Modeling the pharmacokinetics and pharmacodynamics of a unique oral hypoglycemic agent using neural networks.
To develop a predictive population pharmacokinetic/ pharmacodynamic (PK/PD) model for repaglinide (REP), an oral hypoglycemic agent, using artificial neural networks (ANNs). REP, glucose concentrations, and demographic data from a dose ranging Phase 2 trial were divided into a training set (70%) and a test set (30%). NeuroShell Predictor was used to create predictive PK and PK/PD models using population covariates: evaluate the relative significance of different covariates; and simulate the effect of covariates on the PK/PD of REP. Predictive performance was evaluated by calculating root mean square error and mean error for the training and test sets. These values were compared to naive averaging (NA) and randomly generated numbers (RN). Covariates found to have an influence on PK of REP include dose, gender. race, age, and weight. Covariates affecting the glucose response included dose, gender, and weight. These differences are not expected to be clinically significant. We came to the following three conclusions: 1) ANNs are more precise than NA and RN for both PK and PD; 2) the bias was acceptable for ANNs as compared with NA and RN; and 3) neural networks offer a quick and simple method for predicting, for identifying significant covariates, and for generating hypotheses.


Wyman's equation and oxygen flux through the red cell.
Wyman's equation of 1966 describes the facilitation of flux of a reversibly bound substrate such as oxygen, consequent on the translational diffusion of the binding protein (the carrier). While Wyman's equation, or some modification of it such as that by Murray 2, may provide a realistic description of the flux of oxygen through a dilute solution of haemoglobin (see also Wittenburg), it is unlikely to be the complete explanation, nor even the basis, for oxygen transport through the intact red cell. The mature erythrocyte contains approximately 350 g/l haemoglobin, and while this suggests that only 35% of the available water volume is actually occupied by the protein, the remaining 65% is unavailable for protein translational diffusion due to the mutual exclusion of the haemoglobin molecules. For this reason we have examined other possible mechanisms whereby haemoglobin may facilitate the translational diffusion of oxygen within the erythrocyte. Possible alternatives include rotational diffusion by the haemoglobins, intracellular shuffling of haemoglobins due to shape changes by the erythrocyte, and haemoglobin rotations and oxygen exchange consequent on the charge change which accompanies substration and desubstration of the haemoglobin molecule. Finally the dipole interactions are shown to generate significant intermolecular attractions between adjacent haemoglobins.


Characterization of N-nitrosodimethylamine formation from the ozonation of ranitidine.
N-nitrosodimethylamine (NDMA) is an emerging disinfection by-product which is formed during water disinfection in the presence of amine-based precursors. Ranitidine, as one kind of amine-based pharmaceuticals, has been identified as NDMA precursor with high NDMA molar conversion during chloramination. This study focused on the characterization of NDMA formation during ozonation of ranitidine. Influences of operational variables (ozone dose, pH value) and water matrix on NDMA generation as well as ranitidine degradation were evaluated. The results indicate high reactivity of ranitidine with ozone. Dimethylamine (DMA) and NDMA were generated due to ranitidine oxidation. High pH value caused more NDMA accumulation. NDMA formation was inhibited under acid conditions (pH≤5) mainly due to the protonation of amines. Water matrix such as HCO3- and humic acid impacted NDMA generation due to OH scavenging. Compared with OH, ozone molecules dominated the productions of DMA and NDMA. However, OH was a critical factor in NDMA degradation. Transformation products of ranitidine during ozonation were identified using gas chromatography-mass spectrometry. Among these products, just DMA and N,N-dimethylformamide could contribute to NDMA formation due to the DMA group in the molecular structures. The NDMA formation pathway from ranitidine ozonation was also proposed.


A novel series of hybrid compounds derived by combining 2-aminotetralin and piperazine fragments: binding activity at D2 and D3 receptors.
A series of 7-hydroxy-2-[N-alkyl-(N-(4-phenylpiperazine)-alkyl)amino]tetralins was developed based on a novel hybrid approach that combined 2-aminotetralin and arylpiperazine pharmacophoric moieties. Our preliminary study revealed that a four-methylene butyl linker produced very potent compounds for both the D2 and D3 receptors. Further structure-activity studies led to a novel template showing 50- to 100-fold selectivity for the D3 receptor.


Complexities of a protonatable substrate in measurements of Hoechst 33342 transport by multidrug transporter LmrP.
Multidrug transporters can confer drug resistance on cells by extruding structurally unrelated compounds from the cellular interior. In transport assays, Hoechst 33342 (referred to as Hoechst) is a commonly used substrate, the fluorescence of which changes in the transport process. With three basic nitrogen atoms that can be protonated, Hoechst can exist as cationic and neutral species that have different fluorescence emissions and different abilities to diffuse across cell envelopes and interact with lipids and intracellular nucleic acids. Due to this complexity, the mechanism of Hoechst transport by multidrug transporters is poorly characterised. We investigated Hoechst transport by the bacterial major facilitator superfamily multidrug-proton antiporter LmrP in Lactococcus lactis and developed a novel assay for the direct quantitation of cell-associated Hoechst. We observe that changes in Hoechst fluorescence in cells do not always correlate with changes in the amount of Hoechst. Our data indicate that chemical proton gradient-dependent efflux by LmrP in cells converts populations of highly fluorescent, membrane-intercalated Hoechst in the alkaline interior into populations of less fluorescent, cell surface-bound Hoechst in the acidic exterior. Our methods and findings are directly relevant for the transport of many amphiphilic antibiotics, antineoplastic agents and cytotoxic compounds that are differentially protonated within the physiological pH range.


Fresh motile testicular sperm retrieved from nonobstructive azoospermic patients has the same potential to achieve fertilization and pregnancy via ICSI as sperm retrieved from obstructive azoospermic patients.
To compare the fertilization and pregnancy rates using fresh testicular sperm between nonobstructive azoospermic (NOA) patients and obstructive azoospermic (OA) patients. We evaluated sperm quality of testicular sperm retrieved by microdissection testicular sperm extraction (MD-TESE) in NOA patients and compared the fertilization rate and pregnancy rate via intracytoplasmic sperm injection (ICSI) between NOA and OA patients. Private hospital-based infertility research laboratory. A total of 58 couples in which the husband was diagnosed with azoospermia. Analytic examination of the outcomes and description of the NOA cases achieving pregnancies; oocyte retrieval and testicular sperm retrieval were performed simultaneously. Comparison of fertilization rate and pregnancy rate at the first ICSI attempt. Testicular sperm were retrieved from 17 of 40 NOA patients and 18 of 18 OA patients. Motile sperm were successfully retrieved from 16 of the 17 NOA patients. There was no significant difference in fertilization rate and pregnancy rate between OA and NOA cases. Of the 17 NOA patients, nine pregnancies were achieved using fresh motile testicular sperm. Fresh motile testicular sperm retrieved from NOA patients may have the same potential to achieve fertilization and pregnancy as sperm retrieved from OA patients. The MD-TESE technique might contribute to the high retrieval rate of fresh motile testicular sperm even in NOA patients.


A phase II study of (2"R)-4'-0-tetrahydropyranyladriamycin (THP) in hematological malignancies.
A phase II study of new anthracycline, THP, was conducted in 46 patients with hematological malignancies in a cooperative study. THP was given intravenously either at a dose of 13-34 mg/m2 for 3-5 consecutive days or 35-50 mg/m2 at 3-4 week intervals. Of 21 patients with acute leukemia, complete response (CR) was observed in 3 patients and partial response (PR) in 4. Of 22 patients with malignant lymphoma, CR was observed in 2 and PR in 6. The predominant toxicity was myelosuppression. Leukopenia was noted in 73% of patients and thrombocytopenia in 14%. Anorexia, nausea and vomiting were observed in 49%, 26% and 23%, respectively. Alopecia and acute cardiac toxicities were mild and recovered quickly on discontinuation of THP. Thus, THP was found to be effective for acute leukemia and malignant lymphoma.


Ketamine inhibits colorectal cancer cells malignant potential via blockage of NMDA receptor.
Ketamine, a common N-methyl-d-aspartate receptor (NMDAR) antagonist, is an option for cancer pain treatment in clinical practice. Ketamine has been shown to have the capacity to attenuate cancer cells malignancy. However, the underlying mechanism remains elusive. In the present study, we reported that ketamine inhibited the malignant potential of colorectal cancer cells and investigated the possible mechanisms involved. Ketamine suppressed the expression of VEGF, HIF-1α, p-AKT, p-ERK, and p-CaMK II, and reduced intracellular Ca2+ level in a concentration dependent manner (1, 5, 10 μg/ml). Furthermore, AP5 and MK801 (NMDAR inhibitors), and KN93 (CaMK II inhibitor), decreased the expression of VEGF, HIF-1a, p-AKT, p-ERK, and p-CaMK II, which were similar to the effect of ketamine. Further, the anti-tumor effect of ketamine was reversed by d-serine (NMDAR activator). Ketamine did not affect NMDA receptor expression, however knockdown of NMDA receptor using siRNA attenuated the effect of ketamine on cell migration. Collectively, these findings demonstrated that ketamine attenuated the expression of VEGF and cell migration ability in colorectal cancer cells, probably via blockage of NMDA receptor.


A rapid technique for preparation of human fetal and adult skeletal material.
The techniques described above have been found to provide a rapid method of human skeletal preparation, with advantages of speed and applicability to fresh, fixed, or partially decomposed skeletal materials. While other techniques which can be used include the traditional use of Dermestidae beetle colonies, a five-step anatomical procedure, and other combinations of chemical solvents, the antiformin technique appears to have advantages useful to those involved in forensic medicine.


Development of a low cost, GPS-based upgrade to a standard handheld gamma detector for mapping environmental radioactive contamination.
A low cost extension to a standard handheld radiation monitor was developed, allowing one to perform outdoor georeferenced gamma measurements. It consists of a commercial wireless Bluetooth GPS receiver, a commercial RS-232 to Bluetooth converter combined with a standard Bluetooth enabled pocket personal computer (PPC). The system is intended for use in difficult to access areas, typically for foot campaigns. As the operator walks, a straightforward homemade visual basic program alternately reads GPS position and gamma dose rate into the PPC, creating a data log. This allows a single operator on foot to map between 50 and 200 ha of environmental radiation per day in very rugged areas, depending on the accessibility of the terrain and the detail required. On a test field with known contamination, a spatial precision of about 5-10 m was obtainable. The device was also used to reveal complex contamination patterns in the flooding zones of a radioactively contaminated small river.


Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.
Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.


