Miracle-dz/UniFAR-FTUs huggingface dataset:
Population Pharmacokinetic Investigation of Actinomycin‐D in Children and Young Adults

Actinomycin‐D is an antineoplastic agent that inhibits RNA synthesis by binding to guanine residues and inhibiting DNA‐dependent RNA polymerase. Although actinomycin‐D has been used to treat rhabdomyosarcoma and Wilms tumor for more than 40 years, the dose/exposure relationship is not well characterized. The objective of this study was to develop an initial population pharmacokinetic model to describe actinomycin‐D disposition in children and young adults from which a prospective study could be designed. A total of 165 actinomycin‐D plasma concentration measurements from 33 patients, aged 1.6 to 20.3 years, were used for the analysis. The data were analyzed using nonlinear mixed‐effects modeling with the NONMEM software system. Age, weight, and gender were examined as covariates for the ability to explain interindividual variability in actinomycin‐D pharmacokinetics. The final model was qualified via predictive check and nonparametric bootstrap procedures. A 3‐compartment model with first‐order elimination was chosen as the structural model. Allometric expressions incorporating weight were used to describe the effects of body size on actinomycin‐D pharmacokinetics. Age and gender had no discernible effects on actinomycin‐D pharmacokinetics in the population studied. The predictive check showed that the developed model was able to simulate data in close agreement with the actual study observations. The availability of an initial population pharmacokinetic model to describe actinomycin‐D pharmacokinetics will facilitate the development of a large‐scale clinical trial to study the actinomycin‐D dose/exposure relationship in pediatric patients with rhabdomyosarcoma and Wilms tumor. The covariate analysis described by the current data set suggests that indices of body size captured via allometric expressions improve the partition of variation in actinomycin‐D pharmacokinetics from this pilot data set. Relationships between pharmacokinetics and toxicity will be examined in future prospective studies in which children less than 1 year old will be enrolled.
Insulin Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase B (Akt) Pathway Reduces Lipopolysaccharide-Induced Inflammation in Mice

Insulin is used to control pro-inflammatory hyperglycemia in critically ill patients. However, recent studies suggest that insulin-induced hypoglycemia may negate its beneficial effects in these patients. It is noteworthy that recent evidence indicates that insulin has anti-inflammatory effects that are independent of controlling hyperglycemia. To date, the mechanism by which insulin directly reduces inflammation has not been elucidated. It is well established that insulin activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling in many cell types. We and others have shown that this pathway negatively regulates LPS-induced signaling and pro-inflammatory cytokine production in monocytic cells. We hypothesized that insulin inhibits inflammation during endotoxemia by activation of the PI3K/Akt pathway. We used a nonhyperglycemic mouse model of endotoxemia to determine the effect of continuous administration of a low dose of human insulin on inflammation and survival. It is noteworthy that insulin treatment induced phosphorylation of Akt in muscle and adipose tissues but did not exacerbate lipopolysaccharide (LPS)-induced hypoglycemia. Insulin decreased plasma levels of interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein 1 (MCP1)/JE, and keratinocyte chemoattractant, and decreased mortality. The PI3K inhibitor wortmannin abolished the insulin-mediated activation of Akt and the reduction of chemokine and interleukin-6 levels. We conclude that insulin reduces LPS-induced inflammation in mice in a PI3K/Akt-dependent manner without affecting blood glucose levels.
Immunohistochemical diagnosis of Toxoplasma gondii: potential for cross-reactivity with Neospora caninum.

