Microvascular function and inflammatory activation in Takotsubo cardiomyopathy.
The aim of this study was to determine microvascular function in the acute phase of Takotsubo syndrome (TTS) and to identify inflammatory mediators that could reflect TTS-induced pathology. The study included 20 females [median age 65 years; interquarile range (IQR) = 58-70 years] with TTS according to the Mayo diagnostic criteria. During heart catheterization, we determined the index of microvascular resistance (IMR) and drew blood samples almost simultaneously from the aorta and coronary sinus. Cardiac magnetic resonance imaging (MRI) was done in the acute phase. We present descriptive coronary physiology and cardiac MRI data and compare inflammatory biomarkers between samples from the aorta, coronary sinus, and venous samples after 3 months using the Wilcoxon signed-rank test. For comparison, we also analysed the actual biomarkers in venous blood from 15 healthy female controls. A supplementary analysis explored Spearman's rank correlation between the inflammatory biomarkers, IMR, MRI data, and cardiac biomarkers. The median IMR was 16.5 mmHg·s (IQR = 10.5-28.2 mmHg·s), which was only slightly higher than that in the reference populations. Seven (35%) of the study subjects had IMR > 25 mmHg·s, suggesting a microvascular dysfunction. IMR was not affected by time from symptom onset. According to MRI, the apical region of the left ventricle was affected in 65% of the subjects. The median ejection fraction was 41% (IQR = 31-48%). Biomarker analyses revealed elevation of markers for extracellular matrix remodelling and fibrosis, inflammation, immune activation, and upstream inflammation as compared with healthy controls. Only the levels of interleukin (IL)-1 receptor antagonist and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) were higher in the coronary sinus than in the aorta. No variable was significantly correlated with IMR. The IL-6 level in the aorta was inversely correlated with the left ventricular ejection fraction. Growth differentiation factor-15, osteoprotegerin, and von Willebrand factor levels in both aorta and coronary sinus were positively correlated with N-terminal-pro-brain-natriuretic peptide, while the correlations of IL-6 and sTIM-3 with N-terminal-pro-brain-natriuretic peptide were restricted to the aorta and coronary sinus, respectively. While most of the markers were within normal limits after 3 months, matrix metalloproteinase-9 increased during follow-up to reach levels higher than those in the healthy controls. The median IMR was only slightly elevated in this study, but about one-third of the patients had values indicating microvascular dysfunction. The present study supports the involvement of several inflammatory pathways in TTS, including monocyte/macrophage activation, with sTIM-3 as a potential novel marker.


All Hands on Deck: A synchronized whole-of-world approach for COVID-19 mitigation.
The COVID-19 pandemic can no longer be mitigated by a nationwide approach of individual nations alone. Given its scale and accelerating expansion, COVID-19 requires a coordinated and simultaneous Whole- of-World approach that galvanizes clear global leadership and solidarity from all governments of the world. Considering an 'all hands-on deck' concept, we present a comprehensive list of tools and entities responsible for enabling them, as well a conceptual framework to achieve the maximum impact. The list is drawn from pandemic mitigation tools developed in response to past outbreaks including influenza, coronaviruses, and Ebola, and includes tools to minimize transmission in various settings including person-to-person, crowd, funerals, travel, workplace, and events and gatherings including business, social and religious venues. Included are the roles of individuals, communities, government and other sectors such as school systems, health, institutions, and business. While individuals and communities have significant responsibilities to prevent person-to-person transmission, other entities can play a significant role to enable individuals and communities to make use of the tools. Historic and current data indicate the role of political will, whole-of-government approach, and the role of early introduction of mitigation measures. There is also an urgent need to further elucidate the immunologic mechanisms underlying the epidemiological characteristics such as the low disease burden among women, and the role of COVID-19 in inducing Kawasaki-like syndromes in children. Understanding the role of and development of anti-inflammatory strategies based on our understanding of pro-inflammatory cytokines (IL1, IL-6) is also critical. Similarly, the role of oxygen therapy as an anti-inflammatory strategy is evident and access to oxygen therapy should be prioritized to avoid the aggravation of COVID-19 infection. We highlight the need for global solidarity to share both mitigation commodities and infrastructure between countries. Given the global reach of COVID-19 and potential for repeat waves of outbreaks, we call on all countries and communities to act synergistically and emphasize the need for synchronized pan-global mitigation efforts to minimize everyone's risk, to maximize collaboration, and to commit to shared progress.


Understanding the direction of evolution in Burkholderia glumae through comparative genomics.
Members of the genus Burkholderia occupy remarkably diverse niches, with genome sizes ranging from ~3.75 to 11.29 Mbp. The genome of Burkholderia glumae ranges in size from ~5.81 to 7.89 Mbp. Unlike other plant pathogenic bacteria, B. glumae can infect a wide range of monocot and dicot plants. Comparative genome analysis of B. glumae strains can provide insight into genome variation as well as differential features of whole metabolism or pathways between multiple strains of B. glumae infecting the same host. Comparative analysis of complete genomes among B. glumae BGR1, B. glumae LMG 2196, and B. glumae PG1 revealed the largest departmentalization of genes onto separate replicons in B. glumae BGR1 and considerable downsizing of the genome in B. glumae LMG 2196. In addition, the presence of large-scale evolutionary events such as rearrangement and inversion and the development of highly specialized systems were found to be related to virulence-associated features in the three B. glumae strains. This connection may explain why this bacterium broadens its host range and reinforces its interaction with hosts.


Making hypertensive smokers motivated in quitting: developing 'blood pressure equivalence of smoking'.
To express the increased risk from smoking in terms of 'blood pressure' so that hypertensive smokers are motivated into quitting. Mortality risks of smokers were compared with nonsmokers in a large worker cohort in Taiwan (n = 23755 with a 17-year follow-up) for all-cause and for cardiovascular diseases. The blood pressure equivalence of smoking was then identified by the difference in mortality risks between smokers and nonsmokers. Some interaction between hypertension and smoking was found to be synergistic. When hypertension and smoking co-existed, the all-cause mortality outcome [relative risk (RR) = 4.25] was larger than the sum or product of each individual risk for hypertension (RR = 2.16) or for smoking (RR = 1.97). The excess mortality risks of smoking for smokers were converted into a 'blood pressure equivalence'. The results demonstrate that the addition of smoking was similar to an increase of mortality risk approximately equivalent to an increase in blood pressure of 40 mmHg. Smoking cessation in hypertensive patients could provide a reduction of mortality risks similar to a permanent reduction of 40 mmHg in blood pressure, over and above any antihypertensive medications. Appreciating this relationship enables physicians to bridge the clinical disconnection and motivates hypertensive smokers to seek smoking cessation. The use of a 'blood pressure equivalence of smoking' can link the two separate risk factors and may lead to a paradigm shift in overcoming an existing clinical challenge.


Education and depression.
This article is intended to assist educators in the medical field in promoting competency among medical students and trainees on the key issues in child and adolescent depression, including approach, understanding, and management. Using clinical vignettes, up-to-date research, and expert opinion and referencing accessible guidelines, resources, and tools, the authors' goal is to create information that is engaging and useful. It is designed to reach a broad audience with emphasis on trainees who are early in their career path (eg, medical students or interns) and/or who are going into primary care.


Association between skeletal muscle loss and the response to nivolumab immunotherapy in advanced gastric cancer patients.
Skeletal muscle loss is a hallmark of malignancies, including advanced gastric cancer (GC). Although programmed death (PD)-1 inhibitors, including nivolumab, have promising anti-cancer effects, there is limited information regarding markers that can predict these therapeutic effects, which include PD-ligand 1 (PD-L1) expression and the tumor mutation burden. Therefore, we evaluated whether the baseline psoas muscle mass index (PMI, a surrogate for skeletal muscle mass) could predict the response of GC to nivolumab treatment, based on progression-free survival (PFS), the objective response rate, and the disease control rate. This retrospective study evaluated 31 Japanese patients who received nivolumab for advanced GC and underwent imaging analysis between November 2017 and November 2019. The computed tomography results were used to estimate the psoas major muscle mass. Sex-specific cut-off values were used for the PMI, with low PMI values defined as < 3.6 cm2/m2 for male patients and < 2.9 cm2/m2 for female patients. The median PFS interval was 2.3 months for the patients with stage IV GC. Nine patients (29%) had a low baseline PMI, and these patients had significantly shorter median PFS than the group with a non-low baseline PMI (0.5 months vs. 2.4 months, P = 0.004). As a surrogate marker for skeletal muscle loss, the PMI may be useful for predicting the response to nivolumab among patients with advanced GC.


Percutaneous fiducial localization for thoracoscopic wedge resection of small pulmonary nodules.
The advent of high-resolution computed tomography scanning and increase in use of chest imaging for high-risk patients has led to an increase in the identification of small pulmonary nodules. The ability to locate and remove these nodules through a thoracoscopic approach is difficult. The purpose of this study is to report our experience with fiducial localization and percutaneous thoracoscopic wedge resection of small pulmonary nodules. This is a retrospective analysis of our patients who underwent computed tomography-guided fiducial localization of pulmonary nodules. Nodules were identified with intraoperative fluoroscopy and removed by thoracoscopic wedge resection. Sixty-five nodules were removed in 58 patients. Removal was successful in 98% of patients (57 of 58); 79% of the nodules (53 of 65) were cancers; 20% of these were primary lung cancers of which 9 were pure ground-glass opacities. Mean size of the nodules was 9.9 ± 4.6 mm (range, 3 to 24 mm). Mean depth from visceral pleural surface was 18.7 ± 12 mm (range, 2 to 35 mm). Mean procedure time was 58.7 ± 20.1 minutes (range, 30 to 120), and mean length of stay was 2 days (range, 1 to 6). Complications occurred in 3 patients and included fiducial embolization, fiducial migration, and parenchymal hematoma. Fiducial localization facilitates identification and removal of small pulmonary nodules and alleviates the need for direct nodule palpation. As shown by our series, thoracoscopic wedge resection with fiducial localization is an accurate and efficient technique. This method provides a standardized means by which to resect small and deep pulmonary nodules or ground-glass opacities.


