An update on Uniform Resource Locator (URL) decay in MEDLINE abstracts and measures for its mitigation.
For years, Uniform Resource Locator (URL) decay or "link rot" has been a growing concern in the field of biomedical sciences. This paper addresses this issue by examining the status of the URLs published in MEDLINE abstracts, establishing current availability and estimating URL decay in these records from 1994 to 2006. We also reviewed the information provided by the URL to determine if the context that the author cited in writing the paper is the same information presently available in the URL. Lastly, with all the documented recommended methods to preserve URL links, we determined which among them have gained acceptance among authors and publishers. MEDLINE records from 1994 to 2006 from the National Library of Medicine in Extensible Mark-up Language (XML) format were processed yielding 10,208 URL addresses. These were accessed once daily at random times for 30 days. Titles and abstracts were also searched for the presence of archival tools such as WebCite, Persistent URL (PURL) and Digital Object Identifier (DOI). Results showed that the average URL length ranged from 13 to 425 characters with a mean length of 35 characters [Standard Deviation (SD) = 13.51; 95% confidence interval (CI) 13.25 to 13.77]. The most common top-level domains were ".org" and ".edu", each with 34%. About 81% of the URL pool was available 90% to 100% of the time, but only 78% of these contained the actual information mentioned in the MEDLINE record. "Dead" URLs constituted 16% of the total. Finally, a survey of archival tool usage showed that since its introduction in 1998, only 519 of all abstracts reviewed had incorporated DOI addresses in their MEDLINE abstracts. URL persistence parallels previous studies which showed approximately 81% general availability during the 1-month study period. As peer-reviewed literature remains to be the main source of information in biomedicine, we need to ensure the accuracy and preservation of these links.


[Cerebral palsy: prenatal risk factors].
Prenatal risk factors causing cerebral palsy (CP), here defined as a non-progressive motor abnormality of tone or posture, are much more numerous than once believed, when a great deal of brain injury was attributed to factors surrounding delivery. Scientific advances in genetics and biochemistry, as well as clinical technical advances in, for example, amniotic fluid examination or fetal neuroimaging, has permitted us to find a multiplicity of new etiologies causing neonatal encephalopathy, most of which were formerly attributed to perinatal hypoxia-ischemia. This article reviews an expanded list of etiologies, including asphyxia, which has been found to cause only 6-10% of CP in full term infants, and periventricular leukomalacia, which is associated with 30-50% of CP in premature births. We also review a few of the genetic causes of CP, which lead to metabolic encephalopathies in come cases, to congenital anomalies in others, and sometimes to both. We discuss maternal gestational or intrapartum infections which may affect the fetus by direct in utero contagion or by other less direct means. Inborn metabolic errors affecting the fetus, such as diabetes, are touched on, as are the effects of maternal medications or recreational drugs on the fetus. Finally, we briefly cite the curious phenomenon occurring in multiple births, namely the potential of CP in the surviving infant or infants were the others have died in utero.


X-ray self-emission imaging with spherically bent Bragg crystals on the Z-machine.
An x-ray imaging scheme using spherically bent crystals was implemented on the Z-machine to image x rays emitted by the hot, dense plasma generated by a Magnetized Liner Inertial Fusion (MagLIF) target. This diagnostic relies on a spherically bent crystal to capture x-ray emission over a narrow spectral range (<15 eV), which is established by a limiting aperture placed on the Rowland circle. The spherical crystal optic provides the necessary high-throughput and large field-of-view required to produce a bright image over the entire, one-cm length of the emitting column of a plasma. The average spatial resolution was measured and determined to be 18 µm for the highest resolution configuration. With this resolution, the radial size of the stagnation column can be accurately determined and radial structures, such as bifurcations in the column, are clearly resolved. The success of the spherical-crystal imager has motivated the implementation of a new, two-crystal configuration for identifying sources of spectral line emission using a differential imaging technique.