A monoclonal antibody (MAB 3F5) was compared with a commercial polyclonal antibody for specificity for Toxoplasma gondii and cross-reactivity with Neospora caninum in paraffin-embedded tissue sections. Both antibody preparations reliably recognized T. gondii tachyzoites (RH isolate) in animal tissues but did not always label tissue cysts (ME-49 isolate). The commercial antibody strongly cross-reacted with N. caninum tachyzoites, but MAB 3F5 did not when the immunoperoxidase, immunofluorescence, or immunogold procedures were employed, nor did it cross-react with other apicomplexans, e.g., Isospora suis, Eimeria bovis. Sarcocystis cruzi, Hammondia hammondi, or Caryospora bigenetica. Immumoelectron microscopy revealed that MAB 3F5 bound to dense granules in extracellular T. gondii tachyzoites. In western blots of T. gondii tachyzoites, a major band at 38 kDa and a minor band at 32 kDa were labeled by MAB 3F5, but no labeling of the proteins of N. caninum tachyzoites or uninfected host cells occurred at the ultrastructural level or in immunoblots.
A Simple Technique for Surgical Placement of Occipital Nerve Stimulators without Anchoring the Lead

Abstract Introduction Greater occipital nerve stimulation is applied in the treatment of occipital neuralgia, headache, and fibromyalgia. Multiple techniques have been described along with their subsequent complications. The most frequent complications are related to lead migration, infection, and undesired stimulation effects. Revision surgery occurs in up to 60% of the cases. Patients and Methods A total of 92 implantations, 51 trials (6–10 weeks), and 41 permanent implantations (follow-up: 36–72 months) were performed in a single center using a simple technique without an anchoring device. The electrode is tunneled at a 45-degree angle to prevent migration. Complications and additional surgeries were recorded during the follow-up period. Results All patients had bilateral greater occipital nerve stimulation. A total of 16 complications (17.4%) occurred. Seven patients (7.6%) underwent additional surgery. The major complication was infection; lead migration made up only 3.3% of the complications. Conclusions We present a simple technique without the use of an anchoring device that is feasible in achieving bilateral occipital nerve stimulation and decreases the complications, especially lead migration.
In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper

Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time‐consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well‐controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well‐characterized patients with DHR and to develop new tests for diagnosis.
Professional Dialogue as Professional Learning

Abstract: This article discusses professional dialogue as an important aspect of professionalism for early childhood teachers. It draws on the experiences of four qualified early childhood teachers of one teaching team in an early childhood centre who engaged in extensive professional dialogue with each other. Dialogue focused on the values that underpinned and were reflected in their teaching practice. These values were discussed in order to explore the commonalities and differences in teaching philosophies amongst the team. The article outlines both the benefits and the challenges of engaging in professional dialogue by drawing on the perceptions of the teachers who participated. The article contends that professional dialogue should be viewed as an alternative form of professional learning.
Estoques de biomassa e carbono em povoamentos de acácia negra em diferentes idades no Rio Grande do Sul.

O presente trabalho teve como objetivo avaliar os teores e os estoques de biomassa e de carbono na cultura de Acacia mearnsii De Wild com idades variando de 1 a 7 anos, em dois locais de cultivo. Os estoques de biomassa e carbono foram avaliados em diferentes compartimentos da arvore. Foi identificado que os teores de carbono diferem entre os compartimentos da biomassa, sendo maiores na folhagem e menores na madeira. O teor medio de carbono variou de 45,01% a 46,50% ao longo das idades dos povoamentos. A variacao do estoque total de biomassa foi de 3,39 t ha-1, 52,81 t ha-1, 99,71 t ha-1 e 135,63 t ha-1, respectivamente, no primeiro, terceiro, quinto e setimo ano apos o plantio. O estoque total de carbono variou foi de 1,53 t ha-1, 23,77 t ha-1, 45,08 t ha-1 e 60,14 t ha-1, primeiro, terceiro, quinto e setimo ano apos o plantio, respectivamente. A proporcao de biomassa entre os compartimentos variou ao longo dos anos - enquanto que folhas, flores e frutos diminuiram a proporcao com o avanco da idade dos povoamentos, madeira e casca tenderam a aumentar. Na idade de rotacao (aos sete anos) a madeira e a casca representam aproximadamente 80% da biomassa. Os incrementos medios anuais totais de biomassa e carbono, na idade de rotacao (7 anos), foram de 19,37 e 8,59 t ha-1, respectivamente.
The failure of Anti-Corruption Policies A Theoretical Mischaracterization of the Problem

