Kinetic studies of the form of substrate bound by phosphoenolpyruvate carboxylase.
Phosphoenolpyruvate carboxylase isolated from maize (Zea mays L.) leaves was assayed with varying concentrations of free phosphoenolpyruvate at several fixed-varying concentrations of free magnesium higher than required to saturate the enzyme reaction. These assays produced velocity data which were found to form a family of individual lines when plotted against free phosphoenolpyruvate or against total phosphoenolpyruvate, but not when plotted against the concentration of the complex of phosphoenolpyruvate with magnesium. In this latter case, the points from all the fixed-varying concentrations fell on the same line, which can be fitted to a modified Michaelis-Menten equation with a multiple correlation coefficient R(2) = 0.995. Similar results were obtained when the enzyme from the C(4) plant maize was assayed with manganese rather than magnesium and when phosphoenolpyruvate carboxylase from leaves of the C(3) plant wheat (Triticum vulgare Vill.) was assayed with magnesium. However, at pH 7.0 the enzyme from the Crassulacean acid metabolism plant Crassula argentea did not produce a satisfactory single line when plotted against the complex of metal ion and substrate, but did so when the assay pH was raised to 8.0. It is concluded that in general the preferred form of substrate for phosphoenolpyruvate carboxylase is the complex of phosphoenolpyruvate with the metal ion.


Anesthetic-induced preconditioning: previous administration of isoflurane decreases myocardial infarct size in rabbits.
Experimental evidence suggests that ATP-sensitive potassium channels are involved in myocardial ischemic preconditioning. Because some pharmacologic effects of isoflurane are mediated by K(ATP) channels, the authors tested the hypothesis: Isoflurane administration, before myocardial ischemia, can induce or mimic myocardial preconditioning. Myocardial infarct size was measured in three groups of propofol-anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed in their pretreatment: Group 1 (control, N = 13) no pretreatment, Group 2 (ischemic preconditioning, N = 8), 5 min of coronary occlusion and 15 min of reperfusion; Group 3 (isoflurane pretreatment; N = 15), 15 min of isoflurane (1.1% end-tidal) and 15 min of washout. Hemodynamics were monitored serially. Myocardial infarct size and the area at risk were defined using triphenyltetrazolium chloride staining and fluorescent microspheres, respectively, and both were measured using computerized planimetry. Infarct size expressed as a percentage of area at risk was 23.4 +/- 8.5% (mean +/- SD) in the isoflurane group compared with 33.1 +/- 13.3% in controls, and 8.7 +/- 6.2% in the ischemia-preconditioned group. Analysis for coincidental regressions, followed by tests for equality of slope and elevation, showed that the linear relationship between infarct size and area at risk was significantly (P < 0.05) different in all three groups because of differences in line elevation. Minor differences in hemodynamic variables were found between groups, which were unlikely to account for the significant differences in infarct size. Preadministration of isoflurane, before myocardial ischemia, reduces myocardial infarct size, and mimics myocardial preconditioning.


The relevance of MRI blood-sensitive sequences in the diagnostic assessment of late-onset epilepsy.
Sporadic cerebral amyloid angiopathy (CAA) is a degenerative brain small vessel disease of ageing resulting from progressive amyloid deposition in small arteries and arterioles of the cortex and leptomeninges. CAA may be diagnosed by the mean of Boston criteria, particularly with the use of the blood-sensitive T2* MRI sequences (GRE and SWI). Epileptic seizures have rarely been reported in CAA. We describe two patients with late-onset unprovoked seizures due to CAA. A short literature review on this topic is presented. In our two patients with late-onset unprovoked seizures as the first manifestation of CAA, only GRE and SWI sequences lead to a correct diagnosis. In literature, only 15 patients with CAA presenting with seizures have been reported. In these subjects, data on seizures semiology and prognosis are scarce. Our report highlights the importance to perform blood-sensitive sequences in all subjects with LOE of otherwise unknown etiology, not to miss a diagnosis of CAA.


A Model Approach: Mathematical modeling provides an increasingly clear picture of glucose and neural systems.
Mathematical modeling of physiological systems is a fundamental milestone of biomedical engineering. Models allow for the quantitative understanding of the intimate functions of a biological system, estimating parameters that are not accessible to direct measurement and performing in silico trials by simulating and tracking a physiological system in case its function has been deranged. Modeling has always been central in the Italian biomedical engineering community. Here, we review the progress in two areas: glucose and neurocomputational modeling with an emphasis on their clinical impact.


Rapid eye movement sleep behavior disorder: a window on the emotional world of Parkinson disease.
REM sleep behavior disorder (RBD) is a parasomnia characterized by motor activity during sleep with dream mentation. Aggressiveness has been considered a peculiar feature of dreams associated with RBD, despite normal score in aggressiveness scales during wakefulness. We aimed to measure daytime aggressiveness and analyze dream contents in a population of patients with Parkinson disease (PD) with and without RBD. This is a single-center prospective observational study; it concerns the description of the clinical features of a medical disorder in a case series. The study was performed in the Department of Neurosciences of the Catholic University in Rome, Italy. Three groups of subjects were enrolled: patients with PD plus RBD, patients with PD without RBD, and healthy controls. The diagnosis of RBD was determined clinically and confirmed by means of overnight, laboratory-based video-polysomnography. For the evaluation of diurnal aggressiveness, the Buss-Perry Aggression Questionnaire (BPAQ) was used. The content of dreams was evaluated by means of the methods of Hall and Van De Castle. Patients with PD without RBD displayed higher levels of anger, and verbal and physical aggressiveness than patients with PD and RBD and controls. Patients with PD and RBD and controls did not differ in hostility. It can be hypothesized that a noradrenergic impairment at the level of the locus coeruleus could, at the same time, explain the presence of RBD, as well as the reduction of diurnal aggressiveness. This finding also suggests a role for REM sleep in regulating homeostasis of emotional brain function.


Preparedness Education in the Baccalaureate Nursing Curriculum: An Authentic Clinical Experience.
Healthy People 2020 supports the preparation of nurse graduates to assess emergency preparedness needs of defined populations and includes preparedness as one of its objectives. Natural disaster preparedness is addressed through the lens of community-centered care that meets the Quality and Safety Education for Nurses domains of patient-centered care and teamwork and collaboration. This article discusses the development of an authentic clinical experience through collaboration between the American Red Cross and a baccalaureate nursing program.


The association of age and time postinjury with long-term emotional outcome following traumatic brain injury.
To examine the effect of age and time postinjury on emotional distress, 5 to 22 years following traumatic brain injury (TBI). One hundred twelve participants with mild to very severe TBI, aged 16 to 81 years at the time of injury, and 112 healthy controls matched for current age, gender, education, and estimated IQ. The Hospital Anxiety and Depression Scale (HADS). The difference in HADS scores between participants with TBI and controls did not vary according to the separate variables of age at injury or time postinjury. There was an interaction between age at injury and time postinjury whereby the youngest group demonstrated higher HADS scores with longer time postinjury, whereas the older groups displayed lower HADS scores with longer time postinjury, relative to controls. Long-term emotional outcome following TBI is related to the combined influence of age and time postinjury. Higher levels of emotional distress, evident at longer time postinjury in younger individuals, are particularly concerning and warrant attention from clinicians.


[The role of amylase in abdominal fluid in evaluating severity of acute pancreatitis and its prognosis].
Acute pancreatitis (AP) was induced on 22 cats, by injecting the mixture of bile and trypsin at different doses into the main pancreatic duct (MPD). In Group A, 7 cats revealed pancreatic interstitial edema after the injection of the mixture at 0.8 mg/kg. In Group B, 8 cats received the injection of the MPD at 1.0 mg/kg which resulted in significant extensive necrosis of the pancreas. The same pathological change was found in Group C (7 cats), combined with lesions of the lung and the liver. The survival time was different, more than 7 days in Group A, 50.4 hours in Group B and 10.4 hours in Group C (P < 0.001). Amylase concentration also showed marked difference in different groups, 4,890 U/L in Group A; 13 952 U/L in Group B and 23,810 U/L (P < 0.001) in Group C. These results are directly proportional to the severity of AP, but inversely proportional to the survival time. It suggests that amylase concentration in abdominal fluid can be used as an important marker to evaluate the severity of AP and its prognosis.


Ethanol and adult CNS neurodamage: oxidative stress, but possibly not excitotoxicity.
Evidence from experiments with adult rodents chronically treated with ethanol via either repetitive binges or continuous intake/exposure supports the occurrence of brain oxidative stress and, at least in binge intoxication/rat models, its essential causative role in neurodamage. However, pharmacological antagonism experiments reveal that N-methyl-D-aspartate (NMDA) receptor-dependent excitotoxicity is not responsible for adult mammalian brain neurodegeneration caused by repetitive binge ethanol intoxication and withdrawals. Since NMDA receptor antagonists apparently are untested with respect to neuronal death/loss in continuous intake/ingestion rodent models, e.g., ethanol/water or ethanol/liquid diets, it is therefore erroneous to assert, as is often done, that excitotoxicity is an important mechanism for ethanol-induced adult mammalian brain damage. Alternatively, results from several laboratories indicate that neurodegeneration due to chronic binge ethanol exposure/withdrawal may be dependent on redox transcription factor signaling and neuroinflammatory/oxidative stress pathways (increased arachidonic acid mobilization and pro-inflammatory cytokines; decreased anti-inflammatory cytokines) downstream of microglial/astroglial activation and moderate yet significant brain edema.


Age effects on Norway spruce (Picea abies) susceptibility to ozone uptake: a novel approach relating stress avoidance to defense.
Cumulative ozone (O3) uptake and O3 flux were related to physiological, morphological and biochemical characteristics of Norway spruce (Picea abies (L.) Karst.) trees of different ages. Under ambient CO2 conditions, photosynthetic capacity (Amax) declined in mature trees when cumulative O3 uptake into needles, which provides a measure of effective O3 dose, exceeded 21 mmol m-2 of total needle surface area. A comparable decline in Amax of seedlings occurred when cumulative O(3) uptake was only 4.5 mmol m-2. The threshold O3 flux causing a significant decline in Amax ranged between 2.14 and 2.45 nmol m-2 s-1 in mature trees and seedlings subjected to exposure periods of > or = 70 and > or = 23 days, respectively. The greater O3 sensitivity of young trees compared with mature trees was associated with needle morphology. Biomass of a 100-needle sample increased significantly with tree age, whereas a negative correlation was found for specific leaf area, these changes parallel those observed during differentiation from shade-type to sun-type needles with tree ontogeny. Age-dependent changes in leaf morphology were related to changes in detoxification capacity, with area-based concentrations of ascorbate increasing during tree ontogeny. These findings indicate that the extent of O3-induced injury is related to the ratio of potentially available antioxidants to O3 influx. Because this ratio, when calculated for ascorbate, increased with tree age, we conclude that the ratio may serve as an empirical basis for characterizing age-related differences in tree responses to O3.