Effects of ethanol and cocaethylene on cocaine pharmacokinetics in conscious dogs.
Coingestion of cocaine and ethanol is common among cocaine users, and this combination is reported to enhance the euphoric effects of cocaine. The cardiovascular effects of cocaine are increased in the presence of ethanol, although the mechanism(s) involved in this interaction are poorly understood. Recent studies suggest the enhanced cardiac effects may be caused by ethanol-mediated inhibition of cocaine metabolism leading to higher cocaine plasma concentrations. However, these studies were all performed in animals or humans that form cocaethylene when ethanol and cocaine are coadministered. Thus, it is also possible that cocaethylene could inhibit cocaine's metabolism. Preliminary studies in our laboratory indicate the dog does not form detectable quantities of cocaethylene after coadministration of cocaine and intravenous ethanol. Thus, the dog may be a useful model for isolating the individual contributions of ethanol and cocaethylene to this interaction. The purpose of the present study was to confirm this observation, and to determine the effects of ethanol and cocaethylene on cocaine pharmacokinetics in the conscious dog. Six dogs received cocaine (3 mg/kg i.v.) alone, ethanol (1 g/kg i.v.) followed by cocaine (3 mg/kg i.v.), and cocaine (3 mg/kg i.v.) + cocaethylene (3 mg/kg i.v.). Cocaethylene was not detected in any of the plasma samples from the six dogs after administration of cocaine and ethanol. Ethanol and cocaethylene reduced mean cocaine clearance by 47% and 26%, respectively. Inhibition of cocaine's metabolism by both ethanol and cocaethylene may play an important role in mediating the enhanced effects of cocaine in the presence of ethanol.


A personalized approach to acute myeloid leukemia therapy: current options.
Therapeutic options for acute myeloid leukemia (AML) have remained unchanged for nearly the past 5 decades, with cytarabine and anthracyclines and use of hypomethylating agents for less intensive therapy. Implementation of large-scale genomic studies in the past decade has unraveled the genetic landscape and molecular etiology of AML. The approval of several novel drugs for targeted therapy, including midostaurin, enasidenib, ivosidenib, gemtuzumab-ozogamicin, and CPX351 by the US Food and Drug Administration has widened the treatment options for clinicians treating AML. This review focuses on some of these novel therapies and other promising agents under development, along with key clinical trial findings in AML.


1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine: an anticancer agent targeting hypoxic cells.
To target malignant cells residing in hypoxic regions of solid tumors, we have designed and synthesized prodrugs generating the cytotoxic alkylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) after bioreductive activation. We postulate that one of these agents, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119), requires enzymatic nitro reduction to produce 90CE, whereas another agent, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-nitrobenzyloxy)carbonyl]hydrazine (PNBC), can also be activated by nucleophilic attack by thiols such as glutathione (GSH)/GST. We demonstrated that these agents selectively kill hypoxic EMT6 mouse mammary carcinoma and CHO cells. In hypoxia, 50 microM KS119 produced 5 logs of kill of EMT6 cells without discernable cytotoxicity in air; similar effects were observed with CHO cells. PNBC was less efficacious against hypoxic tumor cells and also had some toxicity to aerobic cells, presumably because of GST/thiol activation, making PNBC less interesting as a selective hypoxic-cell cytotoxin. BALB/c mice with established EMT6 solid tumors were used to demonstrate that KS119 could reach and kill hypoxic cells in solid tumors. To gain information on bioreductive enzymes involved in the activation of KS119, cytotoxicity was measured in CHO cell lines overexpressing NADH:cytochrome b5 reductase (NBR), NADPH:cytochrome P450 reductase (NPR), or NADPH: quinone oxidoreductase 1 (NQO1). Increased cytotoxicity occurred in cells overexpressing NBR and NPR, whereas overexpressed NQO1 had no effect. These findings were supported by enzymatic studies using purified NPR and xanthine oxidase to activate KS119. KS119 has significant potential as a hypoxia-selective tumor-cell cytotoxin and is unlikely to cause major toxicity to well oxygenated normal tissues.


