Granulocyte-macrophage colony-stimulating factor and fluconazole enhance anti-cryptococcal activity of monocytes from AIDS patients.
To investigate the effect of human recombinant granulocyte-macrophage colony-stimulating factor (hrGM-CSF) and fluconazole on anti-cryptococcal activity of monocytes from AIDS patients and normal subjects. The effect of GM-CSF and fluconazole on fungistatic and fungicidal activity of monocytes was studied in an in vitro system. Monocytes were treated in vitro with hrGM-CSF and fluconazole or either agent alone for 24 or 48 h, and fungistatic and fungicidal activity was evaluated in a colony-forming unit inhibition assay. CD11b/CD18 expression in monocytes was measured by flow cytometry analysis. Superoxide anion generation by peripheral blood monocytes was measured in the presence of pre-opsonized zymosan. Defective antifungal capacity of monocytes from AIDS patients was observed. GM-CSF treatment of monocytes from AIDS patients increased fungistatic activity, and the combination of hrGM-CSF and fluconazole resulted in fungicidal activity. The mechanisms involved in the GM-CSF-mediated effect appeared to be mediated by (i) enhancement of phagocytic activity, (ii) increase of superoxide anion generation, and (iii) upregulation of CD11b/CD18 expression on the monocyte surface. Our data highlight the effect of GM-CSF on anti-cryptococcal activity of human monocytes and show a synergistic effect of GM-CSF with fluconazole, suggesting a new therapeutic strategy in the treatment of cryptococcosis.


Impact of stroke center certification on rt-PA thrombolysis after acute ischemic stroke in South China from 2015 to 2020.
In China, stroke center certification was launched in 2015, but little is known about its impact on intravenous thrombolysis. This study aimed to evaluate the effects of stroke center certification on the use of intravenous thrombolysis during a five-year period in South China. We retrospectively collected data regarding the use of recombinant tissue plasminogen activator (rt-PA) in 21 cities of Guangdong from 2015 to 2020. The annual thrombolysis rate was defined as the number of patients who underwent intravenous rt-PA therapy divided by the number of those who had acute ischemic stroke within the same year. The density of stroke centers was calculated as the number of stroke centers divided by the corresponding residents. Spearman's correlation analysis was used to determine the correlations between the annual thrombolysis rates and the number/density of stroke centers. Paired t-test was used to compare differences in growth in annual thrombolysis rates before and after having stroke centers. From 2015 to 2020, the annual rt-PA thrombolysis rates of Guangdong increased from 1.4% to 7.2%, which was accompanied by an increase in the number of stroke centers from 0 to 82 and density of stroke centers from 0.00 to 0.71 per million population. The average annual rt-PA use in stroke centers was higher than that in non-stroke centers from 2016 to 2020 (all P < 0.05). There was a positive correlation of annual thrombolysis rates with the number of stroke centers (r = 1.00, P = 0.0028) and with the density of stroke centers in the 21 cities from 2018 to 2020 (all P < 0.05). The growth in annual thrombolysis rates significantly accelerated at the city-level after having stroke centers (1.55%/y vs. 0.77%/y, P < 0.001). Stroke center certification may partially drive the increased use of rt-PA thrombolysis. Stroke center certification should be continually promoted to facilitate access to intravenous thrombolysis for patients with acute ischemic stroke.


Making sense of it: roles of the sensory circumventricular organs in feeding and regulation of energy homeostasis.
Obesity is associated with significant health risks including stroke and heart disease. The prevalence of obesity has dramatically increased over the past 20 years. Although the development of obesity is clearly related to changing lifestyles, the central nervous system plays a key role in regulation of energy balance. To develop effective strategies for treating obesity, we must gain a clearer understanding of the neuro-circuitry and signaling mechanisms involved. Toward this end, recent progress has been made in the understanding of the roles played by the sensory circumventricular organs (CVOs) of the brain. These areas lack the normal blood-brain barrier and thus act as transducers of signals between the blood, other centers in the brain, and the cerebrospinal fluid. This review focuses on the roles played by the sensory CVOs in detecting and responding to a number of signals that carry information regarding nutritional status, including cholecystokinin, amylin, ghrelin, peptide YY, pancreatic polypeptide, leptin, adiponectin, and glucose.


Psoriatic Arthritis: What the Dermatologist needs to Know, Part 1.
Psoriatic arthritis is defined as inflammatory arthritis occurring in patients with psoriasis and is classified as a seronegative spondyloarthropathy associated with human leukocyte antigen B27. Between 25 and 35% of patients with psoriasis go on to develop psoriatic arthritis during the course of their disease. Given that the skin is affected before the joints in most cases, the dermatologist must be able to recognize the signs and symptoms in order to make a diagnosis and start the most appropriate treatment. This review aims to cover key aspects of the initial diagnostic workup and clinical evaluation. It examines the epidemiology, pathogenesis, and manifestations of psoriatic arthritis, as well as the complementary tests and diagnostic tools the dermatologist should be aware of in order to make the correct diagnosis.


Clinicopathological analysis of 502 patients with oral squamous cell carcinoma with special interest to distant metastasis.
Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Distant metastasis (DM) especially bone metastasis (BM) may reduce patients' quality of life and affects the clinical outcome. We performed clinicopathological analysis of 502 patients with OSCC undergoing radical surgery in order to evaluate the correlation values of clinicopathological features for OSCC with special interest in DM. DM was found in 54 cases and among them 44 and 25 cases had pulmonary metastasis (PM) and BM, respectively. Advanced T stage, positive N stage, lower histologic grade and higher score YK classification were the independent significant prognostic factors found in our series of 502 cases of OSCC. Positive lymph node was the most important prognostic factors in DM and BM; on the other hand, in PM, it was lower histological grade. All patients with BM except one had vertebral bone metastasis. These characteristics of DM, including BM and PM, of OSCC are useful for understanding the metastatic process of OSCC.


Device implant technique and consideration of body image: specific procedures for implantable cardioverter defibrillators in female patients.
The purpose of this paper is to describe the psychological effects of implantable cardioverter defibrillator (ICD) implantation in female patients and to make clinical recommendations for providers to optimize health outcomes for women. Traditional ICD implantation produces visible scarring. Changes in physical appearance affect body image in all ICD recipients but may be more onerous in female ICD recipients. Electrophysiologists have described cosmetic approaches to device placement that appear promising and may warrant consideration in female patients. Active discussion and consideration of alternative device implant techniques are indicated in female patients. Female patients should also be given time to make preoperative decisions, and family members should be engaged in decision making. The investigation of cosmetic implants is noteworthy and could improve quality of life, adjustment, and psychological fitness of female ICD recipients.


Magnesium transport through the basal plasma membrane of larval malpighian tubules of Drosophila hydei studied by electron probe X-ray microanalysis.
Magnesium besides calcium is the most important excretion product. In the anterior Malpighian tubules of Drosophila, excretion of magnesium takes place via the hindgut by proteoglycan containing concretions. This study reports on magnesium transport through the basal plasma membrane of the principal cells of the proximal segment of the anterior Malpighian tubules. Measurements by electron probe X-ray microanalysis indicate the existence of two antiporters which transfer magnesium in still unknown stoichiometry from the hemolymph space into the cell: Mg/H and Mg/Na.


Air quality prediction by machine learning models: A predictive study on the indian coastal city of Visakhapatnam.
Clean air is critical component for health and survival of human and wildlife, as atmospheric pollution is associated with a number of significant diseases including cancer. However, due to rapid industrialization and population growth, activities such as transportation, household, agricultural, and industrial processes contribute to air pollution. As a result, air pollution has become a significant problem in many cities, especially in emerging countries like India. To maintain ambient air quality, regular monitoring and forecasting of air pollution is necessary. For that purpose, machine learning has emerged as a promising technique for predicting the Air Quality Index (AQI) compared to conventional methods. Here we apply the AQI to the city of Visakhapatnam, Andhra Pradesh, India, focusing on 12 contaminants and 10 meteorological parameters from July 2017 to September 2022. For this purpose, we employed several machine learning models, including LightGBM, Random Forest, Catboost, Adaboost, and XGBoost. The results show that the Catboost model outperformed other models with an R2 correlation coefficient of 0.9998, a mean absolute error (MAE) of 0.60, a mean square error (MSE) of 0.58, and a root mean square error (RMSE) of 0.76. The Adaboost model had the least effective prediction with an R2 correlation coefficient of 0.9753. In summary, machine learning is a promising technique for predicting AQI with Catboost being the best-performing model for AQI prediction. Moreover, by leveraging historical data and machine learning algorithms enables accurate predictions of future urban air quality levels on a global scale.


Sonographic demonstration of air-fluid levels in abdominal abscesses.
Abdominal sonograms were obtained for three patients who had clinically suspected abscesses. There were abnormal fluid collections that, when viewed from a posterior position, demonstrated a horizontal line representing an air-fluid level. Abdominal abscesses containing air were confirmed by both horizontal beam radiography and surgery. Since ultrasound examination is frequently performed before radiography in patients thought to have abscesses, it is important to look for and recognize the sonographic appearance of an air-fluid level.


Comparison between indocyanine green angiography and fluorescein angiography in normal cats.
To study a new approach to indocyanine green (ICG) angiography for contrasting the ocular fundus in cats. Six healthy laboratory cats. Fluorescein (FLUO) and ICG angiography were performed using an infrared-sensitive charged coupled device-equipped fundus camera on sedated cats. At 12.3 ± 3.4 s after ICG administration, the choroidal arteries could be seen extending radially from the optic disk. The choroidal veins became apparent at 16.2 ± 4.1 s alongside the choroidal arteries. Gradual fading of the choroidal vessels began 5.8 ± 1.5 min postdye administration and diffuse fluorescence of the fundus appeared. Diffuse fluorescence of the optic disk faded at about 18.8 ± 2.9 min. Mean arterial blood pressure at 1 and 3 min after ICG administration showed no significant change when compared to pre-administration (P > 0.05). However, 5 min (P = 0.054) and 10 min (P < 0.05) postadministration, a significant drop in blood pressure occurred. The time lapse between FLUO administration and its appearance in the ocular fundus was 15.7 ± 3.8 s. Retinal veins became apparent at 22.0 ± 3.6 s alongside retinal arteries. At 31.2 ± 4.1 s, full venous fluorescence was visualized throughout the entire fundus. While FLUO angiography shows only the retinal vessels, ICG angiography enabled visualization of the choroidal vasculature. ICG angiography provides clear resolution while remaining reliable and simple; thus, a combination of ICG and FLUO angiography shows promise as a diagnostic aid for clinical evaluation of various chorioretinal diseases in cats.


