Colonization of the Gastrointestinal Tract of Chicks with Different Bacterial Microbiota Profiles.
This study aimed to investigate the consequences of early-life microbiota transplantation using different caecal content sources in broiler chicks. We hypothesized that chicks receiving at-hatch microbiota from organic hens would harbour a distinct microbiota from chicks receiving industry-raised broiler microbiota after six weeks of age. Three hundred Cobb broilers eggs were randomly assigned to one of four groups according to the caecal content received: organic laying hens (Organic); autoclaved caecal content of organic laying hens (Autoclaved); conventionally grown broilers (Conventional); and sterile saline (Control). caecal microbiota transplantation was given by gavage on day 1. Ten birds/group were euthanized on days 2, 7, 14, 28, and 42. The caecal tonsils and contents were collected for cytokines and microbiota analyses. The microbiota from chicks receiving live inocula resembled the donors' microbiota from day seven until day 42. The microbiota composition from the chickens who received the Organic inoculum remained markedly different. Starting on day 7, the Organic group had higher richness. Simpson and Shannon's indices were higher in the Conventional group on days 2 and 7. Chickens in the Conventional group presented higher production of IL-1β and IL-6 in plasma on days 2 and 28, increased IL-6 expression in the caecal tonsils at days 7 and 42, and increased IL-12 expression on day 7. However, the Conventional group was infected with Eimeria spp., which likely caused inflammation. In conclusion, microbiota transplantation using different microbiota profiles persistently colonized newly hatched broiler chicks. Future studies evaluating the importance of microbiota composition during infections with common enteropathogens are necessary. This study also highlights the need for a strict screening protocol for pathogens in the donors' intestinal content.


Causal Genetic Inference Using Haplotypes as Instrumental Variables.
In genomic studies with both genotypes and gene or protein expression profile available, causal effects of gene or protein on clinical outcomes can be inferred through using genetic variants as instrumental variables (IVs). The goal of introducing IV is to remove the effects of unobserved factors that may confound the relationship between the biomarkers and the outcome. A valid inference under the IV framework requires pairwise associations and pathway exclusivity. Among these assumptions, the IV expression association needs to be strong for the casual effect estimates to be unbiased. However, a small number of single nucleotide polymorphisms (SNPs) often provide limited explanation of the variability in the gene or protein expression and can only serve as weak IVs. In this study, we propose to replace SNPs with haplotypes as IVs to increase the variant-expression association and thus improve the casual effect inference of the expression. In the classical two-stage procedure, we developed a haplotype regression model combined with a model selection procedure to identify optimal instruments. The performance of the new method was evaluated through simulations and compared with the IV approaches using observed multiple SNPs. Our results showed the gain of power to detect a causal effect of gene or protein on the outcome using haplotypes compared with using only observed SNPs, under either complete or missing genotype scenarios. We applied our proposed method to a study of the effect of interleukin-1 beta (IL-1β) protein expression on the 90-day survival following sepsis and found that overly expressed IL-1β is likely to increase mortality.


Coexpression of keratin and vimentin filaments in adenoid cystic carcinomas of salivary glands.
Six cases of adenoid cystic carcinoma of salivary glands have been examined with antibodies specific for either keratin or vimentin. Tumor cells in all six cases showed coexpression of keratin and vimentin.


Prolonged concurrent hypotension and low bispectral index ('double low') are associated with mortality, serious complications, and prolonged hospitalization after cardiac surgery.
Low bispectral index (BIS) and low mean arterial pressure (MAP) are associated with worse outcomes after surgery. We tested the hypothesis that a combination of these risk factors, a 'double low', is associated with death and major complications after cardiac surgery. We used data from 8239 cardiac surgical patients from two US hospitals. The primary outcomes were 30-day mortality and a composite of in-hospital mortality and morbidity. We examined whether patients who had a case-averaged double low, defined as time-weighted average BIS and MAP (calculated over an entire case) below the sample mean but not in the reference group, had increased risk of the primary outcomes compared with patients whose BIS and/or MAP were at or higher than the sample mean. We also examined whether a prolonged cumulative duration of a concurrent double low (simultaneous low MAP and BIS) increased the risk of the primary outcomes. Case-averaged double low was not associated with increased risk of 30-day mortality {odds ratio [OR] 1.73 [95% confidence interval (CI) 0.94-3.18] vs reference; P =0.01} or the composite of in-hospital mortality and morbidity [OR 1.47 (95% CI 0.98-2.20); P =0.01] after correction for multiple outcomes. A prolonged concurrent double low was associated with 30-day mortality [OR 1.06 (95% CI 1.01-1.11) per 10-min increase; P =0.001] and the composite of in-hospital mortality and morbidity [OR 1.04 (95% CI 1.01-1.07), P =0.004]. A prolonged concurrent double low, but not a case-averaged double low, was associated with higher morbidity and mortality after cardiac surgery.


Decreased insulin binding to mononuclear leucocytes and erythrocytes from dogs after S-nitroso-N-acetypenicillamine administration.
Nitric oxide (NO) and oxygen free-radicals play an important part in the destruction of beta-cells in auto- immune diabetes although the precise mechanism of interaction is still not known. This study was designed to examine any possible diabetogenic effect of NO by investigating any differences in cellular binding of insulin to its receptor on the cell membranes of erythrocytes and mononuclear leucocytes of dogs treated with the NO donor, S-nitroso-N-acetylpenicillamine (SNAP) and controls treated with captopril. The result obtained showed decreased binding of insulin to its receptor on the cell membranes of erythrocytes and mononuclear leucocytes. Mononuclear leucocytes from SNAP-treated dogs had decreased ability to bind insulin (16.30 +/- 1.24 %) when compared to mononuclear leucocytes from captopril-treated controls (20.30 +/- 1.93 %). Similar results were obtained for erythrocytes from dogs treated with SNAP (27.20 +/- 1.33 %) compared with dogs treated with captopril (34.70 +/- 3.58 %). Scatchard analysis demonstrated that this decrease in insulin binding was accounted for by a decrease in insulin receptor sites per cell, with mononuclear leucocytes of SNAP-treated dogs having 55 % less insulin receptor sites per cell compared with those of captopril-treated controls (P < 0.05). Average affinity and kinetic analysis revealed a 35 % decrease in the average receptor affinity, with mononuclear leucocytes from captopril-treated controls having an empty site affinity of 12.36 +/- 1.12 x 10(-8) M(-1) compared with 9.64 +/- 0.11 x 10(-8) M(-1) in SNAP-treated dogs (P < 0.05). These results suggest that acute alteration of the insulin receptor on the membranes of mononuclear leucocytes and erythrocytes occurred in dogs treated with S-nitroso-N-acetylpenicillamine. These findings suggest the first evidence of the novel role of NO as a modulator of insulin binding and the involvement of NO in the aetiology of diabetes mellitus.


Ugi Cascade Sequence for the Construction of 3-Pyrrolin-2-one Scaffolds: Anti-proliferation in Prostate Cancer Cells.
Herein, a small series of 3-pyrrolin-2-ones was efficiently synthesized through a three-step Ugi cascade sequence. This method features readily available substrates, simple aqueous workup procedures and good yields, dramatically improving generality of reaction. Importantly, the newly product N-benzyl-2-(3-(4-chlorophenyl)-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-phen-ylacetamide exhibited potent anti-proliferation in prostate cancer cell line through G1/S cell cycle arrest and targeted in PI3K/AKT/TSC2 signal pathway.


"The accuracy of the EOS imaging system to assess hip abnormalities in adolescents and adults:" a systematic review and meta-analysis.
To determine the accuracy of the EOS imaging system compared to the gold standard computed tomography (CT) scan, for the measurement of native and postoperative/prosthetic hip parameters in adolescents and adults. Medline, Cochrane Systematic Review, and Web of Science databases were searched to obtain relevant articles published between January 1964 and February 2021. All articles published in English. Inclusion and exclusion criteria were developed according to the Population, Intervention, Comparator, Outcome (PICO) framework. Three reviewers independently assessed the quality of included studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. A narrative synthesis of the articles and a meta-analysis were conducted. The heterogeneity exhibited by the effect sizes was obtained using a forest plot, the Q statistic and the I2 index. Reliability coefficients were transformed into Fisher's Z to normalise their distribution and stabilise the variances. For each meta-analysis, an effect size (average reliability coefficient) and a 95% confidence interval were calculated and presented in a forest plot. The amount of radiation dose between modalities was compared. The search retrieved 75 articles, six of which met inclusion and exclusion criteria. The meta-analysis included five of these six studies (sample size from 20 to 90). Comparing EOS and CT, the estimated average correlation (effect size) for combined studies was significantly high (r = 0.84, 95% CI = 0.78 to 0.88, p-value < 0.001). With respect to Pearson's correlation between EOS and CT, the estimated average correlation for combined studies was significantly high (r = 0.86, 95% CI = 0.80 to 0.90, p-value < 0.001). Average radiation dose for EOS was 0.18 ± 0.05 mGy for the anteroposterior view (AP) and 0.45 ± 0.08 mGy for the lateral view; and for CT was 8.4 to 15.6 mGy. The EOS imaging system has a high correlation with CT for preoperative and postoperative/prosthetic hip measurements, with considerably lower irradiation of patients.


Effect of dietary docosahexaenoic acid in the rat middle cerebral artery thrombosis model.
We investigated the effect of dietary docosahexaenoic acid (DHA) supplementation on the thrombolytic efficacy of recombinant tissue-type plasminogen activator (rt-PA), platelet aggregability, serum cholesterol and phospholipids. Male Wistar rats (6 weeks old) received dietary DHA supplementation (300 mg/kg per day) for 8 weeks. The rat middle cerebral artery (MCA) was occluded by a thrombus induced by photochemical reaction between rose bengal and green light which cause endothelial damage followed by platelet adhesion, aggregation and formation of a platelet and fibrin-rich thrombus at the site of photochemical reaction. The MCA blood flow was monitored using a laser Doppler flowmeter. rt-PA was administered 30 min after the middle cerebral artery had been occluded by a thrombus. This regimen produced a significant (P < 0.05) decrease in serum free-cholesterol and phospholipids levels, inhibited platelet aggregation ex-vivo induced by collagen in whole blood (P < 0.05), reduced thromboxane (TX) B2 formation (P < 0.01) in whole blood and prolonged the time for thrombotic MCA occlusion (P < 0.01) as compared with values obtained from animals on standard diet. Further, dietary DHA enhanced thrombolytic efficacy of rt-PA and reduced the size of ischaemic cerebral lesions. Our findings suggest that dietary DHA produces antithrombotic effects via metabolic conversion to non-atherogenic and non-platelet stimulant metabolites.