Top-Down NOX Emissions of European Cities Based on the Downwind Plume of Modelled and Space-Borne Tropospheric NO₂ Columns.
Top-down estimates of surface NOX emissions were derived for 23 European cities based on the downwind plume decay of tropospheric nitrogen dioxide (NO₂) columns from the LOTOS-EUROS (Long Term Ozone Simulation-European Ozone Simulation) chemistry transport model (CTM) and from Ozone Monitoring Instrument (OMI) satellite retrievals, averaged for the summertime period (April⁻September) during 2013. Here we show that the top-down NOX emissions derived from LOTOS-EUROS for European urban areas agree well with the bottom-up NOX emissions from the MACC-III inventory data (R² = 0.88) driving the CTM demonstrating the potential of this method. OMI top-down NOX emissions over the 23 European cities are generally lower compared with the MACC-III emissions and their correlation is slightly lower (R² = 0.79). The uncertainty on the derived NO₂ lifetimes and NOX emissions are on average ~55% for OMI and ~63% for LOTOS-EUROS data. The downwind NO₂ plume method applied on both LOTOS-EUROS and OMI tropospheric NO₂ columns allows to estimate NOX emissions from urban areas, demonstrating that this is a useful method for real-time updates of urban NOX emissions with reasonable accuracy.


Two successive bidirectional leaders propagated in triggered lightning channel.
A stepped leader propagated along the previous return-stroke channel in triggered lightning. After the stepped leader decayed, the first bidirectional leader went through the process of initiation, propagation and dissipation. Then the second bidirectional leader initiated at the termination of the decayed first bidirectional leader and propagated toward the ground, generating the fourth return-stroke. The observations were synchronously performed through a high-speed camera and electromagnetic field measurements. The first bidirectional leader was characterized by similar average upward and downward velocities of 0.76 × 106 m/s and 0.67 × 106 m/s. The velocity of the upward positive leader of the first bidirectional leader was noticeably fluctuated, ranging 0.39 × 106-1.78 × 106 m/s. The second bidirectional leader was characterized by a sustainable propagating upward end with an average velocity of 1.82 × 106 m/s. The velocity fluctuation trend of the upward end depends on the neutralization amount of the residual negative charge and the positive charge in UPL.


Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy.
Limb-girdle muscular dystrophy type 1D (LGMD1D) was linked to chromosome 7q36 over a decade ago, but its genetic cause has remained elusive. Here we studied nine LGMD-affected families from Finland, the United States and Italy and identified four dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the ubiquitously expressed co-chaperone DNAJB6. Functional testing in vivo showed that the mutations have a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. In vitro studies demonstrated that the mutations increase the half-life of DNAJB6, extending this effect to the wild-type protein, and reduce its protective anti-aggregation effect. Further, we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar myopathy-causing protein BAG3. Our data identify the genetic cause of LGMD1D, suggest that its pathogenesis is mediated by defective chaperone function and highlight how mutations in a ubiquitously expressed gene can exert effects in a tissue-, isoform- and cellular compartment-specific manner.


Effect of NSAIDs on the aminopeptidase activity of cultured human osteoblasts.
Aminopeptidases (APs) are involved in various physiological and pathological processes. In tumor tissues the expression of APs, cyclooxygenase-2 and its metabolites are increased. The objective was to determine the effect of certain NSAIDs on the AP activity of osteoblasts. Primary cultures of osteoblast were treated with different concentrations of indomethacin, meloxicam, naproxen, nimesulide, and piroxicam. The AP activity was fluorimetrically determined using aminoacyl-β-naphthylamides (aa-βNAs) as substrates: Ala-βNA, Arg-βNA, Gly-βNA, Leu-βNA, Lys-βNA, Met-βNA, and Phe-βNA. The five NSAIDs showed an inhibitory effect of AP activity against the study substrates depending on the dose tested. Meloxicam and piroxicam had the highest inhibitory effect on enzymatic activity, with an IC50 of around 70 μM. Our results suggest that the physiological alteration of osteoblasts in the presence of NSAIDs may be a consequence of AP inhibition, suggesting a potential clinical role for these drugs against cancer in combination with chemotherapeutic agents.


A cross-validation study on the relationship between central D2 receptor occupancy and serum perphenazine concentration.
There is a need for laboratory measures to guide clinical treatment with antipsychotic drugs. For serum concentration of the classical antipsychotic drug perphenzine an optimal therapeutic interval has been identified between 2 and 6 nmol/l. Positron emission tomography (PET) studies have suggested an optimal interval in central dopamine D2 receptor occupancy of between 65 and 80%. The aim of the present cross-validation study in clinically stable schizophrenic patients was to examine the relationship between the optimal interval in central D2 receptor occupancy and the therapeutic window for serum perphenazine concentration. Six patients who had responded to maintenance treatment with perphenazine decanoate were examined with PET and [11C]raclopride during steady-state conditions. Blood sampling was carried out for minimum serum perphenazine concentration and during the PET examination. RESULTS. The serum perphenazine concentration was between 1.8 and 9 nmol/l and the D2 receptor occupancy varied between 66 and 82%. The relationship between central receptor occupancy and serum drug concentration was curvilinear. Mild extrapyramidal symptoms were present in the patient with the highest D2 receptor occupancy. CONCLUSIONS. The previously suggested therapeutic window in serum perphenazine concentration is in good agreement with the optimal interval suggested for central D2 receptor occupancy. Serum concentrations at low dose levels may therefore serve as a useful tool in clinical monitoring of antipsychotic drug treatment.


Corrigendum: Gender Differences in Grant Submissions across Science and Engineering Fields at the NSF.
[This corrects the article DOI: 10.1093/biosci/biaa072.].


Three-dimensional sonographic features of nuchal edema.
To describe the three-dimensional (3D) sonographic features of nuchal edema in the early second trimester of pregnancy. From 16 to 22 weeks of gestation 5 cases with nuchal edema were studied using transabdominal 3D sonography. Nuchal edema could be easily imaged with both two-dimensional and 3D sonography; however, visualization of the continuity and curvature of structures was more easily accomplished with 3D sonography. Before 20 weeks of gestation, the skin has a transparent structure, so the bony structures are clearly identified. 3D sonography allowed visualization of nuchal edema in all three dimensions at the same time, providing an improved overview and a more clearly defined demonstration of the adjusted anatomical planes. These results suggest that 3D sonography provides a novel means of visualizing nuchal edema in utero.


Third-degree burn by tincture of iodine--a case study.
It is important that occupational health nurses understand farmers' work and the risks of injury during farm tasks.


Anticancer function of α-solanine in lung adenocarcinoma cells by inducing microRNA-138 expression.
Currently, lung cancer is still a main cause of malignancy-associated death worldwide. Even though various methods for prevention and treatment of lung cancer have been improved in recent decades, the 5-year survival rate has remained very low. Insights into the anticancer function of small-molecule anticancer compounds have opened our visual field about cancer therapy. α-Solanine has been well studied for its antitumor properties, but its effect in lung cancer and associated molecular mechanisms have not yet been evaluated. To explore the anticancer function of α-solanine, we performed an MTT assay, Transwell arrays, colony-forming survival assay, quantitative reverse transcription PCR (qRT-PCR), Western blotting, and dual luciferase reporter assays in A549 and H1299 cells. We found that α-solanine not only inhibited cell migration and invasion ability but also enhanced the chemosensitivity and radiosensitivity of A549 and H1299 cells. Moreover, we discovered that α-solanine could affect the expression of miR-138 and focal adhesion kinase (FAK), both of which were also found to affect the chemosensitivity and radiosensitivity of A549 and H1299 cells. In conclusion, α-solanine could affect miR-138 and FAK expression to restrict cell migration and invasion and enhance the chemosensitivity and radiosensitivity of A549 and H1299 cells. The α-solanine/miR-138/FAK cascade can probably be a potential therapy target against lung adenocarcinoma.


Perspectives and outlook for electron microscopy in biology in general.
The possibilities for improving methods of electron microscopy with the aim of visualizing still finer details of biological relevance are discussed with respect to different goals: discovering and defining new structures in situ, in the cell, in relation to functions, and investigating the fine structure of already morphologically and biochemically defined structures which are available in isolated and purified form. For each of these goals the importance of the inherent limitations are considered: lack of definition due to the unknown nature of heavy metal staining, deformations caused by the physical events of specimen preparation, and radiochemical alterations induced by the electron beam. Methods of investigating and overcoming these limitations by new cryotechniques, new imaging modes and improved crystallographic techniques are outlined. Emphasis is given to relevant biological phenomena, where electron microscopy is potentially the method of choice, e.g., those related to functional proteins situated in and on biological membranes and where relatively large conformational changes are supposed to have occurred to explain the functions.


Factors influencing repeat caesarean section: qualitative exploratory study of obstetricians' and midwives' accounts.
To explore the views of health professionals on the factors influencing repeat caesarean section. Qualitative study involving semi-structured interviews with professionals who care for women in pregnancy and labour. Acute hospital trust with two maternity units and community midwifery service, Leicestershire, UK. Twenty-five midwives and doctors. Interviews with professionals were undertaken using a prompt guide. All interviews were audiotaped and transcribed verbatim. Analysis was based on the constant comparative method, assisted by QSR N5 software. Identification of factors influencing professional decision making about repeat caesarean section. Decision making in relation to repeat caesarean is a complex process involving several parties. Professionals identify the relevance of evidence for decision making for repeat caesarean. However, professionals feel that following strict protocols is of limited value because of the perceived substandard quality of evidence in this area, other external pressures and the contingent, unique and often unanticipated features of each case. Professionals also perceive that the organisation of care plays an important role in rates of repeat caesarean. Decision making for repeat caesarean is a social practice where standardised protocols may have limited value. Attention needs to be given to the multiple parties involved in the decision-making process. Reflective practice, opinion leadership and role modelling may offer ways forward but will require evaluation.


Frontoparietal activity during deceptive responses in the P300-based guilty knowledge test: an sLORETA study.
The cortical source activity during the P300-based guilty knowledge test (GKT) conducted using Korean sentences was investigated. Thirty male students performed a guilty or an innocent scenario, and then underwent an electroencephalogram test. The stimuli consisted of target, probe, and irrelevant stimuli that were presented visually. A target stimulus is a task-relevant stimulus that is presented rarely, attracts subjects' attention, and induces a P300 wave. A probe stimulus, also presented rarely, contains crime-relevant information that induces P300 in a guilty subject. A guilty subject would be also attentive to the probe stimulus as to the target stimulus. An irrelevant stimulus is not related to the task or to the crime, and is frequently presented. Event-related potential (ERP) data showed a marked difference between the guilty and innocent groups. Compared to irrelevant stimuli, the probe stimulus elicited larger P300 amplitude in the bilateral frontoparietal region in the guilty group. However, this pattern was not observed in the innocent group. Standardized low-resolution electromagnetic tomography (sLORETA) analysis showed significant activation increases for the probe stimulus in the guilty group. It appears that the guilty and innocent groups use different cognitive mechanisms when processing the crime-relevant sentence. With regards to the cortical activity in response to the probe stimulus, the frontal activation for verb elements seems to reflect a working memory process, episodic memory retrieval, and response inhibition, while parietal activation for complement (adverb) and object (noun) elements seems to reflect selective attention and target discrimination. To our knowledge, this is the first research to examine the cortical source of the ERP evoked by the P300-based GKT using separate Korean sentence elements.