Multidimensional electronic spectroscopy in high-definition-Combining spectral, temporal, and spatial resolutions.
Over the past two decades, coherent multidimensional spectroscopies have been implemented across the terahertz, infrared, visible, and ultraviolet regions of the electromagnetic spectrum. A combination of coherent excitation of several resonances with few-cycle pulses, and spectral decongestion along multiple spectral dimensions, has enabled new insights into wide ranging molecular scale phenomena, such as energy and charge delocalization in natural and artificial light-harvesting systems, hydrogen bonding dynamics in monolayers, and strong light-matter couplings in Fabry-Pérot cavities. However, measurements on ensembles have implied signal averaging over relevant details, such as morphological and energetic inhomogeneity, which are not rephased by the Fourier transform. Recent extension of these spectroscopies to provide diffraction-limited spatial resolution, while maintaining temporal and spectral information, has been exciting and has paved a way to address several challenging questions by going beyond ensemble averaging. The aim of this Perspective is to discuss the technological developments that have eventually enabled spatially resolved multidimensional electronic spectroscopies and highlight some of the very recent findings already made possible by introducing spatial resolution in a powerful spectroscopic tool.


A new mouse model for mania shares genetic correlates with human bipolar disorder.
Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.


The role of intraoperative narrow-band imaging in transoral laser microsurgery for early and moderately advanced glottic cancer.
Trans-oral laser microsurgery is an established technique for the treatment of early and moderately advanced laryngeal cancer. The authors intend to test the usefulness of narrow-band imaging in the intraoperative assessment of the larynx mucosa in terms of specifying surgical margins. Forty-four consecutive T1-T2 glottic cancers treated with trans-oral laser microsurgery Type I-VI cordectomy were presented. Suspected areas (90 samples/44 patients) were biopsied under the guidance of narrow-band imaging and white light and sent for frozen section. Our study revealed that 75 of 90 (83.3%) white light and narrow-band imaging-guided samples were histopathologically positive: 30 (40%) were confirmed as carcinoma in situ or invasive carcinoma and 45 (60%) as moderate to severe dysplasia. In 6 patients mucosa was suspected only in narrow-band imaging, with no suspicion under white light. Thus, in these 6 patients 18/90 (20%) samples were taken. In 5/6 patients 16/18 (88.8%) samples were positive in frozen section: in 6/18 (33.3%) carcinoma (2 patients), 10/18 (66.6%) severe dysplasia was confirmed (3 patients). In 1 patient 2/18 (11.1%) samples were negative in frozen section. Presented analysis showed, that sensitivity, specificity and accuracy of white light was 79.5%, 20% and 71.1% respectively, while narrow-band imaging was 100%, 0.0% and 85.7%, respectively. The intraoperative use of narrow-band imaging proved to be valuable in the visualization of suspect areas of the mucosa. Narrow-band imaging confirms the suspicions undertaken in white light and importantly, it showed microlesions beyond the scope of white light.


An animal model for progressive multifocal leukoencephalopathy.
JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML), a demyelinating disease in humans. The disease, once considered fatal, is now managed with immune reconstitution therapy; however, surviving patients remain severely debilitated. Until now, there has been no animal model to study JCV in the brain, and research into treatment has relied on cell culture systems. In this issue of the JCI, Kondo and colleagues developed a mouse model in which human glial cells are engrafted into neonatal mice that are both immunodeficient and deficient for myelin basic protein. When challenged intracerebrally with JCV, these mice exhibit some of the characteristics of PML. The establishment of this chimeric mouse model is a significant advance toward understanding the mechanism of JCV pathogenesis and the identification of drugs to treat or prevent the disease.


Clinical effect of ticagrelor administered in acute coronary syndrome patients following percutaneous coronary intervention.
The aim of the present study was to retrospectively analyze the clinical effect and safety of ticagrelor administration in acute coronary syndrome (ACS) patients following percutaneous coronary intervention (PCI). In total, 203 patients were enrolled, who were confirmed with ACS between March 2013 and May 2013, and had successfully undergone PCI. The patients were randomly divided into two groups, including the clopidogrel (group A, n=108) and ticagrelor groups (group B, n=95). Patients in group A were treated with a 600 mg loading dose of clopidogrel followed by 75 mg/day clopidogrel plus 100 mg/day aspirin. Patients in group B received a 180 mg loading dose of ticagrelor followed by 90 mg ticagrelor twice daily plus 100 mg/day aspirin. Light transmission aggregometry was performed to measure the platelet aggregation rate prior to and following 4 weeks of anti-platelet drug treatment. In addition, the rate of cardiovascular events and the adverse drug reactions were recorded within a 1-year treatment period. Compared with the clopidogrel group, the rate of recurrent angina in the ticagrelor group was significantly lower (P=0.05). However, the rate of dyspnea in the ticagrelor group was significantly higher when compared with that in the clopidogrel group (P=0.03). After 4 weeks of treatment, the reduction in the platelet aggregation rate was significantly different between the two groups (P<0.05). Therefore, ticagrelor, which is a novel antiplatelet aggregation drug, may reduce the rate of the adverse cardiovascular events in ACS patients following PCI, but a higher incidence of side-effects, such as dyspnea, may be observed.


Eplerenone Modulates Interleukin-33/sST2 Signaling and IL-1β in Left Ventricular Systolic Dysfunction After Acute Myocardial Infarction.
This study aimed to evaluate the role of eplerenone on the modulation of interleukin (IL)-1β and IL-33/sST2 signaling pathway in an experimental model of left ventricular (LV) systolic dysfunction after acute myocardial infarction (MI). MI rats were randomly assigned to no treatment (MI group, n = 10), to receive eplerenone (Epl group, n = 10), or anakinra (Ana group, n = 10). LV function was assessed by echocardiography. IL-1β, IL-33/sST2, and cardiac fibrosis biomarkers were analyzed by quantitative real-time reverse transcription polymerase chain reaction (PCR). Rats with MI showed significant reduction of LV systolic function, but treatment with eplerenone or anakinra improved left ventricular end-diastolic volume (LVEDV) and LVEDV/mass values. In the infarcted myocardium, compared with sham animals, the MI group had higher level of IL-33, sST2, and IL-1β, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with anakinra downregulated sST2 but with no effects on IL-33. Eplerenone reduced levels of sST2 and IL-1β significantly. Both anakinra and eplerenone treatments were associated with lower levels of fibrosis and inflammatory markers. IL-1β could induce expression of sST2, accelerating the progression of heart failure after acute MI. Eplerenone could improve LV function by reducing expression of IL-1β and sST2.


SILAC-based complexome profiling dissects the structural organization of the human respiratory supercomplexes in SCAFIKO cells.
The study of the mitochondrial respiratory chain (MRC) function in relation with its structural organization is of great interest due to the central role of this system in eukaryotic cell metabolism. The complexome profiling technique has provided invaluable information for our understanding of the composition and assembly of the individual MRC complexes, and also of their association into larger supercomplexes (SCs) and respirasomes. The formation of the SCs has been highly debated, and their assembly and regulation mechanisms are still unclear. Previous studies demonstrated a prominent role for COX7A2L (SCAFI) as a structural protein bridging the association of individual MRC complexes III and IV in the minor SC III2 + IV, although its relevance for respirasome formation and function remains controversial. In this work, we have used SILAC-based complexome profiling to dissect the structural organization of the human MRC in HEK293T cells depleted of SCAFI (SCAFIKO) by CRISPR-Cas9 genome editing. SCAFI ablation led to a preferential loss of SC III2 + IV and of a minor subset of respirasomes without affecting OXPHOS function. Our data suggest that the loss of SCAFI-dependent respirasomes in SCAFIKO cells is mainly due to alterations on early stages of CI assembly, without impacting the biogenesis of complexes III and IV. Contrary to the idea of SCAFI being the main player in respirasome formation, SILAC-complexome profiling showed that, in wild-type cells, the majority of respirasomes (ca. 70%) contained COX7A2 and that these species were present at roughly the same levels when SCAFI was knocked-out. We thus demonstrate the co-existence of structurally distinct respirasomes defined by the preferential binding of complex IV via COX7A2, rather than SCAFI, in human cultured cells.


Total (1)H NMR assignment of 3β-acetoxypregna-5,16-dien-20-one.
This work describes the total and unambiguous assignment of the 750 MHz (1)H NMR spectrum of 3β-acetoxypregna-5,16-dien-20-one or 16-DPA (1), the well-known intermediate utilized in the synthesis of biological important commercial steroids. The task was accomplished by extracting the coupling constant values in the overlapped spectrum region by HSQC, and using these values in the (1)H iterative full spin analysis integrated in the PERCH NMR software. Comparison of the experimental vicinal coupling constants of 1 with the values calculated using Altona provides an excellent correlation. The same procedure, when applied to the published data of progesterone (2) and testosterone (3), afforded an acceptable correlation for 2 and a poor correlation for 3. In the last case, this suggested the reassignment of all four vicinal coupling constants for the methylene signals at the C-15 and C-16 positions, demonstrating the utility of this methodology.