Quasi-retroreflection from corner cubes with refractive free-form surfaces.
Quasi-retroreflection from corner-cube structures with a refractive free-form surface is studied. It is shown that adjustment of the structural parameters of the free-form surface allows control of quasi-retroreflection. Quasi-retroreflection corner-cube array sheets with specified quasi-retroreflection angle are modeled, and their quasi-retroreflection characteristics are analyzed.


Abusive advertising of food and drink products on Brazilian television.
In Brazil, any advertising strategies that take advantage of the child's judgment or induce consumers to make harmful health choices are considered abusive. However, the efficacy of restrictions on their use on television (TV) food advertising remains poorly understood. This study analysed the extent and nature of abusive techniques according to national regulations and patterns in their use in food-related ads. Cross-sectional studyrecorded the programming of the three most popular TV channels (6 am-12 am), during eight non-consecutive days, in April 2018. Data collection was based on the INFORMAS protocol and two national regulations. Descriptive analyses were used to describe the types of food ads and abusive techniques used in ultra-processed products (UPP) ads. Principal component analysis was applied to identify patterns of abusive marketing techniques and to relate them to specific food groups. More than 90% of food ads included at least one UPP. Overall, 10.1% of UPP ads targeted children and 57.7% used some kind of abusive technique directed to children and adolescents. Most ads contained messages inducing harmful health choices did not present adequate and clear information about the product and contained more than one type of abusive technique. Four out of five patterns in the use of abusive techniques in UPP ads were specifically directed to children, and fast-food meals were associated with three out of five patterns. The high abusiveness of food advertising in UPP ads should be considered a public health concern given their impact on children's food choices and health.


Monitoring the survival of islet transplants by MRI using a novel technique for their automated detection and quantification.
There is a clinical need to be able to assess graft loss of transplanted pancreatic islets (PI) non-invasively with clear-cut quantification of islet survival. We tracked transplanted PI in diabetic mice during the early post-transplant period by magnetic resonance imaging (MRI) and quantified the islet loss using automatic segmentation technique. Magnetically labeled islet iso-, allo- and xenografts were injected into the right liver lobes. Animals underwent MRI scanning during 14 days after PI transplantation. MR images were processed using custom-made software, which automatically detects hypointense regions representing PI. It is based on morphological top-hat and bottom-hat transforms. Manually and automatically detected areas, corresponding to PI, differed by 4% in phantoms. Signal loss regions due to PI decreased comparably in all groups during the first week post transplant. Throughout the second week post-transplant, the signal loss area continued in a steep decline in case of allografts and xenografts, whereas the decline in case of isografts slowed down. Automatic segmentation allows for the more reproducible, objective assessment of transplanted PI. Quantification confirms the assumption that a significant number of islets are destroyed in the first week following transplantation irrespective of allografts, xenografts or isografts.


Factors Affecting Patient Decision-Making Regarding Midshaft Clavicle Fracture Treatment.
Introduction Midshaft clavicle fractures are a common problem encountered by orthopedic surgeons. There remains debate between non-surgical and surgical treatment options for certain midshaft clavicle fractures. Due to the lack of a clear treatment strategy, this presents an opportunity for shared decision-making, which has been shown to be important to patients. Methods A 19-question survey was created encompassing basic demographic information, then taking respondents through a simulation of a midshaft clavicle fracture patient encounter. Subjects were subsequently asked their preferred treatment choice as well as shared decision-making preferences for the simulated encounter. A pilot study was performed with medical students from our home institution to assess study sample size. The survey was then distributed through an online software platform (Amazon Mechanical Turk). Statistical analysis was performed using STATA, Microsoft Excel, and Qualtrics. Results 253 subjects responded to the online survey. Over 70% of respondents had no to minimal knowledge of clavicle fractures and potential medical interventions/treatments. 67.6% of respondents preferred shared decision-making, over autonomous or paternalistic models. 45.5% of respondents wanted additional time outside the physician-patient consultation before making a treatment decision. A majority of the respondents who selected surgery (44.3%; 43/97) and no surgery (69.9%; 109/156), based their decisions on outcomes data provided in the simulation alone. There was no statistically significant relationship between income, race/ethnicity, education level, work status, sex, or type of visual fracture representation (i.e., radiograph vs. cartoon image) and treatment decision (p>0.05). Younger age (p=0.007) and being married (p=0.001) were associated with increased likelihood to select surgery as the treatment decision. Conclusion Most respondents had no-to-minimal knowledge about clavicle fractures, placed a high value in shared decision-making for midshaft clavicle fractures, and prioritized outcomes data in making treatment decisions. Younger age and marital status may increase the likelihood of a patient selecting to proceed with surgery over non-operative treatment.


High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells.
There is a considerable lack of understanding about the common molecular defects that form the basis for the occurrence of Hodgkin's lymphoma. Despite a number of molecular tools used thus far in immunophenotypic and karyotypic studies, it has not been possible to establish a single common trait among various Hodgkin (H)-cell lines or primary tumor cells that would allow classification into a particular hematopoietic lineage. With this study, we demonstrate that a characteristic expression pattern of transcription factors provides a unifying principle. Seven different cell lines derived from patients with Hodgkin's disease (HD), as well as primary H/Reed-Sternberg (RS) cells isolated from the pericardial fluid of a patient with HD, were compared with a number of hematopoietic and nonhematopoietic cell lines for the expression of Oct-2, a tissue-specific transcription factor normally restricted to B cells, and nuclear factor kappa B (NF-kappa B), an inducible transcription factor. Regardless of the heterogeneous phenotypes and genotypes of the H cell lines, which varied inconsistently between B-cell-, T-cell-, or monocyte-like properties, all H cells tested displayed expression of Oct-2 protein at levels comparable to those seen in B cells. Furthermore, all cell lines showed an abundant constitutive nuclear NF-kappa B activity. Interestingly, anaplastic large-cell lymphoma (ALCL) cell lines, which have many features in common with H/RS cells, were devoid constitutive nuclear NF-kappa B activity. Unlike the constitutive NF-kappa B activity known for B cells, which mainly consists of the p50 and c-Rel or RelB subunits, we demonstrate by antibody supershifting experiments that H cells contain constitutive nuclear p50 and p65, the dimeric NF-kappa B normally observed only for limited time intervals after stimulation with diverse inducers. Additionally, some H-cell lines also displayed nuclear c-Rel activity, whereas RelB or p52 were not detected as part of the constitutive activity. The expression pattern of Oct-2 and NF-kappa B appears to be a unifying and characteristic property of H cells and might explain the deregulated expression of various cytokines leading to the clinical and pathologic manifestations of HD.


Antibacterial effect of acrylic dental devices after surface modification by fluorine and silver dual-ion implantation.
The purpose of the present study was to examine the effectiveness of fluorine and silver ions implanted and deposited into acrylic resin (poly(methyl methacrylate)) using a hybrid process of plasma-based ion implantation and deposition. The surface characteristics were evaluated by X-ray photoelectron spectroscopy (XPS), contact angle measurements, and atomic force microscopy. In addition, an antibacterial activity test was performed by the adenosine-5'-triphosphate luminescence method. XPS spectra of modified specimens revealed peaks due to fluoride and silver. The water contact angle increased significantly due to implantation and deposition of both fluorine and silver ions. In addition, the presence of fluorine and silver was found to inhibit bacterial growth. These results suggest that fluorine and silver dual-ion implantation and deposition can provide antibacterial properties to acrylic medical and dental devices.


How plausible is an Alzheimer's disease vaccine?
Introduction: Alzheimer's disease (AD) vaccination is one of the last therapeutic options after two decades of stagnation in terms of drug development. About 140 (85%) immunization procedures against Aβ deposition and 25 (15%) against Tau have been reported, but no Food and Drug Administration approval of any AD vaccine has been achieved. This might be attributed to deficient pathogenic targets, inappropriate models, defective immunotherapeutic procedures, and inadequate clinical trial design.Areas covered: The issues covered include the following: AD pathogenic mechanisms, rationale for active and passive immunization, vaccine targets, anti-Aβ/Tau vaccines, vaccine technologies, animal models, and clinical trials.Expert opinion: A vaccine against AD is technically feasible; however, important methodological aspects should be changed for a tentative clinical success, including (i) the development of multitarget AD immunotherapies; (ii) the optimization of antibody titers and epitopes; (iii) the pharmacogenetic/pharmacoepigenetic validation of the immunization procedure; (iv) the prophylactic treatment of genetically stratified patients at a pre-symptomatic stage; and (v) the definition of primary endpoints in prevention, based on objective/multifactorial biomarkers. Even with exquisite protocols, a successful vaccine would be potentially useful in at most 20-30% of defined cases, according to the genetic, epigenetic, and pharmacogenetic background of AD patients.


[Observation on therapeutic effect of acupuncture, moving cupping and blood-letting puncture on chloasma].
To compare therapeutic effects of acupuncture, moving cupping, blood-letting puncture and medicine on chloasma. One hundred and seventy-six cases of chloasma were randomly divided into two groups. The acupuncture, moving cupping, blood-letting puncture group was treated with acupuncture at Ashi points, Xuehai (SP 10), Sanyinjiao (SP 6), moving cup at The Governor Vessel and The Urinary Bladder Channel on the back and then blood-letting puncture at Dazhui (GV 14), Feishu (BL 13), Geshu (BL 17), Xinshu (BL 15), Ganshu (BL 18) and nearby more severe purple stasis regions, and the medication group was treated with oral administration of Vit E and Vit C. Their therapeutic effects were observed after 3 courses. The total effective rate was 96.7% in the acupuncture, moving cupping, blood-letting puncture group and 51.2% in the medication group with a significant difference between the two groups (P < 0.05). The therapeutic effect of acupuncture, moving cupping, blood-letting puncture on chloasma is better than that of the medicine.