Microvascular transplantation of the human fallopian tube.
An unsuccessful human fallopian tube transplant is reported. A microsurgical technique is described which initially secured a viable transplant. However, the allograft subsequently died, probably as a result of rejection. Immunosuppression of the patient caused no complications or difficulties, the donor sharing one HL-A haplotype with the patient. The operative procedure, the risks of immunosuppression, and the ethical aspects of the case are discussed in order to present the problems associated with fallopian tube transplantation.


Termination of early pregnancy by ONO-802 (16,16-dimethyl-trans-delta2-PGE1 methyl ester).
ONO-802 was infused into the uterine cavity for the termination of early pregnancy in 45 healthy volunteers. Forty two (93%) of the 45 cases had complete abortions and two had incomplete abortions. Nine (20%) of the 45 volunteers complained of nausea, 7 (16%) vomited and 5 (11%) complained of abdominal pain. Neither diarrhea nor weakness was observed. These results suggest that ONO-802 is more acceptable for the termination of early pregnancy than is PGF2alpha.


Respiratory damage caused by long-term inhalation of high concentration of sulphur-dioxide in dogs.
It has been tried in this study to produce chronic obstructive bronchitis in dogs by exposing them to high concentrations of SO2. The study was extended to 175 days and during that period the animals were exposed to 300-500 ppm SO2 for a total of 435 h. None of the three dogs developed serious respiratory damage. Most of the symptoms were transitory. Histological examinations showed increased number of goblet cells in trachea, main- and lobar bronchi and a slight alteration of the bronchial glands.


Soft tissue sarcomas: thirteen years experience in the service of medical oncology of a general hospital.
Thirty-seven patients with soft tissue sarcomas were treated between 1981 and 1990. All of them were operated. Thirteen patients with marginal resection received adjuvant radiotherapy. Radiotherapy decreased the rate of local relapses. Sixteen patients received adjuvant chemotherapy with ifosfamide-epirubicin and four of them had a recurrence. Twenty-one patients did not receive chemotherapy and 13 of them relapsed. Adjuvant chemotherapy improved the disease-free survival during the first year, but not benefit appeared in long-term disease-free survival and overall survival.


Anesthesia-Related and Perioperative Cardiac Arrest in Low- and High-Income Countries: A Systematic Review With Meta-Regression and Proportional Meta-Analysis.
The anesthesia-related cardiac arrest (CA) rate is a quality indicator to improve patient safety in the perioperative period. A systematic review with meta-analysis of the worldwide literature related to anesthesia-related CA rate has not yet been performed.This study aimed to analyze global data on anesthesia-related and perioperative CA rates according to country's Human Development Index (HDI) and by time. In addition, we compared the anesthesia-related and perioperative CA rates in low- and high-income countries in 2 time periods.A systematic review was performed using electronic databases to identify studies in which patients underwent anesthesia with anesthesia-related and/or perioperative CA rates. Meta-regression and proportional meta-analysis were performed with 95% confidence intervals (CIs) to evaluate global data on anesthesia-related and perioperative CA rates according to country's HDI and by time, and to compare the anesthesia-related and perioperative CA rates by country's HDI status (low HDI vs high HDI) and by time period (pre-1990s vs 1990s-2010s), respectively.Fifty-three studies from 21 countries assessing 11.9 million anesthetic administrations were included. Meta-regression showed that anesthesia-related (slope: -3.5729; 95% CI: -6.6306 to -0.5152; P = 0.024) and perioperative (slope: -2.4071; 95% CI: -4.0482 to -0.7659; P = 0.005) CA rates decreased with increasing HDI, but not with time. Meta-analysis showed per 10,000 anesthetics that anesthesia-related and perioperative CA rates declined in high HDI (2.3 [95% CI: 1.2-3.7] before the 1990s to 0.7 [95% CI: 0.5-1.0] in the 1990s-2010s, P < 0.001; and 8.1 [95% CI: 5.1-11.9] before the 1990s to 6.2 [95% CI: 5.1-7.4] in the 1990s-2010s, P < 0.001, respectively). In low-HDI countries, anesthesia-related CA rates did not alter significantly (9.2 [95% CI: 2.0-21.7] before the 1990s to 4.5 [95% CI: 2.4-7.2] in the 1990s-2010s, P = 0.14), whereas perioperative CA rates increased significantly (16.4 [95% CI: 1.5-47.1] before the 1990s to 19.9 [95% CI: 10.9-31.7] in the 1990s-2010s, P = 0.03).Both anesthesia-related and perioperative CA rates decrease with increasing HDI but not with time. There is a clear and consistent reduction in anesthesia-related and perioperative CA rates in high-HDI countries, but an increase in perioperative CA rates without significant alteration in the anesthesia-related CA rates in low-HDI countries comparing the 2 time periods.


Composition, Structure and Morphology Evolution of Octadecylamine (ODA)⁻Reduced Graphene Oxide and Its Dispersion Stability under Different Reaction Conditions.
Octadecylamine (ODA) can solve the aggregation problem of graphene sheets in the chemical exfoliation method. However, no attempts have been made to investigate the evolution of ODA⁻reduced graphene oxide (ORGO) with reaction conditions and the modification mechanism, which is the core problem to realize the controllable production and practical application of graphene. In this study, we treated graphene oxide (GO) with ODA under different reaction conditions to prepare ORGO. Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy, atomic force microscopy, Raman spectroscopy, thermogravimetric analysis (TGA), and UV⁻vis spectrophotometry were employed to analyze the composition, structure, morphology and characteristics of the as⁻prepared graphene sheets. The results showed that the reduction reaction could occur under mild conditions, but the edge grafting reaction could only be activated by a higher temperature. Moreover, the ORGO created at 80 °C for 5 h and 120 °C for 0.5 h exhibited the optimized properties, both excellent dispersing stability and high heat resisting property, since they had more edge grafting chains and a suitable reduction degree.


HOTAIR Accelerates Dyskinesia in a MPTP-Lesioned Mouse Model of PD via SSTR1 Methylation-Mediated ERK1/2 Axis.
Homeobox transcript antisense RNA (HOTAIR), has been associated with neuroprotective effects in Parkinson's disease (PD). However, the underlying mechanisms still remain unclear. Hence, this present study attempted to clarify the functional relevance of HOTAIR in PD. We established an in vivo mouse model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and an in vitro cell model of PD by treating dopaminergic neuron MN9D cells with 1-methyl-4-phenylpyridinium species (MPP+). The expressions of somatostatin receptor 1 (SSTR1) and HOTAIR were altered to examine their effects on MN9D cell viability and apoptosis, as well as on movement impairments in MPTP-induced PD mouse model. The results indicated that HOTAIR expression was upregulated and SSTR1 was downregulated in in vivo and in vitro PD models. HOTAIR could bind to the promoter region of SSTR1, resulting in an increase of SSTR1 methylation through the recruitment of DNA methyltransferases in PD cell models. Notably, overexpression of HOTAIR and silencing of SSTR1 enhanced dopaminergic neuron apoptosis in MN9D cells and exacerbated dyskinesia in MPTP-induced PD mouse model. Collectively, overexpressed HOTAIR stimulates DNA methylation of SSTR1 to reduce SSTR1 expression, thereby accelerating dyskinesia and facilitating dopaminergic neuron apoptosis in a MPTP-lesioned PD mouse model via activation of the ERK1/2 axis.


Opioid rotation versus combination for cancer patients with chronic uncontrolled pain: a randomized study.
For cancer patients with inadequate pain relief, a switch to an alternative opioid is the preferred option for symptomatic improvement. However, multiple opioids are often simultaneously administered for anecdotal reasons. This prospective study evaluated pain response to either opioid rotation or combination in patients with uncontrolled cancer pain. Patients suffering with uncontrolled cancer pain despite dose titration were randomly assigned to opioid rotation group or opioid combination group. Patients answered a questionnaire that included items on pain severity (0 to 10) and interferences at baseline and after one week. Of the 50 patients registered, 39 patients answered the questionnaire after one week of treatment. After one week, the mean pain scores were significantly improved in both groups. Ten patients (42%) in the rotation group and 16 patients (62%) in the combination group reported that they achieved relief from pain (p = 0.08). The incidence of adverse events was similar in both groups, but fewer patients experienced constipation with opioid rotation than with combination (17% vs. 42%, respectively; p = 0.05). The frequency of rescue analgesics (50% vs. 69%; p = 0.17) and dose modification (29% vs. 38%; p = 0.49) were similar in the rotation and combination groups. For patients with chronic uncontrolled cancer pain, both opioid rotation and combination strategies appear to provide significant relief of pain and improved patient satisfaction. This study was registered in advance to ClinicalTrials.gov (no. NCT00478101).


Medium engineering for enhanced production of undecylprodigiosin antibiotic in Streptomyces coelicolor using oil palm biomass hydrolysate as a carbon source.
In this study, a biosugar obtained from empty fruit bunch (EFB) of oil palm by hot water treatment and subsequent enzymatic saccharification was used for undecylprodigiosin production, using Streptomyces coelicolor. Furfural is a major inhibitor present in EFB hydrolysate (EFBH), having a minimum inhibitory concentration (MIC) of 1.9mM, and it reduces utilization of glucose (27%), xylose (59%), inhibits mycelium formation, and affects antibiotic production. Interestingly, furfural was found to be a good activator of undecylprodigiosin production in S. coelicolor, which enhanced undecylprodigiosin production by up to 52%. Optimization by mixture analysis resulted in a synthetic medium containing glucose:furfural:ACN:DMSO (1%, 2mM, 0.2% and 0.3%, respectively). Finally, S. coelicolor was cultured in a fermenter in minimal medium with EFBH as a carbon source and addition of the components described above. This yielded 4.2μg/mgdcw undecylprodigiosin, which was 3.2-fold higher compared to that in un-optimized medium.