Platelet aggregation in partially obstructed vessels and its elimination with aspirin.
In 35 open chest anesthetized dogs coronary and aortic blood flow were measured with electromagnetic flowmeters while aortic and distal coronary blood pressure and an epicardial ECG were recorded. A fixed amount of stenosis (60-80%) was produced in the coronary artery by an externally applied plastic cylinder. In 24 of the 35 dogs the coronary blood flow showed cyclical reductions to near zero, with a sudden spontaneous return to near control levels. During reduced flow the epicardial ECG showed ST-segment depression suggestive of ischemia, and ventricular premature beats were often noted. Six animals died acutely during episodes of reduced flow. After 35 mg/kg of aspirin were given intravenously the cyclical reductions in coronary blood flow were abolished and the in vitro platelet aggregations were reduced from a control of 62.1 +/- 15 units (Born technique) to an average of 23.7 +/- 12 units. Histologic sections of the narrowed coronary artery obtained when coronary flow was reduced show an amorphous mass in the lumen which was thought to be a platelet aggregate. Perhaps a similar process of platelet aggregation occurs in the stenosed coronary arteries in man, producing acute coronary obstruction, ischemia, and sudden death.


Falls among stroke survivors: an online survey on perceptions and approaches among physiotherapists in Flanders.
To describe physiotherapists' perceptions of fall risk and appropriate fall prevention interventions in rehabilitating stroke patients. A web-based survey addressed to physiotherapy units on a stroke unit, general neurology department or rehabilitation ward/centre in Flanders. Hospital response rate was 66.3%. Sixty-five physiotherapy units were taken into account. About 84.6% recognised falls among stroke patients as an essential problem and 73.8% thought falls interfered with the outcome. About 56.9% agreed with the need of a standardised fall assessment at the beginning of the treatment and only 36.9% reported that on their department stroke patients are screened on risk of falling. The most used fall risk assessments are: Berg Balance scale and Tinetti-test. The most popular fall prevention measures are: specific exercises for balance, gait and functional abilities (100%), informative education (92.3%) and adapting or intensifying the treatment after a fall (81.5%). Physiotherapy units acknowledge falls as an essential threat, implying a need for risk screening and prevention. However, results reveal that perception of the necessity of such screening is lower and that the performance is even less. This discrepancy underlines the necessity of guidelines and education of therapists working with stroke patients.


Prognostic significance of nuclear receptor coactivator-3 overexpression in primary cutaneous melanoma.
To assess the prognostic significance of nuclear receptor coactivator-3 (NCOA3) overexpression in primary cutaneous melanoma. NCOA3 expression was assessed using immunohistochemical analysis of a melanoma tissue microarray (TMA) containing primary melanomas from 343 patients with defined histology and follow-up. The impact of the presence or absence of various prognostic factors on relapse-free survival (RFS) and disease-specific survival (DSS) of melanoma patients was assessed using Cox regression and Kaplan-Meier analysis. The impact of presence or absence of various factors on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis. Increasing degree of NCOA3 expression was significantly predictive of SLN metastasis (P = .013) and the mean number of SLN metastases (P = .031). Kaplan-Meier analysis demonstrated a significant association between NCOA3 overexpression and reduced RFS (P = .021) and DSS (P = .030). Logistic regression analysis revealed increasing degree of NCOA3 expression to be an independent predictor of SLN status (P = .017). Multivariate Cox regression analysis showed the independent impact of NCOA3 expression on RFS (P = .0095) and DSS (P = .021). NCOA3 was the most powerful factor predicting DSS, outperforming tumor thickness and ulceration. These results identify NCOA3 as a novel, independent marker of melanoma outcome, with a significant impact on SLN metastasis, RFS, and DSS.


Multifunctional Ligands Targeting Phosphodiesterase as the Future Strategy for the Symptomatic and Disease-Modifying Treatment of Alzheimer's Disease.
Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by cognitive impairments such as memory loss, decline in language skills, and disorientation that affects over 46 million people worldwide. Patients with AD also suffer from behavioral and psychological symptoms of dementia that deteriorate their quality of life and lead to premature death. Currently available drugs provide modest symptomatic relief but do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of dementia. A large body of evidence indicates that impaired signaling pathways of cyclic-3',5'- Adenosine Monophosphate (cAMP) and cyclic-3',5'-guanosine Monophosphate (cGMP) may contribute to the development and progression of AD. In addition, Phosphodiesterase (PDE) inhibitors, commonly known as cAMP and/or cGMP modulators, were found to be involved in the phosphorylation of tau; aggregation of amyloid beta; neuroinflammation; and regulation of cognition, mood, and emotion processing. The purpose of this review was to update the most recent reports on the development of novel multifunctional ligands targeting PDE as potential drugs for both symptomatic and disease-modifying therapy of AD. This review collected the chemical structures of representative multifunctional ligands, results of experimental in vitro and in vivo pharmacological studies, and current opinions regarding the potential utility of these compounds for the comprehensive therapy of AD. Finally, the multiparameter predictions of drugability of the representative compounds were calculated and discussed.


Female predominance and transmission distortion in the long-QT syndrome.
Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait. We investigated the distribution of alleles for the long-QT syndrome in 484 nuclear families with type 1 disease and 269 nuclear families with type 2 disease, all with fully genotyped offspring. The families were recruited in five European referral centers for the long-QT syndrome. Mutation segregation, sex ratio, and parental transmission were analyzed after correction for single ascertainment. Classic mendelian inheritance ratios were not observed in the offspring of either female carriers of the long-QT syndrome type 1 or male and female carriers of the long-QT syndrome type 2. Among the 1534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%, P<0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476 [55%]) than to male offspring (394 [45%], P=0.005). Increased maternal transmission of the long-QT syndrome mutations to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long-QT syndrome. Positive selection of the mutated alleles that cause the long-QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the offspring of affected families. Alleles for the long-QT syndrome are more often transmitted to daughters than to sons.


Health promotion in hospitals: the attitudes, beliefs and practices of hospital nurses.
This research paper explores the attitudes, beliefs and health promotion practices of hospital nurses working on acute adult wards, as demonstrated through the use of semi-structured postal questionnaires. Responses were compared with those from hospital-based occupational therapists, physiotherapists, dietitians and medical consultants, in order to examine issues of consistency and continuity between professional groups and their interaction with patients in relation to health promotion activity. The nurses are considered both as a homogeneous group and also in relation to their seniority within the profession. Results demonstrate the lack of a coherent health promotion strategy within acute care settings and highlight the differing educational needs of nurses according to their professional role within the hospital. By addressing these issues, a strategy can be developed to enhance health promotion in hospital by building on the concerns and needs identified by the nurses themselves. Research literature and analysis of this study demonstrate that whilst the current position of health promotion in hospital is generally poor, nurses are keen to integrate health promotion into their practice.


NONADAPTIVE EVOLUTION OF DISEASE RESISTANCE IN AN ANNUAL LEGUME.
Local populations of the plant Amphicarpaea bracteata often contain genetically divergent lineages that differ strongly in disease resistance toward the specialist pathogen Synchytrium decipiens. In one population, lineages with disease resistance were observed to significantly decrease in frequency over a two-year period, despite the continued presence of pathogens. Extensive self-pollination in A. bracteata restricts the opportunity for recombination of alleles affecting separate traits, resulting in strong correlations between disease resistance and other ecologically important characters, including plant morphology, phenology, and patterns of reproductive allocation. Natural selection on these correlated characters may thus cause nonadaptive changes in disease resistance. These results imply that A. bracteata's mating system is a basic constraint interfering with its adaptation to pathogen attack.


High Resistance-Training Frequency Enhances Muscle Thickness in Resistance-Trained Men.
Zaroni, RS, Brigatto, FA, Schoenfeld, BJ, Braz, TV, Benvenutti, JC, Germano, MD, Marchetti, PH, Aoki, MS, and Lopes, CR. High resistance-training frequency enhances muscle thickness in resistance-trained men. J Strength Cond Res 33(7S): S140-S151, 2019-The purpose of this study was to compare the effect a split training routine with muscle groups trained once per week (SPLIT) vs. whole-body split training routine with muscle groups trained 5 days per week (TOTAL) on neuromuscular adaptations in well-trained men. Eighteen healthy men (height = 177.8 ± 6.6 cm; total body mass = 84.4 ± 8.1 kg; age = 26.4 ± 4.6 years) were recruited to participate in this study. The experimental groups were matched according to baseline strength and then randomly assigned to 1 of the 2 experimental groups: SPLIT (n = 9) or TOTAL (n = 9). Prestudy and poststudy testing included 1RM for bench press, parallel back-squat and machine close-grip seated row, as well as an ultrasound analysis of the muscle thickness (MT) of the elbow flexors, triceps brachii, and vastus lateralis. After 8 weeks of training, no significant difference between groups was noted for all 1RM tests (p > 0.05). TOTAL induced a significantly greater increase in MT of the forearm flexors and vastus lateralis (p < 0.05). In conclusion, muscle strength increment is similar regardless of the experimental conditions studied; however, TOTAL may confer a potentially superior hypertrophic effect.


B-cell lymphoma 2 inhibitor ABT-737 induces Beclin1- and reactive oxygen species-dependent autophagy in Adriamycin-resistant human hepatocellular carcinoma cells.
ABT-737, a B-cell lymphoma 2 homology 3 mimetic, not only induces cell apoptosis by inhibiting the interaction of B-cell lymphoma 2 and Bax but also induces cell autophagy by interrupting the interaction of B-cell lymphoma 2 and Beclin1. Several recent studies have reported that ABT-737 has antitumor efficacy in diverse cancers. However, another study showed that hepatocellular carcinoma cells with high B-cell lymphoma 2 expression were resistant to ABT-737 compared to hepatocellular carcinoma cells with low B-cell lymphoma 2 expression. It was also found that ABT-737-induced autophagy is crucial for drug resistance. Here, we observed that of B-cell lymphoma 2 expression in Adriamycin-resistant human hepatocellular carcinoma HepG2/ADM cells is higher than that in human hepatocellular carcinoma HepG2 cells. Therefore, we further confirmed the mechanism and effect of autophagy induced by ABT-737 on apoptosis in HepG2/ADM cells with high B-cell lymphoma 2 expression. Our results showed that ABT-737 induced apoptosis and autophagy in time- and dose-dependent manner in HepG2/ADM cells, and this ABT-737-induced autophagy was Beclin1-dependent. In addition, we demonstrated that ABT-737 induced reactive oxygen species-mediated autophagy, and the reactive oxygen species-inhibitor N-acetyl-l-cysteine suppressed the reactive oxygen species-induced autophagy and ABT-737-induced increase in HepG2/ADM cell apoptosis. Furthermore, autophagy inhibitors increased HepG2/ADM cell apoptosis. In conclusion, our study further confirms that Beclin1- and reactive oxygen species-dependent autophagy induced by ABT-737 also plays a protective function in HepG2/ADM cells, which show B-cell lymphoma 2 expression higher than that in HepG2 cells.


