two hundred ninety-four patients undergoing 313 procedures for 226 femur, 63 pelvis, and 42 acetabular fractures. Definitive fixation. Reasons for delays in fixation after hospital day 2. Delays occurred in 12.5% of procedures (39/313), with 7.7% (24/313) having medical delays and 4.8% (15/313) having nonmedical delays. Nonmedical delays were most commonly due to the operating room being at-capacity (n = 6) and nonpelvic trauma specialists taking weekend call (n = 5). Procedures with nonmedical delays were associated with younger age (median difference -16.0 years, 95% confidence interval [CI], -28 to -5.0; P = 0.006), high-energy mechanisms (proportional difference [PD] 58.5%, 95% CI, 37.0-69.7; P < 0.0001), Thursday through Saturday hospital admission (PD 30.3%, 95% CI, 5.0-50.0; P < 0.0001), pelvis/acetabular fractures (PD 51.8%, 95% CI, 26.7-71.0%; P < 0.0001), and external fixation (PD 33.0%, 95% CI, 11.8-57.3; P < 0.0001). Only 4.8% of procedures experienced nonmedical delays using an early appropriate care model and a DOTR. Nonmedical delays were most commonly due to 2 modifiable factors-the DOTR being at-capacity and nonpelvis trauma specialists taking weekend call. Patients with nonmedical delays were more likely to be younger, with pelvis/acetabular fractures, high-energy mechanisms, external fixation, and to be admitted between Thursday and Saturday. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


On the pathogenesis of Bell's palsy.
The data obtained from the anatomical study of the Fallopian canal, the intraoperative evoked electromyography and the histopathological evaluation of specimens from the greater petrosal nerve support the entrapment neuropathy concept in Bell's palsy.


Harmonizing finite element modelling for non-invasive strength estimation by high-resolution peripheral quantitative computed tomography.
The finite element (FE) method based on high-resolution peripheral quantitative computed tomography (HR-pQCT) use a variety of tissue constitutive properties and boundary conditions at different laboratories making comparison of mechanical properties difficult. Furthermore, the advent of a second-generation HR-pQCT poses challenges due to improved resolution and a larger region of interest (ROI). This study addresses the need to harmonize results across FE models. The aims are to establish the relationship between FE results as a function of boundary conditions and a range of tissue properties for the first-generation HR-pQCT system, and to determine appropriate model parameters for the second-generation HR-pQCT system. We implemented common boundary conditions and tissue properties on a large cohort (N = 1371), and showed the relationships were highly linear (R2 > 0.99) for yield strength and reaction force between FE models. Cadaver radii measured on both generation HR-pQCT with matched ROIs were used to back-calculate a tissue modulus that accounts for the increased resolution (61 µm versus 82 µm), resulting in a modulus of 8748 MPa for second-generation HR-pQCT to produce bone yield strength and reaction force equivalent to using 6829 MPa for first-generation HR-pQCT. Finally, in vivo scans (N = 61) conducted on both generations demonstrated that the larger ROI in the second-generation system results in stronger bone outcome measures, suggesting it is not advisable to convert FE results across HR-pQCT generations without matching ROIs. Together, these findings harmonize FE results by providing a means to compare findings with different boundary conditions and tissue properties, and across scanner generations.


The status of diabetes and its complications in Latin-American population: A review article.
The Latino population consists of distinct cultural groups, with differences in dietary habits and lifestyle that can affect the risk for type 2 diabetes. The best terminology today is Latino/Hispanic, and it should only be used as ethnicity. Latin-America has different races such as Caucasians, Native Americans, Blacks and Asians, and many mixtures of all. The leading cause of death in Latin-America is Cardiovascular diseases and the most important risk factor is diabetes mellitus (DM). According to the latest estimates from the Global Burden of Disease, the burden of DM was greater than expected in Latin America and the Caribbean region. Extensive data illustrates that lower cardiovascular disease risk in Latino group is a paradox. Instead, it is evident that the cardiovascular disease is the leading cause of mortality in Latinos.


23Na NMR study of the interaction between hyaluronan and the bications Ca(++), Mg(++) and Cu(++).
The relaxation rate R = pi Delta nu(1/2) of the quadrupolar (23)Na nucleus was measured at pH approximately 7 using a 200 MHz NMR spectrometer with a view to observe the interaction between hyaluronan and its natural counterion Na(+) and the bications Ca(++), Mg(++) and Cu(++). An interpretation of our results, by means of the "entropy of fluctuations" concept of Na(+), is presented. We show that Cu(++) ions are more effective than Ca(++) and Mg(++). A possible model of complexation of Cu(++) in a cage formed by the 1-4 glycosidic bond, the carboxylate side-chain and the acetoamide side-chain is proposed, according to electrostatic potential computations using the ZINDO1 quantum semi empirical method.


Induction of defensive morphological changes in ciliates.
Freshwater ciliates of the genusEuplotes change their morphology in response to the presence of predators. The morphological transformations limit the ability of the predators to ingest the ciliates. Induction of defensive morphology by the predatorsStenostomum sphagnetorum (Turbellaria),Lembadion bullinum (Ciliata),L. magnum, andAmoeba proteus (Rhizopoda) was studied inEuplotes aediculatus andE. octocarinatus. The results suggest the possibility of natural occurrence of predator-induced defensive morphology inEuplotes. A density of 1 predator ml-1 was sufficient to induce significant changes in the morphology ofEuplotes. L. magnum was found at natural population densities of 5 individuals ml-1. Transformations can take place within 2-4 h. Morphological changes are induced by signal substances released from the predators; direct contact between prey and predators is not necessary. The extent of transformation depends on the concentration of the signal substance. The size frequency distribution of the populations only had one peak that was related to predator density. All individuals of a population ofEuplotes changed their morphology according to the predator abundance. This may reduce energy costs for the prey by prevention of unnecessary morphological changes.Amoeba proteus induces morphological changes inE. octocarinatus, but not inE. aediculatus.


The Efficacy of Hydroxychloroquine Combined with Huangqi Tablets in the Treatment of Diabetic Nephropathy.
This study aimed to analyze the effect of hydroxychloroquine combined with Huangqi tablets in the treatment of diabetic nephropathy (DN). Eighty patients with DN were enrolled and divided into two groups by a random number table. 27 patients received routine treatment + hydroxychloroquine (group A), while 27 patients received routine treatment + hydroxychloroquine + Huangqi tablets (group B) and 26 patients received routine treatment (group C). FPG, 2h PG, and HbA1c levels as well as TC and TG levels were lower in group B than in groups A and C at the end of 3 months of treatment and were lower in group A than in group C (P < 0.05). SCR, BUN, and 24-hour urine protein were reduced in group B after therapy, whereas eGFR was increased and the difference between groups A and C was significant (P=0.05). After treatment, VEGF, IGF-1, and TGF-1 levels were lower in group B than in groups A and C and in group A than in group C (P=0.05). Total symptom scores at 2, 4, and 6 months after treatment was lower in group B than in groups A and C, and they were lower in group A than in group C at all time points (P < 0.05). The total effective rates of treatment in groups A, B, and C were 66.67%, 88.89%, and 38.46% (P < 0.05). The incidence of adverse reactions in groups A, B, and C was 37.04%, 25.93%, and 11.54% (P > 0.05). Hydroxychloroquine combined with Huangqi tablets in the treatment of DN showed the best efficacy, with better control of blood glucose and lipids, which can more effectively delay the progression of renal lesions and effectively inhibit the expression of VEGF, IGF, and TGF-β1 in tethered cells with high safety.


Investigation of the lipid-modifying and antiinflammatory effects of Cornus mas L. supplementation on dyslipidemic children and adolescents.
Cornus mas L. (CM) fruits are rich in anthocyanins and possess both antiinflammatory and antioxidant activities. The current study was conducted to investigate whether supplementation with CM could ameliorate lipid profile and vascular inflammation in dyslipidemic children and adolescents. In this randomized clinical trial, 40 dyslipidemic children and adolescents ages 9 to 16 years were assigned to receive 50 g of CM twice a day after lunch and dinner (n = 20, case group) or to continue their normal diet (n = 20, control group). The serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apo A-I, apo B, intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), C-reactive protein (CRP), and anthropometric indices were determined at baseline and then after weeks 3 and 6 of the trial. After week 6 of the trial, the TC, TG, LDL-C, apo B, ICAM-1, and VCAM-1 levels in the CM group were significantly lower and the HDL-C and apo A-I levels higher than at baseline. After week 6 of the trial, none of these parameters in the control group, except for ICAM-1, was significantly altered from baseline. However, between-group comparison showed a significant difference only for apo A-I (p = 0.016) and a borderline significant difference for ICAM-1 (p = 0.076). No significant difference in body mass index, waist-to-hip ratio, or C-reactive protein was observed between the studied groups. The present findings revealed a trend toward amelioration of lipid profile and vascular inflammation following addition of CM to the daily diet of dyslipidemic children and adolescents but this needs to be verified by larger scale trials.


Polygenic scores for low lung function and the future risk of adverse health outcomes.
Reduced lung function and adverse health outcomes are often observed. This study characterizes genetic susceptibility for reduced lung function and risk of developing a range of adverse health outcomes. We studied 27,438 middle-aged adults from the Malmö Diet and Cancer study (MDCS), followed up to 28.8 years. Trait-specific Polygenic scores (PGS) for forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were constructed for each participant using MDCS genetic data and summary statistics from the latest GWAS of lung function. Linear regression models and cox proportional hazards regression models were used to assess associations between adverse health outcomes and lung function-PGS. FEV1-PGS and FVC-PGS were significantly associated with mean sBP at baseline after adjustments (FEV1-PGS Q1 (highest PGS = highest lung function): 140.7mmHg vs. Q4: 141.5mmHg, p-value 0.008). A low FVC-PGS was significantly associated with the risk of future diabetic events after adjustments (Q4 vs. Q1 HR: 1.22 (CI 1.12-1.32), p-trend < 0.001) and had added value to risk prediction models for diabetes. Low FEV1-PGS was significantly associated with future coronary events (Q4 vs. Q1 HR: 1.13 (CI: 1.04-1.22), p-trend 0.008). No significant association was found between PGS and sudden cardiac death, chronic kidney disease or all-cause mortality. Results remained largely unchanged in a subgroup of subjects when further adjusted for apolipoproteins. Genetic susceptibility for reduced lung function is associated with higher sBP, increased risk of diabetes and to a lesser extent, future coronary events, suggesting etiological roles of lung function on these outcomes. Using PGS, high-risk groups could be early detected to implement early lifestyle changes to mitigate the risk.