With an increased awareness of the detrimental effects of corruption on development, strategies to fight it are now a top priority in policy circles around the world. Since Africa is home to most of the thoroughly corrupt countries in the world, it is no coincidence that the African continent has been the major target of this movement. To date, however, few successes have resulted from the investment. In fact, in some countries corruption even seems to have become more entrenched in step with the efforts to curb it. The aim of this paper is to advance an explanation to why this is the case. Drawing upon the cases of Kenya and Uganda – two arguably typical African countries when it comes to the problem of corruption and anti-corruption reforms – we argue that contemporary anti-corruption reforms in Africa have largely failed because they are based on a mischaracterization of the problem of corruption in contexts with systematic corruption. More specifically, our analysis reveals that while contemporary anti-corruption reforms are based on a conceptualization of corruption as a principal-agent problem, in the African context corruption rather seems to resemble a collective action problem, making the short-term costs of fighting corruption outweigh the benefits. Consequently, even if most individuals morally disapprove of corruption and are fully aware of the negative consequences for the society at large, very few actors show a sustained willingness to fight it. This, in turn, leads to a breakdown of any anti-corruption reform that builds on the principal-agent framework.
Trajectories of stress reactions and somatization symptoms among war veterans: a 20-year longitudinal study

Background There is considerable evidence that immediate and long-term stress reactions are associated with increased somatic symptomatology. However, because of the scarcity of long-term longitudinal studies, the trend of mutual change of these factors has not been assessed. This study examined the chronological inter-relationships between post-traumatic stress reactions and somatization symptoms among combatants over a 20-year period. Method Two groups of veterans were assessed 1, 2, 3 and 20 years after their participation in the 1982 Lebanon War: a clinical group of veterans who had been diagnosed with combat stress reaction (CSR) on the battlefield (n=363), and a matched control group of veterans (n=301). Results The CSR veterans reported higher initial levels of intrusion and avoidance and a steeper decline in those symptoms over time in comparison to the control group. The former also reported higher initial levels of somatization symptoms than the latter. In addition, over the years, stress reactions were positively associated with somatization symptoms. For both study groups, in the first years after the war, stress reaction symptoms predicted somatization symptoms. However, with time, the trend was reversed and somatization symptoms predicted stress reactions. Conclusions The findings suggest that CSR is a marker for future stress reactions and somatization symptoms, and indicate a long-term role for these symptoms in veterans' psychological distress.
Deletion of the GluA1 AMPA receptor subunit impairs recency-dependent object recognition memory

Deletion of the GluA1 AMPA receptor subunit impairs short-term spatial recognition memory. It has been suggested that short-term recognition depends upon memory caused by the recent presentation of a stimulus that is independent of contextual–retrieval processes. The aim of the present set of experiments was to test whether the role of GluA1 extends to nonspatial recognition memory. Wild-type and GluA1 knockout mice were tested on the standard object recognition task and a context-independent recognition task that required recency-dependent memory. In a first set of experiments it was found that GluA1 deletion failed to impair performance on either of the object recognition or recency-dependent tasks. However, GluA1 knockout mice displayed increased levels of exploration of the objects in both the sample and test phases compared to controls. In contrast, when the time that GluA1 knockout mice spent exploring the objects was yoked to control mice during the sample phase, it was found that GluA1 deletion now impaired performance on both the object recognition and the recency-dependent tasks. GluA1 deletion failed to impair performance on a context-dependent recognition task regardless of whether object exposure in knockout mice was yoked to controls or not. These results demonstrate that GluA1 is necessary for nonspatial as well as spatial recognition memory and plays an important role in recency-dependent memory processes.
Characterization of ompA Genotypes by Sequence Analysis of DNA from All Detected Cases of Chlamydia trachomatis Infections during 1 Year of Contact Tracing in a Swedish County