Lipid oxidation, pre-slaughter animal stress and meat packaging: Can dietary supplementation of vitamin E and plant extracts come to the rescue?
Normand cull-cows received a diet enriched in n-3 polyunsaturated fatty acids (PUFA), known to enhance nutritional quality, but to decrease beef lipid stability. Half of the cows received a supplementation of vitamin E and plant extracts rich in polyphenols during the finishing period. Half of each feeding group was slaughtered under limited, the others under added stress conditions. Longissimus thoracis (LT) and Semitendinosus (ST) were evaluated after storage under air, or 70% O2/30% CO2 or vacuum conditions. Irrespectively of diet, pre-slaughter stress i) increased post-mortem malondialdehyde (MDA) formation except in vacuum-stored meat, ii) decreased vitamin A levels in the LT, iii) decreased vitamin E levels in meat stored in 70% O2/30% CO2 and total anti-oxidant status in vacuum stored meat. Effects were global; dietary supplementation with vitamin E and plant extracts was associated with lower MDA levels and MetMb percentage and higher levels of vitamin A and E.


Effect of cancer chemotherapy on dapsone N-acetylation in man.
The effect of cancer chemotherapy on dapsone (DDS) N-acetylation was explored in 28 patients with various malignancies. There was a significant (P = 0.01) increase in plasma monoacetydapsone/dapsone (MADDS/DDS) ratios within 24 h of the start of chemotherapy (CT), indicating an acceleration of N-acetylation.


Differentiating mucosal and hepatic metabolism of budesonide by local pretreatment with increasing doses of ketoconazole in the proximal jejunum.
Many drugs undergo first-pass metabolism both in the gut mucosa and the liver, but little is known about the relative efficiency of these two pathways. The objective of this study was to differentiate between mucosal and hepatic metabolism using budesonide as a probe. After a light breakfast, budesonide, 3mg, was infused locally in the proximal jejunum of eight healthy men on seven occasions, on six occasions after administering the CYP3A4 inhibitor ketoconazole 5 min before in the same jejunal position. The dose range of local inhibitor was 1-128 mg, the highest dose also preceded by an oral dose of 200mg given 12h earlier. Simultaneously with intrajejunal budesonide, deuterium-labelled budesonide (0.2mg) was administered intravenously. Pharmacokinetics of unlabelled and labelled budesonide in plasma was evaluated after LC-MS/MS analysis. Bioavailability of budesonide without inhibition was 27(12-42)%. All ketoconazole doses increased budesonide bioavailability. However, systemic clearance of labelled budesonide was unaffected by ketoconazole doses up to 16 mg but decreased significantly at doses of 64 mg and above. At the two highest doses (128 mg and above) bioavailability approached 100%, showing that budesonide was completely absorbed from jejunum. Ketoconazole doses up to 16 mg appeared to inhibit only mucosal enzymes, while higher doses inhibited also hepatic metabolism. Applying sigmoid E(max)-models of the mean inhibitions in mucosa and liver indicated that, in this study performed under fed conditions, their uninhibited extraction ratios of budesonide were approximately 0.32 and 0.60, respectively. Ketoconazole doses that inhibited half the metabolism were estimated at about 1mg in the mucosa and about 50mg in the liver. In conclusion, this study gave a rough estimate of the relation between mucosal and hepatic first-pass metabolism of budesonide.


Inter-rater reliability of modified hand mobility in scleroderma test.
Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology characterized by excessive collagen production, endothelial cell injury, microvascular obliteration, cutaneous fibrosis and progressive visceral disease. The hands are frequently involved during the progression of the disease, with symmetrical skin thickening as a prominent feature. Modified hand mobility in scleroderma (mHAMIS) test is a measurement method to assess hand mobility in patients with SSc. Knowing the inter-rater reliability of the instrument is important in order for the results from different examiners to be accurately interpreted. The aim of this study was to test inter-rater reliability of the mHAMIS test. Hand mobility for both hands was assessed in 25 female patients with SSc by 2 physiotherapists who have different years of experience. Patients who had flexion contracture in at least 1 finger and undergone hand surgery in the last year due to any injuries, were excluded from the study since hand mobility was prevented. Inter-rater reliability was determined using intra-class correlation coefficients (ICCs). The ICCs were excellent between raters for dominant and non-dominant hands. The values were 0.92 and 0.93, respectively. The inter-rater reliability of the mHAMIS was found to be excellent. This research contributes to the literature by proving that the test can be used without causing bias in clinical trials.


Arginine methylation of hnRNP K enhances p53 transcriptional activity.
Previous studies have illustrated that hnRNP K, which could be methylated at arginine residues, plays a key role in coordinating transcriptional responses to DNA damage as a cofactor for p53. In this study, we observed that hnRNP K was markedly arginine methylated in response to UV radiation. Furthermore, arginine methylation of hnRNP K enhanced its affinity with p53. Inhibition of methylation in hnRNP K attenuated the recruitment of p53 to p21 promoter, and reduced p53 transcriptional activity. These data suggested that arginine methylation of hnRNP K is a key element for p53 transcriptional activity.


Protecting RNA in fixed tissue: an alternative method for LCM users.
RNA degradation is a major drawback in most common fixation protocols in techniques that require both RNA integrity and preserved morphology, such as laser capture microdissection (LCM) followed by RT-PCR. Moreover, RNA isolation kits especially developed for LCM samples are very expensive. Our aim was to determine an easy protocol that ideally must provide an acceptable morphology, allow proper laser capture of selected cells and improve RNA yield and quality. In this study, retinas were dissected, briefly incubated in a RNA preservative and fixed in 2% paraformaldehyde before being cut on a cryostat. LCM was carried out in retinal sections for immediate RNA isolation, by using TRIzol common protocol with minor modifications. Real-time PCR was performed next in order to compare availability of RNA from samples submitted to different protocols. The use of the RNA preservative followed by a fast fixation did not jeopardize tissue morphology, allowing microdissection of selected cells, combined to minor modifications in usual RNA isolation procedures, significantly improved RNA yield and quality. Furthermore, only LCM samples submitted to our protocol provided amplifiable mRNA, as determined by real-time PCR. Taken together, the combination of the described procedures resulted in a reliable alternative for LCM users.


Exome Sequencing Identifies a Novel FBN1 Variant in a Pakistani Family with Marfan Syndrome That Includes Left Ventricle Diastolic Dysfunction.
Cardiomyopathies are diseases of the heart muscle and are important causes of heart failure. Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy that can be acquired, syndromic or non-syndromic. The current study was conducted to explore the genetic defects in a Pakistani family with cardiac disease and features of Marfan's syndrome (MFS). A family with left ventricle (LV) diastolic dysfunction and MFS phenotype was assessed in Pakistan. The clinical information and blood samples from the patients were collected after physical, cardiovascular, and ophthalmologic examinations. An affected individual (proband) was subjected to whole-exome sequencing (WES). The findings were further validated through Sanger sequencing in the family. Through WES and sanger validation, we identified a novel variant NM_000138.4; c.1402A>G in the Fibrillin-1 (FBN1) gene that segregates with LV diastolic dysfunction and MFS. Furthermore, bioinformatic evaluation suggested that the novel variant is deleterious and disease-causing. This study identified for the first time a novel FBN1 variant in a family with LV diastolic dysfunction and MFS in Pakistan.


Soluble FMDV VP1 proteins fused with calreticulin expressed in Escherichia coli under the assist of trigger factor16 (Tf16) formed into high immunogenic polymers.
Foot and mouth disease virus (FMDV) is a highly contagious pathogen propagating among cloven-hoofed animals. As a major immunogenic protein, VP1 plays a pivotal role in the induction of neutralizing antibodies, which therefore is an ideal target for developing subunit vaccines. In current study, four prokaryotic expression clones (rV4C, rC4V, rV5F and rF5V) were constructed by fusing truncated calreticulin (CRT) (120-250 aa or 120-308 aa) at the N/C terminal of vp1 gene, and co-expressed with chaperone trigger factor 16 (Tf16) in E.coli, respectively. The soluble recombinant CRT-fused VP1 proteins could form into homogeneous reactive polymers with average hydrodynamic diameters around 100 nm according to the dynamic light scattering (DLS) data. Immunization of guinea pigs with 10 μg purified CRT-fused VP1 proteins induced high levels of antibodies against naked-VP1 through indirect ELISA. Sandwich ELISA showed that only rC4V could elicit the same level of antibody against FMD virus as commercial inactivated vaccine after booster. The lymphocyte cytokines secretion of immunized rC4V was higher than the other CRT-fused VP1 proteins in guinea pigs. These results showed that the soluble CRT-fused VP1 proteins, especially rC4V, expressed with Tf16 in E. coli might have potential to be used as subunit vaccine candidate against FMDV.


Current issues in the midwifery management of women living with HIV/AIDS.
Changes in the clinical management of women living with human immunodeficiency virus (HIV) have occurred as a result of significant gains in the scientific knowledge of this retrovirus. As the incidence of HIV/AIDS continues to escalate among female adults and adolescents in the United States, all primary health care providers must anticipate the likelihood of encountering clients with HIV infection. Midwives must be adequately prepared to meet the challenges of managing women with HIV in the early stages of the disease. This article presents a comprehensive review of current demographic trends related to the HIV/AIDS epidemic among U.S. women and a brief overview of the essential immunopathogenesis of HIV. Contemporary issues related to universal counseling, updated testing procedures, and reproductive decision-making are covered. Initial primary care concerns and the management of newly infected seropositive women are included, with a focus on gynecologic issues. Guidance in the current management of HIV-positive pregnant women is offered. Updated antiretroviral prophylaxis recommendations are presented, to prevent perinatal transmission and to delay maternal immunosuppression with subsequent opportunistic infections. The article concludes with implications for health care professionals who provide care for this unique cohort of women.


The second-time flap from the previously used anterior thigh donor site for head and neck microsurgical reconstruction.
Multiple free tissue transfer from the same donor site is not well described for microsurgical head and neck reconstruction. Between (8/2011 and 11/2012), 103 patients received 103 free ALT flaps for head and neck reconstruction; flaps were called first-time ALT flaps. Intra-operative findings were used to assess the presence of a favorable anatomy for a future second flap from the same donor site. And, between 9/2009 and 12/2013, second-time flaps from previously used anterior thighs were attempted either freely or guided by the intra-operative data from the previous surgery. A favorable anatomy for a future second-time flap was noted in (n: 96/103). Future second-time flaps were ALT, AMT, and TFL flaps (n: 32, n: 91, n: 96, respectively). The second-time flap was attempted (n: 11) and was successful (n: 8, 72.7%). Harvested second-time flaps were (5 ALT, 2 AMT, 1TFL). All flaps survived. The donor site was closed primarily (n: 6) and skin grafted (n: 2). Thorough exploration of the anatomy of the anterior thigh during the first-time ALT flap surgery with detailed documentation in addition to meticulous surgery are essential for success. The proposed concept limits morbidity to one site, and serves as an alternative donor site or a life-boat.