Measurement of secretory IgA in serum by radioimmunoassay in patients with chronic nonalcoholic liver disease or carcinoma.
The authors describe the development of a double antibody radioimmunoassay specific for human secretory IgA (sIgA), and they report the results of measurements of serum sIgA concentrations in patients with chronic, nonalcoholic liver disease or carcinoma. Above-normal sIgA concentrations (greater than 25 micrograms/mL) were found in 22 of 38 sera from patients with chronic active liver disease and in 37 of 40 sera from patients with primary biliary cirrhosis. Markedly increased concentrations (greater than 118 micrograms/mL) were specific for primary biliary cirrhosis. Above-normal sIgA concentrations were found frequently in patients with colorectal (29/86, 34%), pancreatic (38/70, 54%), gastric (11/30, 37%), or mammary (6/46, 13%) carcinoma. An above-normal concentration of sIgA was more specific for hepatic metastases than an above-normal alkaline phosphatase activity in each type of carcinoma. The authors conclude that measurement of sIgA in serum is a useful diagnostic test in patients with chronic liver disease suspected of having primary biliary cirrhosis or in patients with carcinoma suspected of having hepatic metastases.


Trabecular stress fractures.
This study was conducted to evaluate the theory that increased rigidity in the subchondral cancellous bone and trabecular stress fractures are responsible for the development of osteoarthritis. Histological sections of the entire femoral head were examined in 80 normals, 50 cases with early degenerative changes, and 50 cases with advanced osteoarthritis. It was found that trabecular stress fractures occur normally and show no greater incidence in early osteoarthritis. Increase in thickness of the trabeculae not associated with fractures is seen, but only after considerable cartilage disruption. It is concluded that trabecular stress fractures are not of importance in the development of osteoarthritis.


The quality of life of the dentist.
That elusive concept 'quality of life', which has become a topic of increasing concern in this day among members of the dental profession, has been examined in the light of findings in the behavioral sciences and those of the medical sciences, particularly morbidity and mortality studies. A review of the literature reveals too few studies in the behavioral sciences; and those that do address the problem do so obliquely. Findings from morbidity studies are controvertible. One recent large-scale study of mortality identified no excess mortality from particular causes among United States white male dentists as a group--this included the much often talked about 'excess of suicide'. The position maintained is that the quality of life of the dentist is good relative to other professions or labors in the absence of 'hard' data to the contrary. A plea is made for additional studies in the future and a continued and cooperative association of medical and behavioral scientists to monitor the 'total health' of the profession.


Sulfide in engineered methanogenic systems - Friend or foe?
Sulfide ions are regarded to be toxic to microorganisms in engineered methanogenic systems (EMS), where organic substances are anaerobically converted to products such as methane, hydrogen, alcohols, and carboxylic acids. A vast body of research has addressed solutions to mitigate process disturbances associated with high sulfide levels, yet the established paradigm has drawn the attention away from the multifaceted sulfide interactions with minerals, organics, microbial interfaces and their implications for performance of EMS. This brief review brings forward sulfide-derived pathways other than toxicity and with potential significance for anaerobic organic matter degradation. Available evidence on sulfide reactions with organic matter, interventions with key microbial metabolisms, and interspecies electron transfer are critically synthesized as a guidance for comprehending the sulfide effects on EMS apart from the microbial toxicity. The outcomes identify existing knowledge gaps and specify future research needs as a step forward towards realizing the potential of sulfide-derived mechanisms in diversifying and optimizing EMS applications.


Adapting the self-assessment of contextual fit scale for implementation of evidence-based practices in adolescent HIV settings.
Contextual fit is an important variable in the implementation of evidence-based programs (EBPs). The objectives of the current study were to examine the psychometric properties of the adapted Self-Assessment of Contextual Fit (SACF) measure for HIV clinical care settings (calling it SACF-HIV) and explore how perceptions of contextual fit varied across two different interventions (an intervention to scale up tailored motivational interviewing and an individually focused HIV prevention intervention) and 12 clinical sites. We collected SACF-HIV data as part of a larger cross-project implementation science study (ATN 153). The study sample includes 128 clinicians, community health workers, interventionists, adherence counselors, and other members of the prevention and care team who engage in the implementation of EBPs at 12 HIV prevention and clinical care sites in the USA. We assessed the internal consistency of the SACF-HIV using Cronbach's alpha and examined the sub-dimensionality of the scale with an exploratory factor analysis. To explore concurrent validity, we examined Pearson's correlation coefficients between the adapted scale and fit-related sub-scale scores from the Evidence-Based Practice Attitudes Scale-50 (EBPAS-50). Variation in perceptions of fit by intervention was examined using descriptive statistics. Internal consistency of the adapted scale was strong (α=0.895). Factor analyses revealed two sub-scales-one capturing general insights regarding contextual fit, such as perceptions of skill, experience, and alignment with client needs (loadings ranging from .5 to .84), and a second centering perceptions regarding implementation support, such as resources and administrative support (loadings ranging from .89 to .97). Concurrent validity was supported by statistically significant correlations in the expected direction with EBPAS-50 fit-related sub-scales (r=.33-.35, p ≤ 0.05). SACF-HIV mean fit scores varied by intervention and the difference was statistically significant (2.78 vs. 2.53, p < 0.05). There are relatively few tools assessing perceptions of contextual fit in HIV clinical settings. These results suggest the 12-item adapted SACF is a reliable, valid global assessment of perceptions of contextual fit and implementation support. The SACF-HIV can be used by practitioners and researchers interested in understanding an implementation context when planning to prepare and support EBP implementation. TMI ClinicalTrials.gov NCT03681912; YMPH ClinicalTrials.gov NCT03488914.


Rapid detection of Vibrio species using liquid microsphere arrays and real-time PCR targeting the ftsZ locus.
The development of rapid and sensitive molecular techniques for the detection of Vibrio species would be useful for the surveillance of sporadic infections and management of major outbreaks. Comparative sequence analysis of the ftsZ gene in the predominant Vibrio species that cause human disease revealed distinct alleles for each examined species, including Vibrio cholerae, Vibrio parahaemolyticus and Vibrio vulnificus. Light Upon eXtension (LUX) real-time PCR assays were developed to target these species-specific polymorphisms, and were successful in rapidly differentiating the major pathogenic Vibrio species. Luminex liquid microsphere array technology was used to develop a comprehensive assay capable of simultaneously detecting V. cholerae, V. parahaemolyticus and V. vulnificus. These assays permitted the identification of a presumptive V. parahaemolyticus isolate as Vibrio alginolyticus, which was verified using additional molecular characterization.


Rapid-deployment or transcatheter aortic valves in intermediate-risk patients?
Background Transcatheter aortic valve implantation and rapid-deployment aortic valve replacement represent two emerging therapies for patients with intermediate surgical risk and severe aortic stenosis. However, head-to-head comparisons between such novel therapies are lacking. Methods Severe aortic stenosis patients with intermediate surgical risk treated with rapid-deployment valve replacement at our institution were identified and compared with a propensity-matched population of patients who underwent transcatheter aortic valve replacement. Postoperative echocardiographic findings, in-hospital and midterm clinical outcomes were compared. Results We identified 60 patients who received transcatheter ( n = 30) or rapid-deployment ( n = 30) valve replacement. On postoperative echocardiography, freedom from paravalvular regurgitation was higher in the rapid-deployment valve group ( p < 0.001), while postoperative mean transprosthetic gradient was lower in the transcatheter valve group ( p = 0.03). Permanent pacemaker implantation was required more frequently in transcatheter valve patients ( p = 0.01). Postoperative atrial fibrillation was more common in the rapid-deployment valve group ( p = 0.03). Hospital mortality was similarly low in both groups ( p = 0.33). At midterm follow-up, mortality was comparable ( p = 0.42) but the rapid-deployment valve group still had a lower degree of paravalvular regurgitation. Conclusions Transcatheter and rapid-deployment valve replacement are promising treatment options for patients with intermediate surgical risk. These two techniques are associated with specific patterns of prosthesis function and postoperative complications. Further evaluation of the clinical impact of these therapies in this patient population is needed.


The warden procedure through a posterolateral thoracotomy approach.
The Warden procedure for the correction of a right-sided partial anomalous pulmonary venous connection to the high superior vena cava is well established. It has the advantages of avoiding sinoatrial node dysfunction and pulmonary and systemic venous obstruction. In the case related here, a 3-year-old girl presented with a superior vena cava type of sinus venosus atrial septal defect and an anomalously draining right upper pulmonary vein, with bilateral superior venae cavae. Our approach to the Warden procedure was through a right posterolateral thoracotomy, which provided additional advantages.


Examining the Effectiveness, Acceptability, and Feasibility of Virtually Delivered Trauma-Focused Domestic Violence and Sexual Violence Interventions: A Rapid Evidence Assessment.
The COVID-19 pandemic has forced a rapid shift to virtual delivery of treatment and care to individuals affected by domestic violence and sexual violence. A rapid evidence assessment (REA) was undertaken to examine the effectiveness, feasibility and acceptability of trauma-focused virtual interventions for persons affected by domestic violence and sexual violence. The findings from this review will provide guidance for service providers and organizational leaders with the implementation of virtual domestic violence and sexual violence-focused interventions. The REA included comprehensive search strategies and systematic screening of and relevant articles. Papers were included into this review (1) if they included trauma-focused interventions; (2) if the intervention was delivered virtually; and (3) if the article was published in the English-language. Twenty-one papers met inclusion criteria and were included for analysis. Findings from the rapid review demonstrate that virtual interventions that incorporate trauma-focused treatment are scarce. Online interventions that incorporate trauma-focused treatment for this at-risk group are limited in scope, and effectiveness data are preliminary in nature. Additionally, there is limited evidence of acceptability, feasibility and effectiveness of virtual interventions for ethnically, culturally, and linguistically diverse populations experiencing domestic violence and sexual violence. Accessing virtual interventions was also highlighted as a barrier to among participants in studies included in the review. Despite the potential of virtual interventions to respond to the needs of individuals affected by domestic violence and/or sexual violence, the acceptability and effectiveness of virtual trauma-focused care for a diverse range of populations at risk of violence are significantly understudied.