A novel variant in the QRICH1 gene was identified in a patient with severe developmental delay.
QRICH1 encodes the glutamine-rich protein 1, which contains one caspase activation recruitment domain and is likely to be involved in apoptosis and inflammation. However, the function of the QRICH1 gene was largely unknown. Recently, several studies have reported de novo variants in QRICH1, and the variants have been associated with Ververi-Brady syndrome characterized by developmental delay, nonspecific facial dysmorphism, and hypotonia. Whole exome sequencing, clinical examinations, and functional experiments were performed to identify the etiology of our patient. Here, we added another patient with severe growth retardation, atrial septal defect, and slurred speech. Whole exome sequencing identified a novel truncation variant in the QRICH1 gene (MN_017730.3: c.1788dupC, p.Tyr597Leufs*9). Furthermore, the functional experiments confirmed the effect of genetic variation. Our findings expand the QRICH1 variant spectrum in developmental disorders and provide evidence for the application of whole exome sequencing in Ververi-Brady syndrome.


Some properties of membrane current fluctuations induced by kainate, quisqualate, and NMDA in cultured septal neurons of rat.
Ionic currents induced by glutamate, kainate, quisqualate, and N-methyl-D-aspartate (NMDA) in cultured septal neurons were analyzed by fluctuations analysis. The power spectrum (PWS) of NMDA current fluctuations always fitted a single Lorentzian. PWSs of the other agonists fitted the sum of two Lorentzians; however, the slopes of PWSs became larger and the PWSs became closer to single Lorentzians as the number of drug application increased. This may be explained in such a way that, in multiple conductance channels activated by these agonists, the high frequency component decreases the gating activity in later recordings, whereas the low frequency component keeps its gating kinetics.


Genome-wide identification of auxin-responsive microRNAs in the poplar stem.
Wood (secondary xylem) of forests is a material of great economic importance. Wood development is strictly controlled by both the phytohormone auxin and microRNAs (miRNAs). Currently, the regulatory mechanisms underlying wood formation by auxin-associated miRNAs remain unclear. This report was designed to identify auxin-responsive miRNAs during wood formation. Morphological observation of wood development in the poplar stems was performed under the treatment of different concentrations (0 mg/L, CK; 5 mg/L, Low; 10 mg/L, High) of indol-3-butyric acid (IBA). Using a small RNA sequencing strategy, the effect of IBA treatment on miRNAs expression was genome-widely analyzed. In this study, we found that wood development of poplar was promoted by low concentration of IBA treatment but inhibited by high concentration of IBA treatment. Stringent bioinformatic analysis led to identification of 118 known and 134 novel miRNAs candidates. Sixty-nine unique developmental-related miRNAs, corresponding to 269 target genes, exhibited specific expression patterns in response to auxin, as was consistent with the influence of auxin application on wood formation. Three novel miRNAs had the most number (≥ 9) of target genes, belonging to SPL, GRF and ARF gene families. The evolutionary relationships and tissue expression patterns of 41 SPL, GRF and ARF genes in poplar were thus analyzed. Of them, four representative members and corresponding miRNAs were confirmed using RT-qPCR. Our results may be helpful for a better understanding of auxin-induced regulation of wood formation in tree species.


Taeniasis and cysticercosis due to Taenia solium in Japan.
Taenia solium is a zoonotic cestode that causes taeniasis and cysticercosis in humans. The parasite is traditionally found in developing countries where undercooked pork is consumed under poor sanitary conditions and/or as part of traditional food cultures. However, the recent increase in international tourism and immigration is spreading the disease into non-endemic developed countries such as the United States. Although there has been concern that the number of cysticercosis cases is increasing in Japan, the current situation is not clear. This is largely because taeniasis and cysticercosis are not notifiable conditions in Japan and because there have been no comprehensive reviews of T. solium infections in Japan conducted in the last 15 years. Herein, we provide an overview of the status of T. solium infection in Japan over the past 35 years and point out the potential risks to Japanese society.


Circulatory effects of pancuronium and alcuronium in patients with coronary artery stenosis.
Heart rate and systemic arterial blood pressure were recorded during induction of anaesthesia up to 9 min after endotracheal intubation in 92 patients scheduled for coronary artery bypass surgery, in order to study to what degree the circulatory response to induction of anaesthesia and intubation was modified by different relaxants. Pancuronium (pancuronium bromide) 0.1 mg X kg b.w.-1 and alcuronium (diallyl-nortoxiferine) 0.25 mg X kg b.w.-1 were randomly studied in 36 patients during induction with high-dose fentanyl and in 36 patients induced with thiopentone, diazepam, fentanyl and nitrous oxide. In patients given high-dose fentanyl anaesthesia, systolic blood pressure before, during and after intubation was significantly lower with alcuronium (P less than 0.01). The same difference between alcuronium and pancuronium was observed in balanced anaesthesia before endotracheal intubation. Induction of anaesthesia and intubation were followed by a moderate increase in heart rate, irrespective of the type of anaesthesia and relaxant. Subsequently, 20 patients (10 with high-dose fentanyl and 10 with balanced anaesthesia) were studied. They received pancuronium 0.05 mg X kg b.w.-1 + alcuronium 0.125 mg X kg b.w.-1. This mixture of relaxants produced an intermediate blood pressure response.


Nuclear labelling of leukaemic blast cells with tritiated thymidine triphosphate in 35 patients with acut leukaemia.
A new technique which detects the presence of DNA polymerase and primer-template DNA by measuring the in vitro incorporation of [3H]thymidine-5-triphosphate (3H-TTP) into nuclei of leukaemic blast cells (LBC) was used in 35 patients with acute leukaemia. The 3H-TTP labelling index (3H-TTP LI) exceeded the fraction in DNA synthesis by a factor 1.4-24.3. The values of 3H-TTP labelling in the bone marrow always exceeded those obtained in the blood. In addition 10 normal bone marrows were studied; here, the 3H-TTP LI either exceeded or equalled the fraction of the proliferative pool in DNA synthesis.


Enhancement of airway epithelial cell differentiation by pulmonary endothelial cell co-culture.
Cross-talk between lung epithelial cells and their microenvironment has an important physiological role in development. Using an in vitro model of differentiation of human induced pluripotent stem cells (iPSCs) to air-liquid interface (ALI)-cultured lung epithelial cells, we investigated the contribution of the microenvironment to maintenance of the lung progenitor cell state. Our protocol modeled in vivo cell-to-matrix and cell-to-cell interactions. These included growth of iPSCs on inserts coated with different basement membrane proteins (collagen I, IV, fibronectin, heparan sulfate or Matrigel plus collagen IV) and co-culture with human pulmonary microvascular endothelial cells (HPMECs). Marker gene expression was measured by RT-qPCR and protein expression and localization was confirmed by immunocytochemistry. The results showed that iPSCs grown on collagen IV had the highest success rate in terms of differentiation to robust ALI-cultured lung epithelial cells, followed by fibronectin, collagen I and heparan sulfate. Coating with Matrigel mixed with collagen IV further increased the success rate to > 97 %. Co-culture of iPSCs with HPMECs enhanced the expression of key airway lineage markers (NKX2.1, KRT5, TP63, MUC5AC, MUC16, FOXJ1, CFTR and SCGB1A1) during ALI culture. Cross-talk between iPSCs and their microenvironment during cell differentiation had a significant effect on lung epithelial cell differentiation in these 3D in vitro models. Both matrix proteins and endothelial cells play critical roles in the differentiation of lung progenitor cells.


Comparison of glass-ionomer cements used to repair cast restorations.
Based on SEM analysis, this study evaluates the usefulness of three glass-ionomer cements to repair margins of cast restorations. These findings are compared to those previously obtained for amalgam, resin, and direct gold used as repair materials. This information can assist the clinician in choosing the most appropriate repair material in selected cases.


Temporal characteristics of tactile stimuli influence the response profile of cerebellar Golgi cells.
An increasing number of studies have investigated the effect of stimulation parameters on neuronal response properties. Here, we describe the effect of temporal characteristics of tactile stimuli, more specifically the stimulation frequency and duration, on the response profile of simultaneously recorded cerebellar and cerebral cortical units in ketamine-xylazine anaesthetized rats. Long stimulus durations (>50 ms) elicited ON and OFF excitatory components in response to the stimulus onset and offset respectively, in both the cortex and the cerebellum. Golgi cells responded on average 7.5 ms later to the stimulus withdrawal than to the stimulus onset. Furthermore, the corticopontine OFF responses in the cerebellum and OFF responses in the cortex showed congruent latency decreases and amplitude increases for longer stimulus durations (50-200 ms). Decreasing the stimulus frequency similarly affected the latency and amplitude of the responses for inter-stimuli intervals shorter than 200 ms. In view of these results, we speculate that the stimulus offset is regarded as a novel input, because both paradigms resulted in similar response amplitude and latency modifications. Finally, the results suggest that a 100-200 ms time window can be of particular importance for cerebellar processing of information in the somatosensory system.


The effect of hepatic interposition on insulin-stimulated gastric secretion after proximal gastric vagotomy.
The peak acid output to insulin 10-14 days after proximal gastric vagotomy (PGV) for uncomplicated duodenal ulcer in a control group of 11 men was 1.5 mmol/h, and this rose significantly (P less than 0.01) after a mean interval of 26.1 months to 5.3 mmol/h. The rise in the PAOI in 7 male patients undergoing PGV and hepatic interposition for duodenal ulcer was from 1.0 mmol/h to 4.5 mmol/h (P less than 0.05) over a mean interval of 13.1 months. No significant difference between the changes in the PAOI in the two groups of patients could be detected. It is concluded that separation of the lesser curve of the stomach from the cut edge of the lesser omentum by the left lobe of the liver after PGV in an attempt to block vagal regeneration does not alter the postoperative rise in acid secretion.