Replication of SARS-CoV-2 Omicron BA.2 variant in ex vivo cultures of the human upper and lower respiratory tract.
The Omicron BA.2 sublineage has replaced BA.1 worldwide and has comparable levels of immune evasion to BA.1. These observations suggest that the increased transmissibility of BA.2 cannot be explained by the antibody evasion. Here, we characterized the replication competence and respiratory tissue tropism of three Omicron variants (BA.1, BA.1.1, BA.2), and compared these with the wild-type virus and Delta variant, in human nasal, bronchial and lung tissues cultured ex vivo. BA.2 replicated more efficiently in nasal and bronchial tissues at 33°C than wild-type, Delta and BA.1. Both BA.2 and BA.1 had higher replication competence than wild-type and Delta viruses in bronchial tissues at 37°C. BA.1, BA.1.1 and BA.2 replicated at a lower level in lung parenchymal tissues compared to wild-type and Delta viruses. Higher replication competence of Omicron BA.2 in the human upper airway at 33°C than BA.1 may be one of the reasons to explain the current advantage of BA.2 over BA.1. A lower replication level of the tested Omicron variants in human lung tissues is in line with the clinical manifestations of decreased disease severity of patients infected with the Omicron strains compared with other ancestral strains. This work was supported by US National Institute of Allergy and Infectious Diseases and the Theme-Based Research Scheme under University Grants Committee of Hong Kong Special Administrative Region, China.


Direct evidences on bacterial growth pattern regulating pyrene degradation pathway and genotypic dioxygenase expression.
Pyrene degradation by Mycobacterium sp. strain A1-PYR was investigated in the presence of nutrient broth, phenanthrene and fluoranthene, respectively. Fast bacterial growth in the nutrient broth considerably enhanced pyrene degradation rate, whereas degradation efficiency per cell was substantially decreased. The addition of nutrient broth could not alter the transcription levels of all dioxygenase genotypes. In the PAH-only substrates, bacterial growth completely relied on biological conversion of PAHs into the effective carbon sources, which led to a higher degradation efficiency of pyrene per cell than the case of nutrient broth. Significant correlations were only observed between nidA-related dioxygenase expression and pyrene degradation or bacterial growth. The highest pyrene degradation rate in the presence of phenanthrene was consistent with the highest transcription level of nidA and 4,5-pyrenediol as the sole initial metabolite. This study reveals that bacterial growth requirement can invigorate degradation of PAHs by regulating metabolic pathway and genotypic enzyme expression.


Deep convolutional neural network for differentiating between sarcoidosis and lymphoma based on [18F]FDG maximum-intensity projection images.
To compare the [18F]FDG PET/CT findings of untreated sarcoidosis and malignant lymphoma (ML) and develop convolutional neural network (CNN) models to differentiate between these diseases using maximum intensity projection (MIP) [18F]FDG PET images. We retrospectively collected data on consecutive patients newly diagnosed with sarcoidosis and ML who underwent [18F]FDG PET/CT before treatment. Two nuclear radiologists reviewed the images. CNN models were created using MIP PET images and evaluated with k-fold cross-validation. The points of interest were visualized using gradient-weighted class activation mapping (Grad-CAM). A total of 56 patients with sarcoidosis and 62 patients with ML were included. Patients with sarcoidosis had more prominent FDG accumulation in the mediastinal lymph nodes and lung lesions, while those with ML had more prominent accumulation in the cervical lymph nodes (all p < 0.001). For the mediastinal lymph nodes, sarcoidosis patients had significant FDG accumulation in the level 2, 4, 7, and 10 lymph nodes (all p < 0.01). Otherwise, the accumulation in ML patients tended to be in the level 1 lymph nodes (p = 0.08). The CNN model using frontal and lateral MIP images achieved an average accuracy of 0.890 (95% CI: 0.804-0.977), a sensitivity of 0.898 (95% CI: 0.782-1.000), a specificity of 0.907 (95% CI: 0.799-1.000), and an area under the curve of 0.963 (95% CI: 0.899-1.000). Grad-CAM showed that the model focused on the sites of abnormal FDG accumulation. CNN models based on differences in FDG accumulation sites archive high performance in differentiating between sarcoidosis and ML. We developed a CNN model using MIP images of [18F]FDG PET/CT to distinguish between sarcoidosis and malignant lymphoma. It achieved high performance and could be useful in diagnosing diseases with involvement across organs and lymph nodes. • There are differences in FDG distribution when comparing whole-body [18F]FDG PET/CT findings in patients with sarcoidosis and malignant lymphoma before treatment. • Convolutional neural networks, a type of deep learning technique, trained with maximum-intensity projection PET images from two angles showed high performance. • A deep learning model that utilizes differences in FDG distribution may be helpful in differentiating between diseases with lesions that are characteristically widespread among organs and lymph nodes.


Copper(I)-Catalyzed Interrupted Click Reaction: Synthesis of Diverse 5-Hetero-Functionalized Triazoles.
The 5-heterofunctionalized triazoles are important scaffolds in bioactive compounds, but current click reactions (CuAAC) cannot produce these core structures. A copper(I)-catalyzed interrupted click reaction to access diverse 5-functionalized triazoles is reported. Various 5-amino-, thio-, and selenotriazoles were readily assembled in one step in high yields. The reaction proceeds under mild conditions with complete regioselectivity. It also features a broad substrate scope and good functional group compatibility.


Features of acute and transient psychotic disorders.
Little is known about acute and transient psychotic disorders (ATPD), a diagnostic category introduced with ICD-10. To determine the clinical and sociodemographic features, course and outcome of ICD-10 ATPD in a prospective and longitudinal study. We recruited all consecutive inpatients fulfilling the ICD-10 criteria of ATPD during a 5-year period. Demographic and clinical features were systematically evaluated and follow-up investigations were carried out at an average of 10 years after onset of the disorder using standardized instruments. ATPD patients represented 8.5% of all inpatients with non-organic psychotic disorders. ATPD were characterized by female preponderance. In two-thirds of the cases a typical polymorphic symptomatology was found. In spite of the fact that the possibility of relapse within 5 years was high, the psychopathological and social outcome for most of the patients was very favourable. Schizophrenic episodes during follow-up were rare (7.7% of patients), but a strictly monomorphous course (ATPD episodes only) from index episode to the end of the prospective follow-up was found in only 53.9% of the patients. ATPD are not a sharply demarcated and unchanging nosological entity. Nevertheless, the present data support a delineation of ATPD as a diagnostic category with specific clinical features and with a usually favourable prognosis. Further research on the topic is necessary.


Luminescence and morphological behaviour of the aromatic dipeptide pair having singular structural variability.
In the present manuscript, the luminescence and the self-assembly behaviour of two aromatic dipeptides with a singular structure variable are investigated. The terminally protected dipeptides tryptophan-tyrosine (WYp ) and tryptophan-phenylalanine (WFp ) were synthesized using a standard solution phase procedure. Significant solvatochromic effect was observed for both the dipeptidyl entities; whilst the influence was more pronounced for the WYp entity when compared with WFp . Interesting morphological variation was observed for WFp and WYp , in which discrete and interconnected nanospheres were observed for the respective dipeptides. The results obtained signify the influence of the singular structural variation on modulating the overall functional behaviour of the short peptides motifs.


Specific tissue factor delivery using a tumor-homing peptide for inducing tumor infarction.
Targeting the human blood coagulation-inducing protein tissue factor (TF) to the tumor vasculature to induce infarction and disrupt the blood vessels has proven to be an effective approach for tumor therapy. In this study, we investigated the thrombogenic activity and anti-tumor potential of a novel fusion protein (tTF-CREKA) comprising the extracellular domain of human tissue factor (truncated TF, tTF) and a tumor targeting pentapeptide, Cys-Arg-Glu-Lys-Ala (CREKA). tTF is soluble and inactive in its free state, but when it is targeted to the plasma membrane of both tumor vessel endothelial cells and stromal cells by the CREKA peptide, its native coagulation-inducing activity is restored. Systemic administration of the tTF-CREKA fusion protein into tumor-bearing mice induced tumor-selective intravascular thrombosis and reduced tumor blood perfusion, consequently inhibiting tumor growth. The development of tTF-CREKA introduces a new method for treating a wide spectrum of solid tumors by selectively blocking tumor blood supply.


Outcomes following revision of the revision total elbow arthroplasty.
There is very little information in the literature on the outcomes of revision of revision total elbow arthroplasty (RRTEA). Our aim was to report the outcomes of this rarely performed procedure. We retrospectively identified all patients who had undergone RRTEA between 2007 and 2016. Outcomes were assessed clinically using a number of validated systems, and radiographs were reviewed for prosthesis alignment, cementation by Morrey grading, and heterotopic ossification. We identified 22 patients who underwent RRTEA. Of these patients, 14 were available for assessment (2 died of unrelated causes, 2 could not be contacted, 2 declined to participate because of travel difficulties, and 2 had incomplete data). At the final review, the median age was 73 years (range, 57-83 years), with a median follow-up period of 4.5 years (range, 2-7 years) since the last surgical procedure. The median number of previous revision arthroplasty procedures per patient was 3 (range, 2-6). The indications for RRTEA were aseptic loosening (60%), bushing wear (16%), fracture (14%), and infection (10%). Of the patients, 30% required extra-long or custom-made implants and 50% needed allograft augmentation. At final clinical assessment, 56% of patients had triceps insufficiency, the median flexion-extension arc was 90°, and the median prono-supination arc was 95°. The functional elbow scores revealed good outcomes in the majority of patients (median visual analog scale score, 5; median Oxford Elbow Score, 22; median Mayo Elbow Performance Index score, 55; and median QuickDASH [short version of Disabilities of the Arm, Shoulder and Hand questionnaire] score, 63). Eighty-one percent of patients were satisfied with their RRTEAs. Complications included infection in 2 patients (1 superficial and 1 deep), symptomatic aseptic humeral component loosening in 1, sensory ulnar nerve symptoms in 2, and radial nerve injury in 1. One patient required ulnar nerve release. Radiologic review revealed asymptomatic loosening in 1 patient (humeral component), and overall prosthesis alignment with cementation was adequate in 81%. Heterotopic ossification was present in 38% of cases. RRTEA is a satisfactory treatment option in these complex cases, with good short- to mid-term survival rates but a relatively high complication rate.