Simvastatin.
Simvastatin, or (1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxo-3,4,5,6-tetrahydro-2H-pyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate, C(25)H(38)O(5), is almost isostructural with lovastatin, and the general conformational features are closely related to those of other reported crystal structures of statins. The only hydrogen bond present facilitates the formation of infinite chains of molecules along the b axis.


Comprehensive 3D-RISM analysis of the hydration of small molecule binding sites in ligand-free protein structures.
Hydration is a critical factor in the ligand binding process. Herein, to examine the hydration states of ligand binding sites, the three-dimensional distribution function for the water oxygen site, gO (r), is computed for 3,706 ligand-free protein structures based on the corresponding small molecule-protein complexes using the 3D-RISM theory. For crystallographic waters (CWs) close to the ligand, gO (r) reveals that several CWs are stabilized by interaction networks formed between the ligand, CW, and protein. Based on the gO (r) for the crystallographic binding pose of the ligand, hydrogen bond interactions are dominant in the highly hydrated regions while weak interactions such as CH-O are dominant in the moderately hydrated regions. The polar heteroatoms of the ligand occupy the highly hydrated and moderately hydrated regions in the crystallographic (correct) and wrongly docked (incorrect) poses, respectively. Thus, the gO (r) of polar heteroatoms may be used to distinguish the correct binding poses.


Tumor necrosis factor alpha-induced glucose transporter (GLUT-1) mRNA stabilization in 3T3-L1 preadipocytes. Regulation by the adenosine-uridine binding factor.
Tumor necrosis factor alpha (TNF alpha), 12-O-tetradecanoylphorbol-13-acetate and cAMP stimulate hexose transport in quiescent 3T3-L1 preadipocytes by stabilizing the relatively labile mRNA coding for the basal glucose transporter, GLUT-1. The 3'-UTR of GLUT-1 mRNA contains a single copy of the destabilizing AUUUA motif in the context of an AU-rich region. The adenosine-uridine binding factor (AUBF) is a cytosolic protein which interacts with similar AU-rich regions in a variety of labile cytokine and oncogene mRNAs. Here, we demonstrate that AUBF complexes in vitro with GLUT-1 mRNA through the AU-rich portion of the 3'-UTR. AUBF activity is very low in quiescent preadipocytes, but can be up-regulated by agonists such as TPA, TNF alpha, cAMP, and okadaic acid, all of which stabilize GLUT-1 mRNA. The time courses of TNF alpha- and TPA-mediated AUBF up-regulation and GLUT-1 mRNA stabilization are coincident, suggesting a cause and effect relationship.


Technological and computational approaches to detect somatic mosaicism in epilepsy.
Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and hemimegalencephaly. Recent advances in sequencing and variant calling technologies have identified several genetic causes, including both short/single nucleotide and structural somatic variation. In this review, we aim to provide a comprehensive overview of the methodological advancements in this field while highlighting the unresolved technological and computational challenges that persist, including ultra-low variant allele fractions in bulk tissue, low availability of paired control samples, spatial variability of mutational burden within the lesion, and the issue of false-positive calls and validation procedures. Information from genetic testing in focal epilepsy may be integrated into clinical care to inform histopathological diagnosis, postoperative prognosis, and candidate precision therapies.


Repairing left ventricular outflow after aortic composite graft pseudoaneurysm: case report.
We present a technique for aortic composite graft implantation after left ventricular outflow tract destruction due to its proximal dehiscence. A 53-year-old gentleman with rheumatoid arthritis and history of Bentall procedure, presented with heart failure symptoms for the past month. Transthoracic echocardiogram identified prosthetic valve dysfunction, and transesophageal echocardiogram detected that its mechanism was by dehiscence. After excluding infectious etiology, it was hypothesized that the cause was the absence of endothelialization, owing to immunosuppressive therapy. Repair surgery was successful, and 2 years later, the patient is fully asymptomatic. Immunosuppressive drugs are a rare cause of aortic composite graft dehiscence. Left ventricular outflow tract surgical reconstruction remains an extremely complex and high-risk intervention, with the need for reentry into cardiopulmonary bypass and graft proximal segment implantation in a lower position.


Low affinity hypothalamic [3H]mazindol binding: a probe for hypothalamic body weight regulation?
It has been previously suggested that low affinity [3H]mazindol binding in the hypothalamus correlates with body weight and obesity. Low affinity [3H]mazindol binding in hypothalamic crude synaptosome preparations was carried out in normoglycemic obese mice (C57 B1/6J ob/ob) as well as in their lean littermates (C57 B1/6J +/?). NIH Swiss mice were used as additional controls. Furthermore the effect on this binding site of repeated electroconvulsive shock (ECS), a treatment known to change body weight gain, was studied in rats. Neither Bmax nor Kd were altered in obese mice compared with their lean littermates or NIH Swiss mice. The obese mice had a significantly greater body weight and weight gain than either control group. Once-daily ECS over 10 days (which significantly reduced weight gain in rats) did not change binding parameters for [3H]mazindol in hypothalami. The present data do not appear to support the hypothesis that this low affinity binding site has a physiological function in the control of body weight and obesity, at least in the examined paradigm.


The eBRAIN study: The impact of early adversity on trajectories of brain maturation and mental health in young adolescents - A prospective cohort study.
More than 1 in 10 people are thought to experience a mental health problem during adolescence, with most adult psychopathology beginning during this time. Experiences of stress or adversity during childhood are important risk factors for poorer mental health outcomes and are also associated with alterations in neurodevelopment. There is evidence to suggest that this relationship is mediated by inflammation and the immune system. The eBRAIN study (The Impact of Early Adversity on Trajectories of Brain Maturation and Mental Health in Young Adolescents) will assess how early life adversity might affect trajectories of brain development throughout adolescence, whether these neurobiological changes are associated with psychopathology, and if they can potentially be explained by an activation of the immune system. A cohort of 220 adolescents between the ages of 11-14 will be recruited into this study. Each participant will complete three study visits, each one year apart, at the Institute of Psychiatry, Psychology and Neuroscience, King's College London, London (UK). At each study visit, they will be assessed with structural and functional MRI scans, biological sample collection as well as questionnaires and interviews to collect demographic information, assess experiences of adversity, and details of psychopathology. The study will also collect information about factors such as diet and nutrition, physical exercise, and cognition. Ethical approval for this study has been received by King's College London Research Ethics Committee (REC reference: HR-18/19-9033). Findings from the study will be published in peer-reviewed journals and disseminated at national and international conferences. Patient and public involvement (PPI) is an important component of the study, 'Study Champions' recruited from participants, their parents and teachers at collaborating schools have been invited to take an active role in study governance and dissemination.


Nonsuture surgery for basal cell carcinoma: an alternative method.
Eighty-seven basal cell carcinomas were treated by surgical excision. Sites of removal were allowed to heal by secondary intention. Advantages of this method include histologic monitoring of the adequacy of incision, a less formidable surgical procedure, and a cosmetically acceptable scar.


[Neuropathic pain among hospital in-patients. Analysis of Austrian hospital discharge data].
Neuropathic pain is a common symptom of many diseases among in-patients in hospitals and neuropathic pain itself often requires hospitalisation. It was the aim of this study to examine epidemiological key data related to neuropathic pain among hospital in-patients. The source of the data used was the ICD-10 coded main diagnoses with neuropathic pain of a complete data set of discharges obtained for every Austrian hospital for the year 2002. A total of 49,412 cases (614/100,000 inhabitants) with diagnoses always associated with neuropathic pain were recorded, representing 2.0% of all discharges from Austrian hospitals. Furthermore, there were as many as 353,893 cases with diagnoses which are possibly associated with neuropathic pain, like cancer, diabetes mellitus and stroke, representing 14.3% of all cases discharged from hospitals. Applying the proportion of those suffering from neuropathic pain among patients with these three diagnoses which is known from the literature would result in 5.8% of all hospital in-patients suffering from neuropathic pain. These data represent a first step in the assessment of the epidemiology of neuropathic pain and show the high extent of neuropathic pain in the Austrian in-patient setting.


Multidimensional analysis of job advertisements for medical record information managers.
The rapid growth of the medical industry has resulted in a tremendous increase in medical record data, which can be utilized for hospital management, aiding in diagnosis and treatment, medical research, and other purposes. For data management and analysis, medical institutions require more qualified medical record information managers. In light of this, we conducted an analysis of the qualifications, abilities, and job emphasis of medical record information managers in order to propose training recommendations. From online job posting sites, a sample of 241 job advertisements for medical record information management positions posted by Chinese healthcare institutions were collected. We conducted word frequency and keyword co-occurrence analysis to uncover overall demands at the macro level, and job analysis to investigate job-specific disparities at the micro level. Based on content analysis and job analysis, a competency framework was designed for medical record information managers. The most frequent keywords were "code," "job experience," and "coding certification," according to the word frequency analysis. The competency framework for managers of medical record information is comprised of seven domains: essential knowledge, medical knowledge, computer expertise, problem-solving skills, leadership, innovation, and attitude and literacy. One of the fundamental skills required of medical record information managers is coordination and communication. Similarly, knowledge and skill requirements emphasize theoretical knowledge, managerial techniques, performance enhancement, and innovation development. According to organization type and job differences, the most crucial feature of the job duties of medical record information managers is cross-fertilization. The findings can be utilized by various healthcare organizations for strategic talent planning, by the field of education for medical record information managers for qualification and education emphasis adjustment, and by job seekers to enhance their grasp of the profession and self-evaluation.


[Flow rate, amylase and protein content of parotid saliva in sialadenosis (author's transl)].
Flow rate, protein concentration and amylase activity of parotid saliva were investigated in 17 patients with sialadenosis. The results were compared with the data obtained from 90 healthy controls. Total protein and amylase concentrations of saliva did not change although, under the influence of sialadenosis, the parotid gland clearly shows ultrastructural signs of disturbed protein secretion. Also the flow rates of parotid saliva were the same in sialadenosis patients and the control group. This can be explained by the patho-physiology of parotid secretion from the sialadenotic gland.