Animal corneas as tools for the testing of antiviral compounds.
As a number of viruses can be titrated on corneas of various animals, the corneal method was used to detect antiviral activity of some derivatives of thiazolidine and related compounds with a low toxicity. In herpetic infections of rabbit cornea, 2-(1-isopropylidene)azino-3-(beta-D-ribofuranosyl)-methoxycarbonylmethylenethiazolidine-4-one showed for a mean of 2.1 greater activity than IDU. In piglet corneas, lesions produced by adenovirus type 8 were inhibited by a mean of 3.4 log CID50 by 5-(2,3,5-tribenzoyl-beta-D-ribofuranosyl)-(2H)-tetrazol and by a mean value of 3 log CID50 by 4-(2,3,5-tri-o-benzoyl-beta-D-ribofuranosyl) thiosemicarbazide. The multiple microinoculation technique of calculating corneal infectivity allows many of the advantages of sensitivity and statistical validity usually associated only with cell culture methods to be obtained from an in vivo system. Furthermore it allows observations concerning toxicity of the drug tested on the eye. We believe that this method should form a part of the "biography" of any compound seriously considered for the ocular treatment of virus diseases. This test goes a long way in bridging the gap between in vitro tests and trials in humans.


Benign intracranial hypertension with recurrent spontaneous cerebrospinal fluid rhinorrhoea treated by laparoscopic gastric banding.
We present the case of a 45-year-old woman presenting with a spontaneous cerebrospinal fluid (CSF) rhinorrhoea. A CSF leak, arising from a posterior ethmoidal left cell, was closed using an underlay procedure with a turbinate composite graft with applied fibrin glue. Twenty-three months later the CSF rhinorrhoea recurred. Recurrence was imputed to morbid obesity (BMI 48) responsible for benign intracranial hypertension. The patient underwent a laparoscopic adjustable gastric banding. CSF rhinorrhoea gradually decreased during the 12 months following surgery, in correlation with the weight loss, until total resolution was achieved. To our knowledge, this is the second reported case of a spontaneous CSF leak treated by bariatric surgery. This observation strengthens the theory that severe obesity can cause benign intracranial hypertension which can lead to CSF leak.


Beware the sophomore slump.
All the trends are positive as the insurance industry, the government and healthcare reform advocates gear up for the second year of open enrollment on the federal and state-run insurance exchanges. Competition is up. Price increases are modest. And politicians who thought they could ride Obamacare attack ads to election victory are finding most voters have moved on.


A strategic approach to the psychiatric workforce dilemma.
To help build consensus in the field of psychiatry about future psychiatric manpower needs, a 13-step strategic approach to the workforce issue is described. The steps include recognizing the importance of the assumptions that underlie workforce requirements; selecting credible and professional leadership with vision and courage; adopting a strategic plan to clarify workforce assumptions; re-examining the structure and function of established programs; preparing trainees for work in the 21st century; preserving psychiatry's humanistic tradition; enlisting the support of nonacademic psychiatrists; and reinforcing involvement in the fiscal and political aspects of medicine. They also include focusing attention on important policy issues; securing the support of patients, families, and advocates; endorsing a multidisciplinary, biopsychosocial approach to the evaluation and treatment of mental illness; minimizing divisive conflicts within and between national organizations; and developing strategic alliances with other medical disciplines. Implications of the 13-step approach are outlined for psychiatric clinicians, educators, and researchers, as well as for the organizations that serve them.


Alterations of the Dutt1/Robo1 gene in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats.
Abnormalities of tumor suppressor genes (TSGs) on chromosome 3p are known to be important for the development of human lung cancers. In the present study, we investigated alterations of the Dutt1/Robo1 gene, as a possible tumor suppressor in this region, in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine (BHP). Male Wistar rats, 6-wk-old, were given 2000 ppm BHP in their drinking water for 12 wk and maintained without further treatment until killed at wk 25. A total of 12 lung adenocarcinomas were obtained and total RNAs were extracted from each for assessment of aberrant transcripts of the Dutt1/Robo1 gene by reverse transcription (RT)-polymerase chain reaction (PCR) analysis. Aberrant transcripts bearing deletions of nucleotides (nt) 55-4318, 89-4346, 605-4221, and 929-4318 were detected in four of 12 adenocarcinomas (33.3%). Loss or reduced expression of the Dutt1/Robo1 gene was not found in any of the adenocarcinomas. Genomic DNAs extracted from six adenocarcinomas for Southern blot analysis did not show any evidence of deletion or gross rearrangement of the Dutt1/Robo1 gene. These results suggest that alterations of the Dutt1/Robo1 gene may be involved in the development of some lung adenocarcinomas induced by BHP in rats.


Black Esophagus (Acute Necrotizing Esophagitis) and Wischnewsky Lesions in a Death From Diabetic Ketoacidosis: A Possible Underlying Mechanism.
Acute esophageal necrosis (AEN), also known as black esophagus, is a rare clinical entity. It is recently described to be associated with diabetic ketoacidosis (DKA) in a few case reports. Wischnewsky lesions (WLs) are a classic postmortem finding seen in fatal hypothermia but are recently described to be associated with DKA. Interestingly, the pathogenesis and morphology of AEN and WLs appear to share similar characteristics. Both AEN and WLs are reported to be seen simultaneously in hypothermic deaths and deaths related to alcohol abuse, but not in DKA. We report a death in a 67-year-old woman who died of DKA. At postmortem examination, the esophagus and stomach showed AEN and WLs, respectively. Although not previously reported together, both AEN and WLs have separately been described in cases of DKA. This case raises a possible unifying etiology of AEN and WLs in DKA (and probably also in hypothermic deaths and deaths related to alcohol abuse), manifested in different parts of the gastrointestinal tract.


Evaluation of flow in nodular tumors of the breast by Doppler and duplex scanning.
Evaluation of flow in nodular tumors of the breast may be performed by Doppler and computerized frequency analysis. In 46 nodules of the breast (22 malignant) the nodular flow velocity and frequency analysis revealed a faster flow with a significantly higher peak frequency and mean velocity. The intensity of sound which may be considered an index of the entity of flow in the nodule was larger than that observed in the normal surrounding breast tissue. In malignant nodules and generally in fast growing nodules the flow velocity and intensity was even larger. The flow intensity and velocity was also well correlated with the growth rate as reported by single patients. In elder patients a slow rate of growth even in tumors of larger size was associated with a significantly increased flow in comparison with the normal breast tissue but this increase was not particularly large when compared with fast growing nodules in younger subjects. In conclusion the evaluation of flow characteristics (mainly velocity, frequency analysis and intensity) may be a useful index of the growth rate of nodular tumors of the breast and these data may be useful to evaluate and monitor the evolution and pathophysiology of these nodules.


[Fluoxetine: relations between plasma concentration and therapeutic effects in 32 patients with major depression and treated with 20 mg/day].
The aim of this clinical study was to investigate 32 melancholic patients treated by fluoxetine (20 mg/day). The clinical examination to evaluate the antidepressant effect of fluoxetine was realized by using the HDS/MES criteria. The patients were divided into three groups (responders, partial responders with or without a relapse, non responders) according to their clinical evolution during treatment. Fluoxetine and norfluoxetine were evaluated by HPLC after 3 weeks of treatment. In the present study, 53% of the patients have a positively reaction to the 21 day's treatment. Our results showed no correlation between the psychiatric scores and the plasma concentrations of fluoxetine and norfluoxetine.


Sucralfate versus antacids or H2-antagonists for stress ulcer prophylaxis: a meta-analysis on efficacy and pneumonia rate.
Histamine2 (H2)-receptor antagonists and antacids have been the basic drugs for the prevention of stress bleeding in ICU patients during the past decade. Recently, drugs without major influence on gastric pH have been investigated in stress bleeding prophylaxis. Therefore, a meta-analysis (Mantel-Haenszel test) was undertaken to determine the efficacy of sucralfate in the prevention of macroscopically visible stress bleeding, as well as the influence of sucralfate on the frequency of pulmonary infections. The efficacy of sucralfate was compared with H2-antagonists in nine studies and with antacids in eight studies. Sucralfate was significantly more effective than H2-antagonists (typical odds ratio 0.532, 95% confidence interval 0.303 to 0.933) and equally as effective as antacids (typical odds ratio 0.868, 95% confidence interval 0.452 to 1.667). The pneumonia rates of those patients who were administered sucralfate were compared with the rates of those patients who were given H2-antagonists in five studies and with those patients who were given antacids in four studies. Pneumonia was a significantly more frequent occurrence under prophylaxis with H2-antagonists (typical odds ratio 0.498, 95% confidence interval 0.316 to 0.783) as well as with antacids (typical odds ratio 0.402, 95% confidence interval 0.235 to 0.687). Sucralfate is an effective drug for the prevention of stress bleeding that minimizes the risk of nosocomial pneumonia in long-term ventilated ICU patients.


Phage therapy in allergic disorders?
Allergic disorders pose a growing challenge to medicine and our society. Therefore, novel approaches to prevention and therapy are needed. Recent progress in studies on bacterial viruses (phages) has provided new data indicating that they have significant immunomodulating activities. We show how those activities could be translated into beneficial effects in allergic disorders and present initial clinical data that support this hope. Impact statement Allergic disorders pose a growing challenge to medicine and our society, so new approaches to prevention and therapy are urgently needed. Our article summarizes progress that has been recently made and presents a shift in our understanding of the immunobiological significance of bacterial viruses (phages). Currently, phages may be considered not only as mere "bacteria eaters" but also as regulators of immunity. The new understanding of phages as important factors in maintenance of immune homeostasis opens completely new perspectives for their use in controlling aberrant immune responses. It is likely that this new knowledge could be translated into novel means of immunotherapy of allergic disorders.