Cranial base growth in patients with Down syndrome: a longitudinal study.
The purpose of this study was to assess the growth of the cranial base in a sample of patients diagnosed with Down syndrome (DS). The sample comprised 47 subjects (25 boys, 22 girls) with DS. All patients had at least 2 x-rays that showed the cranial base. To make comparisons among age groups, the sample was divided into 3 groups: prepubescent (8-11 years), pubescent (12-14 years), and postpubescent (15-18 years). A control group included 38 normal subjects (22 boys, 16 girls, without DS) who were part of a longitudinal growth sample. Computerized cephalometric analysis was performed on all subjects, and cephalometric superimpositions were made. Two-way ANOVA was used to study the overall changes between groups. In addition, 1-way ANOVA and the Duncan multiple range test were used to analyze possible differences in the age groups. Cranial base growth in patients with DS from age 8 to 18 was similar to that of the control group. Structural differences in the cranial base are established before 8 years of age and consist of shorter, flatter anterior and posterior bases.


Development and validation of a predictive nomogram for preoperative deep vein thrombosis (DVT) in isolated calcaneal fracture.
The fact that most of the patients with preoperative DVTs after calcaneal fractures are asymptomatic brought challenges to the early intervention, and periodic imaging examinations aggravated the financial burden of the patients in preoperative detumescence period. This study aimed to use routine clinical data, obtained from the database of Surgical Site Infection in Orthopaedic Surgery (SSIOS), to construct and validate a nomogram for predicting preoperative DVT risk in patients with isolated calcaneal fracture. The nomogram was established base on 7 predictors independently related to preoperative DVT. The performance of the model was tested by concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA), and the results were furtherly verified internally and externally. 952 patients were enrolled in this study, of which 711 were used as the training set. The AUC of the nomogram was 0.870 in the training set and 0.905 in the validation set. After internal verification, the modified C-index was 0.846. Calibration curve and decision curve analysis both performed well in the training set and validation set. In short, we constructed a nomogram for predicting preoperative DVT risk in patients with isolated calcaneal fracture and verified its accuracy and clinical practicability.


Inhibitor AN3661 reveals biological functions of Arabidopsis CLEAVAGE and POLYADENYLATION SPECIFICITY FACTOR 73.
Cleavage and polyadenylation specificity factor (CPSF) is a protein complex that plays an essential biochemical role in mRNA 3'-end formation, including poly(A) signal recognition and cleavage at the poly(A) site. However, its biological functions at the organismal level are mostly unknown in multicellular eukaryotes. The study of plant CPSF73 has been hampered by the lethality of Arabidopsis (Arabidopsis thaliana) homozygous mutants of AtCPSF73-I and AtCPSF73-II. Here, we used poly(A) tag sequencing to investigate the roles of AtCPSF73-I and AtCPSF73-II in Arabidopsis treated with AN3661, an antimalarial drug with specificity for parasite CPSF73 that is homologous to plant CPSF73. Direct seed germination on an AN3661-containing medium was lethal; however, 7-d-old seedlings treated with AN3661 survived. AN3661 targeted AtCPSF73-I and AtCPSF73-II, inhibiting growth through coordinating gene expression and poly(A) site choice. Functional enrichment analysis revealed that the accumulation of ethylene and auxin jointly inhibited primary root growth. AN3661 affected poly(A) signal recognition, resulted in lower U-rich signal usage, caused transcriptional readthrough, and increased the distal poly(A) site usage. Many microRNA targets were found in the 3' untranslated region lengthened transcripts; these miRNAs may indirectly regulate the expression of these targets. Overall, this work demonstrates that AtCPSF73 plays important part in co-transcriptional regulation, affecting growth, and development in Arabidopsis.


Comparison of growth rates of fresh and frozen-thawed embryos according to chromosomal status.
To report a comparison of growth rates between fresh and frozen-thawed embryos on day 3 and 4 according to chromosomal status during PGD. Embryos were biopsied on day 3, fluorescent in situ hybridization performed for aneuploidy detection and growth rates monitored. Based on 241 egg pick up-PGD and 133 frozen embryo transfer-PGD cycles. The development rate of embryos despite their chromosomal status was similar on day 3, however, overall, fresh embryos showed a significantly improved development (> or =6 cell stage; 85.7%) compared to frozen embryos (77.0%; p < 0.003). On day 4 fresh embryos showed accelerated development and further developmental improvements were associated with chromosomal normality (56.1% normal vs. 42.2% aneuploid; p < 0.004). Cryopreservation slows embryo development regardless of the chromosomal status. However, chromosomal status did not influence the chance of embryo implantation which was the same for fresh and thawed embryos.


General Access to Modified α-Amino Acids by Bioinspired Stereoselective γ-C-H Bond Lactonization.
α-Amino acids represent a valuable class of natural products employed as building blocks in biological and chemical synthesis. Because of the limited number of natural amino acids available, and of their widespread application in proteomics, diagnosis, drug delivery and catalysis, there is an increasing demand for the development of procedures for the preparation of modified analogues. Herein, we show that the use of bioinspired manganese catalysts and H2 O2 under mild conditions, provides access to modified α-amino acids via γ-C-H bond lactonization. The system can efficiently target 1°, 2° and 3° γ-C-H bonds of α-substituted and achiral α,α-disubstituted α-amino acids with outstanding site-selectivity, good to excellent diastereoselectivity and (where applicable) enantioselectivity. This methodology may be considered alternative to well-established organometallic procedures.


Pelvic recurrence after anterior resection and EEA stapling anastomosis for potentially curable carcinoma of the rectum.
Rectal carcinoma can be treated by anterior resection with EEA anastomosis in order to preserve rectal continuity in those patients in whom anastomosis may be technically difficult. In our initial local experience however, the pelvic recurrence rate has been approximately three times as high as would be expected. The surgical results were good in those patients with Dukes' B lesions. The majority of failures occurred in those with Dukes' C lesions. When the preoperative assessment indicates the strong likelihood of a Dukes' C lesion, consideration of abdominoperineal resection must be given if cure is anticipated. Most surgeons will obtain a more complete pararectal tissue clearance with this procedure than with anterior resection. Those who wish to preserve rectal continuity with curative procedures for rectal carcinoma must become proficient at pararectal tissue clearance if a low rate of pelvic recurrence is to be achieved. The EEA stapler can enable safe anastomosis when these other factors have been accomplished. When cure is anticipated, it can only be provided for the majority of patients at initial surgical resection. The EEA stapler has a unique value in patients who have resectable rectal carcinoma, and yet have distal metastasis by the time initial surgery is performed. The preservation of rectal continuity in such patients is an excellent method of palliation.


Variability of Steady State Oral Baclofen Prescribing Practices in Pediatric Patients With Cerebral Palsy.
The aim of the study was to identify oral baclofen dosing variability at steady state based on weight and Gross Motor Function Classification System level using a retrospective cross-sectional study design. The medical records of 500 pediatric aged patients (age 1-21 yrs) were reviewed to obtain 144 pediatric patients who met inclusion criteria. One-way analysis of variance tests revealed increasing mean doses in baclofen (in milligram per kilogram) with higher Gross Motor Function Classification System levels (P = 0.001). Post hoc Tukey analysis showed patients with higher ambulatory ability (Gross Motor Function Classification System I-II) received a lower total daily dosage than did patients with less ambulatory ability (Gross Motor Function Classification System III-V). A moderate correlation was observed with increasing oral baclofen dose as weight increased (r = 0.43, P < 0.0001). Because of the variability in dosing between Gross Motor Function Classification System levels, prescribing oral baclofen for pediatric patients with cerebral palsy may not follow the traditional model of weight-based dosing seen in other pediatric conditions.


An exploratory study of the factors associated with medication nonadherence among youth in adult mental health facilities in Ontario, Canada.
Although the issue of medication nonadherence among children and youth appears to be high, there is a paucity of research examining associated factors related to medication nonadherence among youth with mental health difficulties. Using logistic regression, this exploratory study sought to examine specific factors associated with medication nonadherence among youth with mental health needs in Ontario, Canada. Data on 3681 youth between the ages of 12-18 years old were obtained from the Resident Assessment Instrument for Mental Health (RAI-MH). Medication nonadherence was observed among 24.6% of the study population. Multivariate results showed that youth who experienced side effects of psychotropic medication were more than 3 times more likely to have failed to adhere to their medication. Other significant factors contributing to medication nonadherence include age, having multiple psychiatric admissions, limited insight into mental health, and having a disturbed/dysfunctional relationship with immediate family members. Tobacco use, cannabis use, depressive symptoms, and positive symptoms were also associated with medication nonadherence. Our data highlights some of the factors associated with medication nonadherence among youth with mental health needs. Physicians, clinicians and mental health care providers need to consider these factors, particularly when planning for discharge.


Frontotemporal dementia as a frontostriatal disorder: neostriatal morphology as a biomarker and structural basis for an endophenotype.
This article reviews the evidence for a re-conceptualisation of a subtype of frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), as a frontostriatal disorder, working towards an endophenotype. We provide an overview of the role of frontostriatal circuits relevant to FTLD and FTD, as a subset of larger-scale distributed brain networks. We discuss the role of a strategic structure in these circuits, the neostriatum. Then we review the relationship of the clinical features of FTLD to frontostriatal circuits, correlating this with neuropsychological and neuropathological data. The unique structure and linkages of the neostriatum make it an ideal structure for in vivo neuroimaging to understand the neuroanatomical basis of FTD. We develop a frontostriatal endophenotypic model for FTD as a platform for further investigation.


Phase behavior in the system water-butylammonium decanoate-decane.
The phase diagram at 298.2 and 281.2 K for the ternary system water-butylammonium decanoate-decane has been determined. An isotropic solution phase extending from the water corner to the decane corner was obtained without any macroscopic phase separation. A large two-phase region extending from the water-decane axis was also observed. In addition to these phases, an anisotropic and optically birefrigent liquid crystalline phase is formed below 290.3 K. Sound velocity, conductivity, and viscosity measurements were used successfully for studies of microstructural transitions in the isotropic solution phase. From these measurements, it was concluded that a transition from normal micelles to reverse micelles takes place while passing through a bicontinuous region.