ABSTRACT In this study we aimed to characterize the ompA gene by sequencing DNA from all detected cases of Chlamydia trachomatis infection in a Swedish county during 2001, in order to improve the efficiency of contact tracing. Approximately 990 bp of the ompA gene was amplified, and sequence analysis was achieved in 678 (94%) of 725 C. trachomatis-positive cases in this unselected population. The most prevalent genotype was serotype E (39%), followed by F (21%), G (11%), D (9%), K (9%), J (7%), H (2%), B (1%), and Ia (1%). Serotype E was found in five genotype variants, with the reference sequence comprising 96% of all E cases. Serotype D was the most variable, and of seven sequence variants, three were identified as recombinants with serotype E. Altogether 29 genetic variants were detected, and mutations and recombination events are discussed. Clinical manifestations were not associated with genotypes. Sequence variation was linked to sexual networks identified by contact tracing and improved epidemiological knowledge but was of limited benefit.
Stress Ultrasound Evaluation of Medial Elbow Instability in a Cadaveric Model

Background: An injury of the ulnar collateral ligament (UCL) is potentially career threatening for elite overhead-throwing athletes. Stress ultrasonography (SUS) allows for a rapid, cost-effective, and noninvasive evaluation of the UCL and elbow joint both at rest and with applied stress. Purpose/Hypothesis: To determine the amount of cadaveric elbow valgus gapping with sequential sectioning of medial elbow structures as measured by SUS. It was hypothesized that the greatest increase in ulnohumeral joint gapping would be noted with release of the anterior bundle of the UCL. Study Design: Descriptive laboratory study. Methods: Twelve cadaveric elbows were divided into 2 groups and dissected in reverse sequences under the direct supervision of an experienced orthopaedic surgeon. Baseline ultrasound and SUS with applied valgus loads were performed by an experienced radiologist. A valgus load was applied at each sectioning interval using a standardized device. Ulnohumeral joint gapping in millimeters was measured by SUS for each step as the width of the medial joint from the trochlea to the sublime tubercle. The mean increases in joint gapping (Δ) between each step were calculated to quantify the additional gapping achieved with release of each sequential stabilizer. Results: Release of the anterior band of the anterior bundle resulted in a mean Δ of 2.0 mm (95% CI, 1.1-2.8 mm). Release of the posterior band of the anterior bundle resulted in a mean Δ of 1.4 mm (95% CI, 0.6-2.2 mm). Release of the entire anterior bundle caused a mean increase in ulnohumeral valgus joint gapping of 3.4 mm (95% CI, 2.4-4.3 mm). Release of the remaining individual structures each resulted in a mean increase in valgus joint gapping of ≤0.8 mm. Conclusion: The results of the current cadaveric study suggest that different amounts of gapping are seen on SUS with sectioning of the medial elbow stabilizers. The hypothesis was confirmed with release of the anterior bundle of the UCL resulting in the greatest increase in joint gapping as measured by SUS. Clinical Relevance: This study illustrates that SUS can identify the contributions of each anatomic portion of the UCL and the flexor-pronator mass to ulnohumeral joint stability in a cadaveric model.
Role of the lower esophageal sphincter on esophageal acid exposure - a review of over 2000 patients.