Improving services for sex partners of chlamydia-infected patients in an HMO.
To improve services for sex partners of chlamydia-infected patients (ie, chlamydia partner services [CPS]) at an HMO. Assessment of current CPS policy, practices, and opinions in Kaiser Permanente Northwest Region (KPNW) and in local health departments, and design, implementation, and evaluation of 4 CPS interventions. We reviewed KPNW policy documents, conducted focus groups with KPNW clinicians, and did phone interviews with KPNW chlamydia-infected patients and health department disease intervention specialists. We then implemented 3 informational interventions: CPS information was added to the after-visit summary given to patients tested for chlamydia; information on how to test, treat, and counsel chlamydia-infected patients was added to KPNW's electronic clinical-decision tool; and CPS information and a direct link to KPNW's chlamydia screening and treatment guidelines were added to KPNW's Web site. We also organized training for KPNW clinicians to review the roles of CPS and disease intervention specialists. We evaluated intervention uptake and impact by reviewing electronic medical charts, Web site "hits," and posttraining evaluations. Clinicians and disease intervention specialists reported that KPNW's CPS policy and the roles of disease intervention specialists regarding KPNW patients were unclear. Clinicians and patients wanted more CPS information. Clinicians commonly used the after-visit summary and Web-based CPS information and reported that training improved CPS knowledge. However, none used the clinical-decision tool. Several simple, centralized informational interventions to improve CPS were feasible and used by KPNW clinicians. These interventions could potentially be used in other settings structured like KPNW.


Dietary supplementation of Scutellaria baicalensis extract during early lactation decreases milk somatic cells and increases whole lactation milk yield in dairy cattle.
Systemic inflammation is common in early lactation dairy cows and is associated with decreased milk production. The Scutellaria baicalensis plant contains flavonoids with anti-inflammatory and anti-oxidative properties, which may counteract the inflammatory state in early lactation dairy cows. The objective of this experiment was to determine whether Scutellaria baicalensis extract (SBE), a source of bioactive flavonoids, would alter the adaptation to lactation. Multiparous Holstein cows (n = 122) were used in a randomized block design to determine the effect of short-term and long-term postpartum administration of SBE on 305-d milk yield, 120-d milk component yield, and early lactation milk markers of inflammation and metabolic function. Treatments were 1) control, 2) short term (5-d) administration of the SBE (SBE5), and 3) long term (60-d) administration of the SBE (SBE60). Treatments were included in a treatment pellet that was identical to a control pellet in ingredient source and composition except for the extract (10 g/d SBE providing 3.3 g/d of the flavonoid baicalin), both provided via an automated milking system beginning on d 1 of lactation. Milk samples were collected on d 1, 3, and once during d 5-12 of lactation, followed by weekly sampling until 120 days in milk (DIM). Milk samples collected in the first 2 wk were used for biomarker analysis (haptoglobin, β-hydroxybutyrate [BHB], and glucose-6-phosphate [G6P]), and all samples were used for composition analysis. Cows were body condition scored every 2 wk prepartum and postpartum. Milk production, programmed pellet allocation, and actual provision of both pelleted feeds were recorded daily. Treatment effects were evaluated by contrasts between control and SBE5 and control and SBE60 for both the treatment (TP; wk 1-9) and carryover periods (CP; wk 10-37). Total pellet offered was greater for SBE60 in both the TP (P < 0.01) and CP (P = 0.02) but was not different for SBE5 during either period (P ≥ 0.13). No treatment effects were observed for body condition score (BCS), milk haptoglobin, BHB, or G6P. SBE5 did not alter milk yield or milk components. SBE60 increased whole-lactation milk yield by 1,419 kg (13%; P = 0.03). SBE60 increased milk lactose and fat yields (P ≤ 0.04) and tended to increase milk protein yield (P = 0.09) during TP, and each increased during CP (P ≤ 0.04). Somatic cell count decreased by 10% in SBE60 during TP (P = 0.02) but not CP (P = 0.13). Mastitis incidence tended to differ by treatment, being lesser for both SBE5 and SBE60 vs. control (14 and 15% vs. 33%). SBE supplementation did not impact time to pregnancy or hazard of leaving the herd. In conclusion, despite no detected treatment effects on BCS or milk biomarkers of inflammation and metabolic status, supplementation of postpartum dairy cows with Scutellaria baicalensis extract for 60 d was effective at increasing whole lactation milk yield.


[Acute perceptive hearing loss and metabolic acidosis as complications of the topical treatment of psoriasis with salicylic acid-containing ointment].
A 36-year-old woman, hospitalized because of an exacerbation of psoriasis, developed fever, sudden deafness and severe metabolic acidosis after treatment with a 10% salicylic acid containing ointment for four days. The use of salicylic acid on large areas of inflamed skin enhances the risk of transcutaneous resorption and intoxication. High serum concentrations (> 300 mg/l) of salicylic acid deregulate the blood glucose metabolism and cause damage to the inner ear. After timely intervention such symptoms are largely reversible.


Plasmon Couplings from Subsystem Time-Dependent Density Functional Theory.
Many applications in plasmonics are related to the coupling between metallic nanoparticles (MNPs) or between an emitter and a MNP. The theoretical analysis of such a coupling is thus of fundamental importance to analyze the plasmonic behavior and to design new systems. While classical methods neglect quantum and spill-out effects, time-dependent density functional theory (TD-DFT) considers all of them and with Kohn-Sham orbitals delocalized over the whole system. Thus, within TD-DFT, no definite separation of the subsystems (the single MNP or the emitter) and their couplings is directly available. This important feature is obtained here using the subsystem formulation of TD-DFT, which has been originally developed in the context of weakly interacting organic molecules. In subsystem TD-DFT, interacting MNPs are treated independently, thus allowing us to compute the plasmon couplings directly from the subsystem TD-DFT transition densities. We show that subsystem TD-DFT, as well as a simplified version of it in which kinetic contributions are neglected, can reproduce the reference TD-DFT calculations for gap distances greater than about 6 Å or even smaller in the case of hybrid plasmonic systems (i.e., molecules interacting with MNPs). We also show that the subsystem TD-DFT can be also used as a tool to analyze the impact of charge-transfer effects.


Not to be overshadowed or overlooked: functional impairments associated with comorbid anxiety disorders in youth with ASD.
This study's objective was to examine associations between comorbid anxiety disorders and difficulties commonly attributed to both anxiety and ASD (autism spectrum disorder) including self-injury, depressive symptoms, functional communication, social skill deficits and parent stress, in a well-characterized sample of youth with ASD. Fifty-nine verbally fluent participants (7-17 years; 93% Caucasian) diagnosed with ASD and their parents completed semistructured diagnostic interviews to confirm ASD diagnosis and assess for anxiety disorders. Parents completed questionnaires on child behavior and social skill as well as parental stress. Co-occurring anxiety disorders were associated with more parent-reported self-injurious behavior, depressive symptoms, and parental stress in youth with ASD, after controlling for other influential variables (e.g., ASD severity, cognitive ability, medication status). In contrast, youth with co-occurring anxiety disorders appeared to have significantly stronger parent-reported functional communication than youth with ASD alone as well as a comparable ability, according to parents, to initiate social interaction and develop relationships. Findings support a profile of challenges and relative strengths associated with the presence of anxiety disorders in youth with ASD. Though more research is needed to determine the direction of these associations, results provide further rationale for improving recognition and targeted treatment of this comorbidity in clinical practice.


A solvatochromic model calibrates nitriles' vibrational frequencies to electrostatic fields.
Electrostatic interactions provide a primary connection between a protein's three-dimensional structure and its function. Infrared probes are useful because vibrational frequencies of certain chemical groups, such as nitriles, are linearly sensitive to local electrostatic field and can serve as a molecular electric field meter. IR spectroscopy has been used to study electrostatic changes or fluctuations in proteins, but measured peak frequencies have not been previously mapped to total electric fields, because of the absence of a field-frequency calibration and the complication of local chemical effects such as H-bonds. We report a solvatochromic model that provides a means to assess the H-bonding status of aromatic nitrile vibrational probes and calibrates their vibrational frequencies to electrostatic field. The analysis involves correlations between the nitrile's IR frequency and its (13)C chemical shift, whose observation is facilitated by a robust method for introducing isotopes into aromatic nitriles. The method is tested on the model protein ribonuclease S (RNase S) containing a labeled p-CN-Phe near the active site. Comparison of the measurements in RNase S against solvatochromic data gives an estimate of the average total electrostatic field at this location. The value determined agrees quantitatively with molecular dynamics simulations, suggesting broader potential for the use of IR probes in the study of protein electrostatics.


In vivo and in vitro evidence for slipped mispairing in mammalian mitochondria.
Slipped mispairing between repeated sequences during DNA replication is an important mutagenic event. It is one of several suggested mechanisms thought to be responsible for generating polymorphic regions and large-scale deletions found in mammalian mitochondrial DNA. In the porcine mitochondrial genome, a domain carrying a 10-bp tandemly repeated sequence displays a unique in vivo pattern of repeat copy number polymorphs. Upon passage in Escherichia coli, a recombinant plasmid containing this domain also displays a unique polymorphic pattern that is different from that seen in the animal. To test the hypothesis that these polymorphisms were slippage induced and that the different polymorphic patterns reflected differences in modes of replication, we performed a series of in vitro primer extension reactions. By utilizing either single- or double-stranded templates containing the repeat domain we were able to correlate in vitro generated repeat polymorphism patterns with those seen in the mitochondria or the bacteria, respectively, thus providing experimental evidence that slippage replication is responsible for a major class of mammalian mutations.


[The AP-94 device for examination of ocular refraction].
The paper provides a brief account and technical data of an AP-94-type device (a refractometer) for examination of ocular refraction, which operates in the infrared spectrum and allows a correct diagnosis to be promptly and qualitatively established and corrective means to be chosen for the patient. The results of clinical tests of the device are given.