Analysis of in situ EXAFS data of supported metal catalysts using the third and fourth cumulant.
X-Ray absorption spectra of supported Pt catalysts with various Pt cluster sizes were collected between 77 and 673 K, in inert and hydrogen atmospheres. When analyzing these spectra with the standard EXAFS equation, a Pt-Pt bond contraction and a large increase in the inner potential correction were observed with increasing temperature. These errors are up to 0.08 A and 10 eV for clusters of 1 nm diameter. They were corrected by including the third and fourth cumulants as fit parameters. Fit guidelines were developed to analyze EXAFS data of supported metal catalysts collected at elevated temperatures, allowing for asymmetry and broadening or sharpening of the pair distribution function. These comprise fixing fit parameters, using different k-weightings and identifying trends in a series of experiments. By fitting the EXAFS spectra using these guidelines, it was determined that in small Pt clusters the Pt-Pt bond is 0.10 A shorter than in bulk Pt. These contracted bonds relax to distances near that of bulk Pt upon hydrogen chemisorption.


Microphotometric quantitation of the reaction product of several indirect immunoperoxidase methods demonstrating monoclonal antibody binding to antigens immobilized on nitrocellulose.
The nitrocellulose model and microphotometry were used to investigate whether in immunoperoxidase cytochemical methods the amount of final reaction product reflects the amount of cell surface antigen. The results obtained with four cytochemical peroxidase methods, i.e., those using diaminobenzidine/H2O2 (DAB/H2O)2, DAB/H2O2/COCl2, DAB/H2O2/imidazole, and silver intensification of the DAB end product, were compared first. The quantitative DAB/H2O2/imidazole method proved to be the most sensitive and was selected for further studies. Cell surface antigens prepared by solubilization of peritoneal macrophages with octyl-beta-D-glucopyranoside were immobilized on nitrocellulose. Monoclonal antibody binding to these cell antigens was detected by peroxidase immunocytochemistry. Comparison of the sensitivity of the indirect immunoperoxidase and the biotin-(strept)avidin immunoperoxidase methods on the basis of the highest detectable dilution of a cell lysate showed that these methods were equally sensitive. A linear relationship between the absorbance of the peroxidase reaction product and the amount of cell lysate immobilized on nitrocellulose was found for all three indirect immunoperoxidase methods. This proves that the amount of final immunocytochemical peroxidase reaction product is proportional to the amount of antigen in cell lysates. However, the relative expression of antigens in intact cells differs from that in cell lysates. Therefore, the present method to solubilize cells and immobilize cell antigens cannot be used to quantitate the antigen content of cells.


Fiber lasers and their applications [Invited].
Fiber lasers have seen progressive developments in terms of spectral coverage and linewidth, output power, pulse energy, and ultrashort pulse width since the first demonstration of a glass fiber laser in 1964. Their applications have extended into a variety of fields accordingly. In this paper, the milestones of glass fiber laser development are briefly reviewed and recent advances of high-power continuous wave, Q-switched, mode-locked, and single-frequency fiber lasers in the 1, 1.5, 2, and 3 μm regions and their applications in such areas as industry, medicine, research, defense, and security are addressed in detail.


[Mortality of psychiatric inpatients in France during World War II: a demographic study].
In France, World War II lasted from 1939 to 1945. Under-nourishment was a national problem, and was more severe in mental hospitals. The mortality of psychiatric inpatients in France during World War II has long been a controversial issue in the country. Some authors wrote of the "soft extermination" of 40 000 mental patients, although this has been proven false. The historical study published in 2007 by Isabelle von Bueltzingsloewen provides in-depth description and analysis of starvation due to food restrictions in French mental hospitals. Although the French official statistic services published detailed data, no demographic study has been published so far. Such studies have been conducted in Norway and in Finland. "The influence of a period of under-nourishment upon mortality in mental hospitals can rarely be seen with a clarity equal to that in this work. The strict rationing was the same for everybody, but, extra muros, there was private initiative and ingenuity to help in alleviating the distress. Naturally, patients in institution had no ability to act on their own. The immense increase during the period of war from 1941 to 1945 appeared both as an increase in the exact death-risk and as an increase in the disproportion with normal mortality. The men reacted more strongly than women; which is readily comprehensible on physiological grounds, as the rations were virtually the same for all." Excess mortality continued after the war. Even though under-nourishment had ceased, death rates from tuberculosis remained high the following year. Both papers state that the poor hygiene and bad living conditions existing in mental hospitals before the war worsened the effects of food restrictions. DEMOGRAPHIC DATA: French data were published by the General Statistics of France (SGF) that became the National Institute of Statistics and Economic Studies (Insee) in 1946. A series of datasets were published each year according to sex, diagnosis and type of psychiatric institution. In 1943, the outdated diagnostic classification was replaced by a more modern one, with reference to ICD. The same year, the age groups also changed (instead of 35-44, it became 30-39). Publication of data by type of institution was discontinued in 1943; from 1945 to 1948, the only available data concerned patients in hospital on 31st December, by age, sex and diagnosis. General population data were published by the National Institute of Demographic Studies (INED). The data referring to civilian population during the war are provided by the Human Mortality Database. This study covers number of people in hospital, mortality rates by sex, age, diagnosis and type of institution, and standardised mortality ratios. These refer to the civilian population which is more relevant since mental patients would not have been allowed to join the armed forces, even if they had not been in hospital. Finally, mortality trends in mental hospitals are compared with those in "hospices for old, disabled or incurable people", in order to ascertain whether all vulnerable populations in institutions suffered to the same extent. The results show that the number of inpatients in 1945 was about half the total recorded in 1940, due to fewer admissions and to a large increase in the number of deaths. However, the number of discharges increased in 1940, even though the number of admissions had begun to slow down: many patients were sent to places offering better food and hygiene. The number of deaths began to rise as from 1939. Mortality rates were high in 1940 and especially in 1941, when almost one man in three and more than one woman in five died. Global rates did not change in 1942. In December that year, a government order stated that mental patients should receive more food. Mortality rates went down in 1943 and 1944, but rates did not return to the prewar values until 1946. In 1939, mortality rates are high but only among patients of 70 years of age or more. In 1940, they were highest above 55; in 1941, rates between ages 15 and 54 were double those of the preceding year. Thus, even though excess mortality affected all ages, its strongest effects were felt from the older patients to the younger ones from 1939 to 1941. Trends according to diagnosis are difficult to interpret because of the change of classification in 1943. The patients suffered greatest hardship in public hospitals, which had no budget of their own and were run by the departments and lowest in private hospitals contributing to the public service, most of which were congregational and received religious funding. In 1941, standardised mortality ratios were more than three times higher than they were before the war. Comparison with people living in hospices shows that during the war mortality rates were 50% higher in these institutions, while they almost tripled in mental hospitals. The number of people who died of starvation and infectious diseases in mental hospitals from 1939 to 1945 can be estimated at about 45,500. However, mental patients were made specially vulnerable by circumstances that existed before the war in mental hospitals, in terms of food, hygiene and staffing, as suggested by an official document quoted in the paper.


Risk of Cardiac Morbidities and Sudden Death in Patients With Epilepsy and No History of Cardiac Disease: A Population-Based Nationwide Study.
To investigate the impact of epilepsy on secondary cardiac morbidities and sudden death in patients with epilepsy. The present cohort study evaluated data obtained from a subset of adult patients listed in the Taiwan National Health Insurance Research Database with an International Classification of Diseases, Ninth Revision, diagnosis code of epilepsy from January 1, 1997, to December 31, 2013; the date of epilepsy diagnosis or antiepilepsy drug prescription was defined as the index date. Patients with cardiac disease prior to the index date were excluded, and the remaining patients were categorized into epilepsy and nonepilepsy groups. Frequency matching was performed to balance the covariates across groups for the comparison of outcomes. The development of myocardial infarction (MI) and arrhythmia and/or the occurrence of sudden death were the outcomes for evaluation. A Cox proportional hazards regression model and competing risk analysis were used to compare the risks of cardiac morbidities and sudden death between groups. The final analysis included a total of 5411 patients with epilepsy and 21,644 participants without epilepsy. The epilepsy group had significantly higher risks for development of MI (hazard ratio [HR], 1.71; 95% CI, 1.62 to 1.81; P<.001) and arrhythmia (HR, 2.11; 95% CI, 1.97 to 2.25; P<.001) and the occurrence of sudden death (HR, 1.83; 95% CI, 1.53 to 2.18; P<.001) compared with the nonepilepsy group. Our results indicate that the risks for development of MI and arrhythmia and the occurrence of sudden death were higher in patients with epilepsy. These findings support the hypothesis that epilepsy may lead to secondary cardiac dysfunction and increases the risk of sudden death.


Effects of endogenous DNA base lesions on transcription elongation by mammalian RNA polymerase II. Implications for transcription-coupled DNA repair and transcriptional mutagenesis.
The blockage of transcription elongation by RNA polymerase II (pol II) is thought to be a trigger for transcription-coupled repair in the pathway of nucleotide excision repair. Purified pol II and oligo(dC)-tailed templates containing a single non-bulky DNA lesion on the transcribed strand such as an apurinic/apyrimidinic (AP) site, uracil, or 8-oxoguanine (8-oxoG) were used for transcription elongation assays. In this system pol II could bypass both the AP site and uracil without pausing and insert cytosine opposite the AP site and either guanine or adenine opposite to uracil. Thus, the AP site on the DNA templates could lead to correct transcription only if depurination at guanine occurred, whereas uracil generated either the correct transcriptional product or an incorrect one with a G:C to A:T transition. In the case of 8-oxoG, pol II stalled at the lesion, but sometimes bypassed it and inserted a cytosine residue or the incorrect adenine residue leading to a G:C to T:A transversion. These findings indicate that 8-oxoG lesions caused a blockage of transcription elongation and/or the misincorporation of a ribonucleotide by pol II, implying the initiation of transcription-coupled repair of 8-oxoG and/or transcriptional mutagenesis.