Luteoloside pretreatment attenuates anoxia-induced damage in cardiomyocytes by regulating autophagy mediated by 14-3-3η and the AMPKα-mTOR/ULK1 pathway.
The relation between ischemia and heart failure is well demonstrated, and several studies suggested that realizing the physiological role of autophagy will be of great importance. Luteoloside (Lut) is one of the main components of Lonicera japonica flos and exhibits antioxidant, anti-inflammatory, and cardioprotective properties. To determine if Lut pretreatment enhanced autophagy by 14-3-3η expression and the AMPKα-mTOR/ULK1 pathway and protected the neonatal rat cardiomyocytes (NRCMs) against anoxia damage, NRCMs were treated using 20 μM Lut for 36 h, and the anoxia damage model was established using NRCMs. The indexes reflecting the condition of NRCMs, oxidative stress level, and mitochondrial function were evaluated. In addition, the expression and phosphorylation of 14-3-3η and AMPKα/mTOR/ULK1, and autophagy markers (LC3II, P62) and the abundance of autophagy lysosomes were detected. Results revealed that Lut pretreatment alleviated anoxia- induced damage in NRCMs, that is, Lut pretreatment could increase cell viability, decrease LDH activity and apoptosis, suppressed ROS generation and oxidative stress, restored intracellular ATP levels, stabilized MMP levels, and inhibited mPTP opening. Furthermore, Lut pretreatment could enhance autophagy via upregulating 14-3-3η, LC3II expression and increasing p-AMPKα/AMPKα and p-ULK1/ULK1 level, whereas P62 expression and p-mTOR/mTOR level decreased; the fluorescence intensity of autolysosomes also increased. However, in the NRCMs treated with pAD/14-3-3η RNAi or incubated with 3-MA (an autophagy inhibitor), the abovementioned effects of Lut pretreatment were reduced. Taken together, Lut pretreatment could enhance autophagy by upregulating 14-3-3η expression to influence the AMPKα-mTOR/ ULK1 pathway against anoxia-induced damage in NRCMs.


Autonomic manifestations of epilepsy: emerging pathways to sudden death?
Epileptic networks are intimately connected with the autonomic nervous system, as exemplified by a plethora of ictal (during a seizure) autonomic manifestations, including epigastric sensations, palpitations, goosebumps and syncope (fainting). Ictal autonomic changes might serve as diagnostic clues, provide targets for seizure detection and help us to understand the mechanisms that underlie sudden unexpected death in epilepsy (SUDEP). Autonomic alterations are generally more prominent in focal seizures originating from the temporal lobe, demonstrating the importance of limbic structures to the autonomic nervous system, and are particularly pronounced in focal-to-bilateral and generalized tonic-clonic seizures. The presence, type and severity of autonomic features are determined by the seizure onset zone, propagation pathways, lateralization and timing of the seizures, and the presence of interictal autonomic dysfunction. Evidence is mounting that not all autonomic manifestations are linked to SUDEP. In addition, experimental and clinical data emphasize the heterogeneity of SUDEP and its infrequent overlap with sudden cardiac death. Here, we review the spectrum and diagnostic value of the mostly benign and self-limiting autonomic manifestations of epilepsy. In particular, we focus on presentations that are likely to contribute to SUDEP and discuss how wearable devices might help to prevent SUDEP.


Multidonor bone marrow transplantation improves donor engraftment and increases the graft versus tumor effect while decreasing graft-versus-host disease.
In partially matched donor transplantation, mandatory T-cell depletion (TCD) increases the risks of rejection/graft failure, relapse, and post-transplant infections. A multi-donor approach was offered to resolve some of these drawbacks. This hypothesis was previously tested in a TCD fully mismatched murine model. However, the effect of multi-donor transplantation (MDT) on graft-versus-host disease (GVHD) and graft versus tumor (GVT) effect were never tested. To assess the safety and efficacy of MDT, we used it in non-TCD transplantation and murine breast carcinoma model. We found that when transplanting non-TCD MDT composed by C57Bl/6 and C3H cells into BALB/c, a consistent trichimerism is established, dominated by C57Bl/6 cells. Following MDT the study animals experienced reduced GVHD compare with those transplanted from C57Bl/6 alone, while the GVT effect was superior. We conclude that MDT may serve as a technique that suppresses GVHD while maintaining the GVT effect.


Oral loading with propafenone for conversion of recent-onset atrial fibrillation: a review on in-hospital treatment.
Atrial fibrillation (AF) is a very common arrhythmia. In order to treat acute AF rapidly, effective drug regimens are required. Propafenone is a class IC antiarrhythmic agent that is suitable for oral loading as it reaches peak plasma concentrations within 2 to 4 hours of administration. The use of propafenone loading in patients with AF must be based on appropriate patient selection in view of the negative inotropic effect and the potential proarrhythmic effects of the drug. A series of controlled trials in patients with recent-onset AF without heart failure who were hospitalised with enforced bed rest has shown that orally loaded propafenone (450 to 600 mg as single dose) exerts a relatively quick effect (within 3 to 4 hours) and a high rate of efficacy (72 to 78% within 8 hours). A potentially harmful effect of class IC agents is the risk of transforming AF into atrial flutter (3.5 to 5% of patients). However, atrial flutter with 1 : 1 atrioventricular response was observed in only two of 709 patients receiving propafenone (0.3% incidence). Nevertheless, the potential negative inotropic effect of propafenone demands careful patient selection, with systematic exclusion of patients with left ventricular dysfunction or congestive heart failure. Oral loading with propafenone can be considered as an episodic treatment in patients with AF recurrences, as has been proposed for other drugs in the past. However, the safety of oral loading with propafenone as an outpatient treatment in appropriately selected patients has to be assessed by appropriately designed prospective studies.


Comparison of frequency of thromboembolic events and echocardiographic findings in patients with chronic nonvalvular atrial fibrillation and coarse versus fine electrocardiographic fibrillatory waves.
In patients with nonvalvular atrial fibrillation, the electrocardiographic fibrillatory wave reflects the structural and electrical remodeling of the atria. This study examined whether the fibrillatory wave amplitude could predict the risk of thromboembolism and demonstrated that this amplitude was related to the duration of atrial fibrillation. We also showed that the presence of fine fibrillatory waves (<1 mm in amplitude) could predict the thromboembolic potential in patients with chronic nonvalvular atrial fibrillation.


Leadership and adolescent girls: a qualitative study of leadership development.
This research investigated youth leadership experiences of adolescent girls who participated in a comprehensive feminist-based leadership program. This qualitative study utilized a grounded theory approach to understand changes that occurred in 10 female adolescent participants. The words of the participants revealed that initially they viewed leadership in traditional terms and were hesitant to identify themselves as leaders or to see themselves included within their concepts of leadership. Following the program their view of leadership expanded and diversified in a manner that allowed for inclusion of themselves within it. They spoke with greater strength and confidence and felt better positioned and inspired to act as leaders. Participants identified having examples of women leaders, adopting multiple concepts of leadership, and participating in an environment of mutual respect and trust as factors that contributed to their expanded conceptualization.


[New perspectives in the laboratory diagnosis of dementia].
Over the past 10 years, the status of laboratory analysis in dementia has increasingly changed from its use for exclusion diagnoses for secondary causes of dementias to determining positive diagnoses of neurodegenerative dementias. This especially applies to the cerebrospinal fluid diagnosis of Alzheimer's disease (AD). Just a few years ago, a lumbar puncture was advised only with sufficiently founded clinical suspicion and with higher priority for the exclusion of inflammatory causes of cognitive dementias. In contrast, pathologically changed biomarkers in the cerebrospinal fluid have already been indexed as supportive attributes of the diagnosis in the 2007 amended research criteria of AD. The lumbar puncture is therefore increasingly becoming part of the clinical routine diagnosis of demential processes and has, to some extent, far-reaching consequences. In this article, we discuss some of the important aspects.


Childbirth related fears and psychological birth trauma in younger and older age adolescents.
The aim of this study is to explore childbirth fears on psychological birth trauma (PBT) by adolescent age. Among adults parity and intrapartum fears including fear of dying, loss of control, pain, and limited support have been associated with negative birth appraisal and symptoms of traumatic stress, defined here as PBT. This cross-sectional study surveyed a convenience sample of 201 adolescents at a large, county hospital. Over 75% of adolescents perceived fear. Younger and older adolescents, similar in fears, were distinguished only by parity. The effects of parity, overall rating of fear, and father of baby absence were found to vary by age on birth appraisal; however, only parity varied by age on IES scores. All age adolescents can be fearful and will benefit with childbirth education and labor support to help reduce fears and subsequent PBT.


Rapid and specific method for the determination of vancomycin in plasma by high-performance liquid chromatography on an aminopropyl column.
A high-performance liquid chromatographic method has been developed for the quantitative analysis of vancomycin in plasma. The method involves protein precipitation with acetonitrile, followed by normal-phase chromatography on an aminopropyl column. The clear supernatant was injected after centrifugation, and the eluent was monitored at 240 nm. No interference was found either with endogenous substances or with many currently used drugs, indicating a good selectivity for the procedure. The standard curve was linear between 0.1 and 100 micrograms/ml, and the detection limit was 0.01 microgram/ml of plasma. The mean intra- and inter-assay coefficients of variation were 2.4 and 4.0%, respectively, in the 10-50 micrograms/ml range. Application of the method to the study of vancomycin pharmacokinetics in a rabbit after a single intravenous dose is also reported.


Clinical trials participation award winners using innovative technology to support clinical research.
Examples show how selected winners of ASCO's Clinical Trials Participation Awards are using new technologies to support their clinical research programs.


Predictors of response to pharmacotherapy in children and adolescents with psychiatric disorders: A combined post hoc analysis of four clinical trial data.
The prediction of response to pharmacotherapy has not been sufficiently explored in children and adolescents with psychiatric disorders, which was addressed in this study. Data from four double-blind, placebo-controlled studies (sertraline and fluvoxamine for anxiety disorders, risperidone for autistic disorder, and fluoxetine for major depressive disorder) in children and adolescents funded by the National Institute of Mental Health were used. The response was defined as a score of 1 or 2 on the Clinical Global Impression-Global Improvement (CGI-I) at the endpoint. Logistic regression analysis was performed to evaluate associations between response status and the following variables: sex, diagnosis, treatment allocation, and CGI-Severity of Illness (CGI-S) score at baseline. Moreover, the presence of early improvement (a score of ≤3 in the CGI-I) at Week 1 was added to the independent variables in an additional binary logistic regression analysis, using the data from two studies. A total of 599 patients were included in the analysis. In the binary logistic regression analysis, active drug use (odds ratio [OR] = 8.64, P < 0.001) and female sex (OR = 1.89, P = 0.002) were significantly associated with treatment response. In the second binary logistic regression, the presence of early improvement in the CGI-I (OR = 3.47, P = 0.009), as well as active drug use (OR = 15.05, P < 0.001) and female sex (OR = 2.87, P = 0.016), were associated with subsequent responses. Allocation to active drugs, female sex, and early improvement may predict treatment response to pharmacotherapy among children and adolescents with psychiatric disorders.