Evaluation of risk scores for risk stratification of acute coronary syndromes in the Myocardial Infarction National Audit Project (MINAP) database.
To compare the discriminative performance of the PURSUIT, GUSTO-1, GRACE, SRI and EMMACE risk models, assess their performance among risk supergroups and evaluate the EMMACE risk model over the wider spectrum of acute coronary syndrome (ACS). Observational study of a national registry. All acute hospitals in England and Wales. 100 686 cases of ACS between 2003 and 2005. Model performance (C-index) in predicting the likelihood of death over the time period for which they were designed. The C-index, or area under the receiver-operating curve, range 0-1, is a measure of the discriminative performance of a model. The C-indexes were: PURSUIT C-index 0.79 (95% confidence interval 0.78 to 0.80); GUSTO-1 0.80 (0.79 to 0.81); GRACE in-hospital 0.80 (0.80 to 0.81); GRACE 6-month 0.80 (0.79 to 0.80); SRI 0.79 (0.78 to 0.80); and EMMACE 0.78 (0.77 to 0.78). EMMACE maintained its ability to discriminate 30-day mortality throughout different ACS diagnoses. Recalibration of the model offered no notable improvement in performance over the original risk equation. For all models the discriminative performance was reduced in patients with diabetes, chronic renal failure or angina. The five ACS risk models maintained their discriminative performance in a large unselected English and Welsh ACS population, but performed less well in higher-risk supergroups. Simpler risk models had comparable performance to more complex risk models. The EMMACE risk score performed well across the wider spectrum of ACS diagnoses.


Hepatic expression of type A and type B receptors for tumor necrosis factor.
We have examined the in-situ distribution of type A and type B receptors for tumor necrosis factor (TNF) in normal and diseased human liver biopsy specimens. In normal liver tissue, no or very small amounts of TNF receptors were found. In acute and chronic inflammatory liver diseases, a strong up-regulation of the expression of both TNF receptors was found on hepatocytes, bile duct epithelium, sinusoidal lining cells and mononuclear inflammatory cells. With immunoelectronmicroscopy, all these cells showed cytoplasmic, in addition to membranous staining, suggesting active synthesis of the receptor or, alternatively, internalization of the receptor and its ligand. This up-regulated expression of both type A and type B receptors for TNF was similar in acute and chronic active hepatitis, and was not related to the etiology of the liver disease, nor restricted to areas of liver inflammation. Our results indicate that hepatocytes, sinusoidal endothelial cells, bile duct epithelial cells and mononuclear inflammatory cells, by displaying receptors for TNFs, represent target cells for both these cytokines. Up-regulated expression of type A and type B receptors for TNFs endows these cells with augmented responsiveness for the pleiomorphic biological activities of these cytokines during liver injury.


Interference of MI-D, a new mesoionic compound, on artificial and native membranes.
MI-D (4-phenyl-5-(4-nitrocinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride), a new mesoionic compound, decreased the rate of swelling induced by valinomycin-K+, as well as induced swelling in the presence of nigericin-K+. Shrinkage was also affected, suggesting interference with the inner mitochondrial membrane, which would affect both fluidity and elasticity. Fluorescence polarization of DPH and DPH-PA, probing the core and outer regions respectively, of the DMPC and native membranes, indicated that MI-D shifts the midpoint of phase transition to higher values and orders of the fluid phase. These alterations in membrane fluidity are thus related to MI-D effects on the energy-linked functions of mitochondria.


Incidence and causes of sepsis in glucose-6-phosphate dehydrogenase-deficient newborn infants.
To determine the susceptibility to sepsis in newborn infants deficient in glucose-6-phosphate dehydrogenase (G6PD), we screened 33,943 Saudi Arab infants. Deficiency of G6PD was found in 18%. Sepsis was determined by the presence of clinical signs of sepsis and confirmed by positive blood cultures. Sepsis was documented in 75 infants (2.2/1000). The incidence of sepsis was significantly higher in 6138 G6PD-deficient infants (3.4/1000) than in the 27,805 with normal G6PD activity (1.9/1000; p less than 0.02). The incidence of catalase-positive organism sepsis was higher in G6PD-deficient infants (2.9/1000) compared with those with normal G6PD activity (1/1000; p less than 0.0002), whereas the incidence of catalase-negative organism sepsis did not differ (p less than 0.2). Deficiency of G6PD was more common in infants with late sepsis (46%) than in those with early sepsis (21%) and in all infants screened (18%) (p less than 0.03 and p less than 0.001, respectively). We conclude that neonates with G6PD deficiency are more susceptible to late sepsis and to infection with catalase-positive organisms. The exact mechanism for the increased susceptibility is not clear, but a partial explanation could be lack of leukocyte bactericidal activity associated with G6PD deficiency, and an increased susceptibility to infection caused by hyperferremia resulting from lysis of G6PD-deficient erythrocytes.


[Plasmodium chabaudi: changes in the surface sialic acids of red blood cells during infection (author's transl)].
Surface sialic acids of mice red blood cells infected with the malarial parasite Plasmodium chabaudi are increased as compared to extracts of red cells from normal mice. This increase occurs coincidentally when reticulocytes increase in the peripheral blood. The same increase of surface sialic acids is shown by studies of reticulocytes from phenylhydrazine treated mice. Similarly, neutral hexoses, fucose, were found in greater quantities in surface glycopeptides obtained after incubation with trypsin of reticulocytes from phenylhydrazine treated mice than in surface glycopeptides of red cells from normal mice. This increase occurs also in Plasmodium chabaudi infected red cells with the development of reticulocytosis, in the same way. These facts suggest the contribution of reticulocytes to the biochemical changes observed during malaria infection.


Synthesis of gamma-substituted peptide nucleic acids: a new place to attach fluorophores without affecting DNA binding.
Molecular beacon strategies using PNA are currently restricted to fluorophore attachment to the ends of the PNA. We report the synthesis of PNA oligomers wherein fluorophores can be attached to the PNA backbone from novel gamma-lysine PNA monomers. Oligomers incorporating the modified PNA showed comparable thermal stability to the corresponding aegPNA oligomer with DNA. When the modified PNA oligomer was annealed with complementary DNA, the fluorescence intensity increased 4-fold over the unbound PNA. [structure: see text]


Bepridil prolongs the action potential duration of guinea pig ventricular muscle only at rapid rates of stimulation.
1. We examined the electromechanical effects of the calcium antagonist, bepridil (1-20 microM), on isolated guinea pig ventricular muscles, driven at various stimulus frequencies (0.1, 0.5, 1, 2 and 5 Hz) in Tyrode's solution containing various K+ concentrations (1.4-43.2 mM). 2. Conventional microelectrode and tension-recording techniques were used. 3. We found that bepridil decreased the maximum upstroke velocity (Vmax) of the action potential with no change in the resting membrane potential (RMP). 4. The former effect depended on both stimulus frequency and the drug concentration used. 5. Bepridil lengthened the duration of the action potential at the level of 25% repolarization (APD25) at the highest frequency (5 Hz), but shortened it at lower frequencies (< or = 2 Hz). 6. The drug also lengthened the APD90 at the highest frequency (5 Hz) but without significant effect at lower frequencies (< or = 2 Hz). 7. Bepridil depolarized the RMP at relatively low extracellular K+ concentrations (< or = 2.7 mM), accompanied by a prolongation of APD90. 8. There were no such effects at much higher K+ concentrations (> or = 5.4 mM), and the drug markedly depressed the Vmax and the action potential amplitude. 9. The drug eliminated the positive staircase phenomenon of twitch contraction, in a concentration-dependent manner. 10. All these findings taken together suggest that bepridil prolongs the action potential duration by inhibiting outward potassium currents (IK and IK1), at rapid rates of stimulation (approximately 300/min), which is comparable to the physiological heart rate of a guinea pig. 11. The prolongation of APD seemed to be secondary to the bepridil-induced reduction of intracellular Ca2+ concentration, [Ca2+]i.


Effect of pentobarbital anesthesia on renal sympathetic nerve activity in the rabbit.
The effects of pentobarbital (PB) anesthesia on arterial pressure, heart rate, and renal nerve activity (RNA) were studied in chronically instrumented intact rabbits and rabbits with sinoaortic baroreceptor denervation (SAD). In intact rabbits, PB caused an initial decrease in mean arterial pressure from 82 +/- 2 to 42 +/- 5 mm Hg, which then returned to the control level within 5 min. RNA increased by 144 +/- 19% in response to hypotension induced by PB then also returned to the control level within 5 min. Heart rate increased by 56 +/- 10 from 244 +/- 11 beats/min and remained elevated for 60 min. Sensitivities of baroreflex control of heart rate and RNA were markedly impaired by PB anesthesia. In SAD rabbits, PB caused hypotension (-46 +/- 5 mm Hg), which lasted for 15 min. RNA decreased initially by 80 +/- 5%, then gradually returned toward the control level. However, at 45 min after injection of PB, RNA was still depressed significantly. Tachycardia induced by PB was abolished by SAD, i.e. heart rate actually decreased by 53 +/- 10 beats/min. These results suggest that in intact rabbits steady-state effects of PB were: no change in mean arterial pressure or RNA, and tachycardia, all due to baroreflex compensation. However, in the absence of baroreflex compensation, PB elicited hypotension, bradycardia, and a decrease in RNA.


Facebook, body esteem, and body surveillance in adult women: The moderating role of self-compassion and appearance-contingent self-worth.
This study examined how Facebook use and specific Facebook activities were associated with body esteem and body surveillance in adult women. This study also examined whether self-compassion and appearance-contingent self-worth moderated the relationship between Facebook appearance comparison and body esteem, and the relationship between Facebook appearance comparison and body surveillance. Self-report measures were administered to adult women (N = 232) between the ages of 20 and 72 (M = 35.91) recruited through MTurk. Results indicated that Facebook appearance-exposure and Facebook appearance comparison significantly related to body surveillance, whereas only Facebook appearance comparison significantly related to body esteem. Overall Facebook use and Facebook intensity were not significantly associated with either body esteem or body surveillance. Self-compassion and appearance-contingent self-worth significantly related to body esteem and body surveillance. However, neither self-compassion nor appearance-contingent self-worth significantly moderated the relationship between Facebook appearance comparison and body surveillance. Similarly, a lack of significant moderation was found for the relationship between Facebook appearance comparison and body esteem. The importance of studying body image and Facebook activities in adult women is discussed. Additionally, the importance for researchers to examine how specific Facebook activities, beyond Facebook use, are linked with body image in this population is also highlighted.


Cardiac biopsy with intracardiac echocardiographic guidance for successful diagnosis of cardiac lymphoma.
The diagnosis and appropriate treatment of cardiac lymphoma are often delayed by the difficulty in obtaining heart tissue biopsies. Intracardiac echocardiography-guided biopsy can improve the prognosis of cardiac lymphoma by decreasing postbiopsy complications and increasing biopsy quality, allowing collection of sufficient material for multilateral analysis.