BACKGROUND AND AIM Three lower esophageal sphincter (LES) characteristics associated with gastro-esophageal reflux disease (GERD) are, LES pressure = 6 mmHg, abdominal length (AL) <1 cm and overall length (OL) <2 cm. The objective of this study was to validate this relationship and evaluate the extent of impact various LES characteristics have on the degree of distal esophageal acid exposure. METHODS A retrospective review of a prospectively maintained database identified patients who underwent esophageal manometry and pH studies at Creighton University Medical Center between 1984 and 2008. Patients with esophageal body dysmotility, prior foregut surgery, missing data, no documented symptoms or no pH study, were excluded. Study subjects were categorized as follows: (1) normal LES (N-LES): patients with LES pressure of 6-26 mmHg, AL = 1.0 cm and OL = 2 cm; (2) incompetent LES (Inc-LES): patients with LES pressure <6.0 mmHg orAL <1 cm or OL <2 cm; and (3) hypertensive LES (HTN-LES): patients with LES pressure >26.0 mmHg with AL = 1 cm and OL = 2 cm. The DeMeester score was used to compare differences in acid exposure between different groups. RESULTS Two thousand and twenty patients satisfied study criteria. Distal esophageal acid exposure as reflected by the DeMeester score in patients with Inc-LES (median=20.05) was significantly higher than in patients with an N-LES (median=9.5), which in turn was significantly higher than in patients with an HTN-LES. Increasing LES pressure and AL provided protection against acid exposure in a graded fashion. Increasing number of inadequate LES characteristics were associated with an increase both in the percentage of patients with abnormal DeMeester score and the degree of acid exposure. CONCLUSION LES pressure (=6 mmHg) and AL (<1 cm) are associated with increased lower esophageal acid exposure, and need to be addressed for definitive management of GERD.
An armamentarium of wart treatments.

Patients and clinicians experience the frustration of cutaneous viral warts caused by infection with the human papilloma virus (HPV). Warts appear in various forms on different sites of the body and include common warts (verruca vulgaris), plane or flat warts, myrmecia, plantar warts, coalesced mosaic warts, filiform warts, periungual warts, anogenital warts (venereal or condyloma acuminata), oral warts and respiratory papillomas. Cervical infection with HPV is now known to cause cervical cancer if untreated. A review of the medical literature reveals a huge armamentarium of wart monotherapies and combination therapies. Official evidence-based guidelines exist for the treatment of warts, but very few of the reported treatments have been tested by rigorous blinded, randomized controlled trials.Therefore, official recommendations do not often include treatments with reportedly high success rates, but they should not be ignored when considering treatment options. It is the purpose of this review to provide a comprehensive overview of the wart treatment literature to expand awareness of the options available to practitioners faced with patients presenting with problematic warts.
Antioxidants J811 and 17β‐estradiol protect cerebellar granule cells from methylmercury‐induced apoptotic cell death

Cerebellar granule cells (CGC) have provided a reliable model for studying the toxicity of methylmercury (MeHg), a well‐known neurotoxicant contaminating the environment. In the present study we report that doses of MeHg ranging from 0.1 μM to 1.5 μM activated apoptosis, as shown by cell shrinkage, nuclear condensation, and formation of high‐molecular‐weight DNA fragments. Nevertheless, caspase‐3‐like activity was not significantly induced, and the broad caspase inhibitor Z‐VAD‐FMK was not capable of protecting the cells. This argues for a minor role of caspases in the intracellular pathways leading to MeHg‐induced cell death in CGC. Instead, proteolytic fragments obtained by specific calpain cleavage of procaspase‐3 and α‐fodrin were increased consistently in samples exposed to MeHg, pointing to a substantial activation of calpain. Notably, two antioxidants, 17β‐estradiol (10 μM) and the Δ8,9‐dehydro derivative of 17α‐estradiol J811 (10 μM), protected from MeHg damage, preventing morphological alterations, chromatin fragmentation, and activation of calpain. These findings underscore the key role of oxidative stress in MeHg toxicity, placing it upstream of calpain activation. The shielding effect of the 17β‐estradiol and the radical scavenger J811 is potentially relevant for the development of therapeutic strategies for MeHg intoxication. J. Neurosci. Res. 62:557–565, 2000. © 2000 Wiley‐Liss, Inc.
Multiple sclerosis – more than one disease?

ABSTRACT – We have previously found an increase in prevalence and incidence of multiple sclerosis (MS) in the county of Hordaland, Western Norway. This study shows that the increase in incidence over a 30‐year period is due to an increase of remittent and remittent/progressive MS. The incidence of the chronic progressive form of MS has remained stable during the same period. The two subgroups of MS also vary in symptomatology and age at onset. This suggests that MS has two different forms which behave differently when considered epidemiologically and clinically. The remitting and progressive forms may therefore each have a different etiology.