Postoperative infection associated with mandibular angle fracture treatment in the presence of teeth on the fracture line: a systematic review and meta-analysis.
The aim of this review was to answer the question: Which is the best procedure to follow when there is tooth involvement in the line of mandibular angle fracture, taking into consideration the occurrence of postoperative infection? A systematic literature review using the PubMed (MEDLINE), Virtual Health Library (VHL), Cochrane Library, and Scopus databases was done, and a total of 1007 articles were found. Among these, 13 articles were included in the final review after the papers were read. A series of 1542 mandibular angle fractures with the presence of teeth in the fracture line was obtained. Of 788 cases where the tooth was removed, a postoperative infection occurred in 84 cases; of 754 cases where the tooth was retained, postoperative infection also occurred in 84 cases. Through this review it was observed that there was no significant statistical difference between removing or retaining the tooth in the line of fracture and the occurrence of postoperative infection.


Establishing a centralised telehealth service increases telehealth activity at a tertiary hospital.
The Princess Alexandra Hospital Telehealth Centre (PAH-TC) is a project jointly funded by the Australian national government and Queensland Health. It seeks to provide a whole-of-hospital telehealth service using videoconferencing and store-and-forward capabilities for a range of specialities. The aim of this study was to investigate whether the introduction of a new telehealth coordination service provided by a tertiary hospital centre increased telehealth activities of a tertiary hospital. Evaluation included service delivery records and stakeholder satisfaction. Telehealth service delivery model before and after the establishment of the centre is described as well as the project implementation. The study retrieved data related to the number and scope of previous, and current, telehealth service episodes, to ascertain any change in activity levels following the introduction of the new telehealth coordination service. In addition, using a cross-sectional research design, the satisfaction of patients, clinicians and administrators was surveyed. The survey focused on technical utility and perceived clinical validity. Introduction of a new centralised telehealth coordination service was associated with an increase in the scope of telehealth from five medical disciplines, in the year before the establishment, to 34 disciplines two years after the establishment. The telehealth consultations also increases from 412 (the year before), to 735 (one year after) and 1642 (two years after) the establishment of the centre. Respondents to the surveys included patients (27), clinicians who provided the consultations (10) and clinical or administrative staff who hosted the telehealth consultations in the remote site (8). There were high levels of agreement in relation to the telehealth option saving time and money, and an important health service delivery model. There was evidence from the remote site that modifying roles to incorporate this new service was challenging. The introduction of a centralised coordination for telehealth service of a tertiary hospital was associated with the increase in the scope and level of telehealth activity of the hospital. The project and model of health care delivery described in this paper can be adopted by tertiary hospitals to grow their telehealth activities, and potentially reduce costs associated with the delivery of services at a distance.


Differential projections from locus coeruleus to olfactory bulb and olfactory tubercle: an HRP study.
The microiontophoretic administration of horseradish peroxidase (HRP) to the olfactory bulb (OB) or olfactory tubercle (OT) in cats and rats yielded similar results in both species. After an OB HRP-injection ipsilateral and contralateral labelled neurons were seen in the piriform cortex, polymorphic layer of OT, magnocellular preoptic region, lateral hypothalamus, ventromedial hypothalamic nucleus and locus coeruleus (LC). In both species more labelled structures were found after an OT HRP-injection than after an OB HRP-injection. The substantia nigra in rats was more abundantly labelled after an OT injection than after an OB one. In cats the dorsal and the ventral raphe were also labelled. In either species, OT HRP-injections resulted in a higher frequency of LC labelled neurons than after OB injections. These results favor the hypothesis that the OT plays an important role as a relay station for efferent inflow from the brain stem en route to the OB.


Hopelessness is associated with decreased heart rate variability during championship chess games.
Clinical observations suggest that negative affects such as helplessness/hopelessness (HE/HO) may induce autonomic duration; affects were assessed for every move after reconstruction of the games. In all games compiled, 18 situation of intense confidence/optimism and 20 of intense helplessness/hopelessness were observed. Intense affects of HE/HO were associated with decreasing HF-HRV (Fisher exact test, p =.003), increasing "nervousness" (p =.0005), decreasing "optimism" (p =.0005), and decreasing "calmness" (p =.0005). Investigation of championship chess game players with an ELO strength > or = 2300 in a natural field setting revealed increasing HE/HO being associated with reduced HF-HRV suggestive of vagal withdrawal. Thus, our data may help link negative mood states, autonomic nervous system disturbances, and cardiac events.


Production of sterigmatocystin by Aspergillus versicolor isolated from roughage.
A total of 69 samples of hay and straw collected during the winter period of 1984/85 were surveyed for their contamination by Aspergillus versicolor. The percentage of A. versicolor-positive samples was 14.5%. Nineteen A. versicolor strains mainly isolated from roughage were tested for the production of sterigmatocystin. All of the isolates examined were capable of producing different levels of sterigmatocystin on a cracked corn substrate. The majority of these strains were highly toxigenic; 53% of the isolates produced more than 500 mg/kg of sterigmatocystin. These findings suggest that corn is a very suitable substrate for sterigmatocystin production and that particularly in the surface layers of feed stocks and corn silos such toxigenic strains of A. versicolor can produce considerable growth and possibly sterigmatocystin, too.


Tetrahydrocurcumin in plasma and urine: quantitation by high performance liquid chromatography.
Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, exhibits many of the same physiologic and pharmacological activities as curcumin and in some systems may exert greater antioxidant activity than curcumin. However, evaluation of clinical efficacy is limited by lack of sensitive methods for quantifying intake/absorption in blood or urine. We have developed a sensitive high performance liquid chromatography (HPLC) analytical method for detection of THC in plasma and urine. The method involves extracting the THC from 0.2 mL samples with 95% ethyl acetate/5% methanol, and beta-17-estradiol acetate as an internal standard. Analysis with a reversed-phase C18 column and UV detection at 280 nm demonstrates linear performance from 0.050 to 6.0 microg/mL in plasma, and 0.060 to 6.0 microg/mL in urine. The coefficients of variation for intra- and inter-assays were each<8.6%. The average recovery of THC from plasma and urine was greater than 98.5%. These data demonstrate a rapid, sensitive and accurate method for HPLC quantification of THC in plasma and urine.


Perivascular pseudorosettes in childhood brain tumours: an ultrastructural and immunohistochemical study.
Perivascular pseudorosettes (PP) in childhood central nervous system tumours were examined with light and electron microscopy and immunohistochemistry for glial fibrillary acidic protein, S-100 protein and albumin. One kind of PP at light microscopy comprised a central thin-walled vessel surrounded by a thick mantle of eosinophilic fibrillary material and rings of usually regular nuclei. Adjacent tumour tissue was compact. This type was correlated closely with ultrastructural evidence of ependymal differentiation. The central vessel showed continuous endothelium in all. Another type of PP comprised a central vessel of varying thickness surrounded by hyaline material, clearly defined tapering processes, and rings of often irregular nuclei. Adjacent tissue showed extensive edema and microcystic change. Ultrastructurally, this type showed no ependymal differentiation except in one myxopapillary ependymoma. Fenestrated vessels were seen in half of the tumours associated with this kind of PP. It is proposed that variation in vascular permeability, rather than in the structure of tumour cells, is the main cause for the difference in histological appearance of the two types of PP. Fenestrated vessels may also be responsible for the "myxoid" change in myxopapillary ependymomas. The amount of extracellular albumin showed no consistent correlation with the presence of fenestrations in vessels. A variable degree of positivity to GFAP and S-100 protein was seen in the tumours associated with both types of PPs with no clear difference in pattern.


The effect of an orally administered proteolytic enzyme on the elasticity and viscosity of nasal mucus.
We have evaluated the effect of serratiopeptidase (SER), a proteolytic enzyme, on the elasticity and viscosity of the nasal mucus in adult patients with chronic sinusitis. SER was administered in a dose of 30 mg/day orally for 4 weeks. Nasal mucus was collected from the nasal cavities of each patient before (week 0) and 4 weeks after the start of the medication (week 4). The storage modulus (G') and the dynamic viscosity (eta') of each specimen of nasal mucus were determined by an oscillating sphere magnetic rheometer at frequencies of 0.5, 1, 5, 10 and 20 Hz at a constant temperature of 25 degrees C. The dynamic viscosity (eta') of the mucus at week 4 was significantly lower than that at week 0 (at frequencies of 5, 10 and 20 Hz). No significant differences were observed in the storage modulus (G') between the mucus at week 0 and week 4. SER reduced the viscosity but not the elasticity of the nasal mucus. These findings are discussed in relation to mucociliary clearance.


The Four mRNA Bases Have Quite Different (Un)folding Free Energies, Applications to RNA Splicing and Translation Initiation with BindOligoNet.
Expression of mRNA is often regulated by the binding of a small RNA (miRNA, snoRNA, siRNA). While the pairing contribution to the net free energy is well parameterized and can be computed in O(N) time, the cost of removing pre-existing mRNA secondary structure has not received sufficient attention. Conventional methods for computing the unfolding free energy of a target mRNA are costly, scaling like the cube of the number of target bases O(N3). Here we introduce a model to describe the unfolding costs of the binding site, which features surprisingly big differences in the free energy parameters for the four bases. The model is implemented in our O(N) algorithm, BindOligoNet. Donor splice site prediction is more accurate when using our calculation of spliceosomal U1-snRNA to mRNA net binding free energy. Our base-dependent free energies also correlate with efficient ribosome docking near the start codon.