Effect of Adjuvant Chemotherapy on Stage II Rectal Cancer Outcomes After Preoperative Short-Course Radiotherapy.
Adjuvant chemotherapy (AC) is offered to patients with stage II rectal cancer, but its use is controversial. We examined population-based outcomes of patients with pathologic stage II rectal cancer treated with AC after preoperative short-course radiotherapy. We included patients diagnosed with pathologic stage II tumors from 1999 to 2009 in British Columbia. The disease-specific survival (DSS), relapse-free (RFS), and overall survival (OS) were assessed. Multivariate models adjusting for age, gender, Eastern Cooperative Oncology Group, and high-risk features (ie, pT4, poor differentiation, < 12 lymph nodes removed, lymphovascular invasion, perineural invasion, or obstruction or perforation) were constructed. Of 851 patients reviewed, 330 had received preoperative short-course radiotherapy, of whom 123 (37%) subsequently received AC. Patients treated with AC were younger (median age 61 vs. 73 years; P < .0001), reported better Eastern Cooperative Oncology Group status (P < .0001), and had more high-risk features (P < .0001). On univariate analysis, AC was associated with improved DSS (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.36-0.94; P = .028), RFS (HR, 0.62; 95% CI, 0.39-0.98; P = .043), and OS (HR, 0.42; 95% CI, 0.30-0.59; P < .0001). On multivariate analysis, these outcomes were not significant (DSS HR, 0.83; 95% CI, 0.43-1.61; P = .58; RFS HR, 0.82; 95% CI, 0.44-1.50; P = .51; OS HR, 0.62; 95% CI, 0.37-1.03; P = .064). Subgroup analysis suggested AC improved DSS (HR, 0.25; 95% CI, 0.07-0.89; P = .033), RFS (HR, 0.24; 95% CI, 0.07-0.85; P = .027), and OS (HR, 0.22; 95% CI, 0.069-0.70; P = .011) only in patients with ≥ 2-high risk features. In the present population-based cohort of patients with stage II rectal cancer, AC did not improve the outcomes in unselected patients. In a small subgroup of patients with ≥ 2 risk factors, we noted improved outcomes with AC use.


Histidine-rich protein genes and their transcripts in Plasmodium falciparum and P. lophurae.
The presence of histidine-rich protein (HRP) related genes and gene products in Plasmodium falciparum was demonstrated using a synthetic pentahistidine-encoding oligonucleotide and a cloned HRP cDNA probe prepared from the avian parasite P. lophurae. In Northern blotting experiments, two knobby clones of P. falciparum were found to contain a 3500 nucleotide RNA species that hybridized with the oligonucleotide and HRP cDNA probes. As this component had the expected size for an mRNA encoding an 80-90 kDa protein and was absent from two knobless clones of P. falciparum, we concluded that it represented a 'knob protein' mRNA. Using the restriction enzyme EcoRI, three identical cross-hydribizing HRP gene fragments were found in the DNA of both knobby and knobless clones of P. falciparum. These fragments differed in size from those present in P. lophurae. These results suggest that the absence of knob protein mRNA in knobless clones is not due to loss of the corresponding gene(s).


Primary omental gangrene mimicking appendicular perforation peritonitis-A case report.
Primary omental torsion is a rare cause of acute abdomen in adults and presents with variable signs and symptoms. Establishing a preoperative diagnosis may be difficult in the emergency setting. It is rarely diagnosed preoperatively as it mimics common surgical emergencies such as acute appendicitis, appendicular perforation, acute cholecystitis and perforated peptic ulcers and can lead to the clinical deterioration of patient if missed A 47 years old male was taken to the operating room with a diagnosis of appendicular perforation peritonitis and during surgery was found to have a primary omental gangrene with pyoperitoneum, for which omentectomy and peritoneal lavage was performed. Torsion of the omentum is a condition in which the organ twists on its long axis to such an extent that its vascularity is compromised. Omental torsion can be primary (idiopathic) or secondary, depending on an underlying cause. Primary omental torsion was first described by Eitel in 1899. However, very few cases have been reported. Our case was a rare case presenting with omental gangrene with pyoperitoneum mimicking appendicular perforation peritonitis. Primary omental torsion is a rare diagnosis. A high index of clinical suspicion is required for a preoperative diagnosis. In doubtful cases a CT scan may be helpful. Surgical excision of the omentum remains the treatment of choice; however, conservative management may be attempted in an uncomplicated omental torsion.


Coding with noisy neurons: stability of tuning curve estimation strongly depends on the analysis method.
An important issue in the neurosciences is a quantitative description of the relation between sensory stimuli presented to an animal and their representations in the nervous system. A standard technique is the construction of a neural tuning curve, that is, a neuron's average firing rate as a function of some parameter characterizing a family of stimuli. It is unavoidable that some of the response data are erroneously attributed to a cell, e.g., during spike sorting. However, the widely used method of statistical analysis based on the sample mean and least-squares approximation for the spike count can perform extremely badly if the noise distribution is not exactly normal, which is almost never the case in applications. Here, we present a method for constructing neural tuning curves that is especially suited for cases of high noise and the presence of outliers. Since it is usually not decidable if an outlier is faulty or not we limit the influence of far outlying points rather than try to identify and discard them. In contrast to traditional methods employing a point-by-point estimation of a tuning curve, we use all measured data from all different stimulus conditions at once in the construction. Given the measured data at only a finite number of stimulus conditions, a robust tuning curve is obtained that approximates the cell's ideal tuning curve optimally in all stimulus conditions with respect to a given distance measure. A measure that assesses the quality of this fitting method with respect to the traditional least-squares fitting method and to a median-based fitting method is introduced. The reliability of inference with respect to the encoding accuracy that can be achieved by a population of neurons is demonstrated in both artificially generated and experimentally recorded data from rat primary visual cortex. While the data shown in this paper are responses to orientation stimuli, the method of tuning curve construction is also viable and maintains its optimality properties for the case in which the stimulus is defined on a finite interval.


Cholecystokinin binding sites in the rat forebrain: effects of acute and chronic methamphetamine administration.
Using the in vitro quantitative receptor autoradiographical technique, changes in the binding parameters of [propionyl-3H] propionylated CCK-8 [( 3H]pCCK-8) binding sites in the rat forebrain were investigated following acute and chronic administration of methamphetamine (MAP). The (Kd)app values of [3H]pCCK-8 binding sites in the frontal medial cortex and anterior cingulate cortex were significantly reduced after a single injection of 4mg/kg MAP. On the other hand, chronic treatment (14 days) with MAP at this dose significantly decreased the Bmax value of [3H]pCCK-8 binding sites in the anterior cingulate cortex accompanied by supersensitivity of locomotor effects to MAP. These findings suggest that dopamine (DA) neurons in these two regions are functionally related to intrinsic CCK-containing cortical neurons, and that CCK subsensitivity, perhaps due to an alteration in DA transmission, is involved in MAP sensitization. These findings may be relevant to the DA hypothesis of schizophrenia.


[Ambulatory monitoring and digital phenotyping in the diagnostics and treatment of bipolar disorders].
Reliable and valid diagnostics and treatment of bipolar disorders and affective episodes are subject to extensive, especially methodological limitations in the clinical practice. The use of smartphones and mobile sensor technology for improvement in diagnostics and treatment of bipolar disorders. Critical discussion of current research on the use of ambulatory monitoring and digital phenotyping with bipolar disorders. In many studies the observation periods were too short and the sensors applied were too inaccurate to enable reliable and valid detection of behavioral changes in the context of affective episodes. The clarification and operationalization of psychopathological constructs to allow for the measurement of objectively observable and ascertainable behavioral changes during depressive and (hypo)manic states are essential for the successful application of modern mobile technologies in the diagnostics and treatment of bipolar disorders.


Seemingly unrelated time series model for forecasting the peak and short-term electricity demand: Evidence from the Kalman filtered Monte Carlo method.
In this extant paper, a multivariate time series model using the seemingly unrelated times series equation (SUTSE) framework is proposed to forecast the peak and short-term electricity demand using time series data from February 2, 2014, to August 2, 2018. Further the Markov Chain Monte Carlo (MCMC) method, Gibbs Sampler, together with the Kalman Filter were applied to the SUTSE model to simulate the variances to predict the next day's peak and electricity demand. Relying on the study results, the running ergodic mean showed the convergence of the MCMC process. Before forecasting the peak and short-term electricity demand, a week's prediction from the 28th to the 2nd of August of 2018 was analyzed and it found that there is a possible decrease in the daily energy over time. Further, the forecast for the next day (August 3, 2018) was about 2187 MW and 44090 MWh for the peak and electricity demands respectively. Finally, the robustness of the SUTSE model was assessed in comparison to the SUTSE model without MCMC. Evidently, SUTSE with the MCMC method had recorded an accuracy of about 96% and 95.8% for Peak demand and daily energy respectively.


Stoichiometric analysis of protein complexes by cell fusion and single molecule imaging.
The composition, stoichiometry and interactions of supramolecular protein complexes are a critical determinant of biological function. Several techniques have been developed to study molecular interactions and quantify subunit stoichiometry at the single molecule level. However, these typically require artificially low expression levels or detergent isolation to achieve the low fluorophore concentrations required for single molecule imaging, both of which may bias native subunit interactions. Here we present an alternative approach where protein complexes are assembled at physiological concentrations and subsequently diluted in situ for single-molecule level observations while preserving them in a near-native cellular environment. We show that coupling this dilution strategy with fluorescence correlation spectroscopy permits quantitative assessment of cytoplasmic oligomerization, while stepwise photobleaching and single molecule colocalization may be used to study the subunit stoichiometry of membrane receptors. Single protein recovery after dilution (SPReAD) is a simple and versatile means of extending the concentration range of single molecule measurements into the cellular regime while minimizing potential artifacts and perturbations of protein complex stoichiometry.