Controversies in Orthognathic Surgery.
Controversy has accompanied orthognathic surgery since its adaptation for the correction of dentofacial deformities. With the development of less invasive and less morbid osteotomy designs, questions regarding overall osteotomy stability have abounded. The transition from prolonged intermaxillary fixation and wire osteosynthesis to rigid internal fixation has spurred questions regarding the most effective fixation technique, and challenged previously accepted hierarchies of stability. These questions represent only the surface of a sea of debate and discussion, as measures have been taken to optimize patient outcome, minimize patient morbidity, and maximize operating room productivity.


Ice-core based assessment of nitrogen deposition in the central Tibetan Plateau over the last millennium.
Atmospheric nitrogen deposition is a unique source of bioavailable nitrogen for ecosystems in remote regions, and has vital impacts on ecological processes. Understanding variations of atmospheric nitrogen deposition in these regions remains challenging due to a lack of observations. Ice cores contain records of nitrogen species of nitrate (NO3-) and ammonium (NH4+), hence provide valuable long-term data to study past variations of atmospheric nitrogen deposition. In this study, we present an annually resolved record of NH4+ and NO3- over the past millennium, derived from the Zangser Kangri (ZK) ice core in the central Tibetan Plateau. The concentration peaks of NH4+ and NO3- coincide with those of Ca2+ (a dust tracer), indicating that variation of nitrogen species in the ZK ice core is largely driven by dust activities. An EOF analysis for all chemical species (Cl-, SO42-, NO3-, Na+, NH4+, K+, Mg2+, Ca2+) reveals significant but separate loadings of NH4+ and NO3- on EOF 2, suggesting an additional source of nitrogen, likely from biogenic emissions of terrestrial ecosystems. Over the past millennium, the EOF 2 series has relatively high values around 1300 CE and 1600 CE, and has increased significantly since the Industrial Revolution. These variations are likely driven by temperature-dependent biogenic emissions on the Tibetan Plateau. Analyses of seasonal air mass backward trajectories and wind fields find that the chemical concentrations in the ZK ice core are mostly influenced by the westerly, but South Asia summer monsoon plays an important role in the transport of nitrogen species generated from biogenic emissions. This is further confirmed by the significant correlation between EOF 2 series and the South Asian summer monsoon index. This study provides new insight into the preindustrial sources, natural variabilities and major drivers of nitrogen deposition on the Tibetan Plateau.


Evaluation of Glass Delamination Risk in Pharmaceutical 10 mL/10R Vials.
Glass delamination is characterized by the dissociation of glass flakes from the glass surface. Since glass delamination is time dependent, 5 vial types were investigated to assess delamination under accelerated stress conditions published as quick tests in literature and compared to stress testing recommended per United States Pharmacopoeia <1660>. A broad panel of analytical techniques was employed to test the solution for visible/subvisible particles and leachables and characterize topography and composition of the surface. The vial types showed significant differences in surface durability when applying the same stress conditions. An increase in glass leachables and change in topography were shown for uncoated vials. An indication for an elevated delamination risk was confirmed for Expansion 33 vials only by the compiled analytical data set including particle assessment and change in elemental composition of the near glass surface investigated by dynamic secondary ion mass spectrometry. The delamination test protocols differ in test solution, handling, and time. Before choosing the most appropriate protocol to predict delamination propensity and mimic real-time conditions, long-term storage data are needed. A combination of analytical techniques to study the risk for long-term corrosion of glass is highly recommended covering the 3 aspects: visible/subvisible particle assessment, solution analysis, and surface characterization.


The experimental manipulation of insect herbivore load by the use of an insecticide (malathion): The effect of application on plant growth.
The effects of insect herbivores on natural communities of plants may be demonstrated by manipulative experimetns. Such experiments, which reduce the natural levels of herbivory by application of insecticide, incorporate the assumption that the insecticide has no direct effect on the vegetation. A test of this assumption should therefore be an integral part of any study of herbivory employing chemical exclusion. Here a single compound (Malathion-60), which is commonly used in such studies, is tested both in the field and on selected plant species under controlled conditions. It was found to have no effect on a range of early successional plant species. The limitations of the tests are discussed.


Gorgonians mass mortality during the 1999 late summer in French Mediterranean coastal waters: the bacterial hypothesis.
Mass mortality by tissue necrosis of several species of gorgons was observed during the 1999 late summer on the Liguro-Provençal Mediterranean coasts. We have investigated the occurrence of vibrios on necrosis affected gorgonians Paramuricea clauata and Eunicella cavolinii, and their ability to induce tissue necrosis. Among the 11 strains tested, only 5, belonging to species Vibrio splendidus, V. pelagius and V. campbellii, were able to induce tissue necrosis in a few days. Temperature experiments carried out at 11 degrees C, 18 degrees C and 23 degrees C showed that necrotic disease may occur only at the higher temperature tested. Statistical analysis suggested that, for these thermical conditions, marine Vibrio strains can significantly speed up the necrotic crisis.


[Polarized luminescence of macromolecules with tryptophan markers. Parameters of high-frequency motion and structure of synthetic polypeptides and proteins].
On the basis of the suggested in previous paper [1] model of high-frequency motions of indol group forming a part of tryptophan residue side group parameters of indol groups torsional vibrations in tryptophan-containing synthetic polypeptides and proteins were analysed. Results of conformational analysis and experimental data on polarized luminescence obtained in [2-5] were used.


Expression of C-fos, Fos-B, Fosl-1, Fosl-2, Dusp-1 and C-jun in the mouse heart after single and repeated chlorpromazine administrations.
Many cases of sudden chlorpromazine (Chl)-related deaths have been identified in forensic autopsies. Because Chl concentration detected in such cases is often low, identifying the cause of death can be difficult. Patients on Chl therapy exhibit arrhythmia and cardiomyopathy. Thus, Chl may affect the heart, particularly, gene expression there. Immediate early genes (IEGs) are expressed following stimulation. Using real-time quantitative-PCR, we investigated the mRNA expression of IEGs, including C-fos, Fos-B, Fosl-1, Fosl-2, Dusp-1 and C-jun, in the mouse heart after once-daily high-dose (7.5 mg/kg) or low-dose (0.75 mg/kg) of Chl single and repeated (1-4 weeks) injections. We showed that single high-dose Chl administration induced IEGs except C-jun. This induction was not observed after the repeated administration, and thus; suggested that the transcriptome is altered after repeated administration and tolerance is developed to Chl. Moreover, C-jun expression decreases after repeated administration. These results reflect that C-jun is down-regulated to avoid cardiomyopathy caused by the over stimulation of C-jun. In future, we intend to clarify the Chl-induced IEG cascade via IEGs in the mouse heart. Chl treatment can result in cardiovascular diseases. Investigation of the transcriptome in the heart after repeated Chl administration will aid in elucidating the patho-physiology of Chl-related cardiovascular diseases.


Anatomical intra-laryngeal anterior branch study of the recurrent (inferior) laryngeal nerve.
The studies are based upon 60 dissections of the recurrent laryngeal n. (inferior laryngeal n.). The authors describe in detail the branches destined for the intrinsic musculature of the larynx. This study is a working approach for interventions of selective laryngeal reinnervation in man. The conclusion is that, it is necessary to resect the inferior cornu of the thyroid cartilage, to reach the abductor and adductor branches of the vocal cord.


Maternity protection for working women in Argentina: legal and administrative aspects in the first half of the twentieth century.
This article discusses the construction of social policies aimed at working women as mothers in Argentina. Thus, we examine the legal corpus, the scope of legislation, and the criticisms of its implementation coming from civil society and from medical, legal and political circles. We focus on the debate about the creation of the Caja de Maternidad (1934) and the shifts in the discussions regarding welfare policy for working women during Perón's first term in office. The methodology is based on a qualitative analysis of parliamentary debates, proposals for legislative reform and reactions in the press.


[Synthesis and pharmacologic activity of 2-arylethenylthiazol-4-acetic and 4-carboxylic acids].
Two new series of 2-aryletenylthiazolo-4-acetic (IV-XII) and 4-carboxylic (XIII-XXI) acids substituted with alkoxy groups in the benzene ring were synthesized. The compounds were subjected to comparative tests of antiinflammatory, analgesic and antipyretic activity.


Pharmacodynamic analysis of magnetic resonance imaging-monitored focused ultrasound-induced blood-brain barrier opening for drug delivery to brain tumors.
Microbubble-enhanced focused ultrasound (FUS) can enhance the delivery of therapeutic agents into the brain for brain tumor treatment. The purpose of this study was to investigate the influence of brain tumor conditions on the distribution and dynamics of small molecule leakage into targeted regions of the brain after FUS-BBB opening. A total of 34 animals were used, and the process was monitored by 7T-MRI. Evans blue (EB) dye as well as Gd-DTPA served as small molecule substitutes for evaluation of drug behavior. EB was quantified spectrophotometrically. Spin-spin (R1) relaxometry and area under curve (AUC) were measured by MRI to quantify Gd-DTPA. We found that FUS-BBB opening provided a more significant increase in permeability with small tumors. In contrast, accumulation was much higher in large tumors, independent of FUS. The AUC values of Gd-DTPA were well correlated with EB delivery, suggesting that Gd-DTPA was a good indicator of total small-molecule accumulation in the target region. The peripheral regions of large tumors exhibited similar dynamics of small-molecule leakage after FUS-BBB opening as small tumors, suggesting that FUS-BBB opening may have the most significant permeability-enhancing effect on tumor peripheral. This study provides useful information toward designing an optimized FUS-BBB opening strategy to deliver small-molecule therapeutic agents into brain tumors.


Toward a Mesoscopic Modeling Approach of Magnetohydrodynamic Blood Flow in Pathological Vessels: A Comprehensive Review.
The investigation of magnetohydrodynamic (MHD) blood flow within configurations that are pertinent to the human anatomy holds significant importance in the realm of scientific inquiry because of its practical implications within the medical field. This article presents an exhaustive appraisal of the diverse applications of magnetohydrodynamics and their computational modeling in biological contexts. These applications are classified into two categories: simple flow and pulsatile flow. An alternative approach of traditional CFD methods called Lattice Boltzmann Method (LBM), a mesoscopic method based on kinetic theory, is introduced to solve complex problems, such as hemodynamics. The results show that the flow velocity reduces considerably by increasing the magnetic field intensity, and the flow separation area is minimized by the increase of magnetic field strength. The LBM with BGK collision model has shown good results in terms of precision. Finally, this literature review has revealed a number of potential avenues for further research. Suggestions for future works are proposed accordingly.


