[Quality evaluation of Styrax based on quantitative determination of 7 chemical components using HPLC wavelength switching method and chemometrics].
In order to evaluate the quality of Styrax more comprehensively,this study attempted to establish an HPLC wavelength switching method to simultaneously determine the content of seven compounds in Styrax,and chemometrics were used to analyze the quality difference between different sources of Styrax,and finally establish a characteristic chromatogram of Styrax. The column was Agilent ZORBAX Extend C18( 4. 6 mm×250 mm,5 μm) with phase a mixture of acetonitrile-0. 1% phosphoric acid aqueous solution as the mobile phase in a gradient elution procedure; the detection wavelength was set as follows: 0-13. 5 min,194 nm( benzoic acid);13. 5-20. 5 min,278 nm( cinnamic acid); 20. 5-32 min,194 nm( benzyl benzoate,benzyl cinnamate,cinnamyl cinnamate,dehydroabietic acid); 32-55 min,241 nm( abietic acid). The methodological verification results showed that when the injection masses of benzoic acid,cinnamic acid,benzyl benzoate,benzyl cinnamate,cinnamyl cinnamate,dehydroabietic acid and abietic acid were0. 006 948-0. 694 8,0. 001 426-0. 142 6,0. 013 16-0. 658 0,0. 006 148-0. 614 8,0. 008 035-0. 803 5,0. 002 121-0. 212 1,and0. 010 172-1. 017 2 μg,respectively,there were good linear relationship between injection mass and peak area. The average recovery rates of seven compounds were in the range from 94. 34% to 105. 8%,and all RSD were less than 3. 0%( n = 6). The methodological verification results showed that the developed HPLC wavelength switching method has good accuracy and repeatability. The results of the sample analysis showed that the quality of Styrax from different sources was quite different. The chromatogram of Styrax reference material( S1) was used as the reference chromatogram to calculate the fingerprint similarity of each batch of samples. The results showed that the similarities of samples S2-S10 were 0. 952,0. 949,0. 981,0. 351,0. 751,0. 969,0. 979,0. 992 and 0. 971,respectively.The similarity values of other batches samples were satisfactory,except for sample S5 and S6,indicating that the quality difference among these samples is small. The similarity values of S11-S20 were 0. 060,0. 055,0. 054,0. 285,0. 092,0. 002,0. 044,0. 044,0. 044,and 0. 040,respectively. The results showed that compared with the sample S1,there was a large quality difference among S11-S20. Based on the chromatograms of S1-S10,the HPLC characteristic chromatograms of Styrax was established and the purpose is to give reference to other pharmaceutical researchers. The newly developed HPLC wavelength switching method have the advantages of simplicity,reproducibility and specificity,and the developed HPLC characteristic chromatograms provided a reference method for the overall quality evaluation of Styrax.


White blood cell and platelet counts could affect whole blood viscosity.
Blood viscosity is correlated with cerebral blood flow and cardiac output, and increased viscosity may increase the risk of thrombosis or thromboembolic events. The relationship between hematocrit and viscosity is well-known, however, the relationships between white blood cell (WBC) or platelet count and viscosity were not fully studied. The aim of the present study was to determine the influences of platelet count and WBC count on blood viscosity. One-hundred and 13 subjects with different hemoglobin, WBC and platelet count were enrolled into the study. The variables measured included serum fibrinogen, cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), complete blood counts including hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, WBC count, whole blood and plasma viscosity. The relationships of these variables with whole blood or plasma viscosity were analyzed. Serum fibrinogen, cholesterol, triglyceride, HDL and LDL did not correlate with whole blood viscosity. Not only hematocrit, hemoglobin and RBC, but also WBC and platelet count, could affect whole blood viscosity. On the other hand, none of the variables could affect plasma viscosity. All the blood cell components, but not the plasma proteins detected above, could affect whole blood viscosity. When patients are with high leukocytosis and thrombocytosis, impaired blood viscosity should also be considered to obtain appropriate clinical management.


Tumor Abnormal Protein as a Novel Biomarker in Papillary Thyroid Carcinoma.
High level of serum tumor abnormal protein (TAP) may be useful in early diagnosis of cancers. This study aims to investigate the diagnostic value of TAP in patients with papillary thyroid carcinoma (PTC). Abnormal sugar chain glycoproteins from peripheral blood of 139 patients with PTC, 39 patients with benign thyroid nodular and 35 healthy individuals were used. Receiver operating characteristic (ROC) curve was performed to evaluate diagnostic value of tumor abnormal protein (TAP). Moreover, the relationship between TAP value and its clinical characteristics was further analyzed. TAP level was significantly higher in PTC patients than in benign thyroid nodular patients or healthy individuals (p < 0.001). We also noted that TAP level was associated with multifocus (p = 0.015), but not associated with other clinical characteristics such as age, gender, tumor size, and extra-thyroidal extension. Based on the area under ROC curve of 0.849 (95% CI: 0.795 - 0.893), the cutoff value of TAP is 122.6 μm2 and the sensitivity and specificity in the diagnosis of PTC is 79.2% and 86.5%, respectively. TAP may be a novel biomarker for PTC and be useful in the adjuvant diagnosis of PTC.


Cognitive Impairment in Patients With Neuropsychiatric and Non-neuropsychiatric Systemic Lupus Erythematosus: A Systematic Review and Meta-analysis.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Its most prevalent manifestation is neuropsychiatric SLE (NP-SLE), which is characterized by increased involvement of the nervous system, with relevant symptoms, such as marked cognitive deficits, which are directly involved in subsequent functional disability. The objective of this study is to identify and compare the profile of cognitive deficits in patients with NP-SLE and patients with non-neuropsychiatric SLE (nonNP-SLE) by means of a systematic review and meta-analysis. We performed a systematic literature search based on the key words "cogn* OR neurocogn* AND lupus AND neuropsychiatry*" and included articles published between April 1999 and December 2016. A total of 244 articles were retrieved. We excluded reviews and meta-analyses, experiments not performed in humans, and single case reports. We included studies that used standardized cognitive measures and had included at least the subgroups NP-SLE and non NP-SLE. The meta-analysis was finally based on six studies, and 10 neuropsychological variables were examined. Significant differences were observed between the groups for six variables. In the remaining four variables, we observed marked heterogeneity between the groups or a low number of studies. The data obtained indicate greater cognitive impairment among NP-SLE patients than among nonNP-SLE patients, at least for the cognitive domains of visuomotor coordination, attention, executive function, visual learning and memory, and phonetic fluency. The identification and definition of cognitive deficits in SLE patients is necessary to develop adequate cognitive remediation programs to improve functional outcomes. (JINS, 2018, 24, 629-639).


[Repeated epidural anesthesia in cesarean section in parturients with uterine scars].
A total of 956 epidural anesthesia procedures during cesarean section have been reviewed. In 234 cases epidural anesthesia was used repeatedly for analgesia during cesarean section in women with scars on the uterus. The course and quality of anesthesia were compared during the first and repeated procedure. High efficacy of analgesia was noted in more than 90% of patients of both groups. The differences between groups in the rate of development, duration of anesthesia, intensity of motor block and quality of analgesia were insignificant. It has been concluded that epidural anesthesia is highly effective during cesarean section in women with scars on the uterus and can be used repeatedly without the quality of analgesia being deteriorated.


Recombinant adenovirus-mediated gene transfer into the adult rat retina.
The present study was designed to evaluate the feasibility of gene transfer into the retina of adult rats, using a recombinant replication-defective adenovirus vector expressing a reporter gene. Purified recombinant adenovirus expressing beta-galactosidase (lacZ) (Ad5.hCMV.lacZ) at doses ranging from 1.4 x 10(2) to 1.4 x 10(6) plaque-forming units (pfu) were injected into the subretinal space of adult Lewis rats. The presence of lacZ was determined by histochemical assay and reverse transcription and polymerase chain reaction analysis (RT PCR) of total RNA extracted from eyes injected with recombinant adenovirus expressing lacZ. As assessed by biomicroscopy, the expression of lacZ was highest in the retinal pigment epithelium in a localized area corresponding to the site of injection. The level of lacZ expression was correlated with the amount of virus delivered to the subretinal space. Persistent but decreasing expression of lacZ was noted over time. RT PCR revealed the expression of messenger RNA for at least sixty days. The results of this study demonstrate that efficient and stable transfer of genetic material into the subretinal space of adult rats may be achieved using a recombinant adenoviral vector. The use of such vectors should prove useful in developing novel applications and approaches to the study of recombinant protein expression in vivo.


Oral prednisolone for 4 days does not increase exercise tolerance in men with COPD.
One of the primary objectives in management of chronic obstructive pulmonary disease (COPD) is preventing decrease in lung function and reducing the annual number of acute exacerbations of COPD (AECOPD). An oral course of systemic corticosteroids is a commonly used treatment in AECOPD. We hypothesize that this treatment also increases exercise performance and decreases muscle fatigue. In a randomized double-blinded, parallel, placebo-controlled trial, we investigated 14 men (8 on prednisolone 37.5 mg vs. 6 on placebo) with severe and very severe COPD. For 5 consecutive days, the patients performed a submaximal endurance test measuring time to exhaustion (TTE, primary endpoint), spirometry, maximal inspiratory and expiratory pressure and maximal isometric contraction of the quadriceps femoris muscle (maximum voluntary contraction (MVC)). At visits 2, 3 and 4, a fatigue protocol was carried out after 40 minutes of cycling at 40% of maximal effort. No differences between groups were found for TTE, lung function or maximal inspiratory or expiratory pressure, however, patients on prednisolone showed significant increased MVC: median 5.15 [3.35; 9.15] against placebo: -2 [-5.57; 3.95] ( p = 0.03). This finding indicates an impact of corticosteroids on muscle groups being exposed to submaximal endurance.