Molecular surveillance of pneumococcal carriage following completion of immunization with the 13-valent pneumococcal conjugate vaccine administered in a 3 + 1 schedule.
In a cross-sectional study, with the use of molecular methods, we aimed to gain insight into oropharyngeal pneumococcal colonization over time in 1212 Greek children recruited in general pediatric settings throughout the country; they were fully vaccinated with PCV13 (3 + 1 schedule). A single sample was obtained from each child at a time interval of 26 days to 70 months after administration of the 4th (booster) PCV13 dose; sampling time was divided into six time intervals. Carriage of Streptococcus pneumoniae was detected by real-time PCR targeting the lytA gene and isolates were serotyped by singleplex real-time PCR assays. Multiple control procedures to avoid false-positive results were applied. We showed an overall S. pneumoniae carriage rate of 48.6%. Serotyping identified typeable isolates in 82% of the total lytA-positive samples. Non-PCV13 serotypes represented 83.8% of total isolates when excluding serogroups with mixed PCV13 and non-PCV13 serotypes. In multivariate analysis daycare/school attendance emerged as the main contributing factor. Notably, serotypes 19A and 3 were the only two PCV13 serotypes the colonization rate of which increased over time (χ2 for trend P < 0.001 and P = 0.012, respectively). The application of the SP2020 gene on lytA-positive serotyped samples showed pneumococcal colonization in 97% of cases, and the overall colonization profile over time closely resembled that of the lytA gene. With the provisions of the methodological approach and age group of our study, the use of the oropharynx emerges as a reliable alternative to the nasopharynx in estimating pneumococcal carriage in epidemiological studies.


Noninvasive Respiratory Support During Pediatric Ground Transport: Implementation of a Safe and Feasible Procedure.
The purpose of this work was to determine the safety and feasibility of noninvasive support in children with acute respiratory failure (ARF) during interhospital ground transport. This was a prospective, single-center observational clinical study in the pediatric transport unit of a tertiary-care pediatric hospital. We included all subjects with ARF transported from November 2010 to March 2013. A specific noninvasive support protocol was used for all cases. Transport ventilators used were the Crossvent 2+ and Oxylog 3000; interfaces were an oronasal mask, nasopharyngeal tube, or nasal prongs. A total of 288 children diagnosed with ARF were transported. Fifty-four subjects (19%) were transported with invasive ventilation, 50 with CPAP, 58 with NIV, and 126 (44%) with oxygen cannula or nebulization. The median age was 3.4 months (interquartile range 1.2-17 months). ARF was mainly due to bronchiolitis (58%), asthma (15%), and pneumonia (15%). Stabilization time, which is defined as the time between the arrival in the parking lot of the referring hospital and departure, was lower with noninvasive support than with invasive ventilation (median 48 min vs 83 min, P < .001). Median transport time was 35 min (interquartile range 20-65). Noninvasive ventilation and oronasal interface use rose progressively during the study period (P < .001 for the NIV and P < .036 for the interface). One complication was observed: One subject required intubation during transport. Evolution of subjects transferred while receiving noninvasive support was recorded in the receptor hospitals: 21% of subjects were intubated, and 55% continued with NIV. NIV seems to be a safe and feasible technique during pediatric ground transport. Careful patient selection, adequate material, and a well-trained transport team are crucial to minimize risks to the patient.


Oxytocin neurons in the supraoptic nucleus receive excitatory inputs from the bilateral dorsomedial hypothalamic nuclei.
To examine whether inputs from the dorsomedial hypothalamic nucleus (DMH) alter the discharge of putative oxytocin (OT) neurons with hypothesis that excitation of DMH neurons would increase the activity of OT neurons, electrical stimulation was applied to the DMH in both sides of the hypothalamus while electrical activity of single OT neurons in the supraoptic nucleus (SON) was recorded in urethane-anesthetized lactating rats. About half of the OT neurons showed orthodromic excitation or inhibition followed by excitation in response to electrical stimulation of the DMH on both sides. Continuous electrical stimulation of the DMH both ipsi- and contralateral to the recording side at 10-50 Hz for 30-60 s increased firing rate in 58% of OT neurons tested. Continuous electrical stimulation of the DMH not only excited spiking activity of single OT neurons but also increased intramammary pressure. The results may suggest that some of the projections from the DMH to the SON are bilateral and possibly contribute to coordinated bilateral activation of OT neurons in the hypothalamus during the milk-ejection reflex.


Management of the subscapularis contracture during shoulder arthroplasty for primary glenohumeral arthritis.
To evaluate the safety and effectiveness of a particular subscapularis release in shoulder arthroplasty for primary glenohumeral arthritis. Twenty-eight patients (19F, 9M) underwent shoulder arthroplasty for primary glenohumeral arthritis. Preoperative average Constant Score (CS) was 31.2 points (range 14-52), active anterior elevation (AAE) 92 degrees (30-100 degrees ) and active external rotation (AER) 11 degrees (-40 to 20 degrees ). During arthroplasty for subscapularis contracture, patients underwent subscapularis release freeing the superior tubular tendon (STT) with a section of the coracohumeral ligament (CHL) and the superior glenohumeral ligament (SGHL) and a deep release consisting of a section of the middle glenohumeral ligament (MGHL), very close to the glenoid labrum, and the inferior glenohumeral ligament (IGHL). An anatomic study was performed on 13 cadavers, verifying the structure of subscapularis tendon and its relationship with the capsule, the surrounding ligaments and the axillary nerve. Moreover, after having placed traction sutures on the subscapularis tendon, its lengthening was measured after STT release alone and after STT and deep release. The complete absence of neurological and vascular lesions was also verified. Average follow-up: 2.9 years. Postoperative mean CS was 70.5 (p[Symbol: see text]0.005), with an absolute gain of 39.1. AAE increased from 92 degrees to 142 degrees (p=0.001) while AER increased from 8 degrees to 48 degrees (p=0.002). At the last follow-up, 19 patients (67.8%) were very satisfied, 5 patients (17.8%) were satisfied, 3 patients (10.7%) partially satisfied and 1 patient (3.5%) unsatisfied. In the anatomic control, the average lengthening of subscapularis tendon was 0.9 cm after STT release alone and 2.5 cm after STT and deep release. No vascular and neurological lesions were observed. The subscapularis release during shoulder arthroplasty is extremely important to obtain the proper balance between anterior and posterior soft tissues and to achieve an optimal range of motion and joint stability. An adequate anatomical dissection could give good tendon mobilisation and lengthening, necessary for a good repair, and lead to a recovery of the range of motion, particularly for external rotation.


Exploring performance obstacles of intensive care nurses.
High nursing workload, poor patient safety, and poor nursing quality of working life (QWL) are major issues in intensive care units (ICUs). Characteristics of the ICU and performance obstacles may contribute to these issues. The goal of this study was to comprehensively identify the performance obstacles perceived by ICU nurses. We used a qualitative research design and conducted semi-structured interviews with 15 ICU nurses of a medical-surgical ICU. Based on this qualitative study and a previously reported quantitative study, we identified seven main types of performance obstacles experienced by ICU nurses. Obstacles related to the physical environment (e.g., noise, amount of space), family relations (e.g., distractions caused by family, lack of time to spend with family), and equipment (e.g., unavailability, misplacement) were the most frequently experienced performance obstacles. The qualitative interview data provided rich information regarding the factors contributing to the performance obstacles. Overall, ICU nurses experience a variety of performance obstacles in their work on a daily basis. Future research is needed to understand the impact of performance obstacles on nursing workload, nursing QWL, and quality and safety of care.


Long-term quality-of-care score for predicting the occurrence of acute myocardial infarction in patients with type 2 diabetes mellitus.
Cardiovascular disease (CVD) is the leading cause of death globally, and diabetes mellitus (DM) is a well-established risk factor. Among the risk factors for CVD, DM is a major modifiable factor. In the fatal CVD outcomes, acute myocardial infarction (AMI) is the most common cause of death. To develop a long-term quality-of-care score for predicting the occurrence of AMI among patients with type 2 DM on the basis of the hypothesis that good quality of care can reduce the risk of AMI in patients with DM. Using Taiwan's Longitudinal Cohort of Diabetes Patient Database and the medical charts of a medical center, we identified incident patients diagnosed with type 2 DM from 1999 to 2003 and followed them until 2011. We constructed a summary quality-of-care score (with values ranging from 0 to 8) with process indicators (frequencies of HbA1c and lipid profile testing and urine, foot and retinal examinations), intermediate outcome indicators (low-density lipoprotein, blood pressure and HbA1c), and co-morbidity of hypertension. The associations between the score and the incidence of AMI were evaluated using Cox regression models. A total of 7351 patients who had sufficient information to calculate the score were enrolled. In comparison with participants who had scores ≤ 1, those with scores between 2 and 4 had a lower risk of developing AMI [adjusted hazard ratio (AHR) = 0.71; 95% confidence interval (95%CI): 0.55-0.90], and those with scores ≥ 5 had an even lower risk (AHR = 0.37; 95%CI: 0.21-0.66). Good quality of care can reduce the risk of AMI in patients with type 2 DM. The quality-of-care score developed in this study had a significant association with the risk of AMI and thus can be applied to guiding the care for these patients.


Prediction of local cooling rates and cell survival during the freezing of a cylindrical specimen.
A finite element numerical model was implemented to simulate the freezing process of an aqueous salt solution in a cylindrical container. Local cooling rates within the container were computed for several defined cooling protocols applied at the boundary. Characteristic cell survival signatures were used to predict the associated local survival rates throughout the system. These calculations show that there are two definite time domains during a typical freezing process: (1) while the surface temperature is changing and (2) after the surface temperature reaches a constant storage value. The calculations also show significant spatial variations in the local cooling rates within the container and considerable local deviation from the volumetric average survival for various simulated freezing protocols.


CagA-positive Helicobacter pylori strain containing three EPIYA C phosphorylation sites produces increase of G cell and decrease of D cell in experimentally infected gerbils (Meriones unguiculatus).
Human infection by Helicobacter pylori is associated with an increase in the number of gastrin-producing G cells and a concomitant decrease of somatostatin-producing D cells. However, to our knowledge, changes in G and D cell numbers in response to infection with H. pylori CagA-positive strains containing different number of EPIYA-C phosphorylation sites have not been analyzed to date. Therefore, the aim of this study was to perform a quantitative analysis of the number of G and D cells in Mongolian gerbils challenged with H. pylori strains with different numbers of EPIYA-C motifs. Mongolian gerbils were inoculated with isogenic H. pylori strains containing one to three phosphorylation sites. Mucosal fragments were evaluated by morphometry and immunohistochemistry using primary polyclonal rabbit anti-gastrin and anti-somatostatin antibodies. Positive cells were counted using an image analyzer. Forty-five days after infection, there was a decrease in the number of D cells and an increase in the G/D cell ratio in the group with three EPIYA-C. Six months after infection, there was a progressive and significant increase in the number of G cells and in the G/D cell ratio, with a concomitant decrease in the number of D cells, especially in the three EPIYA-C group. CagA-positive H. pylori strains containing a large number of EPIYA-C phosphorylation sites induce a decrease in D cell number and an increase in G cell number and G/D ratio, which were correlated with the number of inflammatory cells of the lamina propria.