Corticofugal axons in the lateral geniculate nucleus of the cat.
Injections of horseradish peroxidase (HRP) were made into the optic radiations just above the lateral geniculate nucleus of four cats to trace the anterograde filling of corticofugal axons terminating in the perigeniculate and lateral geniculate nuclei. The different types of axons were classified according to axonal diameter and the morphology of the terminal appendages. Judging from their morphological organization we suggest that the corticofugal axons are, in the main, slowly conducting and that they have a restricted terminal distribution which extends, however, to a multiplicity of levels in both perigeniculate and lateral geniculate nuclei. These morphological characteristics may have physiological implications in determining the role of the corticofugal pathway.


Local delivery of osteoprotegerin may be a way of reinforcing orthodontic anchorage.
One of the most challenging problems in orthodontics is anchorage. The traditional mechanical methods of reinforcing anchorage are limited by multiple factors, but a pharmacological approach aimed at utilizing the known biological mechanisms underlying tooth movement may provide an ideal way of reinforcing orthodontic anchorage. So we make the hypotheses that if the resorptive process of modeling during tooth movement can be inhibited, tooth movement may be inhibited as well. Since osteoprotegerin (OPG) has been found to be a key factor in the inhibition of osteoclast differentiation and activation, and involved in mechano-modulation of bone modeling, its local delivery adjacent to the anchorage teeth may provide a novel pharmacological approach for preventing unneeded tooth movement that is highly desirable for reinforcing orthodontic anchorage.


Arsenic and Lead Determination in D&C Red No. 6 Lakes and D&C Red No. 7 Lakes Containing Barium Sulfate Using X-Ray Fluorescence Spectrometry.
Color additives requiring batch certification by the U.S. Food and Drug Administration have Code of Federal Regulations (CFR) specification limits for certain elements and are usually analyzed by x-ray fluorescence spectrometry (XRF). However, analysis of some color additives presents difficulties. An XRF method was developed for quickly determining whether barium sulfate-containing color additives certifiable as D&C Red No. 6 lakes and D&C Red No. 7 lakes meet the CFR specifications for arsenic (As) and lead (Pb). Difficulties in preparing XRF standards and analyzing As and Pb in matrices with the heavy x-ray absorber barium (Ba) were overcome by first preparing As- and Pb-fortified cellulose, then blending color additive samples with fortified and unfortified cellulose to produce XRF calibration materials. Satisfactory compensation for changes in intensity caused by Ba absorption was achieved by measuring varying concentrations of As and Pb at several concentrations of Ba. Test samples of barium sulfate-containing D&C Red No. 6 lakes and D&C Red No. 7 lakes were analyzed by the XRF method and by an inductively coupled plasma-mass spectrometry (ICP-MS) method. The ICP-MS method poses some difficulties and is time consuming. In contrast, the XRF method requires very little sample preparation, is nondestructive, uses calibrations that are stable for long periods of time, and offers acceptable determination limits (1 mg/kg As, 4 mg/kg Pb) which are less than the CFR specification limits (3 mg/kg As, 20 mg/kg Pb). The new XRF method is applicable for use in routine batch certification.


The active kinome: The modern view of how active protein kinase networks fit in biological research.
Biological regulatory networks are dynamic, intertwined, and complex systems making them challenging to study. While quantitative measurements of transcripts and proteins are key to investigate the state of a biological system, they do not inform the "active" state of regulatory networks. In consideration of that fact, "functional" proteomics assessments are needed to decipher active regulatory processes. Phosphorylation, a key post-translation modification, is a reversible regulatory mechanism that controls the functional state of proteins. Recent advancements of high-throughput protein kinase activity profiling platforms allow for a broad assessment of protein kinase networks in complex biological systems. In conjunction with sophisticated computational modeling techniques, these profiling platforms provide datasets that inform the active state of regulatory systems in disease models and highlight potential drug targets. Taken together, system-wide profiling of protein kinase activity has become a critical component of modern molecular biology research and presents a promising avenue for drug discovery.


Recent Advances of Marine Sponge-Associated Microorganisms as a Source of Commercially Viable Natural Products.
Many industrially significant compounds have been derived from natural products in the environment. Research efforts so far have contributed to the discovery of beneficial natural products that have improved the quality of life on Earth. As one of the sources of natural products, marine sponges have been progressively recognised as microbial hotspots with reports of the sponges harbouring diverse microbial assemblages, genetic material, and metabolites with multiple industrial applications. Therefore, this paper aims at reviewing the recent literature (primarily published between 2016 and 2022) on the types and functions of natural products synthesised by sponge-associated microorganisms, thereby helping to bridge the gap between research and industrial applications. The metabolites that have been derived from sponge-associated microorganisms, mostly bacteria, fungi, and algae, have shown application prospects especially in medicine, cosmeceutical, environmental protection, and manufacturing industries. Sponge bacteria-derived natural products with medical properties harboured anticancer, antibacterial, antifungal, and antiviral functions. Efforts in re-identifying the origin of known and future sponge-sourced natural products would further clarify the roles and significance of microbes within marine sponges.


Prospective randomized controlled trial comparing partially absorbable lightweight mesh and multifilament polyester anatomical mesh in laparoscopic inguinal hernia repair.
Tension-free mesh repair is currently the gold standard treatment for inguinal hernia. Recent evidence has shown that both open and laparoscopic approaches to inguinal hernia repair can achieve good results. Lots of meshes with different properties are available on the market, but direct comparisons between them are scare. We conducted a prospective randomized controlled trial comparing a partially absorbable lightweight mesh (ULTRAPRO™) and a multifilament polyester anatomical mesh (Parietex™) in laparoscopic total extraperitoneal inguinal hernia repair. This study was a single-center, prospective randomized controlled trial to compare the surgical handling and clinical outcomes between two different types of meshes. All operations were performed using a standardized operative protocol. This study was approved by the Institutional Review Board of the Hong Kong East Cluster Health Service in 2009 (reference number: 2009-087). The study was registered in the Australian New Zealand Clinical Trial Registry (ACTRN12610000031066). From October 2009 to August 2011, 85 laparoscopic total extraperitoneal inguinal hernia repairs were performed. The mean mesh handling time was 152 s for the ULTRAPRO group and 206 s for the Parietex group (P = 0.001). There were three cases of seroma formation in the ULTRAPRO group and nine in the Parietex group (P = 0.02). The overall recurrence rate was 2.5%. It took less time to manipulate the flat mesh (ULTRAPRO) than the anatomical mesh (Parietex) in laparoscopic total extraperitoneal inguinal hernia repair, but the time difference was small. Lightweight mesh and heavyweight mesh offered similar clinical outcomes in terms of discomfort sensation and foreign body sensation during long-term follow-up.


Epilepsy in adults with learning disabilities.
Epilepsy is a common problem of adults with learning disabilities. Despite the high prevalence there have been few studies of the epilepsy suffered by adults with learning disabilities. The findings of a Leicestershire study are that multiple seizure types are a common presentation, and that for many (75%) the seizures remain refractory to treatment. Those who suffer tonic-clonic seizures are most likely to achieve remission, whereas for those with simple or complex partial seizures the prognosis is poor. For a significant proportion, status epilepticus, emergency admission to hospital and injuries occur on a regular basis.


Immunogenetic aspects of human thyroglobulin-reactive T cell lines and hybridomas.
The in vitro proliferative response to T cells primed with human thyroglobulin (Tg) was compared in 11 independent haplotypes on B10 background. B10.K and B10.S mice were the most responsive, whereas, with the exception of B10.PL (H-2u), all other B10 congenics were intermediate responders. The two best responders to in vitro challenge with human Tg, of the k and s haplotype, are the same as those showing H-2-linked susceptibility to induction of experimental autoimmune thyroiditis (EAT) with mouse Tg. Since shared epitopes on human and mouse Tgs have been shown to be thyroiditogenic by adoptive transfer studies in CBA (H2k) mice, the findings indicate that shared epitopes may be studied in appropriate (i.e. EAT-susceptible) strains of mice. Therefore, we proceeded to develop methods to produce T-cell lines and hybridomas to human Tg in B10.K and B10.S mice, test their cross-reactivity to heterologous Tgs and their Ia restriction patterns. By using antigen-presenting cells from recombinant strains, we identified restriction elements encoded by the I-A subregion alone and a combinatorial molecule from the I-A/I-E subregions.


Cytotoxicity of the bacterium Actinobacillus actinomycetemcomitans extracts in human gingival fibroblasts.
Filter-sterilized sonic extracts (SE) of strains of Actinobacillus actinomycetemcomitans were shown to inhibit the proliferation of human gingival fibroblasts in vitro. The inhibition was dose-dependent: a 50 per cent inhibitory dose of 2 micrograms protein/ml was found for A. actinomycetemcomitans strain Y4. The inhibitory activity could be neutralized by homologous antiserum and was heat inactivated by temperatures of 80 degrees C or greater. The fibroblast-inhibitory activity was present in SEs of both leukotoxic-producing and non-leukotoxic strains of A. actinomycetemcomitans, suggesting that a separate agent is responsible for leukotoxicity and fibroblast inhibition. A short (10 min) exposure of the fibroblasts to the A. actinomycetemcomitans SE was sufficient to inhibit irreversibly cell proliferation, provided that serum was present at the time that the cells were exposed to the SE. SE-challenged fibroblasts exhibited a marked decrease in the rate of DNA synthesis, but no inhibition of RNA or protein synthesis. Although the SE-treated cells did not proliferate, they appeared to remain intact and viable; and displayed no gross morphological alterations.


Banding of rye (Secale cereale) chromosomes using the restriction enzymes AluI, DraI, HpaII, and MspI.
Mitotic metaphase chromosomes of the rye inbred line L 301, which belongs to the Sortiment of the University of Hohenheim, were treated in situ with the restriction enzymes AluI (recognition sequence: 5′-AC/GT-3′), DraI (recognition sequence: 5′-TTT/AAA-3′), and the isoschizomeres HpaII and MspI (recognition sequence: 5′-C/CGG-3′) and stained with Giemsa. The chromosomes indicated similar banding patterns in comparison with the conventional Giemsa-C-banding. However, we have found in rye chromosomes after restrictase treatment that the telomeric bands were reduced in extension. In a lower degree the centromeric bands of individual chromosomes could be absent in dependence of the used restriction enzymes. The number of the intercalary bands were also reduced. Nevertheless, the tested restriction enzymes produced characteristic banding patterns of the rye genome. This uncomplicated banding technique is suited for a very quick banding method of karyotype analysis especially to obtain a first survey of the band patterns on the rye chromosomes.