[Differential effect of incompatibilities of the HLA-A and HLA-B locus on the success of corneal transplants].
The positive influence of HLA-compatible donor material on successful transplantation was proven especially for prognostically unfavourable cases. Nevertheless it is not clear whether varying importance should be attached to the antigen incompatibilities at the HLA-A and HLA-B locus. 62 keratoplasty patients, 37 of whom had primarily poor prognoses and 25 patients with low risk of transplant rejection were prospectively given transplants in which more than two certain incompatibilities at the HLA-A and HLA-B locus had been ruled out. The number of Ag incompatibilities (separately according to locus) was related retrospectively to postoperative progress. An irreversible transplant failure had occurred in 6 patients (16%) four months after surgery in the high-risk group, whereas 31 transplants (84%) remained clear. The course of healing was without complications within the first four months in all patients with favourable starting position. The influence of the HLA disparities on transplantation success was examined by means of the chi-square test. Taking the Ag incompatibilities of both loci in combination into account showed an only marginally significant (p = 0.1) influence on the survival rate of the transplant. Here HLA-A incompatibilities appear to have only secondary significance, whereas incompatibilities at the HLA-B locus correlated inversely (p = 0.02) with the success of transplantation.


The pulsed dye laser for the treatment of basal cell carcinoma.
Basal cell carcinomas (BCC) have a specialized microvasculature system that can be targeted by the 585-nm pulsed dye laser (PDL) utilizing the theory of selective photothermolysis. Seven volunteers with nine well-defined, biopsy-proven BCCs, were treated with the PDL (585-nm wavelength, a single 450-μs pulse, 7-mm spot size, and 9.0 J/cm(2) energy). The lesions, along with a 4-mm border of normal skin were treated. Pain assessment was carried out immediately after the laser treatment. A deep shave biopsy with histological examination occurred 4 weeks after the laser treatment. Pain was assessed on a scale of 0 (no pain) to 10 (worst pain possible). The average patient score was 2.1 (range 1-4). On histology, 5/9 (55.6%) sites demonstrated no evidence of BCC; however, 4/9 (44.4%) sites showed residual BCC. Although the PDL was able to clear over half of the BCCs in this study, there was an unacceptably high persistence rate of 44.4%. The PDL did not achieve the clearance rate that can be attained with current standard BCC treatment modalities. At this time, we do not recommend that a single treatment with the 585-nm PDL can be used as a primary therapy for BCC.


Directed biosynthesis of peptaibol antibiotics in two Trichoderma strains. I. Fermentation and isolation.
Peptaibols are linear alpha-aminoisobutyric acid-containing peptide antibiotics originating from soil fungi mainly of the genus Trichoderma and biosynthesized in complex mixtures of closely related analogues by a polyenzymatic pathway. Addition of amino acids such as alpha-aminoisobutyric acid (Aib), glutamic acid or arginine, to the fermentation medium of two Trichoderma strains, T. harzianum and T. longibrachiatum, has been shown to result in the simplification of the natural peptaibol mixtures, leading in each case to the almost exclusive biosynthesis of a single peptide. Surprisingly, the obtained peptides are Aib-enriched, whether the added amino acid is Aib, Glu or Arg. By adding Aib to the fermentation medium of T. harzianum, two new Aib-rich peptaibols were isolated. Moreover, adding glutamic acid to the culture medium of T. longibrachiatum, which produces both neutral and acidic 20-residue peptaibols with either glutamine or glutamic acid at position 18, increases the production of the acidic peptides. However, arginine which is a positively charged amino acid generally absent from peptaibol sequences, is not incorporated in trichorzins when added to the fermentation medium of T. harzianum.


Baseline Symptom Score Impact on Benefits of Glycopyrrolate/Formoterol Metered Dose Inhaler in COPD.
The clinical severity of COPD is currently categorized by symptom burden and exacerbation risk. Previous 24-week phase III trials (NCT01854645 and NCT01854658) that demonstrated better improvement of lung function with glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) (an MDI fixed-dose of GFF 18/9.6 μg) over individual monocomponent MDIs included a cross-section of patients with moderate to very severe airflow limitation and a broad range of COPD symptoms. These post hoc analyses of pooled data investigated whether baseline symptom burden, assessed using the COPD Assessment Test (CAT) score, impacted GFF MDI-associated improvements in lung function, health status, rescue medication use, and exacerbation risk. In 3,699 patients, improvement in FEV1 at week 24 between the GFF MDI and monocomponent MDIs and a placebo MDI was similar in magnitude regardless of baseline CAT score. In contrast, the magnitude of mean difference in the St. George's Respiratory Questionnaire total score for GFF MDI vs monocomponent MDIs and the placebo MDI increased with increasing baseline CAT scores. Likewise, reduced rescue medication use and lower exacerbation risk were more pronounced in GFF MDI groups with a higher baseline symptom burden. Beneficial effects of GFF MDI on health status, rescue medication use, and exacerbation risk in symptomatic patients with COPD increased as a function of baseline symptom burden, whereas lung function benefits were independent. These data suggest a greater clinical benefit from dual bronchodilators in symptomatic patients than in patients without symptoms. ClinicalTrials.gov; No.: NCT01854645 and NCT01854658; URL: www.clinicaltrials.gov.


Forced double suicide by fire revealed by autopsy and toxicological examination: a case report.
We report here a forced double suicide by fire. Two burned bodies discovered in the debris of a house fire were identified as a father and his son by odontological findings. In the father, the concentration of carboxyhemoglobin (CO-Hb) in the left ventricle was over 90% and endrin, an organochlorine pesticide, was also detected in the stomach contents. However, 30.5% of CO-Hb in left ventricular blood and gasoline traces from an intratracheal puncture were detected in the son who had been undergoing treatment at a neuropsychiatric clinic. From these results, we determined this case to be a double suicide forced by the father in which the father set a fire with gasoline, thus burning his son to death, and then died in the fire himself after ingestion of Endrin. This case suggests the importance of integration of the results from the detailed forensic pathological and toxicological examinations and the scene investigation.


[Compliance with and acceptability of a new electronic peak flow meter, the PiKo-1].
Monitoring airflow obstruction is an essential component of asthma management. We examined home recording of PEFR using a new electronic peak flow meter in terms of compliance and acceptability in a group of children with asthma. Twenty three children (3 with intermittent asthma and 20 with persistent asthma) (average age 10.9 +/- 3.8 [5-18] yrs) were asked to assess their PEFR every day during a period of 5.8 +/- 1.2 [4-8] weeks and record it in a diary card. Patients were not aware that their data was also being stored on the PiKo-1. At the end of the study, the written data were compared to the stored data. A multiple choice questionnaire was given to each subjectto check the acceptability of the PiKo-1. 2 patients were lost to follow up. The compliance (expressed as a percent of the number of recordings that should have been made) was more that 80% for 14/21(67%) patients and less than 45% for 3/21 (14%). Compliance decreased during the study (96% in the first week, 68% during the fifth). 12% of the values were falsified. The PiKo-1 was considered to be small, attractive and useful. Some children found the mouthpiece too small. The good results for compliance that we observed might have been due to the short duration of the study. PiKo-1 was well accepted by the subjects. It will be possible to monitor PEFR and forced expiratory volume in the first second of expiration at home using this new device.


Magnetic Nanoparticles Cross the Blood-Brain Barrier: When Physics Rises to a Challenge.
The blood-brain barrier is a physical and physiological barrier that protects the brain from toxic substances within the bloodstream and helps maintain brain homeostasis. It also represents the main obstacle in the treatment of many diseases of the central nervous system. Among the different approaches employed to overcome this barrier, the use of nanoparticles as a tool to enhance delivery of therapeutic molecules to the brain is particularly promising. There is special interest in the use of magnetic nanoparticles, as their physical characteristics endow them with additional potentially useful properties. Following systemic administration, a magnetic field applied externally can mediate the capacity of magnetic nanoparticles to permeate the blood-brain barrier. Meanwhile, thermal energy released by magnetic nanoparticles under the influence of radiofrequency radiation can modulate blood-brain barrier integrity, increasing its permeability. In this review, we present the strategies that use magnetic nanoparticles, specifically iron oxide nanoparticles, to enhance drug delivery to the brain.


Process Robustness in Lipid Nanoparticle Production: A Comparison of Microfluidic and Turbulent Jet Mixing.
The recent clinical and commercial success of lipid nanoparticles (LNPs) for nucleic acid delivery has incentivized the development of new technologies to manufacture LNPs. As new technologies emerge, researchers must determine which technologies to assess and how to perform comparative evaluations. In this article, we use a quality-by-design approach to systematically investigate how the mixer technology used to form LNPs influences LNPstructure. Specifically, a coaxial turbulent jet mixer and a staggered herringbone microfluidic mixer were systematically compared via matched formulation and process conditions. A full-factorial design-of-experiments study with three factors and three levels was executed for each mixer to compare process robustness in the production of antisense oligonucleotide (ASO) LNPs. ASO-LNPs generated with the coaxial turbulent jet mixer were consistently smaller, had a narrower particle size distribution, and had a higher ASO encapsulation as compared to the microfluidic mixer, but had a greater variation in internal structure with less ordered cores. A subset of the study was replicated for mRNA-LNPs with comparable trends in particle size and encapsulation, but more frequent bleb features for LNPs produced by the coaxial turbulent jet mixer. The study design used here provides a road map for how researchers may compare different mixer technologies (or process changes more broadly) and how such studies can inform process robustness and manufacturing control strategies.


Cell-to-cell contact-mediated regulation of tumor behavior in the tumor microenvironment.
Tumor growth and progression are complex processes mediated by mutual interactions between cancer cells and their surrounding stroma that include diverse cell types and acellular components, which form the tumor microenvironment. In this environment, direct intercellular communications play important roles in the regulation of the biological behaviors of tumors. However, the underlying molecular mechanisms are insufficiently defined. We used an in vitro coculture system to identify genes that were specifically expressed at higher levels in cancer cells associated with stromal cells. Major examples included epithelial membrane protein 1 (EMP1) and stomatin, which positively and negatively regulate tumor progression, respectively. EMP1 promotes tumor cell migration and metastasis via activation of the small GTPase Rac1, while stomatin strongly suppresses cell proliferation and induces apoptosis of cancer cells via inhibition of Akt signaling. Here we highlight important aspects of EMP1, stomatin, and their family members in cancer biology. Furthermore, we consider the molecules that participate in intercellular communications and signaling transduction between cancer cells and stromal cells, which may affect the phenotypes of cancer cells in the tumor microenvironment.