MicroRNA-144-3p inhibits cell proliferation and induces cell apoptosis in prostate cancer by targeting CEP55.
Previous research reported that miR-144-3p functions as tumor suppressor in several tumors, including glioblastoma and hepatocelluar carcinoma, but the role of miR-144-3p in prostate cancer (PCa) remains unclear. In this study, we aimed to analyze the role of miR-144-3p in PCa. By RT-qPCR, we found that expression of miR-144-3p was markedly down-regulated in PCa tissues and cell lines compared with that in paired adjacent normal tissues and normal cell lines. Moreover, miR-144-3p overexpression in PC-3 and DU145 cells by transfection with miR-144-3p mimics significantly inhibited cell proliferation and in vitro by MTT, colony formation assays and suppressed tumor growth in vivo by nude mice model. Flow cytometry analysis further demonstrated that forced expression of miR-144-3p induced cell cycle G1/S phase arrest and apoptosis. Moreover, centrosomal protein of 55 (CEP55) was confirmed as a direct target of miR-144-3p by bioinformatics analysis and luciferase reporter assays. Overexpression of miR-144-3p decreased the CEP5 mRNA and protein levels in PC-3 and DU145 cells. Using Oncomine database analysis, we further found the expression of CEP55 was significantly upregulated in PCa tissues. In addition, knockdown of CEP55 elicited similar effects with miR-144-3p overexpression in PCa cells. Taken together, our results demonstrate that miR-144-3p functions as a tumor suppressor in PCa by downregulating CEP55, supporting the targeting miR-144-3p might be a potentially effective therapeutic approach for PCa.


β-Amyrin acetate and β-amyrin palmitate as antidyslipidemic agents from Wrightia tomentosa leaves.
The ethanolic extract and fractions of Wrightia tomentosa Roem. & Schult (Apocynaceae) leaves were tested in vivo for their antidyslipidemic activity in high fat diet (HFD) induced dyslipidemic hamsters. Activity guided isolation resulted in identification of antidyslipidemic compounds β-AA and β-AP. Compounds β-AA and β-AP decrease the levels of LDL by 36% and 44%, and increase the HDL-C/TC ratio by 49% and 28%, respectively, at a dose of 10mg/kg. In addition, the isolated compounds β-AA and β-AP showed significant HMG-CoA-reductase inhibition, which was further established by docking studies.


Increased glia-specific transgene expression with glial fibrillary acidic protein promoters containing multiple enhancer elements.
The ability to direct transgene expression to astrocytes has become increasingly important as the roles for these cells continue to expand. Promoters consisting of the 5'-flanking region of the human or mouse glial fibrillary acidic protein (GFAP) gene have generally proved satisfactory. However, a more powerful promoter would be advantageous for several applications, such as expression of dominant negative RNAs or proteins, or for gene therapy. We investigated the possibility of increasing the transcriptional activity of the human GFAP promoter by inserting into it one or three additional copies of putative GFAP enhancer regions. The promoters enhanced with three additional copies gave 75-fold higher LacZ expression levels upon plasmid transfection into GFAP-expressing U251 cells than the parental gfa2 promoter. Surprisingly, in a transgenic mouse model, the enhanced promoters resulted in no or only very low expression of marker genes, probably caused by toxicity. When various cell lines were infected with replication-deficient adenoviral vectors, the enhanced promoters gave LacZ expression levels that were approximately 10-fold higher than those with the parental gfa2 promoter, while retaining specificity for GFAP-expressing cells. Injection of the adenoviral vectors carrying the enhanced promoters into nude mouse brain showed that LacZ expression was limited to GFAP-positive cells. We conclude that gfa2 enhanced promoters are useful for production of short-term, glia-specific, high expression levels of genes in an adenoviral context. Adenoviral vectors containing these enhanced promoters may be useful in glioma gene therapy.


Chemical immobilization of free-ranging North American bison (Bison bison) in Badlands National Park, South Dakota.
Twenty-six free-ranging North American bison (Bison bison) (22 adult bulls, one yearling male and three adult females) were immobilized using a combination of carfentanil and xylazine. For carfentanil the dose range (mean +/- SD) was 1.8-5.0 micrograms/kg (2.4 +/- 0.7 micrograms/kg) and for xylazine 0.004-0.125 mg/kg (0.07 +/- 0.03 mg/kg). Induction time (mean +/- SE) was 14.2 +/- 2.9 min (median 8 min), while the total mean reversal time after administration of a narcotic antagonist was 9.0 +/- 1.4 min (median 8 min). Only one animal that received the highest initial dose of carfentanil (2.5 mg) showed evidence of becoming "re-narcotized." Five animals required two or more doses of carfentanil before becoming immobilized. Overall, small volumes of drug used (mean = 0.62 ml for carfentanil, 0.53 ml for xylazine) enabled the use of 1 to 2 ml darts, increasing both accuracy and impact safety. Darting success approached 100%.


The heparan sulfate proteoglycan Syndecan-1 influences local bone cell communication via the RANKL/OPG axis.
The heparan sulfate proteoglycan Syndecan-1, a mediator of signals between the extracellular matrix and cells involved is able to interact with OPG, one of the major regulators of osteoclastogenesis. The potential of osteoblasts to induce osteoclastogenesis is characterized by a switch of OPG (low osteoclastogenic potential) towards RANKL production (high osteoclastogenic potential). In the present study, we investigated the influence of endogenous Syndecan-1 on local bone-cell-communication via the RANKL/OPG-axis in murine osteoblasts and osteoclasts in wild type and Syndecan-1 lacking cells. Syndecan-1 expression and secretion was increased in osteoblasts with high osteoclastogenic potential. Syndecan-1 deficiency led to increased OPG release by osteoblasts that decreased the availability of RANKL. In co-cultures of Syndecan-1 deficient osteoblasts with osteoclast these increased OPG in supernatant caused decreased development of osteoclasts. Syndecan-1 and RANKL level were increased in serum of aged WT mice, whereas Syndecan-1 deficient mice showed high serum OPG concentration. However, bone structure of Syndecan-1 deficient mice was not different compared to wild type. In conclusion, Syndecan-1 could be regarded as a new modulator of bone-cell-communication via RANKL/OPG axis. This might be of high impact during bone regeneration or bone diseases like cancer where Syndecan-1 expression is known to be even more prevalent.


Activated Ras modifies the proliferative response of rheumatoid synovial cells to TNF-alpha and TGF-alpha.
To study the role of the Ras/mitogen-activated protein kinase (MAPK) pathway in the proliferative response of rheumatoid synovial fibroblast (RSF) to tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-alpha. V-Ki-ras gene was introduced into RSF using a retrovirus and the proliferative response of these cells to TNF-alpha or TGF-alpha was estimated by measuring the uptake of 3H-thymidine. The effect of a mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, was also investigated. Consistent with previous reports, TNF-alpha and TGF-alpha stimulated the proliferation of RSF. When the v-Ki-ras gene was expressed, the basal growth rate of these cells was increased, but their growth was suppressed by TNF-alpha or TGF-alpha. The latter effect was abolished when the cells were exposed to a relatively low concentration of PD98059. Ras modulates the proliferative response of RSF to TNF-alpha and TGF-alpha.


High cardiovascular event rates occur within the first weeks of starting hemodialysis.
Early mortality is high in hemodialysis (HD) patients, but little is known about early cardiovascular event (CVE) rates after HD initiation. To study this we analyzed data in the AROii cohort of incident HD patients from over 300 European Fresenius Medical Care dialysis centers. Weekly rates of a composite of CVEs during the first year and monthly rates of the composite and its constituents (coronary artery, cerebrovascular, peripheral arterial, congestive heart failure, and sudden cardiac death) during the first 2 years after HD initiation were assessed. Of 6308 patients that started dialysis within 7 days, 1449 patients experienced 2405 CVEs over the next 2 years. The first-year CVE rate (30.2/100 person-years; 95% CI, 28.7-31.7) greatly exceeded the second-year rate (19.4/100; 95% CI, 18.1-20.8). Composite CVEs were highest during the first week with increased risk compared with the second year, persisting until the fifth month. Except for sudden cardiac death, temporal patterns of rates for all CVE categories were very similar, with highest rates during the first month and a high-risk period extending to 4 months. Higher or lower cumulative weekly dialysis dose, lower blood flow, and lower net ultrafiltration during dialysis were associated with CVE during the high-risk period, but not during the post high-risk period. Thus, the incidence of CVE in the first weeks after HD initiation is much higher than during subsequent periods which raises concerns that HD initiation may trigger CVEs.


Bilateral renal malacoplakia in systemic lupus erythematosus and adrenogenital syndrome.
We report a case of an 8-year-old girl with adrenogenital syndrome secondary to adrenocortical hyperplasia. Thirteen years later systemic lupus erythematosus developed with lupus nephritis. In spite of complex continuous immunosuppressive therapy, she died from terminal renal failure. At autopsy, extensive bilateral renal malacoplakia was discovered. The role of recurrent urinary tract infections and of immunological disturbances in the pathogenesis of malacoplakia is discussed.


[Experimental studies of protective effects of ischemic myocardium preconditioning and its mechanism].
Recent research has shown that repeated brief myocardial ischemia (RBMI) can increase the tolerance of myocardium to a subsequent sustained ischemia and have protective effects on myocardial cells. With the isolated rat heart Langendorff model, we investigated the effects of RBMI on myocardial morphology, systolic function, coronary flow rates (CFR), myocardial membrane phospholipid (PL) content and its marker enzyme's activity (5'-AMPase). The results showed: After ischemia-reflow, the HR, LVP and CFR in control and experimental groups had no significant difference (P > 0.05). But the PL content and specific activity of 5'-AMPase were significantly higher in the experimental group than that in control group (P < 0.01, P < 0.05). And the observations of ultrastructure suggested that the myocardium of the experimental group was preserved better than that in control group. It was also shown that RBMI had protective effects on myocardial membrane structure, and however effective had no relation to CFR.