Fluorometric assay for detection and quantitation of polyamidoamine dendrimers.
Polyamidoamine dendrimers are protein-like nanomaterials that have many potential biological applications. Research studies using dendrimers often require their detection and quantitation. This article describes a simple, inexpensive, and rapid fluorometric assay based on the ability of dendrimers to bind the fluorescent probe, 8-anilino-1-naphthalene-sulfonic acid. This interaction leads to an enhanced fluorescence intensity of the dye that shows a linear relationship with dendrimer concentration. The procedure is applicable to dendrimers that have various surface functional groups and internal cores. Amine- and hydroxyl-terminated dendrimers gave the best calibration curves under alkaline conditions (pH 7.4). Carboxyl-terminated dendrimers required acidic conditions for their measurement. The assay for dendrimers with an amine surface and an ethylene diamine core was accurate between 0 and 100 microM and produced a within-run coefficient of less than 5%. Under the assay conditions used, the fluorescence signal strength was dependent on type of surface group and core length of the dendrimer.


Muscle fascicle and sarcomere adaptation in response to Achilles tendon elongation in an animal model.
Permanent loss of muscle function seen after an Achilles tendon rupture may partly be explained by tendon elongation and accompanying shortening of the muscle. Muscle fascicle length shortens, serial sarcomere number is reduced, and the sarcomere length is unchanged after Achilles tendon transection (ATT), and these changes are mitigated with suturing. The method involved in this study was a controlled laboratory study. Two groups of rats underwent ATT on one side with a contralateral control (CTRL): A) ATT with 3 mm removal of the Achilles tendon and no suturing (substantial tendon elongation), and B) ATT with suture repair (minimal tendon elongation). The operated limb was immobilized for 2 wk to reduce load. Four weeks after surgery the rats were euthanized, and hindlimbs were analyzed for tendon length, gastrocnemius medialis (GM) muscle mass, length, fascicle length, sarcomere number and length. No differences were observed between the groups, and in both groups the Achilles tendon length was longer (15.2%, P < 0.001), GM muscle mass was smaller (17.5%, P < 0.001), and muscle length was shorter (8.2%, P < 0.001) on the ATT compared with CTRL side. GM fascicle length was shorter (11.2%, P < 0.001), and sarcomere number was lower (13.8%, P < 0.001) on the ATT side in all regions. Sarcomere length was greater in the proximal (5.8%, P < 0.001) and mid (4.2%, P = 0.003), but not distal region on the ATT side. In this animal model, regardless of suturing, ATT resulted in tendon elongation, loss of muscle mass and length, and reduced serial sarcomere number, which resulted in an "overshoot" lengthening of the sarcomeres.NEW & NOTEWORTHY Following acute Achilles tendon rupture, patients are often left with functional deficits. The specific reason remains largely unknown. The shortened muscle leads to reduced fascicle length, in turn leading to adaptation by reduced serial sarcomere numbers. Surprisingly, this adaptation appears to "overshoot" and lead to increased sarcomere length. The present animal model advances understanding of how muscle sarcomeres, which are difficult to measure in humans, are affected when undue elongation takes place after tendon rupture.


Monothiocarbamates Strongly Inhibit Carbonic Anhydrases in Vitro and Possess Intraocular Pressure Lowering Activity in an Animal Model of Glaucoma.
A series of monothiocarbamates (MTCs) were prepared from primary/secondary amines and COS as potential carbonic anhydrase (CA, EC 22.214.171.124) inhibitors, using the dithiocarbamates, the xanthates, and the trithiocarbonates as lead compounds. The MTCs effectively inhibited the pharmacologically relevant human (h) hCAs isoforms I, II, IX, and XII in vitro and showed KIs spanning between the low and medium nanomolar range. By means of a computational study, the MTC moiety binding mode on the CAs was explained. Furthermore, a selection of MTCs were evaluated in a normotensive glaucoma rabbit model for their intraocular pressure (IOP) lowering effects and showed interesting activity.


Mutational background influences P. aeruginosa ciprofloxacin resistance evolution but preserves collateral sensitivity robustness.
Collateral sensitivity is an evolutionary trade-off whereby acquisition of the adaptive phenotype of resistance to an antibiotic leads to the nonadaptive increased susceptibility to another. The feasibility of harnessing such a trade-off to design evolutionary-based approaches for treating bacterial infections has been studied using model strains. However, clinical application of collateral sensitivity requires its conservation among strains presenting different mutational backgrounds. Particularly relevant is studying collateral sensitivity robustness of already-antibiotic-resistant mutants when challenged with a new antimicrobial, a common situation in clinics that has hardly been addressed. We submitted a set of diverse Pseudomonas aeruginosa antibiotic-resistant mutants to short-term evolution in the presence of different antimicrobials. Ciprofloxacin selects different clinically relevant resistance mutations in the preexisting resistant mutants, which gave rise to the same, robust, collateral sensitivity to aztreonam and tobramycin. We then experimentally determined that alternation of ciprofloxacin with aztreonam is more efficient than ciprofloxacin–tobramycin alternation in driving the extinction of the analyzed antibiotic-resistant mutants. Also, we show that the combinations ciprofloxacin–aztreonam or ciprofloxacin–tobramycin are the most effective strategies for eliminating the tested P. aeruginosa antibiotic-resistant mutants. These findings support that the identification of conserved collateral sensitivity patterns may guide the design of evolution-based strategies to treat bacterial infections, including those due to antibiotic-resistant mutants. Besides, this is an example of phenotypic convergence in the absence of parallel evolution that, beyond the antibiotic-resistance field, could facilitate the understanding of evolution processes, where the selective forces giving rise to new, not clearly adaptive phenotypes remain unclear.


Quantitative electrospray LC-MS and LC-MS/MS in biomedicine.
The use of electrospray LC-MS and LC-MS/MS for the quantitative determination of two low molecular weight (< 500 Da) organic compounds in human plasma (Lovastatin) and cell supernatants (Arachidonic acid) and medium molecular weight (> 2000 Da) endogenous peptides (Endothelins) in supernatants of human umbilical vein endothelial cell cultures is reported. These methods make use either of deuterium labelled or structurally similar molecules as internal standards for quantitation and one or more pre-purification steps previous the LC-MS analysis. Linear calibration curves and detection limits around 50 pg ml(-1) were obtained in all three cases.


Factors moderating children's adjustment to parental separation: findings from a community study in England.
Research findings show that there is marked variability in children's response to parental separation, but few studies identify the sources of this variation. This prospective longitudinal study examines the factors modifying children's adjustment to parental separation in a community sample of 5,635 families in England. Children's behavioral/emotional problems were assessed when children were aged 47 and 81 months; marital quality, maternal depression, socioeconomic circumstances, and demographic variables were assessed prior to the separation from maternal report. Results indicated that 346 mothers separated from their partners in the 3-year period. Preseparation differences were found for measures of family process and parent risk factors, with effect sizes ranging from small to trivial. Parental separation was associated with a significant but modest increase in behavioral/emotional problems, independent of marital quality, maternal depression, socioeconomic circumstances, and demographic variables. Moderation analyses showed that children of cohabiting parents had a greater increase in adjustment problems following parental separation than children of married parents. Further research elucidating the factors that moderate children's adjustment to parental separation is needed to improve our understanding of who may most likely benefit from preventive interventions.


Effect of hexachlorobenzene (HCB) on photosynthetic oxygen evolution and respiration of Chlorella pyrenoidosa.
In experiments with Chlorella pyrenoidosa it was shown that an exposure of these cells to HCB at a dose level of 0.1, 1.0, and 5.0 ppm caused an inhibition of photosynthetic oxygen evolution of 33.3, 42, and 51%, respectively. Respiration, however, was inhibited only slightly, if at all.


Giant cavernous hemangiolymphangioma of the bladder without cutaneous hemangiomatosis causing massive hematuria in a child.
We report the first case of cavernous hemangiolymphangioma of the urinary bladder without cutaneous hemangiomatosis. A 5-year-old boy was admitted for investigation of a 2-month episode of gross hematuria accompanied by lower abdominal pain. Radiological investigations revealed a solid enhancing mass at the dome of the bladder with associated low-flow lesion in the posterolateral wall of the bladder. Physical examination did not show any cutaneous vascular malformations. A differential diagnosis of hemangioma or rhabdomyosarcoma bladder was made, but fine-needle aspiration cytology did not reveal any malignant cells. At surgery, a red, wide-based, nodular tumor was found on the dome of the bladder and extending to the base and lateral walls. Partial cystectomy and excision of the cystic lymphangioma was performed. Histological examination of the resected specimen showed it to be a cavernous hemangiolymphangioma. The postoperative course was uneventful and no recurrence was seen after 8 months.


The actions of isoprenaline and mirabegron in the isolated whole rat and guinea pig bladder.
β3-adrenoceptor agonists influence overactive bladder in humans and animal models. However, data is emerging that the mode of action of these drugs is complex. The present study explored the actions of the β3-adrenergic agonist mirabegron and the non-selective agonist isoprenaline on the contractile systems in the rat and guinea pig bladder. Intravesical pressure was measured in isolated whole bladders from female adult animals. In both species spontaneous contractile activity was observed. The muscarinic agonist arecaidine produced complex responses consisting of an initial transient pressure rise followed by complex phasic activity. Three contractile elements were identified: intrinsic micro-contractile activity, initial transient response and steady state phasic activity. The intrinsic and steady state activity could be further divided into a baseline pressure with superimposed phasic activity. The effects of isoprenaline and mirabegron were investigated on these elements. In the rat, the micro-contractile activity could be completely inhibited by isoprenaline (full agonist). The arecaidine-induced initial and steady state baseline pressures were partially reduced, while the phasic activity was little affected. In the guinea pig, both the arecaidine-induced baseline pressure and the phasic activity were affected by isoprenaline. Mirabegron didn't produce significant inhibitory effects in any of the contractile elements in either species. These results show that complex contractile systems operate in the rat and guinea pig bladder that can be modulated by β1/β2-adrenoceptor mechanisms. No evidence was obtained for any β3-dependent regulation of contraction. These data support similar data in humans. Therefore the primary site of therapeutic action of β3-adrenergic agonists remains unknown.