Laparoscopic radical prostatectomy in obese patients: feasible or foolhardy?
More than 70% of men who are candidates for radical prostatectomy can be classified as either overweight or obese by body mass index. The role for laparoscopic radical prostatectomy (LRP) in treating these patients remains to be defined. A wealth of experience from bariatric surgery confirms that laparoscopic procedures can be performed successfully, even in the setting of morbid obesity, despite well-defined derangements in respiratory dynamics. Using the technical modifications outlined here, LRP can be performed safely and effectively in obese patients. Obesity raises the degree of difficulty for LRP, however, resulting in longer operative times and possibly a higher rate of open conversion. For this reason, surgeons early in their LRP experience are advised to avoid obese patients until they have become facile in the performance of LRP in normal-weight individuals.


Sleep and cognitive aging in the eighth decade of life.
We examined associations between self-reported sleep measures and cognitive level and change (age 70-76 years) in a longitudinal, same-year-of-birth cohort study (baseline N = 1091; longitudinal N = 664). We also leveraged GWAS summary data to ascertain whether polygenic scores (PGS) of chronotype and sleep duration related to self-reported sleep, and to cognitive level and change. Shorter sleep latency was associated with significantly higher levels of visuospatial ability, processing speed, and verbal memory (β ≥ |0.184|, SE ≤ 0.075, p ≤ 0.003). Longer daytime sleep duration was significantly associated slower processing speed (β = -0.085, SE = 0.027, p = 0.001), and with steeper 6-year decline in visuospatial reasoning (β = -0.009, SE = 0.003, p = 0.008), and processing speed (β = -0.009, SE = 0.002, p < 0.001). Only longitudinal associations between longer daytime sleeping and steeper cognitive declines survived correction for important health covariates and false discovery rate (FDR). PGS of chronotype and sleep duration were nominally associated with specific self-reported sleep characteristics for most SNP thresholds (standardized β range = |0.123 to 0.082|, p range = 0.003 to 0.046), but neither PGS predicted cognitive level or change following FDR. Daytime sleep duration is a potentially important correlate of cognitive decline in visuospatial reasoning and processing speed in older age, whereas cross-sectional associations are partially confounded by important health factors. A genetic propensity toward morningness and sleep duration were weakly, but consistently, related to self-reported sleep characteristics, and did not relate to cognitive level or change.


Development of a gridded meteorological dataset over Java island, Indonesia 1985-2014.
We describe a gridded daily meteorology dataset consisting of precipitation, minimum and maximum temperature over Java Island, Indonesia at 0.125°×0.125° (~14 km) resolution spanning 30 years from 1985-2014. Importantly, this data set represents a marked improvement from existing gridded data sets over Java with higher spatial resolution, derived exclusively from ground-based observations unlike existing satellite or reanalysis-based products. Gap-infilling and gridding were performed via the Inverse Distance Weighting (IDW) interpolation method (radius, r, of 25 km and power of influence, α, of 3 as optimal parameters) restricted to only those stations including at least 3,650 days (~10 years) of valid data. We employed MSWEP and CHIRPS rainfall products in the cross-validation. It shows that the gridded rainfall presented here produces the most reasonable performance. Visual inspection reveals an increasing performance of gridded precipitation from grid, watershed to island scale. The data set, stored in a network common data form (NetCDF), is intended to support watershed-scale and island-scale studies of short-term and long-term climate, hydrology and ecology.


Breakthrough infection evokes the nasopharyngeal innate immune responses established by SARS-CoV-2-inactivated vaccine.
Nasopharyngeal immune responses are vital for defense against SARS-CoV-2 infection. Although vaccination via muscle immunization has shown a high efficacy in reducing severity and death in COVID-19 infection, breakthrough infection frequently happens because of mutant variants and incompletely established mucosal immunity, especially in the upper respiratory tract. Here, we performed a single-cell RNA and T-cell receptor repertoire sequencing and delineated a high-resolution transcriptome landscape of nasopharyngeal mucosal immune and epithelial cells in vaccinated persons with breakthrough infection and non-vaccinated persons with natural infection as control. The epithelial cells showed anti-virus gene expression diversity and potentially recruited innate immune cells into the nasopharyngeal mucous of vaccinated patients. Upon infection, they released significant pro-inflammatory cytokines and chemokines by macrophages and monocytes and expressed antigen-presenting relevant genes by dendritic cells. Such immune responses of nasopharyngeal innate immune cells would facilitate the strengthened expression of cytotoxic genes in virus-specific T-cell or B-cell differentiation into antibody-secreting cells at the early stage of breakthrough infection through cell interaction between innate and adaptive immune cells. Notably, these alterations of nasopharyngeal immune cells in breakthrough infection depended on the activated Nuclear factor-κB (NF-κB) and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) signaling rather than type I interferon responses due to the general reduction in interferon-stimulated gene expression. Our findings suggest that vaccination potentially strengthens innate immune barriers and virus-specific memory immune cell responses, which could be quickly activated to defend against variant breakthrough infection and maintain nasopharyngeal epithelial cell integrity. Thus, this study highlights the necessity of a boost via nasal mucous after intramuscular immunization.


Type 2 diabetes and risk for functional decline and disability in older persons.
As older adults make up an increasingly lager proportion of the diabetic population, the spectrum of chronic diabetes complications will change and expand. Aside from the traditional long-term complications, diabetes has been associated with excess risk of a number of clinical conditions typical of the geriatric population, including functional decline, physical disability, falls, fractures, cognitive impairment, and depression. These conditions are common and profoundly affect the quality of life of older patients with diabetes. The identification of effective ways of preventing and treating these emerging complications, thus improving quality of life among older diabetic patients, is already a major issue in geriatric medicine. In this narrative review, we describe current epidemiological and clinical evidence supporting the association between diabetes and physical disability in older persons. Furthermore, the potential biological mechanisms underlying such an association are analyzed.


Research on the Rule of Explosion Shock Wave Propagation in Multi-Stage Cavity Energy-Absorbing Structures.
The propagation laws of explosion shock waves and flames in various chambers were explored through a self-built large-scale gas explosion experimental system. The propagation process of shock waves inside the cavity was explored through numerical simulation using Ansys Fluent, and an extended study was conducted on the wave attenuation effect of multiple cavities connected in a series. The findings show that the cavity's length and diameter influenced the weakening impact of shock waves and explosive flames. By creating a reverse shock wave through complicated superposition, the cavity's shock wave weakening mechanism worked. By suppressing detonation creation inside the cavity, the explosive flame was weakened by the cavity's design. The multi-stage cavity exhibited sound-weakening effects on both shock waves and explosive flames, and an expression was established for the relationship between the suppression rate of shock force and the number of cavities. Diffusion cavities 35, 55, 58, and 85 successfully suppressed explosive flames. The multi-stage cavity efficiently reduced the explosion shock wave. The flame suppression rate of the 58-35 diffusion cavity explosion was 93.38%, whereas it was 97.31% for the 58-35-55 cavity explosion. In engineering practice, employing the 58-58 cavity is advised due to the construction area, construction cost, and wave attenuation impact.


Adherence to disease-modifying therapy in multiple sclerosis: Part I.
Multiple sclerosis (MS) is a chronic, debilitating disease for which there is no cure. However, the recent introduction of injectable immunomodulating agents has made it possible to reduce the frequency of relapsing episodes and to possibly slow its progression. The use of these agents is recommended by the National MS Society, however, their true potential cannot be realized if patients do not accept them and healthcare professionals do not promote them. Because MS is unpredictable, and treatments can produce side effects, ensuring adherence to the recommended therapy is a complex and challenging issue. A better understanding of the obstacles to adherence, and the identification of possible solutions, should be of value to nurses, who have numerous opportunities to encourage patients to initiate and continue therapy. This article, which is in two parts, describes the particular problems of treatment adherence, and proposes that the transtheoretical model of behavior change can be useful in achieving treatment goals in MS and in other chronic disease states. This model is based upon the concept that a patient's "readiness for change" is crucial, and that attempts at intervention should be sensitive to the patient's changing conditions and state of mind. Nurses who work with patients with MS and other chronic diseases can apply the model to help their patients accept and adhere to the demands of ongoing treatment.


'Top, bottom, versatile': narratives of sexual practices in gay relationships in the Cape Metropole, South Africa.
Sexual practices among gay and other men who have sex with men are evolving in South Africa and heteronormative stereotypes are being contested. This paper draws from a larger qualitative study on how men construct a gay identity and negotiate their relationships within contemporary South African contexts, following constitutional and legal changes, in this respect. A feminist, social constructionist approach was used to collect and analyse data from in-depth interviews with 15 self-identified gay men, aged 20 to 46 years, drawn from a university in the larger Cape Metropole, South Africa. Interviews were audio-recorded, transcribed verbatim and analysed using thematic and narrative analysis. 'Bottoms' revealed being powerful in receptive sex. Other men deconstructed the binaries of masculine/feminine and resisted heteronormativity by engaging in fluid constructions in their relationships, whereby participants 'switched' or 'flipped' or did not recognise stereotypical roles when practising sex. There may be value in making these flexible and reciprocal sexual practices better known about and promoted as non-normative African models of sexual practice.


Operative management of a non-traumatic cervico-thoracic spondylolisthesis: a case report.
In contrast to spondylolisthesis of the lumbar spine, non-traumatic cervico-thoracic spondylolisthesis is a very rare lesion. Even minor changes in the displacement of the vertebrae or the cord can lead to cervical myelopathy and paralysis. Since only a few cases have been well-documented, there is currently no clear preference between operative techniques. We describe the case of a 63-year-old Caucasian man with a 13 mm spondylolisthesis between C7 and T1. Within a few months, a progressive cervical myelopathy developed as he began to suffer pain and loss of function of his digits and was no longer able to walk unassisted. In an interdisciplinary collaboration between neurological and orthopedic surgeons, a ventral-dorsal-ventral approach was performed on one vertebral section. The ventral removal of the intervertebral disc was followed by laminectomy and dorsal instrumentation. A new application technique was established by inserting bicortical screws into the transverse processes of T2 and T3. The structure was subsequently stabilized by the ventral insertion of a Harms basket. The procedure was successful as it halted progression of the myelopathy. The patient demonstrated improved sensitivity and recovered the ability to walk unassisted. He has now been able to walk unassisted for two years postoperatively. This paper describes a successful treatment for a very rare case of cervico-thoracic spondylolisthesis. The technique of inserting bicortical screws into the transverse processes is a fast, safe and successful method that does not require the use of intraoperative radiographs for placement of the bicortical screws into the transverse processes.