Syntheses and crystal structures of tetracopper(II) complexes bridged by asymmetric N,N'-bis(substituted)oxamides: Molecular docking, DNA-binding and in vitro anticancer activity.
Two new tetranuclear copper(II) complexes of the formulae [Cu4(oxbm)2(phen)2](NO3)2⋅6H2O (1) and [Cu4(oxbpa)2(phen)2](ClO4)2·4H2O (2), where H3oxbm and H3oxbpa stand for N-(2-aminopropyl)-N'- (2-carboxylatophenyl)oxamide and N-hydroxypropyl-N'-(2-carboxylatophenyl)oxamide, respectively, and phen is 1,10-phenanthroline, have been synthesized and characterized by elemental analyses, molar conductivity measurements, IR and electronic spectrum studies, and X-ray single crystal diffraction. In the two tetracopper(II) complexes, the presence of the circular tetracopper(II) cations is assembled by a pair of cis-oxamido-bridged dicopper(II) units through carboxyl bridges, in which Cu1 is located in a distorted square-planar environment, while Cu2 is in a distorted square-pyramidal geometry. Numerous hydrogen bonds link complex 1 or 2 into a 2-D infinite network. The interactions of the two tetracopper(II) complexes with DNA are investigated both theoretically and experimentally, revealing that these tetracopper(II) complexes can interact with HS-DNA in the mode of intercalation, and complex 1 possesses stronger intercalating ability. The molecular docking of the two tetranuclear copper(II) complexes with the self-complementary DNA duplex of sequence d(ACCGACGTCGGT)2 facilitates the binding events. Cytotoxicity experiments indicate that the two tetracopper(II) complexes exhibit cytotoxic effects against human hepatocellular carcinoma cell SMMC-7721 and human lung adenocarcinoma cell A549. Interestingly, the cytotoxic activities of the two tetracopper(II) complexes are consistent with their DNA-binding abilities, following the order of 1>2. The main results suggest that different bridging ligands in tetracopper(II) complexes may play an important role in the DNA-binding properties and cytotoxic activities.


Two cases of Graves' disease with antithyroid hormone antibodies: implication on the role of thyroglobulin as an antigen.
We have experienced two cases of Graves' disease with antithyroid hormone autoantibodies (Case 1: anti-T4; Case 2: anti-T3) who finally underwent subtotal thyroidectomy after antithyroid drug treatment. Using serial sera obtained before and after operation, the correlation between titers of antithyroglobulin (anti-Tg) and anti-T4 or anti-T3 autoantibodies was examined in each case. There was a significant positive correlation between titers of anti-T4 (Case 1, r = 0.90, p less than 0.05), or anti-T3 (Case 2, r = 0.64, p less than 0.01) and anti-Tg antibodies. Using the homogenate of the thyroid tissue, it was found that the sole iodoprotein in the thyroid gland in each patient was 660 KDa Tg. In addition, Tg purified from the thyroid gland from Case 2 showed different immunological activity with normal Tg in two out of four murine monoclonal anti-Tg antibodies tested. On the other hand, Tg from Case 1 had identical immunological activity with normal Tg in every four monoclonal antibodies. These results are consistent with the view that the antigen responsible for the development of antithyroid hormone autoantibodies is Tg, at least in our two cases. The reason for the persistence of anti-T3 autoantibodies in Case 2, despite the subtotal thyroidectomy, could be due to some unidentified structural abnormalities of Tg which was detected only by the monoclonal anti-Tg antibodies.


Time-dependent deformation of artificial muscles based on Nylon 6.
Considering the potential applications of the Nylon 6 with thermal-induced deformation, we studied the creep deformation of non-twisted Nylon 6 wires and Nylon 6 artificial muscles as functions of annealing temperature. For comparison, we also studied the creep deformation of chicken muscle fibers in a temperature range of 20 to 35 °C. The experimental results showed that we could use the standard linear viscoelastic model to describe the creep deformation of the chicken muscle fibers, the non-twisted Nylon 6 wires, and the Nylon 6 artificial muscles. A simple method was developed to calculate the mechanical (elastic) constants and viscous resistance coefficient (viscosity) of the three different materials. The activation energy for the creep deformation of the chicken muscle fibers in the temperature of 20 to 35 °C was 18.79 kJ/mol. For the non-twisted Nylon 6 wires, the activation energy for the creep deformation was generally larger than that of the chicken muscle fibers, and was dependent on the annealing temperature. For the Nylon 6 artificial muscles, the activation energy for the creep deformation was smaller than that of the chicken muscle fibers.


[Sacral neuromodulation in urology. The emperor's new clothes or effective high-tech medicine?].
Sacral nerve modulation (SNM) is an innovative, minimally invasive treatment that uses chronic low-level electrical stimulation of the sacral plexus to recruit residual physiological function of urinary bladder detrusor, pelvic floor muscles, and the anorectal continence structures. Classic indications for sacral neuromodulation in urology are refractory overactive bladder symptoms (urinary urgency ± incontinence) and chronic nonobstructive urinary retention. SNM also offers a therapeutic alternative in refractory chronic pelvic pain syndrome. The exact mechanism of action is still unknown, but it is assumed that electrical stimulation of the sacral nerves leads to neuromodulation as well as clinically beneficial effects in the pelvic floor, the sphincter complex, and the distal colorectum. SNM is a multistep procedure. In a test phase of so-called percutaneous or peripheral nerve evaluation (PNE), the effect of sacral neuromodulation is evaluated over days or weeks during which a bladder diary/pain protocol is kept. The predictive value of PNE is high, while morbidity and surgical trauma are low. The screening phase provided by PNE makes this technique unique and offers an ideal instrument for patient selection. After final implantation of the neurostimulator (InterStim II), the long-term success rate is over 60-90%. At our clinic, 42 patients underwent a PNE procedure between January 2009 and June 2010. Of these, 34 patients had a >50% success rate and had been implanted with the InterStim II device (80.9%). The success rates were 83% for overactive bladder and 89% for chronic retention (mean follow-up 7.8 months). In addition to the surgical procedure, the exact indication and postoperative care are important prerequisites of successful therapy. To date, no information on the number of implanted stimulators in Germany is available. This suggests the need for establishment of a national prospective registry. It would also be appropriate that the experts from the implantation centers form a working group.


Elevations in nociceptive thresholds following locus coeruleus lesions.
Serotonin depletion or lesions of the midbrain dorsal raphe nuclei attenuate both morphine-produced and stimulation-produced analgesia. In contrast, norepinephrine depletion enhances both types of analgesia. To extend these findings, the effects of destruction of the noradrenergic locus coeruleus (LC) upon nociceptive flinch-jump thresholds were investigated. after four preoperative baseline sessions, lesions were placed in the LC bilaterally and nociceptive thresholds were determined for up to five weeks postoperatively. The lesions were localized by monoamine histofluorescence procedures together with conventional histological staining techniques. In 9 of 13 animals, the LC or its ascending dorsal noradrenergic bundle sustained either bilateral or unilateral damage, evidenced by green fluorescent back-up caudal to the lesions. Eight of these animals demonstrated significantly increased jump thresholds. In the remaining four animals, both lesions spared the LC and nociceptive thresholds were either unchanged or significantly decreased. In three of the four, raphe damage was noted, evidenced by yellow fluorescent back-up. The results suggest apparently contrasting roles of norepinephrine and serotonin in nociception.


Inhibition of return and response repetition within and between modalities.
Inhibition of return (IOR) refers to slower responding to stimuli at previously occupied spatial locations. IOR has been vigorously studied because of its possible deep involvement with attention mechanisms. Although IOR occurs both within and across modalities in several experimental paradigms for simple stimulus detection tasks, it has sometimes been difficult to demonstrate in perceptual discrimination tasks. In the preferred target-target paradigm, in which responses are made to a series of targets that vary in spatial location, failure to find IOR could possibly result from mixing of spatial IOR with the facilitating effects of stimulus and/or response repetition on discrimination response times. In this paper we report the first demonstration of auditory/auditory and cross-modality IOR in a target-target paradigm using a discrimination task. Our results show that IOR occurs in this task only on trials on which stimuli and responses are not repeated. These findings present a challenge to purely visual accounts of IOR and support the view that IOR arises within a more general, supra-modal mechanism of attention.


Graves' disease and Turner's syndrome.
A case of a 17-year-old female with Turner's syndrome and Graves' disease is reported. The karyotype analyzed in peripheral blood lymphocytes showed a 45,X0 pattern without mosaicism. The diagnosis of Graves' disease was based on the presence of diffuse goiter and appropriate laboratory data, including elevated thyroid radioiodine uptake, increased serum thyroxine and free thyroxine index, detectable thyroid-stimulating antibody and elevated thyroid microsomal antibody titer. Hyperthyroidism was first recognized when the patient was 13-year-old and treatment wih carbimazole was instituted for 18 months. Relapse of hyperthyroidism occurred 9 months after withdrawal of therapy, and a second course of antithyroid drug treatment was given for two yr. Ovarian dysgenesis has been described with a relatively high frequency in patients with Hashimoto's thyroiditis, while the association with Graves' disease has been only occasionally encountered. This finding is surprising in view of the etiopathogenetic and genetic relationships between these two thyroid autoimmune disorders. Some possible explanations are offered to clarify this problem.


Negative emotion-conditioned prepulse induces the attentional enhancement of prepulse inhibition in humans.
Prepulse inhibition (PPI) is a reduction of the acoustic startle reflex (ASR) when the startling stimulus is preceded by a weaker and non-startling stimulus (i.e., prepulse). Previous studies have revealed that PPI can be top-down modulated by selective attention to the fear-conditioned prepulse in animals. However, few researchers have tested this assumption in humans. Thus, in this study, the negative emotional-conditioned prepulse (CS+) was used to explore whether it could improve participants' attention, and further improve the PPI. The results showed that the CS+ prepulse increased the PPI only in females, PPI produced by CS+ prepulse was larger in females than in males, and the perceptual spatial attention further improved the PPI in both females and males. The results suggested that the PPI was affected by emotional, perceptual spatial attention, and sex. These findings highlight an additional method to measure top-down attentional regulation of PPI in humans. Which may offer a useful route to enhance the diagnosis of affective disorders, such as anxiety, depression, and post-traumatic stress disorder.


Biotherapy of experimental acute kidney injury: emerging novel therapeutic strategies.
Acute kidney injury (AKI) is a complex and heterogeneous disease with high incidence and mortality, posing a serious threat to human life and health. Usually, in clinical practice, AKI is caused by crush injury, nephrotoxin exposure, ischemia-reperfusion injury, or sepsis. Therefore, most AKI models for pharmacological experimentation are based on this. The current research promises to develop new biological therapies, including antibody therapy, non-antibody protein therapy, cell therapy, and RNA therapy, that could help mitigate the development of AKI. These approaches can promote renal repair and improve systemic hemodynamics after renal injury by reducing oxidative stress, inflammatory response, organelles damage, and cell death, or activating cytoprotective mechanisms. However, no candidate drugs for AKI prevention or treatment have been successfully translated from bench to bedside. This article summarizes the latest progress in AKI biotherapy, focusing on potential clinical targets and novel treatment strategies that merit further investigation in future pre-clinical and clinical studies.