Deep Learning for Chondrocyte Identification in Automated Histological Analysis of Articular Cartilage.
Histology-based methods are commonly used in osteoarthritis (OA) research because they provide detailed information about cartilage health at the cellular and tissue level. Computer-based cartilage scoring systems have previously been developed using standard image analysis techniques to give more objective and reliable evaluations of OA severity. The goal of this work was to develop a deep learning-based method to segment chondrocytes from histological images of cartilage and validate the resulting method via comparison with human segmentation. The U-Net approach was adapted for the task of chondrocyte segmentation. A training dataset consisting of 235 images and a validation set consisting of 25 images in which individual chondrocytes had been manually segmented, were used for training the U-Net. Chondrocyte count, detection accuracy, and boundary segmentation of the trained U-Net was evaluated by comparing its results with those of human observers. The U-Net chondrocyte counts were not significantly different (p = 0.361 in a paired t-test) than the algorithm trainer counts (Pearson correlation coefficient = 0.92). The five expert observers had good agreement on chondrocyte counts (intraclass correlation coefficient = 0.868), however the resulting U-Net counted a significantly fewer chondrocytes than the average of those expert observers (p < 0.001 in a paired t-test). Chondrocytes were accurately detected by the U-Net (F1 scores = 0.86, 0.90, with respect to the selected expert observer and algorithm trainer). Segmentation accuracy was also high (IOU = 0.828) relative to the algorithm trainer. This work developed a method for chondrocyte segmentation from histological images of arthritic cartilage using a deep learning approach. The resulting method detected chondrocytes and delineated them with high accuracy. The method will continue to be improved through expansion to detect more complex cellular features representative of OA such as cell cloning. The imaging tool developed in this work can be integrated into an automated cartilage health scoring system and helps provide a robust, objective and reliable assessment of OA severity in cartilage.


Repair of (6-4)photoproducts correlates with split-dose recovery in UV-irradiated normal and hypersensitive rodent cells.
Chinese hamster ovary cells and two UV-hypersensitive derivatives were used to determine the importance of DNA excision repair for split-dose recovery. In the wild-type cells 75% of the maximum theoretical recovery was observed when the fractions were delivered at 2-h intervals. Very little recovery was evident in the two hypersensitive cell lines. Using radioimmunoassays specific for (6-4)photoproducts and cyclobutane dimers, the ability of UV-irradiated repair-deficient cells representing 5 complementation groups to repair these 2 photoproducts was determined. Removal of antibody-binding sites specific for (6-4)photoproducts was 80% complete in 6 h and was defective in the UV-sensitive cells. In contrast, only 20-60% of antibody-binding sites specific for cyclobutane dimers were removed 18 h post-irradiation, and the extent of removal was the same in normal and defective cell lines. We conclude that repair of (6-4)photoproducts accounts for split-dose recovery. In addition, we conclude that a consequence of DNA repair in CHO cells is modification rather than removal of cyclobutane dimers.


Evaluation of the effectiveness of a multi-skill program for training younger drivers on higher cognitive skills.
Training programs exist that prove effective at teaching novice drivers to anticipate latent hazards (RAPT), mitigate hazards (ACT) and maintain attention (FOCAL). The current study (a) measures the effectiveness of a novel integrated training program (SAFE-T) that takes only a third as long to complete compared to the three individual training programs and (b) determines if integrating the training of all the three higher cognitive skills would yield results comparable to the existing programs. Three groups were evaluated: SAFE-T, RAPT and Placebo. The results show that the drivers in the SAFE-T-trained group were more likely to anticipate hazards, quicker and more effective at responding to hazards, and more likely to maintain glance durations under a critical threshold of 2 s as compared to drivers in the Placebo-trained group who received a control program that does not actively train on any of the three cognitive skills. Moreover, the results show that the drivers in the SAFE-T trained group were just as likely to anticipate hazards as the drivers in the RAPT trained group. Finally, when compared with prior studies, the drivers in the SAFE-T trained group showed similar effects of attention maintenance training.


Mastery in middle adolescence: the contributions of socioeconomic status, maternal mastery and supportive-involved mothering.
Mastery, or the feeling of power or control over one's life, is a vital yet understudied covariate of wellbeing in adolescence and adulthood. The goal of the current study was to explore the effects of demographic characteristics (i.e., sex, age, race/ethnicity, and socioeconomic status (SES)), maternal mastery, and supportive-involved mothering on children's mastery at ages 16-17 years. 855 teens (47.6% female) and their mothers provided study data as part of the 1992 and 1998 waves of National Longitudinal Survey of Youth-1979 (NLSY-79; 24.1% Hispanic, 36.6% Black). Hybrid path models indicated that only maternal parenting during middle childhood was linked directly to levels of children's mastery in middle adolescence; a small portion of the association between parenting and adolescent mastery was attributable to SES. The discussion centers on significance of these findings for future research and theory development.


Detection of bovine pancreatic trypsin inhibitor (bPTI) in bovine and ovine pituitaries, bovine brain, and adrenal medulla. A specific radioimmunoassay for bPTI.
An antiserum against bovine pancreatic trypsin inhibitor (bPTI) has been raised in rabbits. The antiserum does not cross-react with known pituitary hormones and other proteins. A specific radioimmunoassay for bPTI has been developed. The ED50 is about 250 fmol per assay tube and the sensitivity is reliable to 15 fmol per tube. Immunoreactivity could be detected in bovine and sheep pituitaries, bovine brain, and adrenal medulla, but not in human, pig, and rat pituitaries. In the bovine pituitary the immunoreactivity is restricted to the posterior lobe.


Patellofemoral instability in trochleodysplastic knee joints and the quantitative influence of simulated trochleoplasty - A finite element simulation.
Patellofemoral instability is a debilitating condition mainly affecting young patients and has been correlated with trochlear dysplasia. It can occur when the patella is insufficiently guided through its range of motion. Currently, there is no literature describing patellofemoral stability in trochleodysplastic knees and the effect of isolated trochleoplasty on patellofemoral stability. The effect of isolated trochleoplasty in trochleodysplastic knees of patients with symptomatic patellofemoral instability was investigated using a quasi-static finite element model. MRI data of five healthy knees were segmented, meshed and a finite element analysis was performed in order to validate the model. A second validation was performed by comparing simulated patellofemoral kinematics to in-vivo values obtained from upright- weight bearing CT scans. Subsequently, five trochleodysplastic knees were modelled before and after simulated trochleoplasty. The force necessary to dislocate the patella by 10 mm and to fully dislocate the patella was calculated in various knee flexion angles between 0 and 45°. The developed models successfully predicted outcome values within the range of reference values from literature. Lateral stability was significantly lower in trochleodysplastic knees compared to healthy knees. Trochleoplasty was determined to significantly increase the force necessary to dislocate the patella in trochleodysplastic knees to comparable values as in healthy knees. This is the first study to investigate lateral patellofemoral stability in patients with symptomatic patellofemoral instability and dysplasia of the trochlear groove. We confirm that patellofemoral stability is significantly lower in trochleodysplastic knees than in healthy knees. Trochleoplasty increases patellofemoral stability to levels similar to healthy.


Dosimetric properties of lithium borate glass doped with dysprosium.
Characterization of thermoluminescence (TL) properties of lithium borate glass samples doped with different concentrations of dysprosium (Dy) was carried out. Samples were prepared using a melting method at 1100°C and irradiated with β-particles. The glass samples doped with 0.1% Dy displayed the best TL dosimetric properties compared with other compositions. Deconvoluted analyses of the glow curves displayed five overlapping TL glow peaks located between 392.0 and 510.3 K. A good linear TL dose-response for β-particles was obtained in the dose range 66.6 mGy to 33.3 Gy. The minimum detectible dose was evaluated to be 205.4 μGy and samples revealed thermal fading in 312 h to 29% of their original value.


Class I and class II major histocompatibility complex antigen expression on hepatocytes: a study in children with liver disease.
Controversy exists regarding major histocompatibility complex antigen expression on hepatocytes. In this study, hepatocyte expression of class I and II major histocompatibility complex antigens was investigated in diseased and normal livers, using indirect immunofluorescent staining of mechanically isolated, viable hepatocytes. Hepatocytes were obtained from 76 children: 10 with autoimmune chronic active hepatitis, nine with primary sclerosing cholangitis, nine with chronic hepatitis B virus infection, five after liver transplantation, 19 with extrahepatic biliary atresia, 11 with alpha 1-antitrypsin deficiency, four with idiopathic neonatal hepatitis and nine with histologically normal liver. Immunohistochemistry was performed in all cases; flow cytofluorimetry was performed for class I antigens in 38 cases and performed for class II antigens in 18 cases. From three children with autoimmune chronic active hepatitis and two with chronic hepatitis B virus infection, isolated hepatocytes were also incubated with gamma-interferon before staining and analysis. By fluorescence microscopy, class I antigens were detected on hepatocytes from all children, the highest percentage (100%) of positive cells and the most intense staining were observed in untreated patients with autoimmune chronic active hepatitis or primary sclerosing cholangitis and in those with acute rejection of a liver transplant. Reduced class I antigen expression occurred in chronic hepatitis B virus infection. Class II antigens were only detected on hepatocytes from eight patients: three with autoimmune chronic active hepatitis and five with primary sclerosing cholangitis, all untreated. Flow cytofluorimetric analysis confirmed the results obtained by fluorescence microscopy, but it also demonstrated a weak class II antigen expression during liver allograft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)


Stress levels over time in the introduced ascidian Styela plicata: the effects of temperature and salinity variations on hsp70 gene expression.
Species distribution, abundance, and long-term survival are determined by biotic and abiotic regimes. However, little is known about the importance of these factors in species range expansion. Styela plicata is a solitary ascidian introduced all over the world by ship fouling, including salt marsh habitats, where introduced populations must tolerate high seasonal variations in temperature and salinity. To determine the seasonal stress levels in a salt marsh population of S. plicata, we quantified heat shock protein (hsp70) gene expression using quantitative real-time PCR throughout a 2-year cycle. Results showed that hsp70 expression varied over time, with higher stress levels recorded in summer and winter. Periodic conditions of high temperatures, particularly when coupled with low salinities, increased hsp70 gene expression. Mortality events observed every year around June were concurrent with sharp increases in temperature (>6°C), indicating that drastic changes in abiotic factors may overwhelm the observed stress response mechanisms. Determining the ability of introduced species to cope with stress, and the thresholds above which these mechanisms fail, is fundamental to predict the potential expansion range of introduced species and design efficient containment plans.


Sinus venosus type of atrial septal defect with partial anomalous pulmonary venous return.
This report describes our method of repairing the sinus venosus type of atrial septal defects. The superior vena cava is compartmentatlized by means of a single double-armed suture. Caval catheters are used as temporary internal shunts, and a vertical U-shaped patch is incorporated into the atriotomy suture line. The experiences with 27 cases are presented.