The mindful trajectory: Developmental changes in mentalizing throughout adolescence and young adulthood.
Mentalizing and psychological mindedness are two key, partially overlapping facets of social cognition. While mentalizing refers to the ability to reflect on one's own mental states and the mental states of others, psychological mindedness describes the ability for self-reflection and the inclination to communicate with others about one's own mental states. This study examined the development of mentalizing and psychological mindedness throughout adolescence and into young adulthood, and the interplay between the two with gender and the Big Five Personality Traits. 432 adolescents and young adults (ages 14-30) were recruited from two independent schools and two universities. Participants completed a set of self-report measures. A curvilinear trend in both mentalizing and psychological mindedness indicated a gradual development of these capacities with age, peaking in young adulthood. Across all age groups, females had consistently higher mentalizing scores than males. For females, scores only changed significantly between age bands 17-18 to 20+ (p<0.001), ES (d = 1.07, 95% CI [.1.52-.62]). However, for males, a significant change in scores appeared between two age bands of 14 to 15-16 (p<0.003), ES (d = .45, 95% CI [.82-.07]), and 17-18 to 20+ (p<0.001), ES (d = .6, 95% CI [.1.08-.1]). The change in psychological mindedness scores differed, and females did not have consistently higher scores than males. Females' scores were only significantly higher for ages 14 (p<0.01), ES (d = .43, 95% CI [.82-.04]), and 15-16 (p<0.01), ES (d = .5, 95% CI [.87-.11]). As with the development of mentalizing abilities, female scores in psychological mindedness remained stable from 14 to 18 years of age, with a significant change between age bands 17-18 and 20+ (p<0.01), ES (d = 1.2, 95% CI [1.7-.67]). Contrastingly, for males significant change occurred between 15-16, 17-18 (p<0.01), ES (d = .65, 95% CI [1.1-.18]) and 20+ (p<0.01), ES (d = .84, 95% CI [1.5-.2]). A significant positive association was found between mentalizing and psychological mindedness and the personality traits of Agreeableness, Openness to Experience and Conscientiousness (p<0.0001). Psychological mindedness had a weaker positive correlation with Extraversion and Openness to Experience (p<0.05). The discussion is focused on the interpretation of the findings in light of social cognition and brain development research.


Morbidity and Functional Outcomes Following Rocky Mountain Spotted Fever Hospitalization-Arizona, 2002-2017.
Rocky Mountain spotted fever (RMSF) is a deadly tickborne disease disproportionately affecting Arizona tribal communities. While the acute clinical effects of RMSF are well-documented, more complete understanding of the long-term health consequences is needed to provide guidance for providers and patients in highly impacted areas. We performed a retrospective review of hospitalized RMSF cases from 2 tribal communities in Arizona during 2002-2017. Medical records from acute illness were abstracted for information on clinical presentation, treatment, and status at discharge. Surviving patients were interviewed about disease recovery, and patients reporting incomplete recovery were eligible for a neurologic examination. Eighty hospitalized cases of RMSF met our inclusion criteria and were reviewed. Of these, 17 (21%) resulted in a fatal outcome. Among surviving cases who were interviewed, most (62%) reported full recovery, 15 (38%) reported ongoing symptoms or reduced function following RMSF illness, and 9 (23%) had evidence of neurologic sequelae at the time of examination. Sequelae included impaired cognition, weakness, decreased deep tendon reflexes, seizures, and cranial nerve dysfunction. Longer hospitalization (25.5 days vs 6.2 days, P < .001), a higher degree of disability at discharge (median modified Rankin score 1 vs 0, P = .03), and delayed doxycycline administration (6.2 days vs 4.1 days, P = .12) were associated with long-term sequelae by logistic regression. Although the etiology of sequelae is not able to be determined using this study design, life-altering sequelae were common among patients surviving severe RMSF illness. Delayed administration of the antibiotic doxycycline after day 5 was the strongest predictor of morbidity.


A Tissue-Like Soft All-Hydrogel Battery.
To develop wearable and implantable bioelectronics accommodating the dynamic and uneven biological tissues and reducing undesired immune responses, it is critical to adopt batteries with matched mechanical properties with tissues as power sources. However, the batteries available cannot reach the softness of tissues due to the high Young's moduli of components (e.g., metals, carbon materials, conductive polymers, or composite materials). The fabrication of tissue-like soft batteries thus remains a challenge. Here, the first ultrasoft batteries totally based on hydrogels are reported. The ultrasoft batteries exhibit Young's moduli of 80 kPa, perfectly matching skin and organs (e.g., heart). The high specific capacities of 82 mAh g-1 in all-hydrogel lithium-ion batteries and 370 mAh g-1 in all-hydrogel zinc-ion batteries at a current density of 0.5 A g-1 are achieved. Both high stability and biocompatibility of the all-hydrogel batteries have been demonstrated upon the applications of wearable and implantable. This work illuminates a pathway for designing power sources for wearable and implantable electronics with matched mechanical properties.


Exploring the social stressors and resources of husbands of women diagnosed with advanced breast cancer in their role as primary caregivers in Kumasi, Ghana.
We aimed to explore the experiences of husbands of women diagnosed with advanced breast cancer, highlighting their stressors and the resources they rely on to cope, in Kumasi, Ghana. An exploratory descriptive qualitative research design was adopted. Fifteen in-depth interviews with participants were conducted. After a participant's written consent, we audio-recorded the interview sessions and transcribed them verbatim. We managed and analysed the data manually. The experiences of husbands as primary caregivers of their wives diagnosed with advanced breast cancer have been broadly categorized under two main themes: stressors and resources. The analyses revealed that the burdens associated with the husband's primary caregiving roles threatened the marriage, their relationships with others, work, and finances. Regardless of the stressors, participants drew on a range of resources such as acceptance, marital obligation and commitment to marital vows, social support, and spirituality to cope. The study is the first of our knowledge to explore the experiences of husbands acting as primary caregivers of their wives who are diagnosed with advanced breast cancer in Ghana. It revealed that they rely on specific resources to cope with the burdens associated with their role. Policies and programs aiming at assisting women diagnosed with advanced breast cancer to manage and cope with the disease should include the partners of the married ones by designing programs that help the husbands to understand the situation and adequately provide the care that promotes the quality of life of the husband, wife, and the family.


Background current reduction and biobarcode amplification for label-free, highly sensitive electrochemical detection of pathogenic DNA.
By using exonuclease I and biobarcode nanoparticles, we describe a novel background current reduction strategy for amplified electrochemical detection of uropathogen specific sequences at ultralow concentrations.


Safety and Efficacy of Immune Checkpoint Inhibitors in Cancer Patients and Preexisting Autoimmune Disease: A Systematic Review and Meta-Analysis in Non-Small-Cell Lung Cancer.
Cancer patients with preexisting autoimmune diseases (AID) have been traditionally excluded from clinical trials of immune checkpoint inhibitors (ICI) due to concerns for toxicity. As indications for ICI expand, more data are needed on the safety and efficacy of ICI treatment in cancer patients with AID. We systematically searched for studies consisting of NSCLC, AID, ICI, treatment response, and adverse events. Outcomes of interest include incidence of autoimmune flare, irAE, response rate, and ICI discontinuation. Study data were pooled using random-effects meta-analysis. Data were extracted from 24 cohort studies, consisting of 11,567 cancer patients (3774 NSCLC patients and 1157 with AID). Pooled analysis revealed an AID flare incidence of 36% (95% CI, 27%-46%) in all cancers and 23% (95% CI, 9%-40%) in NSCLC. Preexisting AID was associated with an increased risk of de novo irAE in all cancer patients (RR 1.38, 95% CI, 1.16-1.65) and NSCLC patients (RR 1.51, 95% CI, 1.12-2.03). There was no difference in de novo grade 3 to 4 irAE and tumor response between cancer patients with and without AID. However, in NSCLC patients, preexisting AID was associated with a 2-fold increased risk of de novo grade 3 to 4 irAE (RR 1.95, 95% CI, 1.01-3.75) but also better tumor response in achieving a complete or partial response (RR 1.56, 95% CI, 1.19-2.04). NSCLC patients with AID are at a higher risk of grade 3 to 4 irAE but are more likely to achieve treatment response. Prospective studies focused on optimizing immunotherapeutic strategies are needed to improve outcomes for NSCLC patients with AID.


Immunisation of calves with Ostertagia ostertagi fourth stage larval antigens failed to protect calves from infection.
Excretory-secretory and somatic antigens of Ostertagia ostertagi fourth stage larvae, emulsified with complete Freund's adjuvant, were intraperitoneally administered to calves on three occasions. Two weeks after the last immunisation all calves were infected with a single dose of 130,000 O. ostertagi third stage larvae. All animals were necropsied 25 days after infection. The immunisation procedure resulted in IgG1 and IgG2 antibodies, however no protective immunity was induced as O. ostertagi worm burdens and worm length were similar in all groups.


Effects of droperidol dosage on postoperative emetic symptoms following pediatric strabismus surgery.
To compare the frequency of postoperative emetic symptoms and side effects in pediatric strabismus surgery using four doses of droperidol. Randomized, blinded study. University eye institute. 82 ASA physical status I and II pediatric patients, aged 1 to 16 years, undergoing outpatient strabismus surgery. Patients were assigned to one of four doses of droperidol (10, 20, 40, or 80 microg.kg(-1)) (Groups 1, 2, 3, and 4, respectively). All patients received the same anesthetic management, with droperidol administered intravenously immediately after induction of anesthesia. Postoperatively, patients were evaluated for emetic symptoms (nausea, retching, and/or vomiting) and side effects (postoperative sedation or extrapyramidal symptoms). There was a dose-dependent reduction of emetic symptoms seen with increasing droperidol dose. Predischarge emetic symptoms were 50%, 15%, 15%, and 5% in Groups 1, 2, 3, and 4, respectively (p < 0.009). Peak emetic symptoms were observed after discharge: 75%, 40%, 35%, and 15% in Groups 1, 2, 3, and 4, respectively (p < 0.003). Convalescence times, including awakening, extubation, recovery, and hospitalization, were unaffected by increasing droperidol dose. Sedation was similar in all groups and no patient exhibited any side effects. However, when patients exhibited emetic symptoms, discharge time increased from 207 +/- 57 minutes to 283 +/- 128 minutes (p < 0.001). Prophylactic administration of droperidol 80 microg.kg(-1) is most effective in reducing postoperative emetic symptoms without increasing time to discharge. In those patients with emetic symptoms who also received prophylactic droperidol, time to discharge was significantly delayed.