Nanosecond relaxation processes of phospholipid bilayers in the transition zone.
Ultrasonic relaxation spectra of dipalmitoyl lecithin vesicles have been recorded as a function of temperature over the frequency range 14-265 MHz. A relaxation process is observed with a time constant of about 10(-8) sec. At the mid-point of the crystalline-liquid crystalline transition (about 41.3 degrees), the relaxation amplitude is maximal. This suggests that the relaxation process is intimately associated with the order-disorder transition. Further support for this conclusion comes from the finding that the volume change of the reaction, as calculated from the relaxation amplitude at the transition midpoint, agrees with that determined independently by equilibrium dilatometry measurements of the deltaV of the transition. The results show that a major step in the transition occurs on a far shorter time scale than previously recognized. Similar fast processes have also been detected in dimyristoyl and distearoyl lecithin vesicles. From a consideration of various lines of evidence, it appears that the relaxation monitors the elementary step associated with the isomerization of lipid chains, such as kink formation through internal bond rotations, as the bilayer transforms between ordered and disordered phases.


Vitamin D influences asthmatic pathology through its action on diverse immunological pathways.
The prevalence of vitamin D insufficiency and deficiency has increased markedly in recent decades to current epidemic levels (Hyppönen E, et al. Am J Clin Nutr 2007;85:860-868). In parallel, there has been an increase in the incidence of a range of immune-mediated conditions ranging from cancer to autoimmune and respiratory diseases, including chronic obstructive pulmonary disease and asthma (Holick MF. N Engl J Med 2007;357:266-281; Finklea et al. Adv Nutr 2011;2:244-253). There is also an association with increased respiratory infections, which are the most common cause of asthma exacerbations (Finklea et al. Adv Nutr 2011;2:244-253). Together, this has resulted in considerable interest in the therapeutic potential of vitamin D to prevent and improve treatment of asthma and other respiratory diseases. To this end, data from clinical trials involving supplementation with active vitamin D, or more commonly a precursor, are starting to emerge. This review considers mechanisms by which vitamin D may act on the immune system to dampen inappropriate inflammatory responses in the airway while also promoting tolerance and antimicrobial defense mechanisms that collectively maintain respiratory health.


Frontal lobe atrophy after prolonged frontal bone defect.
After a frontofacial monobloc in a 12-year-old Crouzon patient, the frontal bone was lost to infection. The patient did not attend postoperative appointments and was lost to follow-up. Nine years later, he reappeared requesting surgical reconstruction. This was performed satisfactorily with a titanium plate; however, it became apparent later that he had considerable atrophy of the frontal lobes and had developed the unstable behavior of patients who have undergone a frontal lobotomy. The atrophy would appear to be the consequence of the long-term absence of the frontal bones and the resultant repetitive frontal lobe microtrauma. Frontal infection and subsequent loss of the frontal bone is a recognized complication of monobloc advancement for faciocraniosynostosis and is mainly caused by the communication between the oronasal cavities and the cranial base. The frontal bone defect would normally be repaired after a delay of 6 months to a year with no significant sequelae. We present the unusual case of a patient whose frontal defect was not reconstructed for 9 years and who, as a result, developed frontal lobe atrophy and subsequent severe psychologic and behavioral difficulties.


NF-kappaB inhibitor dehydroxymethylepoxyquinomicin suppresses osteoclastogenesis and expression of NFATc1 in mouse arthritis without affecting expression of RANKL, osteoprotegerin or macrophage colony-stimulating factor.
Inhibition of NF-kappaB is known to be effective in reducing both inflammation and bone destruction in animal models of arthritis. Our previous study demonstrated that a small cell-permeable NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), suppresses expression of proinflammatory cytokines and ameliorates mouse arthritis. It remained unclear, however, whether DHMEQ directly affects osteoclast precursor cells to suppress their differentiation to mature osteoclasts in vivo. The effect of DHMEQ on human osteoclastogenesis also remained elusive. In the present study, we therefore examined the effect of DHMEQ on osteoclastogenesis using a mouse collagen-induced arthritis model, and using culture systems of fibroblast-like synovial cells obtained from patients with rheumatoid arthritis, and of osteoclast precursor cells from peripheral blood of healthy volunteers. DHMEQ significantly suppressed formation of osteoclasts in arthritic joints, and also suppressed expression of NFATc1 along the inner surfaces of bone lacunae and the eroded bone surface, while serum levels of soluble receptor activator of NF-kappaB ligand (RANKL), osteoprotegerin and macrophage colony-stimulating factor were not affected by the treatment. DHMEQ also did not suppress spontaneous expression of RANKL nor of macrophage colony-stimulating factor in culture of fibroblast-like synovial cells obtained from patients with rheumatoid arthritis. These results suggest that DHMEQ suppresses osteoclastogenesis in vivo, through downregulation of NFATc1 expression, without significantly affecting expression of upstream molecules of the RANKL/receptor activator of NF-kappaB/osteoprotegerin cascade, at least in our experimental condition. Furthermore, in the presence of RANKL and macrophage colony-stimulating factor, differentiation and activation of human osteoclasts were also suppressed by DHMEQ, suggesting the possibility of future application of NF-kappaB inhibitors to rheumatoid arthritis therapy.


Dlk1-Dio3 locus-derived lncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity.
The mammalian imprinted Dlk1-Dio3 locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, including Meg3 (i.e., Gtl2) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By profiling cell types at each stage of embryonic stem cell-derived motor neurons (ESC~MNs) that recapitulate spinal cord development, we uncovered that lncRNAs expressed from the Dlk1-Dio3 locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically, Meg3 and other Dlk1-Dio3 locus-derived lncRNAs facilitate Ezh2/Jarid2 interactions. Loss of these lncRNAs compromises the H3K27me3 landscape, leading to aberrant expression of progenitor and caudal Hox genes in postmitotic MNs. Our data thus illustrate that these lncRNAs in the Dlk1-Dio3 locus, particularly Meg3, play a critical role in maintaining postmitotic MN cell fate by repressing progenitor genes and they shape MN subtype identity by regulating Hox genes.


Ureteral inguinal hernia: an uncommon trap for general surgeons.
Inguinal hernias involving the ureter, a retroperitoneal structure, is an uncommon phenomenon. It can occur with or without obstructive uropathy, the latter posing a trap for the unassuming general surgeon performing a routine inguinal hernia repair. Ureteral inguinal hernia should be included as a differential when a clinical inguinal hernia is diagnosed concurrently with unexplained hydronephrosis, renal failure or urinary tract infection particularly in a male. The present case describes a patient with a known ureteroinguinal hernia who proceeded to having a planned hernia repair and ureteric protection. The case is a reminder that when faced with an unexpected finding such an indirect sliding inguinal hernia, extreme care should be taken to ensure that no structures are inadvertently damaged and that a rare possibility is the entrapment of the ureter in the inguinal canal.


Congenital hemihypertrophy and abnormalities of the cerebral vasculature. Report of two cases.
Two patients are described with congenital hemihypertrophy and vascular abnormalities of the brain on the side of the hypertrophy and in the posterior fossa. The abnormalities observed included giant aneurysm, capillary hemangioma, and arteriovenous malformation. Vascular anomalies in the affected limbs are common in congenital hemihypertrophy, and neurological abnormalities and hypertrophy of the brain have been reported. The presence of vascular abnormalities of the brain in this condition may provide an opportunity to further the understanding of the development of cerebrovascular malformations.


Injury, sepsis, and the regulation of Toll-like receptor responses.
Although we tend to think that the immune system has evolved to protect the host from invading pathogens and to discriminate between self and nonself, there must also be an element of the immune system that has evolved to control the response to tissue injury. Moreover, these potential immune-regulatory pathways controlling the injury response have likely coevolved in concert with self and nonself discriminatory immune-regulatory networks with a similar level of complexity. From a clinical perspective, severe injury upsets normal immune function and can predispose the injured patient to developing life-threatening infectious complications. This remains a significant health care problem that has driven decades of basic and clinical research aimed at defining the functional effects of injury on the immune system. This review and update on our ongoing research efforts addressing the immunological response to injury will highlight some of the most recent advances in our understanding of the impact that severe injury has on the innate and adaptive immune system focusing on phenotypic changes in innate immune cell responses to Toll-like receptor stimulation.


Qualitative Analysis of the Roles of Physicians and Nurses in Providing Decision Support to Patients With Relapsed or Refractory Leukemia and Lymphoma.
This study examined the roles of hematologists and other professionals in providing decision support to patients with relapsed or refractory leukemia and lymphoma. This was a qualitative study using in-depth semi-structured interviews involving 11 hematologists in Japan. We identified 7 categories related to the roles of hematologists in providing direct decision support to patients: (1) preparing patients before informed consent, (2) selecting the information to convey, (3) choosing a method for conveying this information, (4) respecting the intentions of patients and their families, (5) directing decision-making and considering fairness, (6) considering the emotional aspects of patients and their families, and (7) providing support after discussing treatment options. We also identified the following 5 subcategories related to the roles of hematologists in multidisciplinary collaboration: (1) communicating with other professionals, (2) gathering information from them, (3) providing information to them, (4) managing the entire medical team, and (5) encouraging nurses to actively participate with patients throughout the decision-making process. Through content analysis, the hematologist's direct role in decision-making was extracted as preparation and consideration in situations where information about decision-making is communicated, and emotional support after the information is communicated. In addition, active participation in discussions, sharing information about the patient's situation and relevant discussions, and emotional support as the hematologist's expected roles in other professions were extracted. The results therefore suggest that a multidisciplinary team is needed to share information and provide multidimensional support to patients.