Pulmonary Function and Aerobic Capacity Responses to Equine Assisted Therapy in Adolescents with Idiopathic Scoliosis: A Randomized Controlled Trial.
Idiopathic scoliosis is a common spinal malalignment that negatively impacts the respiratory system and physical conditioning in adolescents. Equine-assisted therapy comprises therapeutic horseback riding that optimizes physical performance and mobility in a range of contexts. However, the influence of equine-assisted therapy on pulmonary function remains unclear. To examine the impact of 10 weeks of hippotherapy combined with Schroth exercises on pulmonary function and aerobic capacity in adolescents with idiopathic scoliosis. A randomized controlled trial including 45 patients, randomly assigned to experimental and control groups, was performed. Patients in the experimental group received 15 30-min sessions of hippotherapy over a period of 10 weeks. The 2 groups attended a 60-min session of Schroth exercises 3 times/week for 10 weeks. Pulmonary function and functional capacity were assessed before and after the intervention. Pre- and post-intervention variables (FVC, FEV1, FEV1/FVC, MVV and 6MWT) revealed significant improvement in both groups (p < 0.05). The improvement in the experimental group was significantly higher than in the control group (p < 0.05). The addition of hippotherapy to Schroth exercises resulted in improved pulmonary function and aerobic capacity in adolescents with idiopathic scoliosis.


A review of studies of the socio-familial backgrounds and educational facilities of the homes of moderately educationally subnormal children.
A search of the literature indicates the paucity of information on the backgrounds of ESN(m) children, despite the important contribution made by the home to the cognitive development and educational achievement of the children. The information that is available tends to support the notion of a syndrome of familial moderate educational subnormality. Evidence from one investigation points to certain ethnic differences which may be important in any programme of intervention.


A gene cluster of the ochratoxin A biosynthetic genes inPenicillium.
A putative ochratoxin A (OTA) biosynthetic gene cluster inP. nordicum has been identified. The first part of the gene cluster is located on a DNA fragment of 10 kb in length and harbours three genes. A gene with high homology to an alkaline serine protease gene (accession number AY557343), which represents the upstream border of the cluster. Furthermore the fragment carries a large part (about 2 kb) of the 5' end of a polyketide synthase (otapksPN, accession number AY196315) and a complete non-ribosomal peptide synthetase (otanpsPN, accession number AY534879). The second part of the cluster is located on a 4.3 kb fragment that harbours three open reading frames (ORFs) encoding putative OTA biosynthetic proteins: one incomplete ORF at the 5' end of the fragment demonstrated homology to an organic anion transporter from rat kidneys (otatraPN). This transporter has been described to be responsible for the transport of toxic OTA out of the cell. One complete ORF of 951 nucleotides is also located on this fragment. This gene has limited homology to a chloroperoxidase fromGluconobacter oxidans. At the 3' end of this DNA fragment is an incomplete open reading frame of a potential nitrate transporter. The transcription of all putative OTA biosynthetic genes is increased under OTA conducive conditions. The expression kinetics of the genes resembles that of secondary metabolite biosynthetic genes, in which these genes are co-ordinately expressed during the late growth phase.PCR analysis demonstrated that the gene cluster is only present in the two ochratoxin A producingPenicillium species,P. verrucosum andP. nordicum. P. nalgiovense, a species occurring in the same habitat asP. nordicum carries inactive homologues of the genes. All other species proved to be negative for the genes. This was also true for OTA producing Aspergilli.


Spatiotemporal gait parameters in young individuals wearing an age simulation suit compared to healthy older individuals.
Aging is accompanied by changes in muscle mass, strength and loss of sensory, visual and auditive functions. However, these changes do not occur linearly, most spatiotemporal gait parameters change with aging. Age simulation suits have been invented to give young people an impression of the implications of being older and may be a useful tool in the scientific setting for gerontology research to validate any study concept before it becomes a pilot study. The rationale behind this study was to investigate the effects of an age simulation suit on gait parameters in young healthy adults and to compare the altered gait with healthy older, community-dwelling citizens. Subjects were 14 healthy young adults (6 female) and 8 healthy older (4 female) individuals with a mean (± SD) age of 24.8 ± 3.4 years and 72 ± 1.9 years, respectively. After initial baseline measurements had been taken and a familiarization phase, the younger subjects walked for 15 min without and 15 min with an age simulation suit on an instrumented treadmill. The older subjects walked once for 15 min on the same treadmill without wearing an age simulation suit. The walking speed was self-selected for all subjects. The age simulation suit reduced the walking speed from 4.1 ± 0.7 km/h to 3.3 ± 0.5 km/h (p < 0.001) in young adults with no differences compared to older adults (2.9 ± 0.6 km/h, p = 0.9). Step width increased from 8.7 ± 2.2 cm to 12.1 ± 2.2 cm (p < 0.001) and did not differ from older participants (11.1 ± 4.3 cm, p = 0.37). The stride length was reduced (132.6 ± 5.9 cm vs 118.1 +-6.6 cm, p < 0.001), but still did not match the old control group (94.5 ± 5.6 cm, p < 0.05). Wearing the suit increased thestride time of young subjects (from 1,152 to 1,316 ms, p < 0.001) and was different compared to the older control group (1,172 ms, p = 0.53). The coefficient of variation (COV) of spatiotemporal parameters did not differ between young (both not wearing the suit and wearing the suit) and older subjects. The standard deviation of lateral symmetry, an in-house marker from the instrumented treadmill that serves as a marker of gait variability, differed between young subjects without the suit and older subjects (5.89 ± 1.9 mm vs 14.6 ± 5.7 mm, p < 0.001) but not between young subjects wearing the suit and older subjects (16.4 ± 7.4 mm vs 14.6 ± 5.7 mm, p = 0.53). Wearing an age simulation suit while walking on a treadmill with a self-selected walking speed alters some, but not all, measured spatiotemporal parameters to approximate a gait pattern similar to that of an older individual.


Anthranilic acid based CCK1 antagonists: the 2-indole moiety may represent a "needle" according to the recent homonymous concept.
Recently we described an innovative class of non-peptide CCK(1) antagonists keeping appropriate pharmacophoric groups on the anthranilic acid employed as a molecular scaffold. The lead compound obtained, VL-0395, characterized by the presence of Phe and the 2-indole moiety at the C- and N-termini of anthranilic acid, respectively, is endowed with submicromolar affinity towards CCK(1) receptors. Thus, we have prepared and tested on CCK receptors a library of VL-0395 analogues in order to investigate the precise topological and essential key interactions of the 2-indole group of the lead with the CCK(1) receptor. The obtained results confirm that this group establishes very specific interactions with this receptor sub-site and may be viewed as a "needle" group.


Microsporidial keratitis: Literature review and report of 2 cases in a tertiary eye care center.
Microsporidia are getting more recognized as causative organism of ocular, gastrointestinal, renal, pulmonary, and sinus diseases, in both immunocompetent and immunosuppressed patients. Ocular microsporidiosis can be isolated or may present as part of systemic infection. Recent reports showed increasing number of cases of ocular microsporidiosis in immunocompetent individuals. The ocular type occurs mainly in two forms: keratoconjunctivitis form which is mostly seen in immunocompromised individuals and stromal keratitis form seen in immunocompetent individuals. The ocular cases which present with superficial keratitis in acquired immune deficiency syndrome (AIDS) patients differ from the cases seen in immunocompetent individuals which present mainly as deep stromal keratitis. We are presenting the only two documented cases of microsporidial keratitis diagnosed over 25 years of practice in our institution. The cases are diagnosed by identification of the Acid-fast organisms. Ultrastructure and additional information on species identification in one of the cases. Both cases are eventually managed by therapeutic PKP. Diagnosis and treatment modalities are discussed based on a comprehensive literature review.


Rebaudioside F, a diterpene glycoside from Stevia rebaudiana.
The sweet diterpenoid glycoside, rebaudioside F, was isolated from leaves of a high rebaudioside C producing line of Stevia rebaudiana, and its structure was established by chemical and spectral studies.


Prevalence and Characteristics of Persistent Postoperative Pain After Thoracic Surgery: A Systematic Review and Meta-Analysis.
A systematic review and meta-analysis was conducted to investigate the prevalence and characteristics of persistent (≥3 months) postoperative pain (PPP) after thoracic surgery. For this purpose, Medline, Embase, and CINAHL databases were searched for the prevalence and characteristics of PPP after thoracic surgery from their inception to May 1, 2022. Random-effect meta-analysis was used to estimate pooled prevalence and characteristics. We included 90 studies with 19,001 patients. At a median follow-up of 12 months, the pooled overall prevalence of PPP after thoracic surgery was 38.1% (95% confidence interval [CI], 34.1-42.3). Among patients with PPP, 40.6% (95% CI, 34.4-47.2) and 10.1% (95% CI, 6.8-14.8) experienced moderate-to-severe (rating scale ≥4/10) and severe (rating scale ≥7/10) PPP, respectively. Overall, 56.5% (95% CI, 44.3-67.9) of patients with PPP required opioid analgesic use, and 33.0% (95% CI, 22.5-44.3) showed a neuropathic component. One in 3 thoracic surgery patients developed PPP. There is a need for adequate pain treatment and follow-up in patients undergoing thoracic surgery.


Genetic variants of immune-related genes IL17F and IL10 are associated with functional dyspepsia: A case-control study.
Low-grade inflammation may play an important role in pathogenesis of functional dyspepsia (FD). Since cytokines may influence gastric mucosal inflammation, which is associated with FD, we evaluated singe nucleotide polymorphisms (SNPs) of pro-inflammatory IL17F and anti-inflammatory IL10 cytokine genes in patients with FD and healthy subjects (HS). Two hundred and thirty-seven consecutive patients with FD (Rome III) and 250 HS were genotyped for IL17F (rs2397084: A/G, rs763780: T/C) and IL10 (rs1800896: G/A, rs1800871: C/T) (PCR-RFLP). Patients with FD [173 (73%) men, age 38.4±12 years] were comparable with HS [195 (78%) men, age 37.3±12 years] with respect to age and gender. Out of 237 patients, 26 (11%) had epigastric pain, 55 (23.2%) had post-prandial distress syndromes (EPS, PDS), and 156 (65.8%) had EPS-PDS overlap. Among 237 patients with FD, GG (variant) genotype of IL17F (rs2397084) was more common than HS [15 (6.3%) vs. 4 (1.6%), p=0.015, odds ratio (OR)=4.0, 95% confidence interval (CI)=1.3-12.3]. IL17F (rs763780) and IL10 (rs1800896) were comparable among patients and HS (p=0.56, 0.28), respectively. However, TT (variant) genotype of IL10 (rs1800871) was more common among patients than HS [39 (16.5%) vs. 32 (12.8%), p=0.06, OR=1.7, 95% CI=0.98-2.98]. SNPs of IL17F and IL10 (rs2397084, rs763780, rs1800896 and rs1800871) were comparable among patients among sub-types of FD (p=0.80 and 0.44). SNPs of IL17F (rs2397084) and IL10 (rs1800871) genes are associated with FD.