Interstitial deletion of 10p and atrial septal defect in DiGeorge 2 syndrome.
We present molecular genetic investigations of a 4-year-old boy with craniofacial dysmorphism and developmental delay. Trivial mitral and tricuspid regurgitation without gross structural abnormality was diagnosed by echocardiography. High-resolution chromosome analysis revealed an interstitial deletion, del(10)(p12.1p12.32). To characterize the deletion size and breakpoints, we performed fluorescence in situ hybridization analysis using 27 BAC clones. Our data demonstrate an approximately 5.5 Mb deletion del(10)(p12.1p12.31). Surprisingly, the BAC clone RP11-56H7 that contains NEBL, an apparent downstream gene of the cardiogenic transcription factor HAND2 previously shown to be deleted in the patients with DiGeorge 2 syndrome and 10p13 deletion, was deleted in our patient with 10p12.1-p12.31 deletion. In addition, we provide clinical data and results of molecular analysis for a patient with multiple congenital anomalies including Ebstein's anomaly, kidney malformations, and 10p13-p14 deletion. We also reviewed 19 patients with congenital heart defects and deletions involving 10p and propose that atrial septal defect (ASD) is a common cardiac anomaly associated with DiGeorge 2 syndrome. Based on genotype-phenotype analysis of published patients and those reported herein, we propose an approximately 1.0 Mb critical region between loci D10S547 and D10S2176 in 10p14 to be associated with ASD. Considering that septal defects are the most frequent congenital heart anomaly, we suggest that further investigations in the 10p critical region are important to identify gene(s) responsible for this common birth defect.


COVID-19-Associated Encephalitis: Two Case Reports.
The infection with SARS-CoV-2 is primarily associated with respiratory symptoms. Since its appearance, several neurological symptoms have been reported, most commonly headache and anosmia, as well as less frequent complications such as COVID-19-associated encephalitis and meningitis. In this case report, we describe two patients, who were 49- and 50-year-old infected with SARS-CoV-2, who presented to the emergency department with altered mental status and behavioral changes. A diagnosis of acute meningoencephalitis associated with COVID-19 was considered, and both patients had a good response to corticosteroid treatment.


The value of cell-free DNA for molecular pathology.
Over the past decade, advances in molecular biology and genomics techniques have revolutionized the diagnosis and treatment of cancer. The technological advances in tissue profiling have also been applied to the study of cell-free nucleic acids, an area of increasing interest for molecular pathology. Cell-free nucleic acids are released from tumour cells into the surrounding body fluids and can be assayed non-invasively. The repertoire of genomic alterations in circulating tumour DNA (ctDNA) is reflective of both primary tumours and distant metastatic sites, and ctDNA can be sampled multiple times, thereby overcoming the limitations of the analysis of single biopsies. Furthermore, ctDNA can be sampled regularly to monitor response to treatment, to define the evolution of the tumour genome, and to assess the acquisition of resistance and minimal residual disease. Recently, clinical ctDNA assays have been approved for guidance of therapy, which is an exciting first step in translating cell-free nucleic acid research tests into clinical use for oncology. In this review, we discuss the advantages of cell-free nucleic acids as analytes in different body fluids, including blood plasma, urine, and cerebrospinal fluid, and their clinical applications in solid tumours and haematological malignancies. We will also discuss practical considerations for clinical deployment, such as preanalytical factors and regulatory requirements. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Gene expression in human skeletal muscle: alternative normalization method and effect of repeated biopsies.
The reverse transcriptase-polymerase chain reaction (RT-PCR) method has lately become widely used to determine transcription and mRNA content in rodent and human muscle samples. However, the common use of endogenous controls for correcting for variance in cDNA between samples is not optimal. Specifically, we investigated (1) a new normalization method based on determining the cDNA content by the flourophores PicoGreen and OliGreen, (2) effect of repeated muscle biopsies on mRNA gene expression, and (3) the spatial heterogeneity in mRNA expression across the muscle. Standard curves using oligo standards revealed a high degree of sensitivity and linearity (2.5-45 ng; R2>0.99) with OliGreen reagent, as was the case for OliGreen analyses with standard curves constructed from serial dilutions of representative RT samples (R2 >0.99 for a ten times dilution range of a representative reversed transcribed (RT) sample). Likewise, PicoGreen reagent detected the RNA:DNA hybrid content in RT samples with great sensitivity. Standard curves constructed from both double-stranded lambda DNA (1-10 ng) and from serial dilutions of representative RT samples consistently resulted in linearity with R2 >0.99. The present determination of cDNA content in reversed transcribed human skeletal muscle RNA samples by both PicoGreen and OliGreen analyses suggests that these fluorophores provide a potential alternative normalization procedure for human gene expression studies. In addition, the present study shows that multiple muscle biopsies obtained from the same muscle do not influence the mRNA response induced by an acute exercise bout for any of the genes examined.


Photofragmentations, state interactions, and energetics of Rydberg and ion-pair states: two-dimensional resonance enhanced multiphoton ionization of HBr via singlet-, triplet-, Ω = 0 and 2 states.
Mass spectra were recorded for one-colour resonance enhanced multiphoton ionization (REMPI) of H(i)Br (i = 79, 81) for the two-photon resonance excitation region 79,040-80,300 cm(-1) to obtain two-dimensional REMPI data. The data were analysed in terms of rotational line positions, intensities, and line-widths. Quantitative analysis of the data relevant to near-resonance interactions between the F(1)Δ(2)(v' = 1) and V(1)Σ(+)(v' = m + 7) states gives interaction strengths, fractional state mixing, and parameters relevant to dissociation of the F state. Qualitative analysis further reveals the nature of state interactions between ion-pair states and the E(1)Σ(+) (v' = 1) and H(1)Σ(+)(v' = 0) Rydberg states in terms of relative strengths and J' dependences. Large variety in line-widths, depending on electronic states and J' quantum numbers, is indicative of number of different predissociation channels. The relationship between line-widths, line-shifts, and signal intensities reveals dissociation mechanisms involving ion-pair to Rydberg state interactions prior to direct or indirect predissociations of Rydberg states. Quantum interference effects are found to be important. Moreover, observed bromine atom (2 + 1) REMPI signals support the importance of Rydberg state predissociation channels. A band system, not previously observed in REMPI, was observed and assigned to the k(3)Π(0)(v' = 0) ←← X transition with band origin 80,038 cm(-1) and rotational parameter B(v('))=7.238 cm(-1).


Dissociation of hypnotic-anesthetic actions of alpha 2 agonists from cyclic AMP in the rat.
alpha 2 adrenergic agonists are used clinically for their anesthetic, analgesic, and sympatholytic actions in surgical patients. All alpha 2 adrenergic receptors, when activated by alpha 2-adrenergic agonists, are able to inhibit adenylate cyclase. We have examined the alpha 2-adrenoceptor-mediated anesthetic actions of dexmedetomidine, a highly selective alpha 2-adrenergic agonist, after pretreatment of the animals with rolipram, a cyclic AMP (cAMP)-specific phosphodiesterase inhibitor, cAMP accumulation and monoamine turnover were measured in the locus coeruleus (LC) and hippocampus (HC) following administration of rolipram [275 mg/kg, intraperitoneally (IP)] and dexmedetomidine (100-500 mg/kg, IP). The hypnotic response to dexmedetomidine was also measured in these animals. In other experiments, rats were stereotactically cannulated in the LC with an indwelling catheter, and after the second day, the tail-flick analgesic response to dexmedetomidine (3.5 mg/0.2 ml LC), following rolipram (275 mg/kg, IP) pretreatment, was assessed. In the presence of elevated cAMP levels, the hypnotic, analgesic, and sympatholytic effects of dexmedetomidine persisted. These data suggest that adenylate cyclase activity does not mediate the cellular responses to alpha 2-adrenergic agonists but instead may act in concert with other alpha 2-adrenoceptor-coupled effector mechanisms to transduce the anesthetic actions of these agents.


Convergent-beam EMCD: benefits, pitfalls and applications.
Energy-loss magnetic chiral dichroism (EMCD) is a versatile method for studying magnetic properties on the nanoscale. However, the classical EMCD technique is notorious for its low signal-to-noise ratio (SNR), which is why many experimentalists have adopted a convergent-beam approach. Here, we study the theoretical possibilities of using a convergent beam for EMCD. In particular, we study the influence of detector positioning as well as convergence and collection angles on the detectable EMCD signal. In addition, we analyse the expected SNR and give some guidelines for achieving optimal EMCD results.


Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder.
Cyclin-dependent kinase-like 5 (CDKL5, also known as STK9) is a serine/threonine protein kinase originally identified in 1998 during a transcriptional mapping project of the human X chromosome. Thereafter, a mutation in CDKL5 was reported in individuals with the atypical Rett syndrome, a neurodevelopmental disorder, suggesting that CDKL5 plays an important regulatory role in neuronal function. The disease associated with CDKL5 mutation has recently been recognised as CDKL5 deficiency disorder (CDD) and has been distinguished from the Rett syndrome owing to its symptomatic manifestation. Because CDKL5 mutations identified in patients with CDD cause enzymatic loss of function, CDKL5 catalytic activity is likely strongly associated with the disease. Consequently, the exploration of CDKL5 substrate characteristics and regulatory mechanisms of its catalytic activity are important for identifying therapeutic target molecules and developing new treatment. In this review, we summarise recent findings on the phosphorylation of CDKL5 substrates and the mechanisms of CDKL5 phosphorylation and dephosphorylation. We also discuss the relationship between changes in the phosphorylation signalling pathways and the Cdkl5 knockout mouse phenotype and consider future prospects for the treatment of mental and neurological disease associated with CDKL5 mutations.