The rise and fall of the RNA world.
It is generally believed that there was a time when life on earth was based on RNA rather than on DNA and protein. Considering the relevant evidence from geophysics, geology, paleobiology, and molecular biology, it is possible to set the time frame for the existence of RNA-based life to a 400 million year interval beginning 4.0 to 4.2 billion years ago and ending 3.6 to 3.8 billion years ago. The minimum level of biochemical complexity that existed during this time consists of those functions necessary for the establishment and maintenance of an RNA-based evolving system, namely, an RNA unwinding activity, an RNA replicase activity, and a primitive biosynthetic apparatus leading to enrichment of the local environment with activated D mononucleotides.


Surgical treatment of incompetent cervix during pregnancy by Saito modification of Shirodkar operation.
The Shirodkar operation for the treatment of cervical incompetency during pregnancy was modified by Motoi Saito of our department and has been adopted since 1974. This paper describes the operative techniques of the procedure and reviews the results of 34 cases treated by the modification during the last 10 years. The rate of success was 76.5% for the post-operative delivery after completing 37 weeks of gestation, and, if the 17.6% of the viable premature births were included, the fetal salvage rate by the procedure was 94.1%. The Saito modification procedure provides easy identification of the cervical cerclage ligature and facilitates the complete removal of the suture before or during labor. The 10-year results suggest that the procedure was as effective as the original Shirodkar operation for the prevention of premature birth and fetal loss due to incompetent cervix during pregnancy.


Primary parapharyngeal leiomyosarcoma: A case report.
Leiomyosarcoma is a rare malignant soft-tissue tumor whose cells resemble smooth-muscle tissue. It has been reported to arise in different areas of the head and neck region. Primary leiomyosarcoma of the parapharyngeal space, however, is extremely rare, as only 4 cases have been previously reported to date. We describe the somewhat urgent case of a primary leiomyosarcoma of the right parapharyngeal space in a 30-year-old man. We also review the diagnostic and therapeutic challenges that clinicians face in managing this rare tumor.


Somatostatin-14 and somatostatin-28 pretreatment down-regulate somatostatin-14 receptors and have biphasic effects on forskolin-stimulated cyclic adenosine, 3',5'-monophosphate synthesis and adrenocorticotropin secretion in mouse anterior pituitary tumor cells.
Activation of somatostatin-14 (S-14) receptors on mouse AtT-20 pituitary tumor cells by S-14 or somatostatin-28 (S-28) inhibits forskolin-stimulated cAMP synthesis and ACTH secretion. In this study, the effects of prolonged exposure of cells to S-14 or S-28 was found to reduce, in a time- and concentration-dependent fashion, the density of S-14 receptors without affecting the affinity of these sites for [125I]Tyr11-S-14. This response was rapidly reversible after removal of peptide from incubation media. Additionally, S-14 and S-28 pretreatment also resulted in a time-dependent sensitizing effect on forskolin-stimulated cAMP formation and ACTH secretion which preceded S-14 receptor down-regulation. Enhancement of the forskolin response was concentration dependent, with maximal effects observed at 10(-8) M with either peptide. Higher pretreatment concentrations of S-14 resulted in an abolition of the enhanced biological response to forskolin; pretreatment with S-28 (10(-6) M) depressed forskolin- and (-)isoproterenol-induced cAMP formation below levels observed in nonpretreated cells. The enhancing effect of S-14 and S-28 required new protein synthesis, since it was partially blocked by cycloheximide; the depressor effect was independent of new protein synthesis. Both the enhanced and depressed forskolin responses after peptide pretreatment were reversible after withdrawal of S-14 or S-28; normalization of the forskolin response (cAMP formation and ACTH secretion) followed the return to control levels of S-14 receptor density. Pretreatment of cells with 10(-8) M or 10(-6) M S-28 increased and decreased, respectively, the ACTH secretory response to agonists which act in the absence of prior cAMP synthesis such as 8-bromo-cAMP, A-23187, and phorbol ester. The data suggest that S-14 receptor down-regulation is not causally associated with the sensitizing effects of S-14 and S-28 on adenylate cyclase and that the S-14 receptor may be also coupled to other effector systems which are involved in regulating the secretory function of AtT-20 cells.


Modulation of androgen receptor protein by culture conditions of human skin fibroblasts.
Cultures of skin fibroblasts show variation of androgen binding with culture conditions; binding variations are usually avoided by using confluent cultures. In this work, we analysed the effect of cell density and mitogenic agents on the level of androgen receptor (AR) of cultured human skin fibroblasts. Results demonstrated that in cultures of human skin fibroblasts, cellular binding of dihydrotestosterone was higher in cells grown at low than at high cell density. The reduction in binding resulted from a decrease in the number of high affinity receptors and not from a change in receptor affinity. Immunocytochemistry for AR showed greater staining intensity in cells grown at low than at high cell density. Additionally, immunoblot analysis demonstrated more AR protein in low cell density cultures. On the other hand, it was observed that cells grown at low cell density showed diminished androgen binding capacity after 24 h of treatment with insulin-like growth factor (IGF-l), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), or granulocyte-colony stimulating factor (G-CSF); this effect of growth factors was not observed in cells grown at high cell density. In conclusion, we found that cell density of cultures and mitogenic agents can regulate AR binding activity in human fibroblasts. While we do not yet know how changes in cell density affect the amount of AR, we conclude that the mechanism could be mediated by activation of the tyrosine kinase pathway, as the effect was reproduced by mitogens.


Effects of blood volume restitution following a portal hypertensive-related bleeding in anesthetized cirrhotic rats.
The aim of this study was to investigate the influence of different strategies of blood volume restitution in the outcome of portal hypertension-related bleeding in anesthetized cirrhotic rats. Gastrointestinal hemorrhage was induced by sectioning a first order branch of the ileocolic vein in 38 cirrhotic rats (common bile duct ligation and occlusion). The subsequent hypovolemic shock was treated with no transfusion (n = 17), moderate transfusion (50% of expected blood loss, 5 mL, n = 11), and total transfusion (100% of expected blood loss, 10 mL, n = 10). At the end of the blood transfusion period (minute 15), mean arterial pressure (MAP) partially recovered in rats receiving moderate transfusion or no transfusion but decreased in the 10-mL transfusion group ( downward arrow 12 +/- 43%, P < .05 vs. no transfusion and 5 mL transfusion). After transfusion, groups given no or 5 mL transfusion remained hemodynamically stable. However, rats receiving 10 mL transfusion continued to deteriorate with persistent bleeding and progressive fall in MAP ( downward arrow 65 +/- 12%; P < .05 vs. no transfusion and 5 mL transfusion). Collected blood loss was significantly greater in the 10-mL group (20.0 +/- 1.5 g) than in groups given 5 mL (15.9 +/- 2.8 g; P < .05) or no transfusion (13.2 +/- 2.1 g; P < .05 vs. 10 mL and 5 mL transfusion). Survival in the no transfusion group was 47%. Rats given 5-mL transfusion had 64% survival. The worst survival was observed in the 10-mL transfusion group (0% survival; P < .05). We concluded that a transfusion policy aimed at completely replacing blood loss worsens the magnitude of bleeding and mortality from portal hypertensive-related bleeding in cirrhotic rats. On the contrary, moderate blood transfusion allowed hemodynamic stabilization and increased survival.


Outpatient management of childhood acute diarrhea: survey among pediatricians from a children's hospital in the Autonomous City of Buenos Aires.
The management of acute diarrhea is based on preventing dehydration and reducing disease duration and severity. , Ángela Gentilea INTRODUCTION The study objective was to establish the patterns for the outpatient management of acute diarrhea in children younger than 5 years. Observational, analytical study using a self-administered survey among pediatricians from a children's hospital in the Autonomous City of Buenos Aires.Age, sex, place of work, bibliographic sources, indication of drug and non-drug therapies, and preventive and hygiene measures were recorded. The association between drug prescription and the characteristics of surveyed pediatricians was assessed. In total, 182/216 pediatricians completed the survey. Their mean age was 42.4 ± 10.24 years; 78.6% were females; 59.2% worked in the public sector; 22.4% worked in the emergency department; and 91.2% consulted guidelines and/or consensuses. Also, 92.9% prescribed oral rehydration solutions; 46.2%, antiemetics; 43.4%, antacids and/or gastric protectors; 35.7%, probiotics; and 30.7%, zinc. Early food reintroduction was indicated by 91.7%; breastfeeding, by 96.7%; and preventive and hygiene measures, by 96-100%. The multivariate analysis showed an association between age > 40 years and prescribing antacids/ gastric protectors (odds ratio [OR]: 2.6; 1.22-5.61), probiotics (OR: 3.03; 1.34-6.83), and zinc (OR: 0.39; 0.17-0.87); between working in the private sector and prescribing probiotics (OR: 3.05; 1.565.94); and between working in the emergency department and prescribing antacids/gastric protectors (OR: 2.60; 1.22-5.54). Treatment was mainly based on hydration, early food reintroduction, and breastfeeding. Age and work sector affected the prescription pattern.


Percutaneous treatment of idiopathic chylopericardium.
Chylopericardium is a rare disease that may result from a variety of causes, such as cardiac surgery, trauma, obstruction of the thoracic duct near its drainage into the subclavian vein, or have no identifiable underlying cause. The present report describes a case of idiopathic chylopericardium in which percutaneous transabdominal occlusion of the thoracic duct was performed as an alternative to surgical duct ligation. The procedure was successful, resulting in a decrease in pericardial fluid accumulation. However, it failed to cure the patient, as constrictive pericarditis developed 2 months later, requiring surgical pericardectomy. Whether this could have been avoided by early (percutaneous) pericardial fenestration is unknown.


Antihyperlipidemic and Antioxidant Effects of Averrhoa Carambola Extract in High-Fat Diet-Fed Rats.
The present study explored the antihyperlipidemic potential of a standardized methanolic extract of Averrhoa carambola (A. carambola) leaf (MEACL) in high-fat diet (HFD)-fed rats. The standardized MEACL was orally administered at different doses (250, 500, and 1000 mg/kg) to HFD-induced hyperlipidemic rats for five weeks. Serum lipid profile, body weight changes, body mass index (BMI), daily food intake, relative organ weight, and histology of the liver were evaluated. In addition, the effect of MEACL on HMG-CoA reductase and pancreatic lipase activities as well as hepatic and fecal lipids was demonstrated. MEACL supplementation reduced serum lipids in HFD-fed rats in a dose-dependent manner. Histopathological scores revealed that 1000 mg/kg MEACL restored the damage to liver tissue in hyperlipidemic rats. MEACL decreased the body mass index (BMI), atherogenic index, and hepatic cholesterol and triglycerides and increased fecal cholesterol and bile acids in HFD-fed rats. Also, MEACL ameliorated lipid peroxidation and improved antioxidant defenses in the liver of HFD-fed rats. Furthermore, HMG-CoA reductase and lipase were suppressed by MEACL. In conclusion, this study shows the potential effect of MEACL to ameliorate hyperlipidemia and oxidative stress in HFD-fed rats. It prevented hepatic lipid accumulation and exerted an inhibitory effect on HMG-CoA reductase and lipase.