Monkeypox associated myocarditis: A case report.
Monkeypox is a zoonotic Orthopoxvirus infection usually present in regions of Africa. Recent outbreaks of Monkeypox infection have been reported in non endemic region and human-to-human contact is believed to be the main driver for propagation. While the disease is usually self-contained, severe complications, such as neurological and ocular involvements may arise. We report the case of a 34-year-old male who presented with myocarditis and concurrent genital Monkeypox infection. Other usual causes of myocardial injury were ruled out. We believe it to be the first documented case of myocarditis secondary to Monkeypox. We report a new complication of the disease and the possible underlying mechanisms. Our case report raises awareness about possible unknown complications of Monkeypox as outbreaks continue to happen around the world.


Ovarian tumours in children--a review of 40 cases.
The records of 40 children treated for ovarian tumours in Manchester since 1940 are reviewed. The series includes 12 dysgerminomas, nine endodermal sinus tumours, six malignant teratomas, three granulosa theca cell tumours, one Sertoli-Leydig cell tumour, one mixed chorioncarcinoma/dysgerminoma and eight cases of non-germ cell or uncertain origin. Presenting features and treatment are discussed. Survival is generally poor apart from the dysgerminomas, granulosa theca and Sertoli-Leydig cell tumours, all but one of whom are alive and disease free. The need for routine post-operative radiotherapy in cases in dysgerminoma confined to one ovary following total resection is questioned. Combination chemotherapy may improve survival in the future, particularly of children with endodermal sinus tumour. The only surviving child other than those mentioned above has had combination chemotherapy for an endodermal sinus tumour.


The protease SENP2 controls hepatic gluconeogenesis by regulating the SUMOylation of the fuel sensor AMPKα.
Uncontrolled gluconeogenesis results in elevated hepatic glucose production in type 2 diabetes (T2D). The small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is known to catalyze deSUMOylation of target proteins, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic gluconeogenesis and the occurrence of T2D remain unknown. Herein, we established SENP2 hepatic knockout mice and found that SENP2 deficiency could protect against high-fat diet-induced hyperglycemia. Pyruvate- or glucagon-induced elevation in blood glucose was attenuated by disruption of SENP2 expression, whereas overexpression of SENP2 in the liver facilitated high-fat diet-induced hyperglycemia. Using an in vitro assay, we showed that SENP2 regulated hepatic glucose production. Mechanistically, the effects of SENP2 on gluconeogenesis were found to be mediated by the cellular fuel sensor kinase, 5'-AMP-activated protein kinase alpha (AMPKα), which is a negative regulator of gluconeogenesis. SENP2 interacted with and deSUMOylated AMPKα, thereby promoting its ubiquitination and reducing its protein stability. Inhibition of AMPKα kinase activity dramatically reversed impaired hepatic gluconeogenesis and reduced blood glucose levels in SENP2-deficient mice. Our study highlights the novel role of hepatic SENP2 in regulating gluconeogenesis and furthers our understanding of the pathogenesis of T2D.


Potential antineoplastics. 4th communication: N-mustard derivatives of estrone).
The nitrogen mustards 5 and 9 are synthesized as potential mammatropic antineoplastic agents from estrone via 2--4 or 6--8, respectively. 5 and 9 show a binding affinity to the cytoplasmic estrogen receptor of the rat uterus of 1--10% compared to that of estrone. Both mustard compounds are irreversibly bound to the estrogen receptor.


Factors associated with mortality in patients with extremity necrotizing soft-tissue infections: a single academic center experience.
Necrotizing soft-tissue infection (NSTI) is a surgical emergency associated with high mortality. This study primarily aimed to identify the factors associated with in-hospital mortality due to NSTI in the extremities at a single institution. Secondarily, we aimed to clarify the effectiveness of the optimal combination of hyperbaric oxygen therapy (HBOT) and surgery for NSTI treatment. Retrospective observational study. This study included all patients newly diagnosed with NSTI in the extremity from 2003 to 2021 in our hospital. Factors associated with mortality, including patient's characteristics, duration from onset to hospitalization, NSTI type, and clinical data at the initial visit; acute disseminated intravascular coagulation (DIC), laboratory risk indicator for necrotizing fasciitis score, and sequential organ failure assessment score; treatment, initial surgery, surgery times, amputation, HBOT, combined surgery with HBOT, and clinical outcomes; amputation rate, mortality rate, and hospitalization duration were examined. A total of 37 cases were treated for NSTIs. The median age was 64 years (range: 22-86). Five cases (13.5%) died during hospitalization. Ten patients were diagnosed with DIC at the initial visit, of whom four died. HBOT combined with surgery was performed in 23 cases, and 16 cases underwent multiple surgeries. Factors associated with mortality included DIC (p = 0.015, 95% confidence interval [CI]: 0.015-0.633) and multiple surgeries combined with HBOT (p = 0.028, 95% CI: 1.302-95.418). This study demonstrates that DIC at the initial visit is associated with mortality in extremity NSTI. Additionally, HBOT might improve prognosis when combined with multiple surgeries.


Integrative processing of vibratory information in cat dorsal column nuclei neurones driven by identified sensory fibres.
1. In decerebrate or anaesthetized cats, the vibration-induced responses of dorsal column nuclei neurones were examined, first, when their input came from simultaneously recorded pairs or other combinations of identified Pacinian corpuscle (P.c.) afferent fibres of the interosseous nerve, and secondly, when different convergent sets of P.c. fibres were engaged by footpad vibration. 2. Suprathreshold actions were observed on individual dorsal column nuclei neurones from two or more identified P.c. fibres. Recruitment of these convergent fibres usually led to summation in the dorsal column nuclei neurone as reflected in higher response levels compared with those evoked by single-fibre inputs. 3. When the input was increased from one to two or more identified P.c. fibres the dorsal column nuclei neurones could retain a single, dominant phase of response to high-frequency (greater than 100 Hz) vibration even though these fibres, in isolation, evoked responses in the target neurone at substantially different latencies. However, on average, phase locking was significantly tighter in response to single-fibre input than to multiple P.c.-fibre input. 4. Dorsal column nuclei neurones were also able to retain phase-locked responses to high-frequency vibration when phase differences between different convergent inputs were systematically introduced to alter the degree of synchrony in the activity arriving over convergent, identified P.c. fibres. 5. When the input to dorsal column nuclei neurones came from the skin it was found that with the recruitment of two converging sets of P.c. fibres the dorsal column nuclei neurones were able to retain phase-locked responses to high-frequency vibration even when phase shifts were introduced between the two sets of P.c. inputs. 6. In conclusion, the observed integrative processing by dorsal column nuclei neurones of vibration-induced inputs arriving over identified, convergent P.c. fibres, or sets of P.c. fibres, is consistent with our hypothesis that the retention of phase-locked responses to vibration at frequencies greater than or equal to 100 Hz may reflect the functional domination of the target neurone by just one or a few of its convergent input fibres.


Highly selective red- and green-emitting two-photon fluorescent probes for cysteine detection and their bio-imaging in living cells.
Two highly selective two-photon fluorescent probes for cysteine over homocysteine, N-acetyl-L-cysteine, dithiothreitol, glutathione and other amino acids, and their fluorescent imaging in living cells have been shown.


Disseminated cryptococcal infection in a patient who had kidney transplant: discrepancy between clinical symptoms and microbiological findings.
A 29-year-old man complained of a 2-day history of frontal headache and new-onset fever but no other symptoms. Two months prior to admission, he underwent his third kidney transplantation. Clinical and laboratory examinations were unremarkable. Brain MRI showed a meningeal irritation consistent with viral meningitis. A diagnosis of cryptococcal meningitis and fungaemia was made after detection of a remarkably high and visible load of Cryptococcus neoformans in the cerebrospinal fluid.


The effects of 12 weeks of HMR 3339, a novel selective estrogen receptor modulator, on markers of coagulation and fibrinolysis: a randomized, placebo-controlled, double-blind, dose-ranging study in healthy postmenopausal women.
To investigate the short-term effects of HMR 3339, a novel selective estrogen receptor modulator, on markers of coagulation and fibrinolysis. In a multicenter, 14-week, randomized, placebo-controlled, double-blind, dose-ranging study, healthy postmenopausal women received daily placebo (n = 22), HMR 3339 2.5 mg (n = 25), HMR 3339 10 mg (n = 24), HMR 3339 50 mg (n = 24), or raloxifene 60 mg (n = 23). Statistical analysis was performed using standard parametric tests. After 12 weeks, compared with placebo, HMR 3339 50 mg induced the largest mean percentage changes in antithrombin (-14.6%, P < .001), protein C (-12.9%, P = .029), and fibrinogen (-26.3%, P = .001). Decreases were observed in the HMR 3339 2.5 mg group, compared with placebo, in tissue-type plasminogen activator (-55.0%, P = .026 after 4 weeks), plasmin-alpha2-antiplasmin complex (-85%, P = .031 and -63.3%, P = .008, respectively, after 4 and 12 weeks), and D-dimer (-91.4%, P = .018 after 12 weeks). Compared with placebo, raloxifene 60 mg decreased total protein S (-8.2%, P = .009) after 4 weeks and antithrombin (-6.0%, P = .034) and fibrinogen (-18.1%, P = .007) after 12 weeks. HMR 3339 and raloxifene decreased fibrinogen levels. In the low dosage, HMR 3339 showed potentially beneficial effects on some markers of fibrinolysis. Both drugs impaired the anticoagulatory potential.


Large-scale and tunable transparent displays based on silver nanoparticles metasurface.
We report a transparent display based on a metasurface of silver nanoparticles (Ag NPs), consisting of a transparent substrate and a layer of Ag NPs deposited by a dielectric film. The Ag NPs metasurface is prepared by a simple and direct annealing process. It presents a deep transmission valley at the wavelength ofλ= 468 nm and enables desired transparent display by projecting the monochromatic image onto the metasurface. We also demonstrate that the formed Ag NPs can be approximated as truncated nanospheres, which have obvious directional scattering properties, and can radiate most of the scattered energy into the backward hemisphere with a relatively large angular beamwidth (the full width at half maximum of the scattered intensity) of ∼90°. Therefore, the fabricated displays possess wide viewing angles and high brightness characteristics. Additionally, the transmission modes can be red-shifted to the wavelength ofλ= 527 nm by controlling the thickness of the deposited dielectric film. This approach using traditional thin film deposition and moderate annealing processing techniques enables simple, low-cost, and scalable fabrication in large areas for transparent displays.