[Pilot study on personality disorders evaluation. Categorical DSM-IV vs. dimensional five factor models].
This paper evaluates the relationship between a dimensional method of personality assessment (five factor model) and a categorical one (DSM-IV). Thirty-eight consecutive outpatients without concurrent diagnosis of axis I, were assessed with the categorical instrument I.P.D.E. (International Personality Disorders Examination) and the dimensional one B.F.Q. (Big-Five Questionnaire). Extraversion differences were found among cluster and its components, Dominance and Dynamism. Extraversion, Dynamism, Cooperation and Persistence differences were found among personality disorders of cluster A. Personality disorders of cluster B were different in Mental Openness, Dynamism and Cooperation. Finally, Extraversion, Mental Openness, Dynamism, Cordiality, Openness to culture and Openness to experience differences were found among personality disorders of cluster C. This pilot study proposes the possibility of developing dimensional models to predict a possible personality disorder in future. Longitudinal studies with great samples are necessary to get this purpose, in where to be gathered a high percent from each personality disorder.


In vitro electrophysiologic effects of morphine in rabbit ventricular myocytes.
Morphine is widely used in patients undergoing surgical operations and is also reported to mediate cardioprotection of preconditioning. The current study determined effects of morphine at therapeutic to pharmacologic concentrations on cardiac action potential, L-type Ca2+ current (ICa.L), delayed rectifier K+ current (IK), and inward rectifier K+ current (IK1) in isolated rabbit ventricular myocytes. Ventricular myocytes were enzymatically isolated from rabbit hearts. Action potential and membrane currents were recorded in current and voltage clamp modes. Morphine at concentrations from 0.01 to 1 microM significantly prolonged cardiac action potential, and at 0.1 and 1 microM slightly but significantly hyperpolarized the resting membrane potential. In addition, morphine at 0.1 microM significantly augmented ICa.L (at +10 mV) from 5.9 +/- 1.9 to 7.3 +/- 1.7 pA/pF (by 23%; P < 0.05 vs. control) and increased IK1 (at -60 mV) from 2.8 +/- 1.0 to 3.5 +/- 0.9 pA/pF (by 27%; P < 0.05 vs. control). Five microM naltrindole (a selective delta-opioid receptor antagonist) or 5 microM norbinaltorphimine (a selective kappa-opioid receptor antagonist) prevented the increase in ICa.L induced by morphine, but 5 microM CTOP (a selective mu-opioid receptor antagonist) did not. The three types of opioid antagonists did not affect the augmentation of IK1 by morphine. Morphine had no effect on IK. These results indicate that morphine prolongs action potential duration by increasing ICa.L, an effect mediated by delta- and kappa-opioid receptors. It also hyperpolarizes cardiac resting membrane potential by increasing IK1, which is not mediated by opioid receptors.


Potential mechanisms of hypothalamic renin-angiotensin system activation by leptin and DOCA-salt for the control of resting metabolism.
The renin-angiotensin system (RAS), originally described as a circulating hormone system, is an enzymatic cascade in which the final vasoactive peptide angiotensin II (ANG) regulates cardiovascular, hydromineral, and metabolic functions. The RAS is also synthesized locally in a number of tissues including the brain, where it can act in a paracrine fashion to regulate blood pressure, thirst, fluid balance, and resting energy expenditure/resting metabolic rate (RMR). Recent studies demonstrate that ANG AT1A receptors (Agtr1a) specifically in agouti-related peptide (AgRP) neurons of the arcuate nucleus (ARC) coordinate autonomic and energy expenditure responses to various stimuli including deoxycorticosterone acetate (DOCA)-salt, high-fat feeding, and leptin. It remains unclear, however, how these disparate stimuli converge upon and activate this specific population of AT1A receptors in AgRP neurons. We hypothesize that these stimuli may act to stimulate local expression of the angiotensinogen (AGT) precursor for ANG, or the expression of AT1A receptors, and thereby local activity of the RAS within the (ARC). Here we review mechanisms that may control AGT and AT1A expression within the central nervous system, with a particular focus on mechanisms activated by steroids, dietary fat, and leptin.


Employment of enhanced permeability and retention effect (EPR): Nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer.
In tumorous tissues, the absence of vasculature supportive tissues intimates the formation of leaky vessels and pores (100 nm to 2 μm in diameter) and the poor lymphatic system offers great opportunity to treat cancer and the phenomenon is known as Enhanced permeability and retention (EPR) effect. The trends in treating cancer by making use of EPR effect is increasing day by day and generate multitudes of possibility to design novel anticancer therapeutics. This review aimed to present various factors affecting the EPR effect along with important things to know about EPR effect such as tumor perfusion, lymphatic function, interstitial penetration, vascular permeability, nanoparticle retention etc. This manuscript expounds the current advances and cross-talks the developments made in the of EPR effect-based therapeutics in cancer therapy along with a transactional view of its current clinical and industrial aspects.


Feasibility of Electronic Health Record Assessment of 6 Pediatric Type 1 Diabetes Self-management Habits and Their Association With Glycemic Outcomes.
A low-burden electronic health record (EHR) workflow has been devised to systematize the collection and validation of 6 key diabetes self-management habits: (1) checks glucose at least 4 times/day or uses continuous glucose monitor (CGM); (2) gives at least 3 rapid-acting insulin boluses per day; (3) uses insulin pump; (4) delivers boluses before meals; (5) reviewed glucose data since last clinic visit, and (6) has changed insulin doses since the last clinic visit. To describe the performance of these habits and examine their association with hemoglobin A1c (HbA1c) levels and time in range (TIR). This cross-sectional study included individuals with known type 1 diabetes who were seen in a US pediatric diabetes clinic in 2019. Habit performance, total habit score (sum of 6 habits per person), HbA1c levels, and TIR. Of 1344 patients, 1212 (609 [50.2%] males; 66 [5.4%] non-Hispanic Black; 1030 [85.0%] non-Hispanic White; mean [SD] age, 15.5 [4.5] years) were included, of whom 654 (54.0%) were using CGM and had a TIR. Only 105 patients (8.7%) performed all 6 habits. Habit performance was lower among older vs younger patients (age ≥18 years vs ≤12 years: 17 of 411 [4.1%] vs 57 of 330 [17.3%]; P < .001), Black vs White patients (3 [4.5%] vs 95 [9.2%]; P < .001), those with public vs private insurance (14 of 271 [5.2%] vs 91 of 941 [9.7%]; P < .001), and those with lower vs higher parental education levels (<college degree vs ≥college degree: 35 of 443 [7.9%] vs 66 of 574 [11.5%]; P < .001). After adjustment for demographic characteristics and disease duration, for every 1-unit increase in total habit score, we found a mean (SE) 0.6% (0.05) decrease in HbA1c among all participants and a mean (SE) 2.86% (0.71) increase in TIR among those who used CGMs. Multiple regression models revealed that performing each habit was associated with a significantly lower HbA1c level (habit 1: -0.16% [95% CI, -1.91% to -1.37%]; habit 2: -1.01% [-1.34% to -0.69%]; habit 3: -0.71% [95% CI, -0.93% to -0.49%]; habit 4: -0.97% [95% CI, -1.21% to -0.73%]; habit 5: -0.44% [95% CI, -0.71% to -0.17%]; habit 6: -0.75% [95% CI, -0.96% to -0.53%]; all P < .001). There were differences in HbA1c according to race, insurance, and parental education, but these associations were attenuated with the inclusion of the 6 habits, which had more robust associations with HbA1c levels than the demographic characteristics. These findings suggest that a focus on increasing adherence to the 6 habits could be critical for improving disparities in glycemic outcomes; these metrics have been adopted by the Type 1 Diabetes Exchange Quality Improvement Collaborative for continuous quality improvement.


Radiographic and α-fetoprotein response predict pathologic complete response to immunotherapy plus a TKI in hepatocellular carcinoma: a multicenter study.
Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.


Characterization of dysplastic tissue morphology and biochemistry in Barrett's esophagus using diffuse reflectance and light scattering spectroscopy.
LSS and DRS are techniques that provide diagnostically useful information based on changes in the intensity of backscattered light that has experienced either a single or multiple scattering events. These changes can be detected effectively using statistical and model-based algorithms. In addition to providing a means to detect the presence of dysplasia noninvasively, the latter approach yields potentially significant insights into the processes that are involved in the development of dysplasia in BE. Because DRS and LSS provide complementary information to each other and to other spectroscopic modalities, such as fluorescence, it is possible that a combination of all these techniques will ultimately provide a highly accurate real-time method for detecting BE dysplasia. Extending point spectroscopic measurements to imaging of the esophagus will be challenging, but continuous progess in the development of powerful light sources, sensitive detectors, and micro-optical elements should allow this method to become a reality in the near future.


The role of entirely subcutaneous ICD™ systems in patients with dilated cardiomyopathy.
The subcutaneous implantable-cardioverter defibrillator (S-ICD™, Boston Scientific, Natick, MA, USA) is an important advance in device therapy for the prevention of sudden cardiac death (SCD). Although current guidelines recommend S-ICD™ use, long-term data are still limited, especially in subgroups. Dilated cardiomyopathy (DCM) is a common reason for the implantation of an ICD. However, there are no sufficient data on the performance of the S-ICD™ in this patient cohort. All S-ICD™ patients with DCM as the main indication for ICD implantation (n=47 patients) in our large-scaled single-center S-ICD™ registry (n=294 patients) were included in this study. Baseline characteristics, appropriate and inappropriate shocks, and complications were documented in a mean follow-up of 22.9±18.5 months. A total of 47 patients with DCM as the underlying structural heart disease received an S-ICD™ in our institution. Mean left ventricular ejection fraction was 37±12% and a 28% had a history of ventricular tachyarrhythmia. During follow-up eight ventricular tachyarrhythmias were adequately terminated in three patients. In four patients, oversensing resulting in an inappropriate shock was observed, which could be managed by changing the sensing vector. There was no need for a change to a cardiac resynchronization (CRT) system while one system was changed to a VVI-ICD due to S-ICD™ wound infection. The S-ICD™ seems to be a valuable option for the prevention of SCD in patients with DCM and no indication for CRT. As clinically relevant ventricular arrhythmias consisted of ventricular fibrillation or fast ventricular tachycardia in all patients in our cohort, no change to transvenous ICDs for anti-tachycardia pacing delivery was necessary.