Clinical situations and information needs of physicians during treatment of diabetes mellitus patients: a triangulation study.
Physicians should have access to the information they need to provide the most effective health care. Medical knowledge and patient-oriented information is dynamic and expanding rapidly so there is a rising risk of information overload. We investigated the information needs of physicians during treatment of Diabetes mellitus patients, using a combination of interviews, observations, literature research and analysis of recorded medical information in hospitals as part of a methodical triangulation. 446 information items were identified, structured in a set of 9 main categories each, as well as 6 time windows, 10 clinical situations and 68 brief queries. The physician's information needs as identified in this study will now be used to develop sophisticated query tools to efficiently support finding of information in an electronic health record.


Measurement of serum and tissue concentration of moxalactam using high pressure liquid chromatography.
We describe a sensitive high pressure liquid chromatographic (HPLC) procedure for the analysis of the new beta-lactam antibiotic moxalactam. Conditions are described for either measurement of total drug concentration or the concentration of the individual isomers. The proteins in a 1.0 ml plasma sample are denatured with isopropyl alcohol which is then extracted into a chloroform reagent, leaving the drug in the aqueous phase. An aliquot is then injected into a mu-bondapak phenyl column. A similar extraction procedure was employed for tissue homogenates. Linear regression analysis and comparison of the HPLC assay with the microbiological assay gave a correlation coefficient of 0.97. Analysis of tissue samples indicated that significant concentrations of moxalactam were obtained at the site of infection.


Pathological manifestations in murine Lyme disease: association with tissue invasion and spirochete persistence.
The clinical manifestations of human Lyme disease present with a spectrum of tissue or organ involvement and severity of symptoms. The murine model of Lyme disease has proved to be an accurate reflection of many of the human symptoms of disease and has been particularly useful for studying development of subacute arthritis and tendonitis. Direct tissue invasion by Borrelia burgdorferi and persistence of high levels of spirochetes in tissues are important components of arthritis development. The outer-surface lipoproteins contain a biologically active lipid-modified moiety with potent ability to stimulate inflammatory cytokine production and other inflammatory mediators such as nitric oxide. Localized inflammation stimulated by these lipoproteins may be the trigger for neutrophil infiltration, synovial proliferation, and other events associated with this arthritis. Invasion of maternal uterine tissue, but not direct invasion of fetal tissue, is associated with low levels of pregnancy loss in mice infected during gestation, consistent with the detrimental effect of inflammatory cytokines on pregnancy.


Glutamate in opioid dependence.
The present review will concentrate on a discussion of recent investigations which implicate a critical linkage of three facets of the central nervous system mediation of opioid dependence, as evidenced by expression of acutely-precipitated withdrawal events. These are the kappa-opioid receptor subtype, the glutamatergic neuronal system and a specific brain locus, the locus coeruleus. The impetus for this line of investigation derives from a recognition that opioid analgesics, such as butorphanol (Stadol), exhibit a markedly different profile of activity at opioid receptors than does morphine yet have abuse liability and cause dependence readily. Emphasis will be placed on demonstration of a rodent model in which butorphanol administration induces dependence through a unique (in comparison with morphine) activation of the kappa-opioid receptor. The use of in vivo microdialysis techniques clearly identifies, in this model, that acutely-precipitated withdrawal from dependence on butorphanol results in focal increases in extracellular levels of glutamate within the locus coeruleus, and that the withdrawal syndrome can be mimicked by intracerebroventricular administration of exogenous glutamate, acting through the N-methyl-D-aspartate glutamate receptor subtype. The data confirm the participation of glutamate as a general phenomenon in opioid dependence, identify the locus coeruleus as a primary site for glutamatergic mediation of dependence, and suggest novel aspects to the neuropharmacology of opioid dependence with respect to the role of the kappa-opioid receptor.


The comparative performance of mobile telemedical systems based on the IS-54 and GSM cellular telephone standards.
The performance of mobile telemedical communications links based on the IS-54 and GSM cellular telephone standards (the most widely used commercial systems in North America and Europe, respectively) was studied by computer simulations. A photoplethysmography signal was used to investigate the transmission of medical data over simulated mobile phone channels. Various conditions were simulated in the communications path between a mobile transmitter and receiver, from perfect to distorted conditions. The results showed successful transmission, with bit error rates of better than 10(-7) at the receiver for the IS-54 standard. The performance of the IS-54 standard was superior to that of GSM in terms of minimum path delay variations, especially in built-up (urban) areas.


The elusive diagnosis: recurrent benign lymphocytic meningitis.
Recurrent benign lymphocytic meningitis (RBLM) or Mollaretmeningitis is a rare disease with a prevalence of 1-2.2/100,000 population. It is characterized by recurrent episodes of aseptic meningitis. The diagnosis is made via history fitting Bruyn's criteria, and confirmatory detection of HSV-2 in cerebrospinal fluid (CSF) via polymerase chain reaction (PCR). A 59-year-old female with a past medical history (PMH) of rheumatoid arthritis in remission and 11 prior episodes of aseptic meningitis presented with sudden and severe headache, photophobia, nausea, vomiting, and meningismus without focal findings. CSF analysis revealed aseptic meningitis with Herpes simplex 2 virus (HSV-2) present by PCR. RBLM remains a rare and elusive diagnosis but PCR technology has made it easier to diagnose. We present a 59-year-old female with classic features of RBLM, now suffering a 12th episode of aseptic meningitis. Heightened awareness of RBLM among clinicians may allow for an earlier diagnosis, reduced use of unnecessary antibiotics, shortened hospitalizations, and lower costs.


[Sagittal rhinoplasty for broad noses].
Normal profile wide noses, without osteo-cartilaginous bump, are rare and very few cases have been described in the literature, to our knowledge. Based on a short experience of 4 cases, we describe a surgical variant of the classic rhinoplasty technique. The resection of two osteo-cartilaginous symmetrical quadrilaterals resolves this specific problem with no risk of profile modification with sagging and necessity of reinclusion.


[Bipolarity: from manic-depressive disease to bipolar disorder].
Until recently, bipolar disorder was viewed as a relatively rare condition characterized by periods of euphoric excitement and depressive retardation which was easy to diagnose, and easy to treat thanks with lithium and new prophylactic treatments. In fact, bipolar disorder encompasses a variety of conditions, whose overall lifetime prevalence in the general population may be between 5 and 8%. Long term with lithium and other compounds are very effective but must be combined with non pharmacological therapies. Over the past two decades, advances in genetic, brain imagings, and biochemical have improved our knowledge on the pathophysiological mechanisms underlying these disorders.


Collective dynamics of chaotic chemical oscillators and the law of large numbers.
Experiments on the nontrivial collective dynamics and phase synchronization of populations of nonidentical chaotic electrochemical oscillators are presented. Without added coupling no deviation from the law of large numbers is observed. Deviations do arise with weak global or short-range coupling; large, irregular, and periodic mean field oscillations occur along with (partial) phase synchronization.


Outcomes of emergency room treatment of children with asthma.
Duration of symptoms, medication use and follow-up medical care were examined over an 8-week period in children following emergency room treatment for an acute asthma episode. Two groups of children were compared: Short-course (N = 90) and Continuous Medication Users (N = 46). Over a third of Short-Course Users continued to report symptoms up to 6 weeks following the index episode with 31% reporting medication use at 8 weeks. Relapse, resulting in an emergency room visit, occurred in 26% of all study children. Factors associated with relapse included maternal smoking, female gender, prior hospitalization for asthma, cough, and medication use during the follow-up period.


[Iatrogenic injuries of the colon during colonoscopy].
Endoscopic examinations of hollow organs, similarly as other invasive operations, are associated with a certain percentage of sometimes very serious complications. Iatrogenic perforations of the gut, in particular during the procedure belong to the most dramatic ones. During the period of 1990-2000 the authors had the opportunity to deal in collaboration with the medical department with five cases.


Liquidity connectedness in cryptocurrency market.
We examine the dynamics of liquidity connectedness in the cryptocurrency market. We use the connectedness models of Diebold and Yilmaz (Int J Forecast 28(1):57-66, 2012) and Baruník and Křehlík (J Financ Econom 16(2):271-296, 2018) on a sample of six major cryptocurrencies, namely, Bitcoin (BTC), Litecoin (LTC), Ethereum (ETH), Ripple (XRP), Monero (XMR), and Dash. Our static analysis reveals a moderate liquidity connectedness among our sample cryptocurrencies, whereas BTC and LTC play a significant role in connectedness magnitude. A distinct liquidity cluster is observed for BTC, LTC, and XRP, and ETH, XMR, and Dash also form another distinct liquidity cluster. The frequency domain analysis reveals that liquidity connectedness is more pronounced in the short-run time horizon than the medium- and long-run time horizons. In the short run, BTC, LTC, and XRP are the leading contributor to liquidity shocks, whereas, in the long run, ETH assumes this role. Compared with the medium term, a tight liquidity clustering is found in the short and long terms. The time-varying analysis indicates that liquidity connectedness in the cryptocurrency market increases over time, pointing to the possible effect of rising demand and higher acceptability for this unique asset. Furthermore, more pronounced liquidity connectedness patterns are observed over the short and long run, reinforcing that liquidity connectedness in the cryptocurrency market is a phenomenon dependent on the time-frequency connectedness.