What the 'ell? Testicle is a diminutive!
The frequency of diminutives in anatomical Latin has often been noted to be high, but that is not unusual in postclassical Latin. Although the connotation of "little" is well known, many of the diminutives in anatomical Latin do not have that meaning. The morphology of regular, irregular, and secondary diminutives is presented, along with that of adjectival forms of diminutives. Several transgendered and malformed diminutives are discussed. Clin. Anat. 31:1100-1103, 2018. © 2018 Wiley Periodicals, Inc.


Enzymatic generation of galactose-rich oligosaccharides/oligomers from potato rhamnogalacturonan I pectic polysaccharides.
Potato pulp by-product rich in galactan-rich rhamnogalacturonan I (RG I) was investigated as a new source of oligosaccharides with potential prebiotic properties. The efficiency of selected monocomponent enzymes and multi-enzymatic preparations to generate oligosaccharides/oligomers from potato RG I was evaluated. These overall results of yield were dependent on the activity profile of the multi-enzymatic preparations. Highest oligo-RG I yield of 93.9% was achieved using multi-enzymatic preparation (Depol 670L) with higher hydrolytic activity toward side chains of RG I as compared to its backbone. Main oligo-RG I products were oligosaccharides with DP of 2-12 (79.8-100%), while the oligomers with DP of 13-70 comprised smaller proportion (0.0-20.2%). Galactose (58.9-91.2%, w/w) was the main monosaccharide of oligo-RG I, while arabinose represented 0.0-12.1%. An understanding of the relationship between the activity profile of multi-enzymatic preparations and the yield/DP of oligo-RG I was achieved. This is expected to provide the capability to generate galacto- and galacto(arabino) oligosaccharides and their corresponding oligomers from an abundant by-product.


Contribution to the analysis of the essential oil of Helichrysum italicum (Roth) G. Don. Determination of ester bonded acids and phenols.
The essential oil of Helichrysum italicum (Roth) G. Don (everlasting or Immortelle essential oil) was isolated by hydrodistillation and analysed by GC and GCMS. Forty four compounds were identified. The main components were alpha-pinene(12.8%), 2-methyl-cyclohexyl pentanoate (11.1 %), neryl acetate (10.4%), 1,7-di-epi-alpha-cedrene (6.8%) and other compounds. The oil was fractionated and ester-containing fraction was hydrolysed with KOH/H(2)SO(4). The liberated volatiles were analysed by GC and GC-MS: three phenols and twenty seven volatile carboxylic acids were identified[70% low fatty acids (C(2)-C(5)), 15% C(10)-C(12) acids and 15% other acids]. The main acids were acetic acid (24.3%) propanoic acid (17.2%), 2-methylpropanoic acid (11.4%),dodecanoic acid (8.7%), 2-methylbutanoic acid (8.3%), (Z)-2-methylbutenoic acid(5.1%) and decanoic acid (4.6%). With respect to the identified bonded carboxylic acids,the minimal number of esters in the oil was twenty seven, but their overall quantity was probably larger due to different possible combinations of alcohols with acids to form esters. On the other hand, only six main esters were identified in the oil before fractionation and hydrolysis.


The prevalence and impact of anemia in hospitalized older adults: A single center experience from Bahrain.
This study reports the prevalence of anemia and investigates its associated correlates and outcomes among elderly hospitalized patients in a single hospital in Bahrain. A retrospective study was conducted on 227 consecutive elderly patients admitted under general internal medicine in the biggest tertiary hospital in Bahrain. Medical records were reviewed for all patients, including clinical characteristics, laboratory results, and outcomes. Anemia was highly prevalent among hospitalized elderly patients (71.6%). Males were significantly more affected than females (p = 0.031). In terms of severity, the most common type was moderate anemia (56.1%); with regards to etiology, the most common type was anemia associated with chronic disease (48.1%). Anemia was as common as other comorbidities, including hypertension (71.4%) and diabetes mellitus (53.7%). When comparing anemic to non-anemic patients, the length of hospital stay was significantly longer (p < 0.001) and inversely correlated to the level of hemoglobin; furthermore, 1-year mortality was significantly higher (p < 0.001). When compared to those with mild anemia, patients with moderate/severe anemia were more likely to die (odds ratio [OR] = 2.2, 95% confidence interval [CI]: 1.27-4.92). The prevalence of anemia in our study was higher than previously reported. Even so, anemia receives minimal attention and is usually seen as a minor problem. Our results reiterate the need to recognize the high importance of anemia especially when diagnosing and treating older patients. This, in turn, could positively affect a number of outcomes such as mortality, length of stay, and the functional decline of admitted individuals.


Mortality postponed and the unmasking of age-dependent non-fatal conditions.
Mortality occurs at older ages in our growing and salubrious population. At present, fewer than 20% of all deaths, in Sweden, occur before age 65 with 18% of the Swedish population 65 and over. In the United States, 24% of deaths occur before age 65 with only 12% of the population age 65 and over. All countries in the developed world will have approximately 20% of their populations age 65 and over by about 2020. At that time, the percentage of deaths occurring prior to age 65 should range from 14%-16%. Thus future gains in morbidity and mortality will be influenced, to a lesser extent, by events prior to age 65 and prevention and health promotion strategies post age 65 become increasingly important. Active life expectancy, a developing concept, refers to the years lived in good health with no functional limitations. The period after active life expectancy consists of years of compromised health and well being. At present, each year gained of active life expectancy incurs almost four years of compromised health. A group of age-dependent nonfatal conditions are largely responsible for increased prevalence of social and physical deficits with age. These include dementia, osteoarthritis, diminished hearing and visual acuity, incontinence, depression, widowhood, isolation and institutionalization. Age-specific incidence of most of these conditions is unknown. There is little evidence, however, that adding years to life has postponed their age at onset. For these conditions, postponement is the major mechanism of prevention. We are attempting to construct time trends concerning the age-specific incidence and the ability to postpone age-dependent conditions.(ABSTRACT TRUNCATED AT 250 WORDS)


Unfavorable effect of levetiracetam on cultured hippocampal neurons after hyperthermic injury.
The aim of this study was to examine the viability of neurons and the putative neuroprotective effects of second-generation antiepileptic drug, levetiracetam (LEV), on cultured hippocampal neurons injured by hyperthermia. Primary cultures of rat's hippocampal neurons at 7day in vitro (DIV) were incubated in the presence or absence of LEV in varied concentrations under hyperthermic conditions. Cultures were heated in a temperature of 40°C for 24h or in a temperature of 41°C for 6h. Flow cytometry with Annexin V/PI staining as well as fluorescent microscopy assay were used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, the release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. Assessment was performed after 9DIV and 10 DIV. Incubation of hippocampal cultures in hyperthermic conditions resulted in statistically significant increase in the number of injured neurons when compared with non-heated control cultures. Intensity of neuronal destruction was dependent on temperature-value. When incubation temperature 40°C was used, over 80% of the population of neurons remained viable after 10 DIV. Under higher temperature 41°C, only less than 60% of neurons were viable after 10 DIV. Both apoptotic and necrotic pathways of neuronal death induced by hyperthermia were confirmed by Annexin V/PI staining. LEV showed no neuroprotective effects in the current model of hyperthermia in vitro. Moreover, drug, especially when used in higher concentrations, exerted unfavorable intensification of aponecrosis of cultured hippocampal neurons.


Decreased glucose oxidation during short-term starvation.
Prolonged fasting (for days or weeks) decreases glucose production and oxidation. The effects of short-term starvation (ie, less than 24 hours) on glucose metabolism are not known. To evaluate this issue, glucose oxidation and glucose turnover were measured after 16-hour and subsequently after 22-hour fasting. Glucose oxidation was calculated by indirect calorimetry in 12 healthy men (age 22 to 44 years); glucose turnover was measured by primed, continuous infusion of 3-3H-glucose in eight of these 12 volunteers. After 16-hour fasting net glucose oxidation was 0.59 +/- 0.17 mg x kg-1 x min-1 and glucose tissue uptake 2.34 +/- 0.12 mg x kg-1 x min-1. No correlation was found between net glucose oxidation and glucose tissue uptake. Prolonging fasting with an additional 6 hours resulted in decreases of respiratory quotient (0.77 +/- 0.01 v 0.72 +/- 0.01) (P less than .005), plasma glucose concentration (4.7 +/- 0.1 v 4.6 +/- 0.1 mmol/L) (P less than .05), glucose tissue uptake (2.10 +/- 0.12 mg x kg-1 x min-1) (P less than .05), net glucose oxidation (0.09 +/- 0.04 mg x kg-1 x min-1) (P less than .005), and plasma insulin concentration (8 +/- 1 v6 +/- 1 mU/L) (P less than .005). Net glucose oxidation expressed as a percentage of glucose tissue uptake decreased from 22% +/- 8% to 2% +/- 1% (P less than .05). There was no net glucose oxidation in seven of 12 controls after 22-hour fasting.(ABSTRACT TRUNCATED AT 250 WORDS)


Biomimetic Magnetite Nanoparticles as Targeted Drug Nanocarriers and Mediators of Hyperthermia in an Experimental Cancer Model.
Biomimetic magnetic nanoparticles mediated by magnetosome proteins (BMNPs) are potential innovative tools for cancer therapy since, besides being multifunctional platforms, they can be manipulated by an external gradient magnetic field (GMF) and/or an alternating magnetic field (AMF), mediating targeting and hyperthermia, respectively. We evaluated the cytocompatibility/cytotoxicity of BMNPs and Doxorubicin (DOXO)-BMNPs in the presence/absence of GMF in 4T1 and MCF-7 cells as well as their cellular uptake. We analyzed the biocompatibility and in vivo distribution of BMNPs as well as the effect of DOXO-BMNPs in BALB/c mice bearing 4T1 induced mammary carcinomas after applying GMF and AMF. Results: GMF enhanced the cell uptake of both BMNPs and DOXO-BMNPs and the cytotoxicity of DOXO-BMNPs. BMNPs were biocompatible when injected intravenously in BALB/c mice. The application of GMF on 4T1 tumors after each of the repeated (6×) iv administrations of DOXO-BMNPs enhanced tumor growth inhibition when compared to any other treatment, including that with soluble DOXO. Moreover, injection of DOXO-BMNPs in the tumor combined with application of an AMF resulted in a significant tumor weight reduction. These promising results show the suitability of BMNPs as magnetic nanocarriers for local targeted chemotherapy and as local agents for hyperthermia.