Food Supply Chain Stakeholders' Perspectives on Sharing Information to Detect and Prevent Food Integrity Issues.
One of the biggest challenges facing the food industry is assuring food integrity. Dealing with complex food integrity issues requires a multi-dimensional approach. Preventive actions and early reactive responses are key for the food supply chain. Information sharing could facilitate the detection and prevention of food integrity issues. This study investigates attitudes towards a food integrity information sharing system (FI-ISS) among stakeholders in the European food supply chain. Insights into stakeholders' interest in participating and their conditions for joining an FI-ISS are assessed. The stakeholder consultation consisted of three rounds. During the first round, a total of 143 food industry stakeholders-covering all major food sectors susceptible to food integrity issues-participated in an online quantitative survey between November 2017 and February 2018. The second round, an online qualitative feedback survey in which the findings were presented, received feedback from 61 stakeholders from the food industry, food safety authorities and the science community. Finally, 37 stakeholders discussed the results in further detail during an interactive workshop in May 2018. Three distinct groups of industry stakeholders were identified based on reported frequency of occurrence and likelihood of detecting food integrity issues. Food industry stakeholders strongly support the concept of an FI-ISS, with an attitude score of 4.49 (standard deviation (S.D.) = 0.57) on a 5-point scale, and their willingness to participate is accordingly high (81%). Consensus exists regarding the advantages an FI-ISS can yield towards detection and prevention. A stakeholder's perception of the advantages was identified as a predictor of their intention to join an FI-ISS, while their perception of the disadvantages and the perceived risk of food integrity issues were not. Medium-sized companies perceive the current detection of food integrity issues as less likely compared to smaller and large companies. Interestingly, medium-sized companies also have lower intentions to join an FI-ISS. Four key success factors for an FI-ISS are defined, more specifically with regards to (1) the actors to be involved in a system, (2) the information to be shared, (3) the third party to manage the FI-ISS and (4) the role of food safety authorities. Reactions diverged concerning the required level of transparency, the type of data that stakeholders might be willing to share in an FI-ISS and the role authorities can have within an FI-ISS.


Second-generation pseudorabies virus vaccine with deletions in thymidine kinase and glycoprotein genes.
A modified-live pseudorabies virus (PRV) vaccine, designated PRV(dlg92/d1tk), with deletions in the thymidine kinase (tk) and glycoprotein-gIII (g92) genes, was derived from the PRV (Bucharest [BUK]-d13) vaccine strain. The vaccine virus also contained a deletion in glycoprotein gI. Despite 3 deletions, PRV(dlg92/d1tk) replicated to high titers in cell culture from 30 C to 39.1 C. Enzyme assays and autoradiography revealed that PRV(dlg92/d1tk) did not induce a functional tk activity in infected tk- RAB(BU) cells (rabbit skin). Rabbit skin cells were infected with PRV(dlg92/d1tk), with vaccine strains derived from BUK or Bartha K strains of PRV or with the virulent Illinois (ILL), Indiana-Funkhauser (IND-F), and Aujeszky (Auj) strains of PRV and were labeled with [3H]mannose from 4 or 5 to 24 hours after infection to investigate whether these viruses induced the synthesis of glycoprotein gIII. Nonionic detergent extracts were prepared and immunoprecipitated with antisera from pigs vaccinated with tk(-)-PRV(BUK-d13) or tk+-Bartha K, pigs vaccinated with tk+-PRV(BUK) strains and then challenge exposed to tk+-PRV(IND-F), naturally infected domestic or feral pigs, and pigs vaccinated with tk-)-PRV(dlg92/d1tk). Mouse monoclonal antibodies against PRV glycoproteins gIII, gp50, and gII were also studied. After immunoprecipitation, labeled PRV-specific proteins were analyzed by sodium dodecylsulfate-polyacrylamide gel electrophoresis and autoradiography. The PRV glycoprotein-gII complex, but not glycoprotein gIII, was synthesized in PRV(dlg92/d1tk)-infected cells. Glycoprotein gII and gIII were made in cells infected with PRV vaccine strains BUK, Bartha K, and BUK-d13 and with virulent PRV strains ILL, IND-F, and Auj. Cells infected with PRV(dlg92/d1tk) and with PRV strains ILL, IND-F, Auj, Bartha K, BUK, and BUK-d13, excreted into the cell culture medium a highly sulfated glycoprotein gX of about 90 kilodaltons. Antibodies to glycoprotein gIII were not detected in the sera of pigs inoculated with PRV(dlg92/d1tk), but were found in all other swine sera.


Women with obstetric fistula in Ethiopia: a 6-month follow up after surgical treatment.
To quantify surgical and quality of life outcomes 6 months after obstetric fistula repair. A prospective study. Women were examined and questioned at discharge and at follow-up appointment. The Barhirdar Hamlin Fistula Centre, a dedicated unit treating women with obstetric fistula in northern Ethiopia. All women admitted to the Barhirdar Hamlin Fistula Centre suffering from vesicovaginal (WF) and rectovaginal fistulae (RVF). All women were asked to return for a follow-up appointment 6 months after surgical treatment. A standardised questionnaire and examination were used and information entered into a database. Urinary and anal continence status; extent of return to previous family situation, employment, social activities and reproductive capabilities. Continence status at discharge was largely maintained at 6 months and quality of life was improved. Many of those incontinent on discharge improved; a small number apparently cured at discharge had later recurrence of incontinence. Surgical treatment for obstetric fistula is successful in maintaining continence and improving quality of life of women at 6-months follow up.


Vesicular nucleotide transporter mediates ATP release and migration in neutrophils.
Neutrophils migrate to sites infected by pathogenic microorganisms. This migration is regulated by neutrophil-secreted ATP, which stimulates neutrophils in an autocrine manner through purinergic receptors on the plasma membrane. Although previous studies have shown that ATP is released through channels at the plasma membrane of the neutrophil, it remains unknown whether it is also released through alternate secretory systems involving vesicular mechanisms. In this study, we investigated the possible involvement of vesicular nucleotide transporter (VNUT), a key molecule for vesicular storage and nucleotide release, in ATP secretion from neutrophils. RT-PCR and Western blotting analysis indicated that VNUT is expressed in mouse neutrophils. Immunohistochemical analysis indicated that VNUT mainly colocalized with matrix metalloproteinase-9 (MMP-9), a marker of tertiary granules, which are secretory organelles. In mouse neutrophils, ATP release was inhibited by clodronate, which is a potent VNUT inhibitor. Furthermore, neutrophils from VNUT-/- mice did not release ATP and exhibited significantly reduced migration in vitro and in vivo These findings suggest that tertiary granule-localized VNUT is responsible for vesicular ATP release and subsequent neutrophil migration. Thus, these findings suggest an additional mechanism through which ATP is released by neutrophils.


Vaccine-Preventable Admissions to an Irish Paediatric Intensive Care.
In the Republic of Ireland, the schedule of state-funded immunisation for children is comprehensive and includes diphtheria, pertussis, tetanus, pneumococcus, hepatitis B, meningococcus C, haemophilus B, polio, measles, rubella and mumps. Varicella and meningococcal B vaccines are commercially available but are not currently funded by the government. Each of the illnesses preventable by these vaccines can cause substantial morbidity, and rarely mortality, in infants and children. Our PICU continues to see serious illness due to avoidable infection. There were 39 admissions in a 4 year period, with 34 children surviving to discharge. Nine children were infected with pneumococcus, with 4 deaths. There was one case of pertussis, causing death. Most infections occurred in previously healthy children. These preventable conditions represent a significant burden on children, families, and on social and healthcare resources.


Point-of-care platelet reactivity determination with VerifyNow-P2Y12 following administration of clopidogrel or prasugrel: data from a real-world, clinical care inpatient setting.
To describe VerifyNow-P2Y12 (VN-P2Y12, Accumetrics, San Diego, CA) results from patients treated with either clopidogrel or prasugrel who were seeking care in a hospital setting. VN-P2Y12 is a point-of-care device that measures platelet reactivity to adenosine diphosphate. Past assessments of thienopyridine therapy utilizing VN-P2Y12 have largely come from clinical trial settings. There are limited data from real-world settings. Electronic medical record data from Huntsville Hospital (Huntsville, AL) for those who underwent VN-P2Y12 testing for clopidogrel or prasugrel between January 1, 2009 and October 31, 2010 were analyzed. The VN-P2Y12 data included P2Y12 reaction units (PRUs) and device-reported percentage of inhibition. Descriptive analyses were conducted with t tests, and a logistic regression model was estimated to assess the association between patient characteristics and the likelihood of platelet nonresponse. In total, 2882 tests (2476 with clopidogrel and 406 with prasugrel) were analyzed. For clopidogrel and prasugrel, respectively, mean PRU standard deviation (SD) was 206 (90) and 107 (93; P < 0.0001) and mean % inhibition (SD) was 31% (26%) and 63% (31%; P < 0.0001). Treatment with clopidogrel alone (odds ratio [OR] = 5.25; P < 0.0001), being non-Caucasian (OR = 1.48; P = 0.0440), obese (OR = 1.49; P = 0.0010), anemic (OR = 3.29; P < 0.0001), diabetic (OR = 1.75; P < 0.0001), and having a history of myocardial infarction (OR = 1.57; P < 0.0001) were significant predictors of having PRU ≥ 235. This real-world data analysis shows results that are consistent with clinical trial results, namely that compared with clopidogrel, prasugrel is associated with significantly lower PRU and greater percentage of inhibition, regardless of age, race, gender, diabetes, obesity, or proton pump inhibitor use.


Nocturnal periodic breathing in primary pulmonary hypertension.
Cheyne-Stokes respiration is frequently observed in congestive heart failure. Among other factors, prolongation of circulation time, hypocapnia and hypoxia are thought to underlie this sleep-related breathing disorder. Primary pulmonary hypertension (PPH) is also characterized by reduced cardiac output and blood gas alterations. Therefore, the aim of the present study was to determine whether a nocturnal periodic breathing (PB) occurs in PPH. A total of 20 consecutive patients with PPH who had been admitted for pharmacological investigation of pulmonary vasoreactivity were investigated by lung function testing, right heart catheterization and full-night attended polysomnography. PB was detected in six patients (30%) (mean +/- SEM: apnoea/hypopnoea index 37 +/- 5 h(-1); arterial oxygen saturation was <90% during 56 +/- 6.5% of total sleep time). The patients with PB had more severe haemodynamic impairment than those without. They also had a more marked reduction in the pulmonary diffusion capacity and greater arterial hypoxia. PB was markedly improved or even eradicated by nasal oxygen during the night. Periodic breathing occurs in patients with advanced primary pulmonary hypertension and can be reversed by nocturnal nasal oxygen. The clinical and prognostic significance of periodic breathing in primary pulmonary hypertension needs to be determined by further studies.


Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults.
VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor. This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD). The age range of the study volunteers was 21-50 years; 51% of study volunteers were male and 49% were female. Primary objectives were safety and tolerability of VRC01LS intravenous (IV) infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 12-week intervals, and subcutaneous (SC) delivery at 5 mg/kg delivered once, or three times at 12-week intervals. Secondary objectives were pharmacokinetics (PK), serum neutralization activity, and development of antidrug antibodies. Enrollment began on November 16, 2015, and concluded on August 23, 2017. This report describes the safety data for the first 37 volunteers who received administrations of VRC01LS. There were no serious adverse events (SAEs) or dose-limiting toxicities. Mild malaise and myalgia were the most common adverse events (AEs). There were six AEs assessed as possibly related to VRC01LS administration, and all were mild in severity and resolved during the study. PK data were modeled based on the first dose of VRC01LS in the first 25 volunteers to complete their schedule of evaluations. The mean (±SD) serum concentration 12 weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 μg/mL (n = 7) and 326 ± 35 μg/mL (n = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 μg/mL (n = 2) and 25 ± 5 μg/mL (n = 9), respectively. Over the 5-40 mg/kg IV dose range (n = 16), the clearance was 36 ± 8 mL/d with an elimination half-life of 71 ± 18 days. VRC01LS retained its expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. Potential limitations of this study include the small sample size typical of Phase I trials and the need to further describe the PK properties of VRC01LS administered on multiple occasions. The human bnMAb VRC01LS was safe and well tolerated when delivered intravenously or subcutaneously. The half-life was more than 4-fold greater when compared to wild-type VRC01 historical data. The reduced clearance and extended half-life may make it possible to achieve therapeutic levels with less frequent and lower-dose administrations. This would potentially lower the costs of manufacturing and improve the practicality of using passively administered monoclonal antibodies (mAbs) for the prevention of HIV-1 infection. ClinicalTrials.gov NCT02599896.


Effect of anterior corneal surface asphericity modification on fourth-order zernike spherical aberrations.
To evaluate the theoretical influence of the change in corneal asphericity (ΔQ) on the change in fourth-order Zernike spherical aberration coefficient (ΔC(4)0) with customized aspheric refractive correction of myopia and hyperopia. The initial anterior corneal surface profile was modeled as a conic section of apical radius of curvature R0 and asphericity Q₀. The postoperative corneal profile was modeled as a conic section of apical curvature R1 and asphericity Q1, where R1 was computed from defocus D, and Q₁ selected for controlling the postoperative asphericity. The corresponding change in fourth-order spherical aberration (ΔC(0)4) was computed within a 6-mm optical zone using inner products applied to the incurred optical path changes. These calculations were repeated for different values of D, R₀, Q₀, and various intended ΔC(4)0 values. Increasing negative spherical aberration (ΔC(4)(0) < 0) requires a change toward more negative values of asphericity (increased prolateness; ΔQ < 0) for hyperopic and low myopic corrections, but more positive values (ΔQ < 0) for high myopic correction. The larger the intended change in corneal spherical aberration (ΔC(4)(0)), the more myopic the threshold value for which the required change in asphericity, ΔQ, becomes positive. The influence of the magnitude of paraxial defocus correction is less pronounced when larger changes in C(4)(0) are intended. These results provide a basis for controlling the direction (sign) and the magnitude of spherical aberration changes when using customized aspheric profiles of ablation.


Effects of surface treatment on the microtensile bond strength of ceramic materials to dentin.
This study evaluated the effects of distinct surface treatments on the micro-tensile bonding strength (microTBS) of different ceramic materials. The occlusal surfaces of eighteen human maxillary molars were flattened perpendicularly to the long axis and divided in groups based on surface treatment (sandblasting: s; hydrofluoric acid: a; tribochemical silica coating: t): DP-s, DP-a, DP-t, IE-s, IE-a, IE-t, IC-s, IC-a, IC-t) and ceramic materials (Duceran Plus: DP, IPS Empress 2: IE, In-Ceram Alumina, IC). Panavia F luting resins were used according to the manufacturers' instructions to bond ceramic materials to the exposed dentin specimens under a load of 7.5 N. After 3-day storage, microTBS was tested at a cross-head speed of 1 mm/min. Data were analyzed with ANOVA and Tukey's test. ANOVA results showed that the microTBS of DP and IC were significantly different. The microTBS of DP-a was significantly higher than those of DP-s and DP-t. The microTBS of IC-t was significantly higher than those of IC-s and IC-a. Ceramic materials with different chemical formulations and applications yielded significantly different bond strengths to human dentin and must receive distinct surface treatments accordingly.


Assessment of the impact of dosing time on the pharmacokinetics/pharmacodynamics of prednisolone.
Prednisolone is widely used for the treatment of inflammation and auto-immune diseases. It exhibits nonlinear pharmacokinetics (PK); and its induced systemic effects (pharmacodynamics (PD)) are commonly evaluated with two biomarkers, cortisol and blood lymphocytes in plasma. Circadian patterns are observed in both biomarkers. Furthermore, the disease itself may show a circadian pattern. For example, in rheumatoid arthritis patients, better therapeutic outcomes have been reported when prednisolone was administered in the very early morning. The aim of this study is to evaluate the impact of dosing time on the PK/PD of prednisolone with a simulation approach using an interactive algorithm. A series of simulations were performed with either intravenous or oral administration of prednisolone or prednisone. The results showed that the initial or maximum concentration and trough concentration of total prednisolone were lower when the drug was administered in the early morning around 6 AM: . Oscillation patterns were observed in cumulative cortisol suppression (CCS) and alteration of total lymphocyte trafficking in blood. When the drug was given in the morning within the therapeutic dose range, or around 6 PM: for a small dose amount (<1 mg), the minimum CCS and maximum effect on lymphocytes were observed. These results indicated that the PK/PD of prednisolone are time- and dose-dependent, and suggested that it is necessary to consider the application of chronotherapy to achieve better clinical outcomes with fewer side effects of prednisolone, and a PK/PD simulation approach could provide a valuable tool to evaluate and predict time-dependency in the system.


Computational Insights into Iron Heterometal Installation in Polyoxovanadate-Alkoxide Clusters.
Polyoxovanadate-alkoxide clusters are a new class of electroactive species with applications in a wide variety of fields from redox catalysis to energy storage. Heterometallic installation in these species can be used to modulate the redox properties of polyoxovanadate-alkoxide clusters and thus their applications. However, the formation mechanism of heterometallic polyoxovanadate alkoxides during the solvothermal process is unknown, limiting our understanding regarding what thermodynamic driving forces and/or kinetic barriers are present in the heterometal insertion. Here, we present a computational study on the nucleation pathways of the iron-functionalized mixed-valent hexameric [VV2VIV3O5(μ6-O)(μ2-OCH3)12(FeIIICl)] polyoxovanadate-alkoxide cluster.


[Effect of nitrogen,phosphorus and potassium formula fertilizer on growth and chemical composition content of Inula japonica].
Inula japonica was used as the research object, "3414" fertilization experiment were conducted to study the effects of nitrogen,phosphorus and potassium formula fertilizer on the growth and chemical composition content of I. japonica. The characteristics of fertilizer requirement were preliminarily revealed and the study provided fertilization guidance for artificial cultivation of I. japonica. The results showed that different nitrogen,phosphorus and potassium formula fertilizers had significant effects on plant morphology,physiological and biochemical indexes,dry matter accumulation and chemical composition content. The growth indexes and chemical components of I. japonica showed an upward trend with the increase of fertilization amount,especially the nitrogen fertilizer was the most significant. The indicators were analyzed by membership function. After comprehensive evaluation,the optimal nitrogen,phosphorus and potassium formula fertilization level was N3 P2 K2,namely high level nitrogen fertilizer,medium level phosphorus fertilizer and potassium fertilizer. I. japonica is a high fertilizer demand plant,and the rational fertilization scheme is " applying nitrogen fertilizer again and applying phosphorus and potassium fertilizer properly".


Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade.
Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin and CCI-779, have shown preclinical potential as therapy for multiple myeloma. By inhibiting expression of cell cycle proteins, these agents induce G1 arrest. However, by also inhibiting an mTOR-dependent serine phosphorylation of insulin receptor substrate-1 (IRS-1), they may enhance insulin-like growth factor-I (IGF-I) signaling and downstream phosphatidylinositol 3-kinase (PI3K)/AKT activation. This may be a particular problem in multiple myeloma where IGF-I-induced activation of AKT is an important antiapoptotic cascade. We, therefore, studied AKT activation in multiple myeloma cells treated with mTOR inhibitors. Rapamycin enhanced basal AKT activity, AKT phosphorylation, and PI3K activity in multiple myeloma cells and prolonged activation of AKT induced by exogenous IGF-I. CCI-779, used in a xenograft model, also resulted in multiple myeloma cell AKT activation in vivo. Blockade of IGF-I receptor function prevented rapamycin's activation of AKT. Furthermore, rapamycin prevented serine phosphorylation of IRS-1, enhanced IRS-1 association with IGF-I receptors, and prevented IRS-1 degradation. Although similarly blocking IRS-1 degradation, proteasome inhibitors did not activate AKT. Thus, mTOR inhibitors activate PI3-K/AKT in multiple myeloma cells; activation depends on basal IGF-R signaling; and enhanced IRS-1/IGF-I receptor interactions secondary to inhibited IRS-1 serine phosphorylation may play a role in activation of the cascade. In cotreatment experiments, rapamycin inhibited myeloma cell apoptosis induced by PS-341. These results provide a caveat for future use of mTOR inhibitors in myeloma patients if they are to be combined with apoptosis-inducing agents.