The influence of fixed sagittal plane centers of rotation on motion segment mechanics and range of motion in the cervical spine.
The center of rotation (CoR) has become an increasingly used metric for biomechanical evaluation of spinal joints however traditional methods of determination remain prone to high degrees of uncertainty. The objective was to use a novel robotic testing protocol to investigate the effects of placement of fixed CoRs in the cervical spine. Human cadaveric C4-C5 (n=3) and C6-C7 (n=5) motion segment units (MSU) were rotated in flexion-extension to limits of 2.5 N m bending or 225 N resultant force about three points in a disc plane (A1, C1, P1) located at 25%, 50% and 75% along the length of the midline of the intervertebral disc respectively in the sagittal view, and three points (A2, C2, P2) in a sub-adjacent plane 5mm below the disc plane. Significant differences in range of rotation occurred between CoRs within the same plane but not between the same points in different planes (e.g. A1-A2). In flexion and extension axial forces at posterior points of rotation (P1, P2) were significantly different from those at anterior and central points. Shear forces were significantly different between points within the same plane except for the disc plane in extension, and between the same points in different planes in flexion and extension. The results indicate that the native cervical MSU is highly sensitive to the CoR location in terms of mechanics and range of motion, and that the CoR location likely varies between flexion and extension. The methodology developed has potential for application towards investigation of optimal CoR locations and in-vitro evaluations of the effects of implantable instrumentation.


Draft EEC method for the determination of the global migration of plastics constituents into fatty-food simulants: applicability to lacquers, plastics and laminates.
An experimental study was carried out to establish whether the draft EEC method for the determination of the global migration of constituents from plastics packaging materials into fatty food simulants could be applied to all plastics, including lacquers and laminates. Some difficulties were encountered in the use of the EEC method for melamine, for hotmelt-coated packaging materials and for laminates containing one or more layers of materials sensitive to moisture, such as paper, cardboard or regenerated cellulose film.


Effect of pH on the affinity of phospholipids for cholesterol.
The ability of multilamellar vesicles of phosphatidylcholine and phosphatidylethanolamine in aqueous phase to prevent access to cholesterol by a nonpolar solvent was examined. Phosphatidylethanolamine vesicles. In mixed vesicles, cholesterol was retained in proportion to the amount of phosphatidylcholine. To alter the charge and hydration of head groups, pH was adjusted from 1.2 to 12.5. Above pH 8, both phosphatidylethanolamine and phosphatidylcholine retained sterol in a 1:1 molar ratio of phospholipid to cholesterol, regardless of acyl side chain composition. Between pH 2.0 and pH 8.0, sterol retention varied with type of head group and side chain. Lipids with 16-carbon saturated side chains retained more sterol than 18-carbon unsaturated or 12-carbon saturated side chains. Between pH 1.1 and 2.0, none of the phosphatidylethanolamines retained sterol, but long chain phosphatidylcholines, saturated or unsaturated, retained sterol in a 1:1 molar ratio of phospholipid to sterol. Short chain phosphatidylethanolamines and phosphatidylcholines retained 0 to 20% at the low- to mid-pH range. Size of multilamellar vesicles, measured by Doppler effect light scattering analysis, had no bearing on sterol retention. Sonication of vesicles, which increases surface curvature, increases the retention of sterol. Fluorescence polarization indicated that cholesterol does not interact with DPPC or DLPC side chains. The observations can be interpreted in terms of space requirements of head groups, including charge repulsion and hydration. Other factors, such as monovalent cation replacement by protons, juxtaposition of charged groups on vesicle surfaces and length and unsaturation of acyl side chains affect the affinity of phospholipids for cholesterol.


Organ preservation in patients with invasive bladder cancer: initial results of an intensified protocol of transurethral surgery and radiation therapy plus concurrent cisplatin and 5-fluorouracil.
To assess safety, tolerance, and disease control of transurethral resection of the bladder tumor (TURB) plus concurrent cisplatin, 5-fluorouracil (5-FU), and radiation therapy (RT) with selective organ preservation in patients with bladder cancer. Forty-five patients with muscle-invading or high-risk T1 (G3, associated carcinoma in situ, multifocality, >5 cm) bladder cancer were entered into a protocol of TURB followed by concurrent cisplatin (20 mg/m(2)/day, 20-min infusion) and 5-FU (600 mg/m(2)/day, 120-hour continuous infusion), administered on Day 1-5 and 29-33 of RT (single dose 1.8 Gy, total dose to the bladder 54-59.4 Gy). Response was evaluated by restaging TURB 6 weeks later. In case of invasive residual or recurrent tumor, salvage cystectomy was recommended. Median follow-up was 35 months (range: 8-80 months). Thirty-nine patients (87%) had no detectable tumor at restaging TURB; 29 patients (64%) have been continuously free of tumor in their bladders. A superficial relapse occurred in 4 patients, a muscle-invasive relapse in 6 patients. Overall survival and survival with preserved bladder was 67% and 54%, respectively, at 5 years. Hematologic Grade 3/4 toxicity occurred in 10%/4%; Grade 3 diarrhea occurred in 9%. Thirty-four patients (76%) completed the protocol as scheduled or with only minor deviations. One patient required salvage cystectomy because of a shrinking bladder. This protocol of concurrent cisplatin/5-FU and RT has been associated with acceptable toxicity. The complete response rate of 87% and the 5-year survival with intact bladder of 54% are encouraging and compare favorably with our historical control series using RT with carboplatin and cisplatin alone.


Structure-toxicity relationship of monoketones: in vitro effects on beta-adrenergic receptor binding and Na(+)-K(+)-ATPase activity in mouse synaptosomes.
The structure-toxicity relationship of monoketones, a class of organic solvents widely used in industry, was investigated with respect to their in vitro effects on synaptosomal membrane proteins. The toxic parameters used were Na(+)-K(+)-adenosine triphosphatase (Na(+)-K(+)-ATPase), a well-known marker enzyme often used as a membrane toxicity model, and 3H-dihydroalprenolol (3H-DHA)-labeled beta-adrenergic receptor binding that has been shown to be vulnerable to solvent-induced changes in membrane fluidity. In vitro treatments with 12 kinds of monoketones (carbon chain length from 3-10) dose-dependently inhibited both 3H-DHA binding to mouse synaptosomes and Na(+)-K(+)-ATPase activity. The potency of inhibition (IC50) for both the two parameters was linearly related to n-octanol/water partition coefficient and synaptosome/buffer partition coefficient of the test compounds. Additions of monoketones did not significantly alter the number of 3H-DHA binding sites but markedly decreased their affinity. In each monoketone, the IC50 values for 3H-DHA binding and Na(+)-K(+)-ATPase activity were generally within the same range. The anisotropy of fluorescence probe 1,6-diphenyl-1,3,5-hexatriene-labeled synaptosomal membranes was dose-dependently decreased by the monoketones, implying increased membrane fluidity. These results indicate that increasing lipophilicity of monoketones results in increased solvent penetration of synaptic membrane preparations, leading to conformational changes in membrane structure and increased ability to inhibit both neuroreceptor binding and enzyme activity. The present data confirm the importance of the lipid micro-environment of membranes in maintaining the normal functions of membrane-bound proteins.(ABSTRACT TRUNCATED AT 250 WORDS)


Safe Limit of Shortening of the Spinal Cord in Thoracolumbar Bivertebral Column Resections: An Experimental Study in Goats.
To clarify the safe limit of shortening of the spinal cord in thoracolumbar bivertebral column resection in a goat model. Ten healthy goats were selected for the experiment. Radiographs were taken before surgery to measure the height of T13, L1, and the initial osteotomy segment (distance from the lower end plate of T12 to the upper end plate of L2). A procedure of thoracolumbar bivertebral column resection (T13 and L1) was completed under the monitoring of somatosensory evoked potential (SSEP) monitoring. The SSEP measured after vertebral resection was set as the baseline. SSEPs decreased by 50% from the baseline amplitude and/or delayed by 10% relative to the baseline peak latency were set as positive results, indicating spinal cord injury. The initial height of the osteotomy gap was measured first and the spinal column was gradually shortened until the SSEP monitoring did not show a positive result. Then the height of the osteotomy gap was recorded again. The safe limit of shortening was measured and recorded when any morphologic change of the spinal cord was observed. Hindlimb function was evaluated by the Tarlov scores on day 2 postoperatively. The safe limit of shortening of the spinal cord in thoracolumbar bivertebral columns resection was 35.2 ± 2.6 mm, which was roughly equal to 127.6% of the mean osteotomy vertebral height and 57.1% of the initial osteotomy gap height. Pearson correlation test showed that the safe limit of shortening of the spinal cord was correlated with the height of T13, the height of L1, the mean height of T13 and L1, and the height of the initial osteotomy gap. The safe limit of shortening distance of the bivertebral column resection was roughly equal to 127.6% of the mean osteotomy vertebral height and 57.1% of the initial osteotomy gap height with good correlation. Moreover, the safe limit of shortening distance of the bivertebral column resection was longer than that in single vertebral column resection. Increasing the number of vertebrae resected may prevent spinal cord injury because of excessive shortening.


Structures and metabolism of inositol tetrakisphosphates and inositol pentakisphosphate in bovine adrenal glomerulosa cells.
In adrenal glomerulosa cells, angiotensin II stimulates rapid increases in inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) and inositol 1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4), followed by slower increases in two additional inositol tetrakisphosphate (InsP4) isomers. One of these InsP4 isomers was previously identified as Ins-1,3,4,6-P4 and shown to be a precursor of inositol pentakisphosphate (InsP5). Analysis of the third InsP4 isomer, purified from cultured bovine adrenal cells labeled with [3H]inositol and stimulated by angiotensin II, revealed that the polyol produced by periodate oxidation, borohydrate reduction, and dephosphorylation was [3H]iditol. This finding is consistent with precursor structures of either Ins-1,4,5,6-P4 or Ins-3,4,5,6-P4 (= L-Ins-1,4,5,6-P4) for the third InsP4 isomer. The [3H]iditol was readily converted to [3H]sorbose by the stereospecific enzyme, L-iditol dehydrogenase, indicating that it originated from Ins-3,4,5,6-P4. Chicken erythrocytes labeled with [3H]inositol also contained high levels of Ins-1,3,4,6-P4 and Ins-3,4,5,6-P4, as well as InsP5, but only small amounts of Ins-1,3,4,5-P4. Both [3H]Ins-1,3,4,6-P4 and [3H]Ins-3,4,5,6-P4, but not [3H]Ins-1,3,4,5-P4, were phosphorylated to form InsP5 in permeabilized bovine glomerulosa cells. In addition, InsP5 itself was slowly dephosphorylated to Ins-1,4,5,6-P4, indicating that its structure is Ins-1,3,4,5,6-P5. These results demonstrate that the higher inositol phosphates are metabolically interrelated and are linked to the receptor-regulated InsP3 response by the conversion of Ins-1,3,4-P3 through Ins-1,3,4,6-P4 to Ins-1,3,4,5,6-P5. The source of Ins-3,4,5,6-P4, the other precursor of InsP5, is not yet known but its elevation in angiotensin II-stimulated glomerulosa cells suggests that its formation is also influenced by agonist-regulated processes.