[Therapeutic effect of ossicular reconstruction with bioceramic or porous macromolecular polyethylene partial ossicular replacement prosthesis in patients with tympanosclerosis].
To evaluate the effect of ossicular reconstruction with partial ossicular replacement prosthesis (PORP) in patients with tympanosclerosis. The data of 31 cases of tympanosclerosis treated between 1992 and 2009 were reviewed. Of the 31 patients, 17 (17 ears) underwent ossicular reconstruction with porous macromolecular polyethylene PORP, and 14 (14 ears) with bioceramic PORP. All the patients were followed up for 3-24 months. Significant improvement was found in postoperative speech frequency (500, 1000, 2000 Hz) pure tone average (PTA) and air-bone gap (ABG) (P < 0.05) after the treatments without statistically significant differences between the two groups (P > 0.05). Porous macromolecular polyethylene and bioceramic are valuable ossicular prosthesis for tympanosclerosis.


Machine learning and geometric morphometrics to predict obstructive sleep apnea from 3D craniofacial scans.
Obstructive sleep apnea (OSA) remains massively underdiagnosed, due to limited access to polysomnography (PSG), the highly complex gold standard for diagnosis. Performance scores in predicting OSA are evaluated for machine learning (ML) analysis applied to 3D maxillofacial shapes. The 3D maxillofacial shapes were scanned on 280 Caucasian men with suspected OSA. All participants underwent single night in-home or in-laboratory sleep testing with PSG (Nox A1, Resmed, Australia), with concomitant 3D scanning (Sense v2, 3D systems corporation, USA). Anthropometric data, comorbidities, medication, BERLIN, and NoSAS questionnaires were also collected at baseline. The PSG recordings were manually scored at the reference sleep center. The 3D craniofacial scans were processed by geometric morphometrics, and 13 different supervised algorithms, varying from simple to more advanced, were trained and tested. Results for OSAS recognition by ML models were then compared with scores for specificity and sensitivity obtained using BERLIN and NoSAS questionnaires. All valid scans (n = 267) were included in the analysis (patient mean age: 59 ± 9 years; BMI: 27 ± 4 kg/m2). For PSG-derived AHI≥15 events/h, the 56% specificity obtained for ML analysis of 3D craniofacial shapes was higher than for the questionnaires (Berlin: 50%; NoSAS: 40%). A sensitivity of 80% was obtained using ML analysis, compared to nearly 90% for NoSAS and 61% for the BERLIN questionnaire. The auROC score was further improved when 3D geometric morphometrics were combined with patient anthropometrics (auROC = 0.75). The combination of 3D geometric morphometrics with ML is proposed as a rapid, efficient, and inexpensive screening tool for OSA. NCT03632382; Date of registration: 15-08-2018.


Temperature dependent luminescence of a europium complex incorporated in poly(methyl methacrylate).
An europium β-diketonate complex with a dipyrazolyltriazine derivative ligand, Eu(TTA)3DPBT, has been incorporated into poly(methyl methacryate) (PMMA). The influence of temperature on its luminescence properties has been investigated. The fluorescence emission spectra and luminescence lifetimes showed temperature sensitivity. The analysis of the relative intensity ratio (R) of (5)D0 → (7)F2 to (5)D0 → (7)F1 transition and Judd-Ofelt experimental intensity parameters Ω2 indicated that the local structure and asymmetry in the vicinity of europium ions show no obvious change when the temperature is increased.


Computer assistance in hip preservation surgery-current status and introduction of our system.
Preservation surgery of the hip with open or arthroscopic approach has always been challenging as complex 3-D anatomy and limited surgical access make intraoperative evaluation difficult. Recent advances in computer technology offer a wide range of innovative solutions with a goal to improve accuracy and safety of corrective procedures on human joints. The author critically reviews currently available literature in the field of computer assistance in hip preservation surgery. Basic features of unique planning software and navigation surgical system used in treatment of femoroacetabular impingement and hip dysplasia are introduced. Currently available software provides preoperative identification of hip deformity on CT-based 3-D model and planning of the surgical correction using kinematic protocols. Real-time intraoperative 3-D orientation is possible, and execution of surgical correction can be performed either with navigation of surgical tools or with printed templates. Computer assistance in hip preservation surgery is in the developing phase. First clinical experiences of its use in treatment of femoroacetabular impingement, hip dysplasia, hip tumors, and avascular necrosis of the femoral head are promising. Computer assistance has been applied for treatment of several hip disorders. Technical advances are suggested and quality basic studies and clinical trials are encouraged for the novel technology to become more user friendly and widely accepted.


Elimination of variable vasomotor tone in studies with repeated quantitative coronary angiography.
In quantitative coronary angiographic studies, unintentional changes of coronary vasomotor tone may have a significant influence on the coronary artery diameters, thereby increasing the variability in the measurements. To obtain objective data on these measurement variabilities, two protocols were designed to assess the influences of ionic and nonionic radiographic contrast media on the mean diameters of angiographically normal coronary arteries. The vessel sizes were determined with the CAAS using automated edge detection techniques. In 21 patients (study no. I), coronary angiograms were taken in identical angiographic projections before (control), and immediately following several (at average 7) subsequent diagnostic dye injections administered over a period of about 7 min. The ionic contrast agent diatrizoate 76% induced a coronary dilation of 19 +/- 7% (mean +/- s.d., p less than 0.001; n = 10); the nonionic agent iopromide 370 increased the coronary artery diameters by only 6 +/- 4% (p less than 0.01; n = 11). In another 11 patients (study no. II) coronary angiograms were obtained using the nonionic contrast medium iopamidol 300 at 5, 8, 10 and 11 min after the control acquisition; this protocol was repeated in the same patients with diatrizoate 76%. With iopamidol, coronary diameter changes were not significant at any time; with diatrizoate, however, coronary dilation was measured at 10 min (2 +/- 2%; p less than 0.01) and at 11 min (10 +/- 3%; p less than 0.001). In a third study it was tested, whether standardization of coronary vasomotor tone (e.g. in coronary angiographic follow-up studies) is possible by the induction of a reproducible maximum coronary dilation with nitrocompounds. In 12 patients, the mean diameters of angiographically normal coronary segments were analyzed before and at various times after i.v. administration (over 4 min) of 0.025 mg SIN-1/kg bodyweight. Coronary dilation was maximal at 10 or 15 min after the onset of the SIN-1-infusion (29 +/- 5%; p less than 0.001). 0.8 mg nitroglycerin given s.l. at 15 min did not further dilate the coronary arteries (28 +/- 7%). One hour after SIN-1, coronary dilation still amounted to an average of 24 +/- 8% (p less than 0.001) and became 'maximal' again, when 0.8 mg nitroglycerin was again administered sublingually (28 +/- 8%; p less than 0.001). In conclusion, short-term variability of coronary vasomotor tone induced by ionic radiographic contrast media can be eliminated by the use of nonionic contrast agents and observation of injection intervals of at least 2 min. In quantitative coronary angiographic follow-up studies, as well as during acute interventions (e.g., PTCA), identical baseline vasomotor tone can be achieved by induction of the maximal coronary dilation using nitrocompounds.


Kinetics of ethanol fermentation with high biomass concentration considering the effect of temperature.
A model of ethanol fermentation considering the effect of temperature was developed and validated. Experiments were performed in a temperature range from 28 to 40 degrees C in continuous mode with total cell recycling using a tangential microfiltration system. The developed model considered substrate, product and biomass inhibition, as well as an active cell phase (viable) and an inactive (dead) phase. The kinetic parameters were described as functions of temperature.


Linkage Study Revealed Complex Haplotypes in a Multifamily due to Different Mutations in CAPN3 Gene in an Iranian Ethnic Group.
Calpainopathy is an autosomal recessive form of limb girdle muscular dystrophies which is caused by mutation in CAPN3 gene. In the present study, co-segregation of this disorder was analyzed with four short tandem repeat markers linked to the CAPN3 gene. Three apparently unrelated Iranian families with same ethnicity were investigated. Haplotype analysis and sequencing of the CAPN3 gene were performed. DNA sample from one of the patients was simultaneously sent for next-generation sequencing. DNA sequencing identified two mutations. It was seen as a homozygous c.2105C>T in exon 19 in one family, a homozygous novel mutation c.380G>A in exon 3 in another family, and a compound heterozygote form of these two mutations in the third family. Next-generation sequencing also confirmed our results. It was expected that, due to the rare nature of limb girdle muscular dystrophies, affected individuals from the same ethnic group share similar mutations. Haplotype analysis showed two different homozygote patterns in two families, yet a compound heterozygote pattern in the third family as seen in the mutation analysis. This study shows that haplotype analysis would help in determining presence of different founders.


Characterization of inflammatory markers and transcriptome profiles of differentially activated embryonic stem cell-derived microglia.
Microglia, the immune cells of the CNS, are highly adaptive cells that can acquire different pro- and anti-inflammatory activation states with distinct functions in CNS homeostasis and pathologies. To study microglial function in vitro, primary microglia or immortalized cell lines are commonly used. An alternative to these cells are embryonic stem cell-derived microglia (ESdM). ESdM have previously been shown to be very similar to primary microglia in terms of expression profiles and surface molecules. In this study, ESdM and primary microglia were treated with different inflammatory stimulants to analyze their ability to adopt different activation states. Using quantitative real-time PCR, comparative transcriptomics, ELISA, and flow cytometry, we found that different activation states can be induced in ESdM, which are similar to those found in primary microglia. These states are characterized by specific sets of inflammatory marker molecules and differential transcriptome signatures. Our results show that ESdM are a valuable alternative cell model to study microglial functions and neuroinflammatory mechanisms.


Zagreb Topological Properties of Hexa Organic Molecular Structures.
In connection with the study of chemical graph theory, it has been explored that a single number can capture the numerical representation of a molecular structure, and this number is known as a topological property (index). This study aimed to explore a few Zagreb topological properties for four hexa organic molecular structures (hexagonal, honeycomb, silicate, and oxide) based on the valency and valency sum of atoms in the structure. We employed the technique of partitioning the set of bonds according to the valency and valency-sum of end atoms of each bond and then performed the computation by using combinatorial rules of counting (that is, the rule of sum and the rule of product). The obtained results were also compared numerically and graphically. Exact values of five valencies based and five valency-sum-based Zagreb topological properties were found for the underline chemical structures.