Protein kinase CK2 and cell polarity.
There is increasing evidence that protein kinase CK2 is involved, among a wide variety of cellular processes, in the maintenance of mammalian cell morphology and cell polarity. Here, we show that in epithelial cells, a fraction of CK2 is associated to the plasma membrane and that this localization is controlled by cell-matrix interactions. In addition, inhibition of CK2 activity in mammary epithelial cells (MCF10A), using either the specific CK2 inhibitor TBB or siRNA-mediated CK2beta knockdown, induced differential phenotypes revealing an important role of this enzyme in epithelial cell morphology.


Assessing Preferences for Animals in Children with Autism: A New Use for Video-Based Preference Assessment.
The inclusion of animals into interventions for children with autism spectrum disorder (ASD) is a growing practice known as animal-assisted intervention (AAI). The choice of the animal to include in an intervention is often solely up to the interventionist and depends on their experience, subjective judgment, and ease of access to different animals. For individuals with ASD who are non-verbal and unable to indicate preferred stimuli or activities, incorporating preference into interventions has been linked to increases in positive behaviors and enhanced quality of life. We propose that animal choice based on a participant's preference may enhance the experience of AAI and maximize its outcomes. A common technique used to reliably determine preferred interactions and activities in interventions for children with ASD is a stimulus preference assessment. The video-based multiple-stimulus without replacement (MSWO) procedure, in particular, allows for discrimination of complex stimuli that could not feasibly be presented all at once, which is the case when choosing an animal. Based on the well-documented reliability of this technique in the field of applied behavior analysis, we propose that a future direction in AAI is utilizing video-based MSWO to guide animal selection.


Increased degradation of lipoprotein(a) in atherosclerotic compared with nonlesioned aortic intima-inner media of rabbits: in vivo evidence that lipoprotein(a) may contribute to foam cell formation.
To investigate a potential role of lipoprotein(a) [Lp(a)] in foam cell formation, we have measured the degradation rates of Lp(a) and LDL in the rabbit aorta in vivo. Lp(a) (or LDL) was labeled with both 113I-TC and 125I and injected into 17 rabbits with extensive aortic atherosclerosis and into 16 rabbits without atherosclerosis. As the protein moiety of the doubly labeled lipoproteins is degraded, 131I-TC is trapped in the cell, whereas 125I diffuses out of the cell. Twenty-four hours after injection, 12 samples of the aorta and biopsies from 9 other tissues were removed. The degradation rate of Lp(a) (percent of plasma pool per gram tissue per day) was less than that of LDL in the adrenals and in the intestine. In contrast, degradation rates of Lp(a) and LDL were similar in liver, spleen, kidney, heart, lung, skeletal muscle, and adipose tissue. In nonlesioned aortic intima-inner media, the degradation rate of Lp(a) was 39% of that of LDL (t test: P <.05 in aortic arch and thoracic aorta), whereas the degradation rates of Lp(a) and LDL were similar in atherosclerotic aortic intima-inner media. Lp(a) degradation rates were markedly increased in atherosclerotic compared with nonlesioned aortic intima-inner media: 28.2+/-9.2 x 10(-7)% and 5.0+/-0.6 x 10(-7)% of the plasma pool per gram tissue per day in the intima-inner media of the proximal segment of atherosclerotic and nonlesioned aorta, respectively (t test: P <.01). These results suggest that the metabolism of Lp(a) is different from that of LDL in nonlesioned arterial intima, possibly reflecting that Lp(a) is degraded by LDL receptors in arterial intima less efficiently than LDL. The results also indicate that the degradation rate of Lp(a) is markedly increased in atherosclerotic lesions of rabbits, supporting the idea that Lp(a) contributes to foam cell formation during the development of atherosclerosis.


[Association between clinical features and histopathological findings in patients with left ventricular non-compaction cardiomyopathy].
To investigate the association between clinical and histopathological features in patients with left ventricular non-compaction cardiomyopathy (LVNC). Histopathological examinations were made on 11 LVNC recipient hearts from June 2004 to June 2014 in Fuwai Hospital, myocardial ultrastructure changes were detected using transmission electron microscopy. Association between clinical and pathological features were analyzed. Patients were (24 ± 11) years old. There were 6 patients with mucus matrix LVNC, 3 patients with fibrous fatty infiltration, and 2 patients with cardiomyocytes proliferation. The gross morphological changes of LVNC hearts were characterized by numerous and prominent trabeculations with deep intratrabecular recesses in left ventricular myocardium. Ratios of the thicker noncompacted endocardial layer (N) and thin epicardial compacted layer (C) (N/C ratio) were ≥ 2.0, and the most serious lesions were located in the left ventricular apex, and followed by the left ventricular free wall. Histological microscopic examinations evidenced numerous matrix-like material and immature cardiomyocytes on endocardial tissue. Transmission electron microscopy revealed mitochondrial abnormalities on morphology, number, and distribution, underdeveloped cardiomyocytes and anomalies of intercalated disc structure, increased deposition of extracellular matrix-like substance and perinuclear glycogen. Pathological changes on cytoplasmic matrix and intercalated disc were present in all three tissue types of LVNC in this cohort and mitochondria hyperplasia was detected in patients with fibrous fatty infiltration. Heart weight ≥ 350 g is often associated with increased number of mitochondria. Increased cytoplasmic matrix was often detected in patients with LVEF ≥ 30% while intercalated disc anomalies were often detected in patients with LVEF < 30%. Histological changes were closely related clinical features in patients with LVNC.


[Effect of chemotherapy in primary tumor of MSI-H colon cancer aged 50 years or younger].
Microsatellite instability( MSI) in colorectal carcinoma is reportedly associated with resistance to 5-fluorouracil-based chemotherapy. Moreover, colorectal cancer patients aged ≤ 50 years could potentially have Lynch syndrome. In the present study, we examined 11 colorectal cancer patients with unresectable Stage IV disease who underwent resection of the primary tumor between January 2006 and December 2012. The relationship between the MSI status and the efficacy of first- line oxaliplatin-based chemotherapy was retrospectively examined. The MSI status included MSI-H in 1 patient, MSS-L in 2 patients, and MSS in 8 patients. The MSI-H in 1 patient was associated with familial adenomatous polyposis. Following chemotherapy, among 8 MSS patients, 3 showed stable disease (SD) and 1 showed partial response (PR). Moreover 2 MSH-L patients and 1 MSI-H patient showed progressive disease (PD) after chemotherapy. However, additional data collection is required to determine the effect of oxaliplatin-based chemotherapy for MSS-H or MSS-L colorectal patients aged ≤ 59 years.


[Further comment on central venous catheter infections].
Many reports from the surgical literature document the incidence of catheter related sepsis varies between 1 and 10 per cent. In many instances sepsis is secondary to contamination from normal saprophyte cutaneous bacteria. In our Institute we set down a standardized methodology to reduce the contamination of venous central access from cutaneous bacteria. Of 31 patients studied, none had bacteria in the last 5 cm of central venous catheter, 2 had streptococcus alpha haemolytic colonies and coagulase negative staphylococcus colonies at the same time on skin over the region of venepuncture. With our paper we had attained one's awareness that it is very difficult to obtain zero per cent in contamination of central venous catheter, mainly in immunodepressed or critical patients, but with careful dressing and with new technology it is possible to reduce the contamination and following sepsis.


[Plak-out and Broxojet 3007. Clinical study].
It is known that chlorhexidine, a plaque preventing agent, can cause discolorations and other side effects when used in mouthwashes at the concentration of 0.1% or more. By diluting the amount of chlorhexidine used in a mouthwash in the much greater volume of water used in a pulsating device, one could try to avoid these side-effects and, possible keep the antiplaque properties of chlorhexidine. Furthermore, it was interesting to check whether plaque, which is normally not removed by the mechanical action of a pulsating device, could be removed when the water of the device contains chlorhexidine. In the first part of the study, the effectiveness of chlorhexidine given by mouthwash (10 ml at 0.1%) has been compared to that of the same amount of chlorhexidine diluted in 400 ml of water of a pulsating device (conc. 0.0025%). The average gingival index of inflammation and plaque index, as well as the amount of gingival fluid have been measured, by previously standardized procedures, in a group of 18 students with healthy gingivae before and after a 7-days period of no-brushing. One third of the students used chlorhexidine solution in daily mouthwashes, one third used chlorhexidine in the Broxojet and the last 6 students used Broxojet with a placebo. The part of the study concerning the Broxojet was carried out in double blind. At the concentration of 0.1% in mouthwashes, chlorhexidine was found, as expected, to inhibit plaque formation. The same amount of drug diluted in the liquid of a pulsating device was, on the contrary, much less effective. Staining was noticed in most of the volunteers. The second part of the study was similarly designed and performed in the aim of checking whether higher amounts of chlorhexidine were effective in preventing plaque when used in the Broxojet: in the pulsating device, chlorhexidine was found to be effective only at the concentrations of 0.025%.


An Unusual Cause of Pacemaker Lead Displacement: 'Reverse Ratchet' Syndrome.
Lead displacement is a common complication of pacemaker device implantation, often resulting in prolonged hospital stays and increased costs. The frequency of long-term lead displacement ranges between 1.8% and 8.0%. In our case, the patient did not present any symptoms and the lead displacement was seen at a relatively late stage. During a routine pacemaker follow up, it was noted that the right ventricular (RV) threshold had increased and deteriorated over time. The pacemaker box had rotated anticlockwise and the RV lead had developed a loop that eventually led to its retraction from the RV implantation position into the pulmonary artery. The patient was asymptomatic; however, he underwent RV lead revision. Patient education, opening an appropriate pocket for the size of the generator, fixing the sleeves to an appropriate tightness and securing the battery with a strong suture all can be used to avoid lead displacement.