The behavioural effects of intrathecally administered [D-PRO2, D-TRP7,9]-substance P, an analogue with presumed antagonist actions, in the rat.
[D-Pro2, D-Trp7,9]-substance P, an analogue of the putative nociceptive primary afferent neurotransmitter substance P, was administered to rats via chronically implanted intrathecal catheters (0.5-2.5 nmol per rat). Several animals showed large elevations of thermal and mechanical nociceptive thresholds, but these effects were always accompanied by profound, often long-lasting, impairments of motor function and thus cannot be regarded as a specific antinociceptive effect of the drug. These behavioural effects are considered to be probably due to direct spinal actions of the drug rather than antagonism of spinal substance P systems.


First Report of a Wastewater Treatment-Adapted Enterococcus faecalis ST21 Harboring vanA Gene in Brazil.
Enterococcus faecalis has emerged as an important opportunistic pathogen due to its increasing resistance to antimicrobials, mainly to vancomycin, which leads substantial cases of therapeutic failures. Wastewater treatment plants (WWTP), in turn, are considered hotpots in the spread of antimicrobial resistance according to One Health perspective. In this study, we present the first report of a vancomycin-resistant E. faecalis strain recovered from treated effluent in Brazil. For this purpose, the whole-genome sequencing (WGS) was carried out aiming to elucidate its molecular mechanisms of antimicrobial resistance and its phylogenetic relationships amongst strains from other sources and countries. According to Multilocus Sequence Typing (MLST) analysis this strain belongs to ST21. The WGS pointed the presence of vanA operon, multiple antibiotic resistance and virulence genes, and a significant pathogenic potential for humans. The phylogenomic analysis of E. faecalis 6805 was performed with ST21 representatives from the PubMLST database, including the E. faecalis IE81 strain from clinical sample in Brazil, which had its genome sequenced in this study. Our results demonstrated a strain showing resistance to vancomycin in treated effluent. To the best of our knowledge, this is an unprecedented report of vanA-carrying E. faecalis ST21. Furthermore, it is the first description of a vanA-harboring strain of this species from environmental sample in Brazil. Our data highlight the role of WWTP in the spread of AMR, since these environments are favorable for the selection of multidrug-resistant pathogens and the treated effluents, carrying antibiotic resistance genes, are directed to receiving water bodies.


Indices of leg resistance artery function are independently related to cycling V̇O2 max.
While maximum blood flow influences one's maximum rate of oxygen consumption (V̇O2 max), with so many indices of vascular function, it is still unclear if vascular function is related to V̇O2 max in healthy, young adults. The purpose of this study was to determine if several common vascular tests of conduit artery and resistance artery function provide similar information about vascular function and the relationship between vascular function and V̇O2 max. Twenty-two healthy adults completed multiple assessments of leg vascular function, including flow-mediated dilation (FMD), reactive hyperemia (RH), passive leg movement (PLM), and rapid onset vasodilation (ROV). V̇O2 max was assessed with a graded exercise test on a cycle ergometer. Indices associated with resistance artery function (e.g., peak flow during RH, PLM, and ROV) were generally related to each other (r = 0.47-77, p < .05), while indices derived from FMD were unrelated to other tests (p < .05). Absolute V̇O2 max (r = 0.57-0.73, p < .05) and mass-specific V̇O2 max (r = 0.41-0.46, p < .05) were related to indices of resistance artery function, even when controlling for factors like body mass and sex. FMD was only related to mass-specific V̇O2 max after statistically controlling for baseline artery diameter (r = 0.44, p < .05). Indices of leg resistance artery function (e.g., peak flow during RH, PLM, and ROV) relate well to each other and account for ~30% of the variance in V̇O2 max not accounted for by other factors, like body mass and sex. Vascular interventions should focus on improving indices of resistance artery function, not conduit artery function, when seeking to improve exercise capacity.


IRMPD spectroscopy and quantum-chemical simulations of the reaction products of cisplatin with the dipeptide CysGly.
The inorganic antineoplastic drug cisplatin was made to react in solution with the dipeptide cysteinylglycine (CysGly), chosen as a functional model of glutathione, and the reaction products were analyzed using electrospray ionization mass spectrometry (ESI-MS). Selected complexes, i.e., the primary substitution product cis-[PtCl(NH3)2(CysGly)]+ and the chelate cis-[PtCl(NH3)(CysGly)]+, were submitted to IR multiple photon dissociation (IRMPD) spectroscopy obtaining their vibrational features. The experimental IR ion spectra were compared with the calculated IR absorptions of different plausible isomeric families, finding CysGly to bind preferentially platinum(II) via its deprotonated thiolic group in the monovalent complex, cis-[PtCl(NH3)2(CysGly)]+, and to evolve in the S,N-bound chelate structure cis-[PtCl(NH3)(CysGly)]+ through the SH and NH2 functionality of the cysteine residue. Moreover, our findings indicate that the platination reaction does not affect the CysGly peptide bond, which remains in its trans configuration. These results provide additional insights into the reactivity of Pt(II)-complexes with glutathione which is involved in cellular cisplatin resistance.


A Form of Metabolic-Associated Fatty Liver Disease Associated with a Novel LIPA Variant.
The LIPA gene on chromosome 10q23.31 contains 10 exons and encodes lipase A, the lysosomal acid lipase (LAL) containing 399 amino acids. Pathogenic variants in the LIPA result in autosomal recessive Wolman disease and cholesteryl ester storage disease (CESD). Here, we report a novel missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA in an Iranian family with fatty liver disease identified by whole-exome sequencing and confirmed by Sanger sequencing. A 28-year-old woman referred with lean NASH cirrhosis and extremely high cholesterol levels. Fatty liver disease was found in six of her family members using vibration-controlled transient elastography (VCTE). Baseline routine laboratory tests were performed and whole-exome sequencing and confirmation by Sanger sequencing were done. The index case had severe dyslipidemia and cirrhosis despite a body mass index of 21.09 kg/m2 . Six other family members had dyslipidemia and fatty liver or cirrhosis. A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of LIPA which caused LAL-D was found to be associated with fatty liver disease and/or cirrhosis. A homozygous missense variant (NM_001127605.3:c.928T>A, p.Trp310Arg) of the LIPA gene which caused LAL-D was found to be associated with dyslipidemia, fatty liver disease and/or cirrhosis in six members of an Iranian family. These results should be confirmed by functional studies and extending the study to at least three families.


The History of Neurocritical Care as a Subspecialty.
The role of the neurointensivist as a subspecialist has been cemented in modern medicine globally. It was forged through the collaboration of neurologists, neurosurgeons, internists, anesthesiologists, general surgeons, emergency medicine physicians, and pediatricians. As with all critical care areas, it requires a multiprofessional environment. Neurocritical care harnesses knowledge, technology, resources, and research opportunities to embrace a multisystem approach to care for the neurologically critically ill. Although recently formally recognized, its crucial role to serve patients with acute, life-threatening neurologic insults has been well established.


A glutamine-based single α-helix scaffold to target globular proteins.
The binding of intrinsically disordered proteins to globular ones can require the folding of motifs into α-helices. These interactions offer opportunities for therapeutic intervention but their modulation with small molecules is challenging because they bury large surfaces. Linear peptides that display the residues that are key for binding can be targeted to globular proteins when they form stable helices, which in most cases requires their chemical modification. Here we present rules to design peptides that fold into single α-helices by instead concatenating glutamine side chain to main chain hydrogen bonds recently discovered in polyglutamine helices. The resulting peptides are uncharged, contain only natural amino acids, and their sequences can be optimized to interact with specific targets. Our results provide design rules to obtain single α-helices for a wide range of applications in protein engineering and drug design.


[Arterial elasticity, arterial hypertension and antihypertensive therapy].
Semi-automated methods for pulse wave analysis enable the early diagnosis of changes in the elasticity of large and small blood vessels. Currently two methods are in routine use: a) The augmentation index and b) the compliance of the large and the small blood vessels (C1, C2). It has been shown that both measurements are able to predict cardiovascular mortality independent of other established risk factors. It remains to be shown whether antihypertensive therapy with drugs which improve compliance, in addition to lowering blood pressure, are superior to drugs which only lower blood pressure without affecting compliance. An increase of pulse pressure represents a later stage in the development of atherosclerosis and is therefore less sensitive than the above named elasticity measurements. Changes in elasticity occur very early in the development of atherosclerosis therefore these methods should prove very useful in preventive medicine. It is to be hoped that these methods will be increasingly used for detecting incipient atherosclerosis.


A clinico-epidemiological study of herpes zoster.
Herpes zoster is a common viral infection of skin caused by reactivation of varicella zoster virus infection from the spinal ganglia. The clinico-epidemiological patterns of this disease in an Indian setting required to be studied. A cross sectional study was conducted on all consecutive cases of herpes zoster reporting to the Dermatology Outpatient Department at a Tertiary Care Hospital in Bangalore during a period of one year from 01 Jun 2013 to 31 May 2014. Detailed history, examination, HIV screening and Tzanck smear were carried out in all cases. 84 cases of herpes zoster were seen with a mean age of 30 years. Majority (39%) of cases were seen in the 21-30 year age group. Thoracic segments were involved in 65.4%, cervical in 11.9%, cranial in 11.5%, lumbar in 8.3% and sacral segments in 3.5%. 63% of cases had zoster associated pain. One case had motor involvement.3.57% of the patients were HIV positive. This study shows a lower age incidence of herpes zoster HIV positivity and zoster associated pain as compared to other studies. The pattern of segmental involvement in herpes zoster seen in this study was similar to other studies.