Designing an extended release waxy matrix tablet containing nicardipine-hydroxy propyl β cyclodextrin complex.
The current study aimed to prepare a sustained release tablet for a drug which has poor solubility in alkaline medium using complexation with cyclodextrin. Nicardipine hydrochloride (NC) a weak basic drug was chosen as a model drug for this study. Firstly the most suitable binary system NC-HPβCD was selected in order to improve drug solubility in the intestinal media and then embedding the complexed drug into a plastic matrix, by fusion method, consists of glycerol monostearate (GMS) as an inert waxy substance and polyethylene glycol 4000 (PEG4000) as a channeling agent, after that the final solid dispersion [(NC:HPβCD):GMS:PEG4000] which was prepared at different ratios was mixed with other excipients, avicel PH101, lactose, and talc, to get a tablet owning dissolution profile complying with the FDA and USP requirements for the extended release solid dosage forms. Infrared spectroscopy (IR), differential scanning colorimetry (DSC), polarized microscopy and X-ray diffractometry proved that the coevaporation technique was effective in preparing amorphous cyclodextrin complexes with NC and trapping of NC within the HPβCD cavity by dissolving both in ethanol and evaporate the solvent using a rotavapor at 65 °C. Dissolution profile of NC enhanced significantly in pH 6.8 from NC:HPβCD inclusion complex prepared by the rotavapor (t-test Student p < 0.05). The release of NC from tablet containing [(NC:HPβCD):GMS:PEG4000] [(1):0.75:0.5] (w/w/w) solid dispersion (F8) was complying with the FDA dissolution requirements for extended release dosage forms, and studying the kinetics of the release showed that the diffusional contribution is the major factor controlling the drug release from that formula. The prepared waxy matrix tablet containing NC complexes with CD shows promising results as extended release tablets.


DNA polymerases at the replication fork in eukaryotes.
The Kunkel laboratory has recently assigned polymerase (Pol) epsilon as the leading strand polymerase. In a recent issue of Molecular Cell, they now assign Pol delta as the lagging strand polymerase.


Genetic effects of space hadrons on bacteriophage under Alpine conditions.
A dried film culture of bacteriophage T4Br + was kept in a lead bioblock for 366 days under Alpine conditions at an altitude of 6100 m above sea level to study the genetic effect of space hadrons. In the gelatin-like film under study we discovered some film plots with markedly reduced bacteriophage survival. In such plots, the mutation frequency exceeded the spontaneous background mutation rate 60-100 times. The spectrum of r mutations as classified into standard groups rI, rII and rIII differed from that found for other model radiation systems such as gamma-ray radiation in buffer or nutrient broth, and hadron and HZE particle radiation under space flight conditions. Reversion analysis of 159 rII mutants showed that 54.4% had small and elongated deletions, 23.16% had point mutations, and 22.5% of all the mutants had both small deletion and point mutations.


Statistical modeling and knowledge-based segmentation of cerebral artery based on TOF-MRA and MR-T1.
For cerebrovascular segmentation from time-of-flight (TOF) magnetic resonance angiography (MRA), the focused issues are segmentation accuracy, vascular network coverage ratio, and cerebral artery and vein (CA/CV) separation. Therefore, cerebral artery segmentation is a challenging work, while a complete solution is lacking so far. The preprocessing of skull-stripping and Hessian-based feature extraction is first implemented to acquire an indirect prior knowledge of vascular distribution and shape. Then, a novel intensity- and shape-based Markov statistical modeling is proposed for complete cerebrovascular segmentation, where our low-level process employs a Gaussian mixture model to fit the intensity histogram of the skull-stripped TOF-MRA data, while our high-level process employs the vascular shape prior to construct the energy function. To regularize the individual data processes, Markov regularization parameter is automatically estimated by using a machine-learning algorithm. Further, cerebral artery and vein (CA/CV) separation is explored with a series of morphological logic operations, which are based on a direct priori knowledge on the relationship of arteriovenous topology and brain tissues in between TOF-MRA and MR-T1. We employed 109 sets of public datasets from MIDAS for qualitative and quantitative assessment. The Dice similarity coefficient, false negative rate (FNR), and false positive rate (FPR) of 0.933, 0.158, and 0.091% on average, as well as CA/CV separation results with the agreement, FNR, and FPR of 0.976, 0.041, and 0.022 on average. For clinical visual assessment, our methods can segment various sizes of the vessel in different contrast region, especially performs better on vessels of small size in low contrast region. Our methods obtained satisfying results in visual and quantitative evaluation. The proposed method is capable of accurate cerebrovascular segmentation and efficient CA/CV separation. Further, it can stimulate valuable clinical applications on the computer-assisted cerebrovascular intervention according to the neurosurgeon's recommendation.


Effect of polyelectrolytes on serine proteinase secretion by Bacillus subtilis.
Addition of polycations with molecular masses of 5-40 kDa as well as Na+, stimulated serine proteinase secretion by Bacillus subtilis cells. Polyanions and higher-molecular-mass polycations (100-200 kDa) were inefficient. The enzyme yields in the presence of polycations or Na+ were equal in magnitude. The results indicate that the cations, apparently counteracting the negative surface charge of the bacterial plasma membrane, cause the desorption of the serine (alkaline) proteinase. The synthesis of the proteinase is inferred to be stopped as the enzyme is bound to the outer surface of the plasma membrane. The desorption of the enzyme thus induces the synthesis of the new portions of proteinase.


Long-term outcomes of successful left atrial appendage occlusion with focus on stroke prevention: 10-year follow-up of a single-center registry.
Percutaneous left atrial appendage occlusion (LAAO) is an alternative to anticoagulation in the prevention of stroke in patients with nonvalvular atrial fibrillation, especially in patients with a contraindication for oral anticoagulation therapy (OAT). The study sought to obtain long-term patient outcomes after successful LAAO in everyday clinical practice. In this single-center registry spanning over 10 years, data of all consecutive patients that underwent percutaneous LAAO were collected. Observed thromboembolic and major bleeding event rates after successful LAAO during follow-up were compared with expected event rates based on CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category) and HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol) scores. Furthermore, anticoagulation and antiplatelet use during follow-up was evaluated. Of 230 patients scheduled for LAAO (38% women, 69.5 ± 8.2 years of age, CHA2DS2-VASc score 3.9 ± 1.6, HAS-BLED score 2.9 ± 1.0), 218 patients had a successful implantation (95%) with a follow-up duration of 5.2 ± 3.1 years. The procedure was combined with catheter ablation in 52% of the patients. Fifty thromboembolic complications (24 ischemic stroke, 26 transient ischemic attack) were observed during follow-up in 40 (18%) of 218 patients. Ischemic strokes occurred with a rate of 2.1 per 100 patient-years, accounting for a 66% relative risk reduction compared with the CHA2DS2-VASc predicted event rate. Device-related thrombus was observed in 5 (2%) patients. Sixty-five nonprocedural major bleeding complications occurred in 24 (11%) of 218 patients with a rate of 5.7 per 100-patient years, which is comparable to estimated HAS-BLED-bleeding rates under OAT use. At end of follow-up 71% of all patients were on single antiplatelet or no antiplatelet or anticoagulation treatment, while 29% were on OAT. Thromboembolic event rates during long-term follow-up after successful LAAO remained consistently lower than expected supporting the efficacy of LAAO.


Transesterification of RNA model induced by novel dinuclear copper (II) complexes with bis-tridentate imidazole derivatives.
Two novel bis-tridentate imidazole derivatives were conveniently synthesized using a 'one-pot' method. Their dinuclear (Cu2L1Cl4, Cu2L2Cl4) and mononuclear (CuL1Cl2, CuL2Cl2∙H2O) copper (II) complexes were synthesized to comparably evaluate their reactivities in the hydrolytic cleavage of 2-hydroxypropyl p-nitrophenyl phosphate (HPNP) as a classic RNA model. Single crystals of Cu2L1Cl4 and Cu2L2Cl4 indicate that both of them are centrosymmetric, and each central copper ion is penta-coordinated. Regarding the transesterification of HPNP, both of dinuclear ones exhibited excess one order of magnitude rate enhancement in contrast with auto-hydrolysis reaction. Under comparable conditions, dinuclear complexes displayed no more than twofold increase in activity over their mononuclear analogues, which verifies the lack of binuclear cooperation effect due to long Cu-to-Cu space.


Nrf2 activation: a potential strategy for the prevention of acute mountain sickness.
Reactive oxygen species (ROS) formed during acute high altitude exposure contribute to cerebral vascular leak and development of acute mountain sickness (AMS). Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) is a transcription factor that regulates expression of greater than 90% of antioxidant genes, but prophylactic treatment with Nrf2 activators has not yet been tested as an AMS therapy. We hypothesized that prophylactic activation of the antioxidant genome with Nrf2 activators would attenuate high-altitude-induced ROS formation and cerebral vascular leak and that some drugs currently used to treat AMS symptoms have an additional trait of Nrf2 activation. Drugs commonly used to treat AMS were screened with a luciferase reporter cell system for their effectiveness to activate Nrf2, as well as being tested for their ability to decrease high altitude cerebral vascular leak in vivo. Compounds that showed favorable results for Nrf2 activation from our screen and attenuated high altitude cerebral vascular leak in vivo were further tested in brain microvascular endothelial cells (BMECs) to determine if they attenuated hypoxia-induced ROS production and monolayer permeability. Of nine drugs tested, with the exception of dexamethasone, only drugs that showed the ability to activate Nrf2 (Protandim, methazolamide, nifedipine, amlodipine, ambrisentan, and sitaxentan) decreased high-altitude-induced cerebral vascular leak in vivo. In vitro, Nrf2 activation in BMECs before 24h hypoxia exposure attenuated hypoxic-induced hydrogen peroxide production and permeability. Prophylactic Nrf2 activation is effective at reducing brain vascular leak from acute high altitude exposures. Compared to acetazolamide, methazolamide may offer better protection against AMS. Nifedipine, in addition to its known vasodilatory activities in the lung and protection against high altitude pulmonary edema, may provide protection against brain vascular leak as well.