Combination treatment using percutaneous transluminal angioplasty and low-density lipoprotein apheresis in a patient with peripheral arterial disease and a history of chronic hemodialysis.
Peripheral arterial disease (PAD) is very common in dialysis patients, who tend to have diffuse calcification and severe peripheral arterial stenosis that make it difficult to treat limbs using only surgical or endovascular interventions. Better ways to treat this condition are therefore required and also follow-up studies to evaluate the effects of these treatments on the microcirculation. A 59-year-old man who had a cadaveric kidney transplant five years previously after 25 years of regular hemodialysis complained of pain at rest in his right lower limb and subsequently developed an intractable decubitus ulcer on his right fifth toe (Fontaine IV). Digital subtraction angiography revealed a severe obstruction of the right femoral artery and diffuse stenosis of the right superficial femoral artery. The patient underwent percutaneous transluminal angioplasty (PTA) and six sessions of low-density lipoprotein apheresis (LDL apheresis). At the end of these sessions his complaints were almost completely alleviated. The mean elevation in skin temperature after each session was (1.58 ± 0.99)°C [mean ± SD] over the right dorsalis pedis artery and (1.52 ± 0.88)°C at the tip of the right fifth toe. Ultrasound-measured blood flow rates in the right dorsalis pedis artery were 9.2 cm/s before PTA and 20.2 cm/s one month after PTA. Hemodialysis was resumed 3 days after the PTA due to contrast-induced nephropathy. The combination of PTA and LDL apheresis is useful for treating PAD in hemodialysis patients, with the changes in peripheral artery patency are able to be evaluated effectively by measuring skin temperature.


Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection.
GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitro activity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivo pharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniae and Haemophilus influenzae (mouse lung model) and with Staphylococcus aureus (rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependent in vivo efficacy against multiple isolates of S. pneumoniae, H. influenzae, and S. aureus. Dose fractionation studies with two S. pneumoniae and S. aureus isolates showed that therapeutic outcome correlated best with the free AUC/MIC (fAUC/MIC) index in S. pneumoniae (R(2), 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus (R(2), 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis and for a 1-log10 reduction in bacterial burden were 8.1 and 14.4 for 11 S. pneumoniae isolates (R(2), 0.62) and 7.2 and 13.0 for five H. influenzae isolates (R(2), 0.93). The data showed that for eight S. aureus isolates, fAUC correlated better with efficacy than fAUC/MIC (R(2), 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 4 μg/ml). Median fAUCs of 2.1 and 6.3 μg · h/ml were associated with stasis and 1-log10 reductions, respectively, for S. aureus.


Domain 4 (D4) of Perfringolysin O to Visualize Cholesterol in Cellular Membranes-The Update.
The cellular membrane of eukaryotes consists of phospholipids, sphingolipids, cholesterol and membrane proteins. Among them, cholesterol is crucial for various cellular events (e.g., signaling, viral/bacterial infection, and membrane trafficking) in addition to its essential role as an ingredient of steroid hormones, vitamin D, and bile acids. From a micro-perspective, at the plasma membrane, recent emerging evidence strongly suggests the existence of lipid nanodomains formed with cholesterol and phospholipids (e.g., sphingomyelin, phosphatidylserine). Thus, it is important to elucidate how cholesterol behaves in membranes and how the behavior of cholesterol is regulated at the molecular level. To elucidate the complexed characteristics of cholesterol in cellular membranes, a couple of useful biosensors that enable us to visualize cholesterol in cellular membranes have been recently developed by utilizing domain 4 (D4) of Perfringolysin O (PFO, theta toxin), a cholesterol-binding toxin. This review highlights the current progress on development of novel cholesterol biosensors that uncover new insights of cholesterol in cellular membranes.


Screen for small molecules increasing the mitochondrial membrane potential.
The identification of small molecules that positively modulate the mitochondrial respiratory function has broad applications in fundamental research, therapeutic target validation, and drug discovery. We present an approach in which primary screens for mitochondrial function in yeast are used to efficiently identify a subset of high-value compounds that can in turn be rapidly tested against a broad range of mammalian cell lines. The ability of the yeast assay to successfully identify in a high-throughput format hit compounds that increase the mitochondrial membrane potential and adenosine triphosphate (ATP) levels by as little as 15% was demonstrated. In this study, 14 hits were identified from a collection of 13,680 compounds. Secondary testing with myotubes, fibroblasts, and PC-12 and HepG2 cells identified two compounds increasing ATP levels in hepatocytes and two other compounds increasing ATP in fibroblasts. The effect on hepatocytes was further studied using genomic and mitochondrial proteomic tools to characterize the changes induced by the two compounds. Changes in the accumulation of a series of factors involved in early gene response or apoptosis or linked to metabolic functions (i.e., β-Klotho, RORα, PGC-1α, G6PC, IGFBP1, FTL) were discovered.


[The quality of the registry of perinatal deaths. Asturias, 1986-90].
The quality of official perinatal mortality statistics in a geographical and administratively well defined region (Asturias, Spain) is studied in a five years period (1986-90). The official figures were compared with those collected, retrospectively, from multiple hospital sources. Under-registration of perinatal death was 35% (45.5% of fetal death and 22.5% of early neonatal death, these occurred in the first 24 hours). Validity of mentioned statistics is discussed.


Error sources affecting thermocouple thermometry in RF electromagnetic fields.
Thermocouple thermometry errors in radiofrequency (typically 13, 56 MHZ) electromagnetic fields such as are encountered in hyperthermia are described. RF currents capacitatively or inductively coupled into the thermocouple-detector circuit produce errors which are a combination of interference, i.e., 'pick-up' error, and genuine rf induced temperature changes at the junction of the thermocouple. The former can be eliminated by adequate filtering and shielding; the latter is due to (a) junction current heating in which the generally unequal resistances of the thermocouple wires cause a net current flow from the higher to the lower resistance wire across the junction, (b) heating in the surrounding resistive material (tissue in hyperthermia), and (c) eddy current heating of the thermocouple wires in the oscillating magnetic field. Low frequency theories are used to estimate these errors under given operating conditions and relevant experiments demonstrating these effects and precautions necessary to minimize the errors are described. It is shown that at 13.56 MHz and voltage levels below 100 V rms these errors do not exceed 0.1 degrees C if the precautions are observed and thermocouples with adequate insulation (e.g., Bailey IT-18) are used. Results of this study are being currently used in our clinical work with good success.


Comparison of immune preservation between CO2 pneumoperitoneum and gasless abdominal lift laparoscopy.
Carbon dioxide (CO2) pneumoperitoneum has been implicated as a possible factor in early immune preservation in laparoscopic surgery. Although the current analysis was not adequate to clarify this issue, the aim of this study was to compare CO2 insufflation laparoscopic cholecystectomy to gasless abdominal wall lift laparoscopic cholecystectomy with respect to preservation of the immune system. An analysis of the temporal immune responses was performed in 2 similar groups of patients (n = 50) who were divided randomly into the categories of gas or abdominal wall lift laparoscopic cholecystectomy. The patients were matched with respect to age, weight, and operation time. The immune parameters (serum white blood cell count, cortisol, erythrocyte sedimentation rate [ESR], tumor necrosis factor-alpha [TNF-alpha], interferon-y [INF-gamma], interleukin-6 [IL-6], interleukin-8 [IL-8]) were assessed at preoperative 24 hours and at postoperative 24 and 72 hours for the 2 groups. During the operation, the levels of cytokines that were cultured in the peritoneal macrophages were also checked. The serum white blood cell count, cortisol, and ESR levels were not statistically different in either of the 2 groups. Further, the serum TNF-alpha, INF-gamma, IL-6, and IL-8 levels in both groups were not significantly different from each other at preoperative 24 hours, and postoperative 24 and 72 hours. However, an immediate decrease in the cytokine levels at 24 hours after the operation was significant in both groups. The cytokine levels were particularly higher in the cultured peritoneal macrophages than in the serum, but were not statistically different between the 2 groups. Our results showed that the beneficial immune response obtained in the CO2 gas insufflation laparoscopic procedure could also be obtained in the gasless abdominal wall lift laparoscopic procedure. An immediate preservation of the immune functions in the postoperative period was detected similarly in the 2 groups.


Bilateral subthalamic nucleus stimulation in the treatment of advanced Parkinson's disease. Five years' personal experience.
The objective of the study was to assess bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with advanced Parkinson disease (PD). The study population included 5 patients with bilateral STN DBS who completed a 5-year postoperative follow-up period. In all patients electrodes (Model 3387 or 3389) were stereotactically bilaterally inserted into the STN using a Leksell stereotactic G frame. The clinical rating tests included Unified Parkinson's Disease Rating Scale (UPDRS) and two motor-timed tests derived from CAPIT (rapid movements between two points and stand-walk-sit test). All patients were assessed in off and on condition before implantation and 1, 3 and 5 years in medication on and off condition and stimulation on condition and stimulation off condition. To compare preoperative to postoperative UPDRS scores, only mean values and standard deviations are presented because of the small study population. The stimulation effect was noted in the off state, resulting in a 59% improvement in motor scores of UPDRS at 5-year follow-up, when compared to preoperative scores. In the on state the stimulation improved motor scores by 17%. At 5-year follow-up, reduction of daily levodopa dose was 50%. Bilateral STN DBS is an effective and safe treatment for patients with advanced PD. Bilateral STN DBS contributes to improvement of parkinsonian symptoms in the off state and levodopa-induced dyskinesia. This can be correlated with a 50% reduction of daily levodopa dose 5 years postoperatively.


Protective effects of cholestyramine in rats fed a low-fiber diet containing toxic doses of sodium cyclamate or amaranth.
Immature male rats were fed a purified, low-fiber diet containing massive doses of sodium cyclamate or amaranth (FD and C Red No. 2). Sodium cyclamate when incorporated at a 5% level in the purified, low-fiber diet resulted in toxic manifestations which were counteracted by the concurrent administration of the anion exchange resin cholestyramine at a 2 1/2% level in the diet. Other anion exchange resins were also active in this regard. Cholestyramine at a 2 1/2% level of supplementation was also active in counteracting the toxic effects induced by amaranth when the latter was incorporated at a 5% level in the purified, low-fiber diet.


A model of the coupling between grip aperture and hand transport during human prehension.
It has been repeatedly demonstrated that the opening between the index finger and thumb (grasp component) during an object-directed reach-to-grasp movement achieves maximum aperture approximately two-thirds of the way through the duration of the reaching movement (transport component). Here we offer a quantitative model of the temporal coupling between grip aperture and wrist velocity which shows experimentally that the correlation between grip aperture and object size is a sigmoidal function of movement duration. When wrist velocity reaches its peak value, the correlation between the grip aperture and the size of the goal object has reached half of the correlation that is achieved by the end of the movement.