Misincorporation of nucleotides opposite five-membered exocyclic ring guanine derivatives by escherichia coli polymerases in vitro and in vivo: 1,N2-ethenoguanine, 5,6,7,9-tetrahydro-9-oxoimidazo[1, 2-a]purine, and 5,6,7,9-tetrahydro-7-hydroxy-9-oxoimidazo[1, 2-a]purine.
A variety of exocyclic modified bases have been shown to be formed in DNA from various procarcinogens (e.g., acrolein, malonaldehyde, vinyl chloride, urethan) and are also found in untreated animals and humans, presumably arising as a result of lipid peroxidation. 1, N2-Ethenoguanine (1,N2-epsilon-Gua), a product known to be formed from several 2-carbon electrophiles, was placed in a known site (6256) in bacteriophage M13MB19 and mutations were analyzed in Escherichia coli, with 2.05% G-->A, 0.74% G-->T, and 0.09% G-->C changes found in uvrA- bacteria. 5,6,7, 9-Tetrahydro-7-hydroxy-9-oxoimidazo[1,2-a]purine (HO-ethanoGua), formally the hydrated derivative of 1,N2-epsilon-Gua, is a stable DNA product also derived from vinyl halides. When this base was placed in the same context, the mutation rate was 0.007-0.19% for G-->A, C, or T changes. The saturated etheno ring derivative of 1, N2-epsilon-Gua, 5,6,7,9-tetrahydro-9-oxoimidazo[1,2-a]purine (ethanoGua) produced G-->A and G-->T mutations (0.71% each). All mutants were SOS-dependent and were attenuated by uvrA activity in E. coli. In vitro studies with four polymerases showed strong blocks to addition beyond the adduct site in the order ethanoGua > HO-ethanoGua > 1,N2-epsilon-Gua. Both E. coli polymerases (pol) I exo- and II exo- and bacteriophage pol T7 exo- showed extensive misincorporation opposite ethanoGua in vitro, with pol I exo- incorporating G and T, pol II exo- incorporating A, and pol T7 exo- incorporating A and G. All modified bases reduced the use of the minus strand bearing the modified guanine in E. coli cells. It is of interest that even though the normal base pairing site of guanine is completely blocked, all of the five-membered ring derivatives incorporate the normal base (C) in >80% of the replication events in E. coli. Major differences in blockage and misincorporation are seen due to what might appear to be relatively modest structural differences, and polymerases can differ dramatically in their selectivities.


Topology-Based Approach to Predict Relative Stabilities of Charged and Functionalized Fullerenes.
Understanding the relationship between structure and stability is one of the fundamental aspects of fullerene chemistry, as the number of possible cage isomers is very large and complexity increases by orders of magnitude when chemical groups are attached to the fullerene cage. The well-established stability rules valid for neutral fullerenes do not apply to many charged or functionalized fullerenes. Here we present the theory, implementation, and applications of two simple topology-based models that allow one to predict the relative stability of charged and functionalized fullerenes without the need for quantum chemistry calculations: (i) the charge stabilization index (CSI) model, based on the concepts of cage connectivity and frontier π orbitals, which offers a general framework for the relative stability of both positively and negatively charged fullerenes, as well as endohedral metallofullerenes, and (ii) the exohedral fullerene stabilization index (XSI) model, which incorporates all key factors governing the stability of exohedral fullerenes, namely, π delocalization, σ strain, and steric hindrance between addends. Based exclusively on topological information, both models are powerful prescreening tools for predicting the most stable structures of a large number of charged and functionalized fullerenes. For easy use by fullerene chemists, both models have been implemented in the FullFun (for Fullerene Functionalization) software package, whose effectiveness and efficiency are demonstrated by some illustrative examples.


Expression of Wnt and MMP in epithelial cells during corneal wound healing.
To study the expression of Wnt during corneal wound healing and to understand the signaling mechanism involved. Rat cornea was demarcated on the central area by 4-mm trepine, and the epithelium within this area was removed by scalpel. The epithelium was scraped and isolated to extract RNA. To determine the proliferation of corneal epithelial cells, corneoscleral rims from human donors were treated with dispase II for 15 minutes, and epithelial cells were isolated. Cells were plated on a 3T3 feeder cells layer. The proliferation of corneal epithelial cells was evaluated by colony-forming efficiency. Wnt 5b and 7a were rapidly induced in wounded cornea, and Wnt 7a promoted proliferation of corneal epithelial cells. In addition, matrix metalloproteinase (MMP)-12 was expressed in wounded rat corneal epithelium. Transcription of MMP-12 was responsive to Wnt/beta-catenin signaling. Function blockade of MMP-12 delayed Wnt 7a-induced cell proliferation. These results indicate that Wnt proteins and MMP-12 regulate the proliferation of corneal epithelial cells and that Wnt signaling contributes to the resurfacing of defective areas during corneal wound healing.


Anti-epileptic effects of focal micro-injection of excitatory amino acid antagonists.
The role of excitatory synaptic activity at various brain regions in the development and spread of seizure activity has been investigated by the focal microinjection of 2-amino-7-phosphono-heptanoate (2-APH), a selective antagonist at the N-methyl-D-aspartate preferring receptor, or gamma-D-glutamyl-aminomethyl sulphonate (GAMS), a partially selective antagonist at the kainate receptor. In genetically epilepsy prone rats the seizure response to a loud sound in most effectively suppressed by focal injections of 2-APH, 0.1-1.0 nmol, in the inferior colliculus. Protection is also seen after injections of 2-APH, 25 nmoles, in the substantia nigra (pars reticulata) or the midbrain reticular formation. Motor limbic seizures induced by pilocarpine, 380 mg/kg intraperitoneally, are prevented by prior injection into the substantia nigra, pars reticulata, or the entopeduncular nucleus, of 2-APH, 10 nmol or 10 pmol, respectively. Similar protection follows the injection of 2-APH, 1-5 pmol in the piriform cortex. The convulsant effects of pilocarpine are also blocked by the focal injection of GAMS, 10 nmol in the entopeduncular nucleus. This experimental approach can indicate critical sites at which seizure activity is initiated in particular models (e.g., inferior colliculus in sound-induced seizures, and piriform cortex in limbic seizures) and the pathways controlling seizure expression, such as the basal ganglia outputs. It also identifies specific receptors at which anticonvulsant drugs may operate.


Delayed 18F-FDG PET imaging provides better metabolic asymmetry in potential epileptogenic zone in temporal lobe epilepsy.
To investigate the value of 18F-FDG positron emission tomography/computed tomography (PET/CT) two time point imaging for the identification of the potential epileptogenic zone (EZ) in temporal lobe epilepsy (TLE). Fifty-two patients with TLE were prospectively enrolled in the 18F-FDG PET/CT two time point imaging study. The early imaging was obtained approximately 40 min (43.44 ± 18.04 min) after 18F-FDG injection, and the delayed imaging was obtained about 2 to 3 h (160.46 ± 28.70 min) after the injection. Visual and semi-quantitative analysis of 18F-FDG uptake were performed at the two time points in EZ and contralateral symmetrical region. The mean standardized uptake value (SUVmean) of EZ and contralateral symmetrical region was calculated to determine the asymmetry index (AI) of the early and delayed images, as well as in the MRI positive and negative patient groups. Semi-quantitative analysis demonstrated that AI of the early and delayed 18F-FDG PET/CT images was 13.47 ± 6.10 and 16.43 ± 6.66, respectively. The ΔAI was 2.95 ± 3.05 in 52 TLE patients between the two time points. The AI of the EZ was significantly elevated in delayed images compared to the early images (p < 0.001). The AI of delayed imaging was also significantly elevated compared to the early imaging in both MRI positive (ΔAI = 2.81 ± 2.54, p < 0.001) and MRI negative (ΔAI = 3.21 ± 3.91, p < 0.003) groups, and more pronounced in MRI negative group. Visual analysis also showed that the delayed imaging appeared to be superior to the early imaging for identification of potential EZ. Delayed 18F-FDG PET imaging provided significantly better than the early imaging in the identification of potential EZ, which can be valuable during epilepsy pre-surgical evaluation in patients with TLE.


Economic evaluations of acute pain service programs: a systematic review.
The purpose was to review the literature on the economic benefits associated with Acute Pain Service (APS) programs systematically. APSs have received widespread acceptance and formal support from institutions and organizations, but little is known about its economic benefits. MEDLINE and other databases were searched for economic evaluations of APSs. The study characteristics and methodological quality was assessed using standardized tools. All costs were adjusted to 2005 US dollars. Ten economic evaluations (involving 14,774 patients) were identified that met eligibility criteria. There were wide variations in study designs, methodological quality, and outcome measures. There was insufficient data to identify which APSs model (anesthesiologist-based/nursing support or nurse-based/anesthesiologist supervised) was more cost-effective. The cost of APSs for surgical patients from direct and indirect effects (improved pain management from education in patients not receiving APS) varied from $2.28 to $5.08/patient/d. The level of evidence to support the cost-savings associated with APSs (shorter duration of intensive care unit and hospital stays) were limited to partial economic analyses. There was insufficient evidence to draw conclusions about the cost-effectiveness and cost-benefit of APSs as the quality of life and patient's willingness to pay for an APS intervention were not measured, respectively. The overall quality of published economic evaluations of APSs was poor. There is a lack of high-quality economic studies to support the cost-effectiveness and cost-benefits of APSs.


Acetazolamide during acute hypoxia improves tissue oxygenation in the human brain.
Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O2 metabolism (CMRO2 ) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (PtiO2 ) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral PtiO2 from MRI measurements of cerebral blood flow (CBF) and cerebral venous O2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2 , or PtiO2 . During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml·100 ml(-1)·min(-1) (hypoxia), P < 0.05] and CMRO2 [1.54 (0.19) to 1.79 (0.25) μmol·ml(-1)·min(-1), P < 0.05] and a dramatic decline in PtiO2 [25.0 to 11.4 (2.7) mmHg, P < 0.05]. Acetazolamide prophylaxis mitigated these rises in CBF [53.7 (20.7) ml·100 ml(-1)·min(-1) (hypoxia + acetazolamide)] and CMRO2 [1.41 (0.09) μmol·ml(-1)·min(-1) (hypoxia + acetazolamide)] associated with acute hypoxia but also reduced O2 delivery [6.92 (1.45) (hypoxia) to 5.60 (1.14) mmol/min (hypoxia + acetazolamide), P < 0.05]. The net effect was improved cerebral tissue PtiO2 during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P < 0.05]. In addition to its renal effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and PtiO2 during acute hypoxia.