Fracture behavior of cantilever fixed dental prostheses fabricated from different zirconia generations.
The aim of this study was to compare the fracture behavior of cantilever fixed dental prostheses (FDPs) fabricated from 3Y-TZP, 4Y-TZP, or 5Y-TZP zirconia. Posterior cantilever FDPs (three groups, each n = 16) were digitally designed and milled. After sintering, eight specimens/group were stored in demineralized water for 72 hours; eight specimens/group were subjected to accelerated aging using chewing simulation with thermal cycling (1,200,000 × 50 N; 2 × 3,000 × 5°C/55°C; H2O, 2 minutes/cycle) and finally stored in demineralized water for 24 hours. The cantilever FDPs were then statically loaded to failure to determine fracture load. Phase transformation towards the monoclinic phase was controlled with x-ray diffractometry. One failure was identified after accelerated aging in the 5Y-TZP group. Fracture load decreased with increasing yttria content and decreasing bending strength. Accelerated aging using chewing simulation with thermal cycling caused a significant decline in fracture load. All FDPs failed in the area of the prepared tooth and in proximity to the cantilever, where the largest bending moment occurred. The yttria content had no influence on the type of fracture. With increasing yttria content, the relation between deformation and fracture load decreased only slightly. On the surface of FDPs that had been subjected to chewing simulation, no phase transformation towards the monoclinic phase (eg, low temperature degradation) was detected. Within the limitations of a laboratory study, the data indicate that 3Y-, 4Y-, and 5Y-TZP may be employed as material for the fabrication of permanent posterior cantilever FDPs. However, more data are necessary to finally advocate the application of 5-Y-TZP. (Quintessence Int 2022;53:414-422; doi: 10.3290/j.qi.b2793243).


Immunohistochemical localization of the IAP protein survivin in bladder mucosa and transitional cell carcinoma.
In the current study, the immunohistochemical localization of survivin was correlated with the histologic diagnosis in healthy transitional cell epithelium, transitional cell carcinoma (TCC) in situ, and TCC of the urinary bladder. Forty-five TCCs (grades 1-3, 15 of each), 14 cases of TCC in situ, and II healthy bladder mucosal specimens were selected from archival collections of formalin-fixed bladder tissues. Slides were reacted with an anti-survivin antibody using a conventional immunohistochemical method and then were scored for nuclear and cytoplasmic staining. Statistical analysis of survivin expression was performed to evaluate the correlation of staining pattern with histologic diagnosis and clinical outcome. Nuclear staining for survivin was detected in 26 of 45 TCCs and in 2 of 14 cases of TCC in situ, but was not detected in healthy bladder mucosa. The association of nuclear staining with TCC versus both healthy bladder mucosa and TCC in situ was statistically significant (P < 0.001). Patients with TCC and a nuclear pattern of survivin localization had a greater period of disease-free survival (27.2 months) than was observed in patients with TCC that showed no nuclear staining for survivin (9.9 months); however, the differences were not statistically significant. Nuclear localization of survivin is a marker of TCC but is rarely present in premalignant or benign bladder mucosal specimens.


Uric acid in multiple sclerosis.
Peroxynitrite, a reactive oxidant formed by the reaction of nitric oxide with superoxide at sites of inflammation in multiple sclerosis (MS), is capable of damaging tissues and cells. Uric acid, a natural scavenger of peroxynitrite, reduces inflammatory demyelination in experimental allergic encephalomyelitis. Some studies reported lower serum levels of uric acid in MS patients compared with controls, whereas other studies found no difference. A critical appraisal of these studies favors the view that reduced uric acid in MS is secondary to its peroxynitrite scavenging activity during inflammatory disease activity, rather than a primary deficiency. Serum uric acid levels could be used as a biomarker for monitoring disease activity in MS. Therapeutic strategies aimed at raising serum uric acid levels may have a glial/neuroprotective effect on MS patients.


[Analysis of Treatment Response and Chest CT Characteristics for Patients treated by EGFR-TKI in Relapse Advanced Lung Adenocarcinoma.].
For previously treated recurrent non-small cell lung cancer, many studies have proven that inhibitors of the tyrosine kinase of epidermal growth factor receptor (EGFR-TKI),such as gefitinib and erlotinib can increase survival, especially in non-smoker adenocarcinoma. The objective of this study is to investigate the relationship between the characteristics of chest Computed tomography(CT) and objective response of gefitinib and erlotinib for recurrent lung adenocarcinoma. Thirty-seven patients with recurrent advanced lung adenocarcinoma were treated from Jan 1, 2004 to Mar 31, 2007 in our department. The patients consisted of 17 males and 20 females previously treated with 1-6 cycle of platinum-based chemotherapy. The age changed from 54 to 85 yrs (media 67.5 yrs). The gefitinib and erlotinib was given 250 mg and 150mg respectively per day until disease progression. The characteristics of chest CT were evaluated before therapy and reviewed every 2 month as follow up. The objective response was analyzed according to RECIST system. In 37 patients, 21 patients benefited (including 7 partial response and 14 stable disease) from the treatment. Chest CT characteristic analysis showed that, the benefit rate was 79.9%(15/19)in patients with greater than 3 metastasis of lung or diffused disease, vs. 33.3%(6/18) in others,P <0.05; the benefit rate was 73.1%(19/26)and 67.4% (31/46)respectively in patients with pleural effusion and moderate contrast disease focus in enhancement CT scanning,vs. 22.2%(2/9)and 37.5%(9/24) in patients without pleural effusion and non-enhancement respectively,P <0.05. But Cox regression analyses show no relationship between CT presentation and progress free survival (PFS) or overall survival (OS), HR, 0.766, P >0.05. For advanced lung adenocarcinoma, CT presentation of multiple metastasis of lung or diffused disease,pleural effusion and enhancing contrast disease focus may be a predictor for response when treated by EGFR-TKI. But those CT character does not represent as independent factor for prognosis.


Phase stability of a garnet-type lithium ion conductor Li7La3Zr2O12.
The phase stability of Li7La3Zr2O12 (LLZ) was investigated using high temperature X-ray diffraction (HT-XRD). An Al-free tetragonal LLZ phase transformed into a non-quenchable cubic phase around 650 °C. The phase transformation process between the tetragonal phase and the new cubic phase showed perfect reversibility. The thermal analysis showed a pair of endothermic and exothermic peaks around 640 °C that is in good agreement with the phase transformation process observed in the HT-XRD study. The non-quenchable high temperature cubic phase showed high ionic conductivity with extraordinarily low activation energy (0.117 eV). The tetragonal phase showed another phase transformation to a low temperature (LT) cubic phase around 150-200 °C in air by absorbing CO2 into the structure. The preferred temperature for the CO2 absorption process was around 200 °C and the absorbed CO2 was extracted once the temperature reached 450 °C or above resulting in the phase transformation back to the tetragonal phase. On the other hand the high temperature (HT) cubic phase which shows high ionic conductivity was stabilized by Al substitution. A Li-poor LLZ containing impurity phases such as La2Zr2O7 and La2O3 effectively reacted with γ-Al2O3 resulting in the formation of a pure Al-stabilized cubic LLZ, while the stoichiometric LLZ took a much longer time to complete the Al-substitution. The result suggested that the formation of Li vacancies is the primary step in the formation of the Al-stabilized cubic phase.


Mutations in hpyAVIBM, C⁵ cytosine DNA methyltransferase from Helicobacter pylori result in relaxed specificity.
The genome of Helicobacter pylori is rich in restriction-modification (RM) systems. Approximately 4% of the genome codes for components of RM systems. hpyAVIBM, which codes for a phase-variable C(5) cytosine methyltransferase (MTase) from H. pylori, lacks a cognate restriction enzyme. Over-expression of M.HpyAVIB in Escherichia coli enhances the rate of mutations. However, when the catalytically inactive F9N or C82W mutants of M.HpyAVIB were expressed in E. coli, mutations were not observed. The M.HpyAVIB gene itself was mutated to give rise to different variants of the MTase. M.HpyAVIB variants were purified and differences in kinetic properties and specificity were observed. Intriguingly, purified MTase variants showed relaxed substrate specificity. Homologues of hpyAVIBM homologues amplified and sequenced from different clinical isolates showed similar variations in sequence. Thus, hpyAVIBM presents an interesting example of allelic variations in H. pylori where changes in the nucleotide sequence result in proteins with new properties.


[Analysis of the results of total cervical disc arthroplasty using a M6-C prosthesis: a multicenter study].
Cervical spondylosis and intervertebral disc (IVD) degeneration are the most common cause for compression of the spinal cord and/or its roots. Total IVD arthroplasty, as a modern alternative to surgical treatment of IVD degeneration, is gaining popularity in many neurosurgical clinics around the world. Aim - the study aim was to conduct a multicenter analysis of cervical spine arthroplasty with an IVD prosthesis M6-C ('Spinal Kinetics', USA). The study included 112 patients (77 males and 35 females). All patients underwent single-level discectomy with implantation of the artificial IVD prosthesis M6-C. The follow-up period was up to 36 months. Dynamic assessment of the prosthesis was based on clinical parameters (pain intensity in the cervical spine and upper extremities (visual analog scale - VAS); quality of life (Neck Disability Index - NDI)); and subjective satisfaction with the results of surgical treatment (Macnab scale) and instrumental data (range of motion in the operated spinal motion segment, degree of heterotopic ossification (McAfee-Suchomel classification), and time course of degenerative changes in the adjacent segments).


Heterologous Expression of Active Dehalobacter Respiratory Reductive Dehalogenases in Escherichia coli.
Reductive dehalogenases (RDases) are a family of redox enzymes that are required for anaerobic organohalide respiration, a microbial process that is useful in bioremediation. Structural and mechanistic studies of these enzymes have been greatly impeded due to challenges in RDase heterologous expression, potentially because of their cobamide-dependence. There have been a few successful attempts at RDase production in unconventional heterologous hosts, but a robust method has yet to be developed. Here we outline a novel respiratory RDase expression system using Escherichia coli. The overexpression of E. coli's cobamide transport system, btu, and anaerobic expression conditions were found to be essential for production of active RDases from Dehalobacter-an obligate organohalide respiring bacterium. The expression system was validated on six enzymes with amino acid sequence identities as low as 28%. Dehalogenation activity was verified for each RDase by assaying cell extracts of small-scale expression cultures on various chlorinated substrates including chloroalkanes, chloroethenes, and hexachlorocyclohexanes. Two RDases, TmrA from Dehalobacter sp. UNSWDHB and HchA from Dehalobacter sp. HCH1, were purified by nickel affinity chromatography. Incorporation of the cobamide and iron-sulfur cluster cofactors was verified; however, the precise cobalamin incorporation could not be determined due to variance between methodologies, and the specific activity of TmrA was consistent with that of the native enzyme. The heterologous expression of respiratory RDases, particularly from obligate organohalide respiring bacteria, has been extremely challenging and unreliable. Here we present a relatively straightforward E. coli expression system that has performed well for a variety of Dehalobacter spp. RDases. IMPORTANCE Understanding microbial reductive dehalogenation is important to refine the global halogen cycle and to improve bioremediation of halogenated contaminants; however, studies of the family of enzymes responsible are limited. Characterization of reductive dehalogenase enzymes has largely eluded researchers due to the lack of a reliable and high-yielding production method. We are presenting an approach to express reductive dehalogenase enzymes from Dehalobacter, a key group of organisms used in bioremediation, in Escherichia coli. This expression system will propel the study of reductive dehalogenases by facilitating their production and isolation, allowing researchers to pursue more in-depth questions about the activity and structure of these enzymes. This platform will also provide a starting point to improve the expression of reductive dehalogenases from many other organisms.