The localization of a histamine H2-receptor adenylate cyclase system in canine parietal cells and its inhibition by prostaglandins.
A method is described for the preparation of parietal cell-enriched suspensions from dog gastric mucosa. Histamine and E type prostaglandins produce an elevation of cyclic AMP concentration in mixed cell preparations. Parietal cell-rich fractions respond to histamine but only weakly to prostaglandins whilst in fractions virtually free from parietal cells the converse is observed. Prostaglandins which are good antisecretory agents, PGE1, PGE2 and 16,16 dimethyl PGE2 are potent inhibitors of the histamine elevations of cyclic AMP in parietal cell-rich fractions, whilst PFG2alpha shows 1% of their potency. The experiments described support the view that histamine stimulates gastric acid secretion by excitation of an H2-receptor adenylate cyclase system in the plasma membrane of the parietal cell and that acid secretory inhibition by prostaglandins is a result of inhibition of that system.


The management of ovarian cysts by sono-guided transvaginal cyst aspiration.
Nineteen transvaginal, sono-guided ovarian cyst punctures were performed in 18 patients. These patients, who were high surgical risks, were diagnosed to possess benign ovarian tumors as revealed with sonography. Aspiration curettage of the inner surface of the cyst present during aspiration was also performed to facilitate cytologic diagnosis. The recurrence rate was 11.1%. Sono-guided transvaginal cyst aspiration has been demonstrated here to be the treatment of choice for dealing with an ovarian cyst in patients at high surgical risk.


The role of gastric mucosal dysplasia in the development of gastric carcinoma.
It is widely acknowledged that most stomach carcinomas developed from dysplastic lesions of gastric mucosa. They can be found in known precancerous conditions as chronic gastritis, gastric adenoma, giant rugal hypertrophy, chronic peptic ulcer, gastric stump after partial resection and pernicious anemia. Several grading systems of gastric dysplasia have been suggested. Nagayo's or the ISGGC classification was applied to 367 biopsy specimens of 258 patients between 1979-1995. The frequency of moderate and severe dysplasia was 0,84% regarding all gastric endoscopies in the same period of time. Follow-up studies were performed in 56 cases in a period of 1 7 ys. In this group cancer developed during 14 patients. The authors' recommendation is to follow up the patients gastric dysplasia for least 10 ys after with diagnosis.


Feeder-layer free culture system for human embryonic stem cells.
Human embryonic stem cells (hESCs) are pluripotent stem cells derived from the inner cell mass of the blastocyst. Due to their unique properties, hESCs might be used for research fields such as self-renewal, specific lineage differentiation, human developmental biology, and teratology. hESCs also have outstanding potential to serve for clinical purposes as a source for cell-based therapies. Traditionally, these cells are cultured and derived with mouse embryonic fibroblast as supportive layer, using a medium supplemented with fetal bovine serum. Future industrial and clinical implementation of hESCs will require the use of a defined medium and an animal-free culture method that will prevent their possible exposure to animal pathogens. This chapter discusses the advancements in the development of methods for the defined culture of hESCs and describes a simple method for animals serum-free and feeder layer-free culture of hESCs.


The association between pre-gravid and first trimester maternal weight and its implications for clinical research studies.
In clinical research, weight measurement in first trimester is often treated as a surrogate for pre-pregnancy weight. The validity of this critical assumption, however, is uncertain. Thus, we sought to prospectively evaluate the relationship between pre-gravid weight and first trimester weight. In this prospective preconception observational cohort study, 474 newly-married women in Liuyang, China, underwent pre-gravid evaluation at median 17.7 weeks before a singleton pregnancy, during which they had weight measurement in first trimester. The relationship between pre-gravid and first trimester weight was assessed by Bland-Altman analysis, Concordance Correlation Coefficient, and Pearson correlation. Mean pre-gravid weight was 49.8 ± 6.4 kg and mean weight in first trimester was 51.1 ± 7.0 kg. The Concordance Correlation Coefficient between pre-gravid and first trimester weight was 0.76 (95% limits of agreement: 0.72-0.80) and Pearson correlation was r = 0.78 (p < 0.0001), indicative of good concordance and correlation. As the timing of the weight measurement in first trimester increased in weekly increments from < 8 weeks to 14 weeks, the Concordance Correlation Coefficient ranged between 0.69 to 0.76 and the Pearson correlation ranged from 0.71 to 0.78 (all p < 0.0001). In conclusion, the observed concordance between pre-gravid weight and weight measured at any point in the first trimester provides a measure of validation for the widespread practice in clinical research of treating first trimester weight measurement as a surrogate for maternal weight before pregnancy.


A novel CCBE1 mutation leading to a mild form of hennekam syndrome: case report and review of the literature.
Mutations in CCBE1 have been found to be responsible for a subset of families with autosomal recessive Hennekam syndrome. Hennekam syndrome is defined as the combination of generalized lymphatic dysplasia (ie. lymphedema and lymphangiectasia), variable intellectual disability and characteristic dysmorphic features. The patient we describe here has a lymphatic dysplasia without intellectual disability or dysmorphism caused by mutation in CCBE1, highlighting the phenotypic variability that can be seen with abnormalities in this gene. Our patient is a 5 week old child of Pakistani descent who presented to our center with generalized edema, ascites, and hypoalbuminemia. She was diagnosed with a protein losing enteropathy secondary to segmental primary intestinal lymphangiectasia. As the generalized edema resolved, it became clear that she had mild persistent lymphedema in her hands and feet. No other abnormalities were noted on examination and development was unremarkable at 27 months of age. Given the suspected genetic etiology and the consanguinity in the family, we used a combination of SNP genotyping and exome sequencing to identify the underlying cause of her disease. We identified several large stretches of homozygosity in the patient that allowed us to sort the variants found in the patient's exome to identify p.C98W in CCBE1 as the likely pathogenic variant. CCBE1 mutation analysis should be considered in all patients with unexplained lymphatic dysplasia even without the other features of classic Hennekam syndrome.


Inhibition by digoxin and SC4453 of (Na+ + K+)-ATPase prepared from human heart, guinea-pig heart and guinea-pig brain.
SC4453 is a digoxin analogue with a pyridazine instead of a lactone ring on C17 beta. SC4453 was compared with digoxin with respect to inhibition of (Na+ + K+)-ATPase prepared from human heart, guinea-pig heart and guinea-pig brain. SC4453 was slightly less potent than digoxin but showed a similar sensitivity to K+. As for cardenolides, species differences in sensitivity to SC4453 were accounted for by differences in the rate of dissociation from the receptors. These observations confirm that the human heart is one of the tissues most sensitive to cardiac glycosides.


Transmission of Chlamydia and genital warts during sleepwalking.
A boy aged 15 years infected a girl of 13 years with Chlamydia and genital warts. The boy has been engaged in sexual activities for the last four years. There was no dispute that the boy had had sex with the girl. He was prosecuted but acquitted by the Court on the ground of 'defence of sleepwalking'. This is the first case where sexually transmitted infections like Chlamydia and genital warts have been transmitted sexually through sleepwalking. This case also raises the issues of underage sex and issues of confidentiality.


Identification of quantitative trait loci for related traits of stalk lodging resistance using genome-wide association studies in maize (Zea mays L.).
Stalk lodging is one of the main factors affecting maize (Zea mays L.) yield and limiting mechanized harvesting. Developing maize varieties with high stalk lodging resistance requires exploring the genetic basis of lodging resistance-associated agronomic traits. Stalk strength is an important indicator to evaluate maize lodging and can be evaluated by measuring stalk rind penetrometer resistance (RPR) and stalk buckling strength (SBS). Along with morphological traits of the stalk for the third internodes length (TIL), fourth internode length (FIL), third internode diameter (TID), and the fourth internode diameter (FID) traits are associated with stalk lodging resistance. In this study, a natural population containing 248 diverse maize inbred lines genotyped with 83,057 single nucleotide polymorphism (SNP) markers was used for genome-wide association study (GWAS) for six stalk lodging resistance-related traits. The heritability of all traits ranged from 0.59 to 0.72 in the association mapping panel. A total of 85 significant SNPs were identified for the association mapping panel using best linear unbiased prediction (BLUP) values of all traits. Additionally, five candidate genes were associated with stalk strength traits, which were either directly or indirectly associated with cell wall components. These findings contribute to our understanding of the genetic basis of maize stalk lodging and provide valuable theoretical guidance for lodging resistance in maize breeding in the future.


Driving ability in cancer patients receiving long-term morphine analgesia.
When given in single doses to healthy volunteers, opioid analgesics impair reaction time, muscle coordination, attention, and short-term memory sufficiently to affect driving and other skilled activities. Despite the increasing use of oral morphine daily, little is known about the effect of long-term opioid therapy on psychomotor performance. To examine the effects of continuous morphine medication, psychological and neurological tests originally designed for professional motor vehicle drivers were conducted in two groups of cancer patients who were similar apart from experience of pain. 24 were on continuous morphine (mean 209 mg oral morphine daily) for cancer pain; and 25 were pain-free without regular analgesics. Though the results were a little worse in the patients taking morphine, there were no significant differences between the groups in intelligence, vigilance, concentration, fluency of motor reactions, or division of attention. Of the neural function tests, reaction times (auditory, visual, associative), thermal discrimination, and body sway with eyes open were similar in the two groups; only balancing ability with closed eyes was worse in the morphine group. These results indicate that, in cancer patients receiving long-term morphine treatment with stable doses, morphine has only a slight and selective effect on functions related to driving.


Regression of gadolinium-enhanced lesions in patients affected by neurofibromatosis type 1.
Neurofibromatosis type I is a genetic condition with an autosomal dominant transmission characterized by neurocutaneous involvement and a predisposition to tumor development. Central nervous system manifestations include benign areas of dysmyelination and possibly hazardous glial tumors whose clinical management may result challenging. Here, we report on three patients diagnosed with Neurofibromatosis type I whose brain MRI follow-up showed the presence of gadolinium-enhancing lesions which spontaneously regressed. In none of the three cases, the lesions showed any clinical correlate and eventually presented a striking reduction in size while gadolinium enhancement disappeared despite no specific therapy administration during the follow-up. Although their nature remains undetermined, these lesions presented a benign evolution. However, they might be misdiagnosed as potentially life-threatening tumors. Hitherto, a similar behavior has been described only in scattered cases and we believe these findings may be of particular interest for the clinical management of patients affected by neurofibromatosis type I.