Solid-state investigations of erythromycin A dihydrate: structure, NMR spectroscopy, and hygroscopicity.
The crystal structures of the commercially available form of erythromycin A dihydrate and clarithromycin anhydrate, in addition to the structure of erythromycin B dihydrate, are reported in this paper. In light of the crystallographic data, analysis of the structural information provides insight into the physical properties of these pharmaceuticals. The propensity of these pharmaceuticals to form solvated structures is discussed and the hygroscopicity of erythromycin A dihydrate is investigated. Solid-state 13C NMR was used to monitor changes that occur when the dihydrate form of erythromycin A is stored under conditions of low relative humidity. Although erythromycin A dihydrate retains its crystallographic order at low humidity, as indicated by its X-ray powder diffraction pattern, the local chemical environment is dramatically influenced by the loss of the water molecules and results in dramatic changes in its solid-state 13C NMR spectrum.


The efficacy of transiently evoked otoacoustic emissions in the detection of middle-ear pathology.
Transiently evoked otoacoustic emissions (TEOAEs) is an objective diagnostic method of assessing the cochlear status. The aim of this study was to present the results of hearing screening in children and to evaluate TEOAEs in the diagnosis of middle-ear pathology compared with tympanometry and pure-tone audiometry. A group of school-aged children underwent otolaryngological evaluation, tympanometry, TEOAEs, and audiometry. We analyzed data from both ears with abnormal tympanograms and ears with normal tympanograms but abnormal otoscopic findings or positive otologic history. Included in our study were 497 ears. Two hundred ten (42%) ears had a tympanogram of type A, 102 (20.5%) of type B, and 185 (37.5%) of type C. Otoacoustic emissions were found in 200 (95%), 37 (36%), and 145 (78%) of these ears, respectively. In ears with a tympanogram of B type and present otoacoustic emissions, a pure-tone average (PTA) worse than 30 dB HL was found in 16 ears (43%), whereas in ears with a tympanogram of B type and absent otoacoustic emissions, PTA worse than 30 dB HL was found in 47 ears (72.3%). The respective numbers for ears with a tympanogram of C type were 18 (12.4%) and 19 (47.5%). TEOAEs may be recorded in significant percentages of ears with abnormal tympanograms and middle-ear pathology. Although the sensitivity of this method is low, it may be used in conjunction with other methods of evaluating the middle ear and may give some information about the hearing status of the ear.


[Cardiometabolic factors in a comunity located at Valencia city, Venezuela].
Assessing the prevalence of cardiometabolic factors in residents from a community in the north of Valencia city, Venezuela, and establishing clustering patterns for the cardiometabolic alterations. One hundred people aged 19 to 77 were studied. Weight, height, abdominal circumference, blood pressure, glucose, lipid profile and insulin were all measured. Insulin resistance was estimated by HOMA. The five most prevalent cardiometabolic factors were low HDLc (90 %), overweight/obesity (78 %), abdominal obesity (68 %), hypercholesterolemia (59 %) and insulin resistance (54,8 %). Low HDLc frequency was higher in women (p <0,01). Subjects aged 35 to 55 demonstrated higher cardiometabolic factor frequency. Metabolic syndrome prevalence was 57 %, prevailing in women. Three or four factors were found in most individuals. The most commonly occurring factors in the identified clusters were overweight/obesity, hypercholesterolemia, abdominal obesity and low HDLc. The body mass index and insulin resistance predicted metabolic syndrome in the evaluated group. High cardiometabolic factor prevalence was found in the community being studied as well as a high tendency for several of these factors to cluster, thereby indicating the need to execute programmes focusing on reducing cardiometabolic risk.


Tinea capitis: An update.
Tinea capitis is an important superficial infection and affects children globally. A literature review was conducted to identify recent findings and the current understanding of this fungal infection. Here, we highlight updates on important aspects of tinea capitis including advances in dermatophyte detection and diagnosis and comparing these new methods to more traditional techniques. Additionally, aspects of treating tinea capitis are discussed, including the importance of mycological confirmation and current means of treatment, and the treatment of asymptomatic carriers are reviewed. This review also examines the subject of laboratory monitoring of patients undergoing treatment with systemic antifungals; we discuss the opinions of prominent researchers and currently accepted guidelines. Lastly, we provide answers to several common questions that practitioners may encounter when treating a child with tinea capitis.


Experimental study on thioredoxin redox inhibitor 1-methylpropyl 2-imidazolyl disulfide promoting apoptosis of multiple myeloma cells in vitro and in vivo.
To explore the in vitro and in vivo experimental study of thioredoxin-1(Trx1) inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) promoting multiple myeloma H929 cell apoptosis, investigate the relationship between the inhibitory effect of PX-12 on H929 cells and reactive oxygen species (ROS). Inhibition of PX-12 on H929 cells in relation to reactive oxygen species (ROS), cell cycle, and apoptosis were assessed by flow cytometry. ELISA kit, IVIS Imaging, Hematoxylin and eosin (H&E) staining and immunohistochemical staining assessment were applied to assess the anti-myeloma effect in the SCID mice model established by H929EL cells. PX-12 inhibited proliferation of H929 cells performed time and dose dependent style. Furthermore, it significantly induced a G2/M phase arrest of the cell cycle in H929 cells. It also increased intracellular ROS and caspase-3 activity in H929 cells indicating that cells have undergone apoptosis. There was an almost 3-5-fold decrease in tumor viability measured by the Living-Imaging system after 21 and 28 days after PX-12 injection compared with the control group. Importantly, PX-12 caused significant decrease in expression of Kappa chain in vivo assessed by immunohistochemical staining. The results suggest that PX-12 may be a potential strategy for the treatment of MM, and the inhibition of TRX-1 in the treatment of myeloma deserves further research.


Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia.
To further investigate vascular morphology and function in type 2 (non-insulin-dependent) diabetes mellitus (type 2D), small arteries were examined in vitro from carefully defined cohorts of patients with or without concomitant hypertension and the results compared with those from selected normotensive nondiabetic control subjects and a group of untreated patients with essential hypertension (EH). Blood vessels were studied through the use of pressure myography to determine vascular morphology, mechanics, and myogenic responsiveness, together with testing of constrictor and dilator function. Small arteries from patients with EH demonstrated eutrophic inward remodeling and an increased distensibility. Vessels from type 2D patients demonstrated hypertrophy, a further increase in distensibility, and a highly significant loss of myogenic responsiveness compared with patients with EH and control patients. Vasoconstrictor function to norepinephrine was normal in patients with type 2D and type 2D+H and EH. Endothelium-dependent dilation was normal in patients with EH but abnormal in patients with type 2D and type 2D+H. There was a significant correlation between dilator impairment and the degree of dyslipidemia recorded in all groups. These results demonstrate vascular hypertrophy in small arteries from patients with type 2D. This could be a consequence of impaired myogenic responsiveness, which will increase wall stress for a given intraluminal pressure, which may be a stimulus for vascular hypertrophy. A substantial proportion of endothelial dysfunction can be attributed to an effect of the abnormal lipid profile seen in such patients.


The effect of nutrition on testicular growth in mature Merino rams involves mechanisms that are independent of changes in GnRH pulse frequency.
In mature Merino rams, changes in diet to below or above the requirements for maintenance of body weight lead to changes in gonadotrophin secretion and testicular growth. However, the effects on testicular growth persist for much longer than those on LH and FSH secretion so that the gonadal and gonadotrophin responses are poorly correlated over time. This suggests that the gonadal effects may be partly independent of changes in the hypothalamic secretion of GnRH, an hypothesis tested in this study. In a short-term experiment (November, late spring, non-breeding season), we tested whether a high frequency of exogenous GnRH pulses could override the endogenous system and mimic the change in gonadotrophins seen in rams fed a high plane of nutrition. Mature Merino rams (scrotal circumference (mean +/- S.E.M.) 33.6 +/- 0.5 cm, body weight (mean +/- S.E.M.) 59.0 +/- 0.9 kg) were fed 900 g chaff + 1.6 kg lupin grain (High diet) or 360 g chaff + 60 g lupin grain (Low diet) and infused with 8 pulses of GnRH or saline daily for 5 weeks (n = 5/group). Blood was sampled every 20 min for 12 h on days-1 and 14 relative to the start of treatments. Relative to pre-treatment levels, LH pulse frequency and FSH concentrations were decreased on day 14 in saline-infused rams fed the Low diet and increased in saline-infused rams fed the High diet (P < 0.001). In GnRH-infused rams, gonadotrophin secretion was not affected by diet and the patterns of secretion of LH and FSH were similar to those in saline-infused rams fed the High diet. This model was used for a more complete endocrine analysis in a longer experiment designed to test the hypothesis that the effect of nutrition on testicular growth is partly independent of changes in the secretion of GnRH. The same treatments were imposed for 35 days on a different group of similar rams in March (autumn, mid-breeding season). Body weight and scrotal circumference were measured weekly and blood was sampled on days -1 and 14. On days -1 and 35, testosterone secretion in response to LH was tested by injecting exogenous ovine LH (NIADDK-oLH-25; 200 ng/kg body weight) to all rams. Body weight increased in rams fed the High diet and decreased in those fed the Low diet (P < 0.001) and was not affected by treatments as in experiment 1.(ABSTRACT TRUNCATED AT 400 WORDS)


Direct likelihood analysis versus simple forms of imputation for missing data in randomized clinical trials.
In many clinical trials, data are collected longitudinally over time. In such studies, missingness, in particular dropout, is an often encountered phenomenon. We discuss commonly used but often problematic methods such as complete case analysis and last observation carried forward and contrast them with broadly valid and easy to implement direct-likelihood methods. We comment on alternatives such as multiple imputation and the expectation-maximization algorithm. We apply these methods in particular to data from a study with continuous outcomes. The outcomes are modelled using a general linear mixed-effects model. The bias with CC and LOCF is established in the case study and the advantages of the direct-likelihood approach shown. We have established formal but easy to understand arguments for a shift towards a direct-likelihood paradigm when analysing incomplete data from longitudinal clinical trials, necessitating neither imputation nor deletion.


Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording.
Parotid swelling (PSW) is a major predictor of non-Hodgkin's lymphoma (NHL) in primary SS (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localization was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localization of NHL at onset. PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to >12 months. NHL was prevalently localized in the parotid glands of the cases. A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localizes in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis.


Amelioration of hepatocellular integrity and inhibition of sinusoidal oxidative stress by N-acetylcysteine pretreatment in cold ischemia-reperfusion injury of rat liver.
Further improvements of donor liver preservation are still required in liver transplantation. In the present study, we investigated whether intraportal injection of N-acetylcysteine (NAC) 15 min before flush-out of UW solution (NAC pretreatment) improves liver dysfunction after cold preservation or has a protective effect on sinusoidal oxidative stress. The effect of NAC pretreatment was examined using an isolated perfused rat liver model. The NAC pretreatment significantly reduced sinusoidal oxidative stress relative to a control dextrose 5% injection. Under a glutathione-depleted condition produced by L-buthionine-[S-R]-sulfoximine, the NAC pretreatment also significantly reduced hepatocellular as well as sinusoidal oxidative stress, resulting in improvement of hepatocelllar integrity relative to a control dextrose 5% injection.


A radiation hybrid map of the rat genome containing 5,255 markers.
A whole-genome radiation hybrid (RH) panel was used to construct a high-resolution map of the rat genome based on microsatellite and gene markers. These include 3,019 new microsatellite markers described here for the first time and 1,714 microsatellite markers with known genetic locations, allowing comparison and integration of maps from different sources. A robust RH framework map containing 1,030 positions ordered with odds of at least 1,000:1 has been defined as a tool for mapping these markers, and for future RH mapping in the rat. More than 500 genes which have been mapped in mouse and/or human were localized with respect to the rat RH framework, allowing the construction of detailed rat-mouse and rat-human comparative maps and illustrating the power of the RH approach for comparative mapping.


Iron complexes of (e)- and (z)-1,2-dichlorodisilenes.
Novel disilene-iron complexes [(E)- (1E) and (Z)-(eta2-R3SiClSi=SiClSiR3)Fe(CO)4 (1Z), SiR3 = tBu2MeSi] were synthesized by the reaction of the corresponding tetrachlorodisilane with an excess amount of K2Fe(CO)4, and the structures of 1E and 1Z were determined by X-ray crystallography. These complexes constitute not only the first transition-metal complexes with E,Z-isomerism but also the first complexes with halogen-substituted disilene ligands. The initial formation of 1Z during the synthetic reaction and the slow one-way isomerization of 1Z to 1E are rationalized by the intervention of the corresponding silylene complex (R3SiCl2Si)(R3Si)Si=Fe(CO)4.


Synthetic Lethality in PTEN-Mutant Prostate Cancer Is Induced by Combinatorial PI3K/Akt and BCL-XL Inhibition.
The bone-conserved metastatic phenotype of prostate cancer is a prototype of nonrandom metastatic behavior. Adhesion of prostate cancer cells to fibronectin via the integrin α5 (ITGA5) has been proposed as a candidate bone marrow niche localization mechanism. We hypothesized that the mechanisms whereby ITGA5 regulates the adhesion-mediated survival of prostate cancer cells will define novel therapeutic approaches. ITGA5 shRNA reduced expression of BCL-2 family members and induced apoptosis in PC-3 cells. In these PTEN-mutant cells, pharmacologic inhibition of the PI3K signaling pathway in combination with ITGA5 knockdown enhanced apoptosis. Chemical parsing studies with BH3 mimetics indicated that PI3K/Akt inhibition in combination with BCL-XL-specific inhibition induces synergistic apoptosis specifically in PTEN-mutant prostate cancer cells, whereas single-agent PI3K/Akt inhibitors did not. Given the importance of PTEN loss in the progression of prostate and other cancers, synthetic lethality induced by combinatorial PI3K/Akt and BCL-XL inhibition represents a valuable therapeutic strategy. Activation of the PI3K pathway through PTEN loss represents a major molecular pathway in the progression of prostate and other cancers. This study defines a synthetic lethal therapeutic combination with significant translational potential. Synthetic lethality in PTEN-mutant prostate cancer cells with combined PI3K/Akt and BCL-XL inhibition. PTEN-mutant prostate cancer cells expressing ITGA5 bind to fibronectin in the putative bone marrow niche and transduce survival signals to BCL-XL Additional PTEN-regulated signals independent of the PI3K/Akt pathway likely feed into the BCL-XL-regulated survival program to explain synthetic lethality observed with the combination.Visual Overview: http://mcr.aacrjournals.org/content/early/2016/12/02/1541-7786.MCR-16-0202/F1.large.jpg. Mol Cancer Res; 14(12); 1176-81. ©2016 AACR.


Removal of Ingested Magnetic Bodies via Laparoscopic Appendectomy.
Ingestion of a foreign body is a frequent diagnosis in the pediatric population. In a small percentage of cases, foreign bodies themselves are strong magnets, and swallowing of multiple magnetic bodies can lead to serious complications in the gastrointestinal tract. Two consecutive case reports of patients who swallowed two magnetic beads are presented. In both cases, the abdominal radiograph described two magnets in contact, one in the area of the left hypochondrium and one in the right hypogastrium. Attempts of endoscopic localization and removal were unsuccessful. Due to the failure of magnet progression, laparoscopic revision of the abdominal cavity was indicated in both patients on the 25th and 4th day after swallowing. Using the magnetic forces between the magnets and the laparoscopic instruments, the foreign bodies were localized in the appendix of the first patient and in the cecum of the other one. The magnets were extracted together with the removal of the appendix in both patients. This is one of the first articles describing the successful extraction of foreign magnetic bodies from the gastrointestinal tract via laparoscopic appendectomy.


Aspergillus airway colonization and invasive disease after lung transplantation.
Invasive Aspergillus is an important cause of morbidity and mortality among lung transplant recipients. The diagnosis can be difficult and treatment is often unsuccessful so many centers preemptively treat all Aspergillus airway isolates to prevent invasive disease. This approach is untested as little is known about the relationship between Aspergillus airway colonization and invasive disease. This study was undertaken to evaluate the incidence of Aspergillus airway colonization after lung transplantation and the risk of invasive disease after colonization. All cultures and histologic specimens obtained from a consecutive series of 151 lung transplant cases were reviewed for the presence of Aspergillus and compared with clinical data. Aspergillus was isolated from the airway in 69 (46%) of 151 transplant recipients. Invasive disease occurred in five cases and was uniformly fatal, accounting for 13% of all posttransplant deaths. Results of cytologic examination of BAL fluid were normal in all cases of invasive disease and cultures were positive in only one of five patients prior to invasion. Invasive disease occurred exclusively in patients who died or were colonized with Aspergillus fumigatus within the first 6 months posttransplant. Patients growing A. fumigatus from the airway during the first 6 months were 11 times more likely to develop invasive disease relative to those not colonized. Aspergillus airway colonization after lung transplantation is common and in most cases, transient. In contrast, invasive Aspergillus disease is less common, but fatal. Bronchoscopy with cytologic examination and fungal culture are not sensitive or timely predictors of invasive disease. Invasive Aspergillus occurred only in patients initially colonized with A. fumigatus within the first 6 months posttransplant. A trial of empiric anti-Aspergillus therapy limited to the first 6 months posttransplant may be warranted.


Cancer vaccines, a critical review--Part I.
Cancer vaccines are more properly referred to as 'active specific immunotherapy', and are used to treat cancers rather than to prevent them, at least at present. Vaccines augment already established tumor immunity, are far more specific against the tumor than cytokines, have little or no toxicity, and thus may easily be combined with other types of immunotherapy. They also elicit immunological memory, which may check recurrence of the tumor. Melanoma vaccines have received the most attention thus far. Among the several vaccines in clinical trials are whole cell lysates, such as Melacine, hapten-treated autologous melanoma cells (M-Vax) and irradiated allogeneic cells (CancerVax). Regressions of metastatic nodules have been noted with each preparation. Controlled trials of Melacine indicate prolongation of survival in patients with resected stage IIB disease, particularly those with one or more of the following HLA class I alleles: HLA-A2 or -A28 (-A6802), HLA-B12, -44 or -45, and HLA-C3. A combination of interferon-alpha2b and Melacine appears to enhance the anti-tumor response in advanced (stage IV) disease, and is being tested in a large randomized controlled trial in resected stage III disease. An irradiated autologous colon carcinoma vaccine has improved relapse-free survival in resected stage II disease (Dukes B) in a controlled trial. Second-generation whole cell vaccines include those incorporating genes such as GM-CSF or CD80 (B7-1) to improve immunogenicity, and the use of immunogenic cell membranes such as large multivalent immunogen (LMI). Upregulation of HLA class II molecules and concomitant inhibition of the Ii molecule are also being explored as a strategyfor improved presentation of tumor-associated antigens in vaccines. Complex whole cell-derived vaccines have given clinically superior responses compared to vaccines containing well-defined antigens, such as peptides or gangliosides; however, well-defined vaccines are theoretically more desirable because of their reproducibility.


Intercensal population change in the Belfast urban area 1971-91: the correlates of population increase and decrease in a divided society.
"This paper analyses population change in the Belfast Urban Area (BUA) [of Northern Ireland] between 1971 and 1991 in its socio-economic context to understand the nature of urban social change. Although considering religious factors as a cause of population change, the research compares the BUA with other urban areas and relates developments in Belfast to some literature on sociospatial polarisation and the ¿underclass'.... The results suggest that population change is not driven by explicitly religious factors, the relationship between religion and socio-economic well-being has changed, and that changes in religious mixing and segregation occur in many contexts. The BUA is like other urban areas, albeit with unique features arising from the influence of religion."