Why is an energy metabolic defect the common outcome in BMFS?
Inherited bone marrow failure syndromes (BMFS) are rare, distressing, inherited blood disorders of children. Although the genetic origin of these pathologies involves genes with different functions, all are associated with progressive haematopoietic impairment and an excessive risk of malignancies. Defects in energy metabolism induce oxidative stress, impaired energy production and an unbalanced ratio between ATP and AMP. This assumes an important role in self-renewal and differentiation in haematopoietic stem cells (HSC) and can play an important role in bone marrow failure. Defects in energetic/respiratory metabolism, in particular in FA and SDS cells, have been described recently and seem to be a pertinent argument in the discussion of the haematopoietic defect in BMFS, as an alternative to the hypotheses already established on this subject, which may shed new light on the evolution of these diseases.


Identifying Isolated Systolic Hypertension From Upper-Arm Cuff Blood Pressure Compared With Invasive Measurements.
Isolated systolic hypertension (ISH) is the most common form of hypertension and is highly prevalent in older people. We recently showed differences between upper-arm cuff and invasive blood pressure (BP) become greater with increasing age, which could influence correct identification of ISH. This study sought to determine the difference between identification of ISH by cuff BP compared with invasive BP. Cuff BP and invasive aortic BP were measured in 1695 subjects (median 64 years, interquartile range [55-72], 68% male) from the INSPECT (Invasive Blood Pressure Consortium) database. Data were recorded during coronary angiography among 29 studies, using 21 different cuff BP devices. ISH was defined as ≥130/<80 mm Hg using cuff BP compared with invasive aortic BP as the reference. The prevalence of ISH was 24% (n=407) according to cuff BP but 38% (n=642) according to invasive aortic BP. There was fair agreement (Cohen κ, 0.36) and 72% concordance between cuff and invasive aortic BP for identifying ISH. Among the 28% of subjects (n=471) with misclassification of ISH status by cuff BP, 20% (n=96) of the difference was due to lower cuff systolic BP compared with invasive aortic systolic BP (mean, -16.4 mm Hg [95% CI, -18.7 to -14.1]), whereas 49% (n=231) was from higher cuff diastolic BP compared with invasive aortic diastolic BP (+14.2 mm Hg [95% CI, 11.5-16.9]). In conclusion, compared with invasive BP, cuff BP fails to identify ISH in a sizeable portion of older people and demonstrates the need to improve cuff BP measurements.


Acute aortic thrombosis. A case report.
We report a case of a patient with acute aortic thrombosis. A discussion of the reported literature, presentation, surgical management, and natural history follows. This is an interesting addition to a rare vascular condition.


Recording Neural Activity Based on Surface Plasmon Resonance by Optical Fibers-A Computational Analysis.
An all optical, non-destructive method for monitoring neural activity has been proposed and its performance in detection has been analyzed computationally. The proposed method is based on excitation of Surface Plasmon Resonance (SPR) through the structure of optical fibers. The sensor structure consists of a multimode optical fiber where, the cladding of fiber has been removed and thin film of gold structure has been deposited on the surface. Impinging the laser light with appropriate wavelength inside the fiber and based on the total internal reflection, the evanescent wave will excite surface plasmons in the gold thin film. The absorption of light by surface plasmons in the gold structure is severely dependent on the dielectric properties at its vicinity. The electrical activity of neural cells (action potential) can modulate the dielectric properties at its vicinity and hence can modify the absorption of light inside the optical fiber. We have computationally analyzed the performance of the proposed sensor with different available geometries using Finite Element Method (FEM). In this regard, we have shown that the optical response of proposed sensor will track the action potential of the neuron at its vicinity. Based on different geometrical structure, the sensor has absorption in different regions of visible spectrum.


Applicability of BSID-II in diagnosing developmental delay at Kaohsiung area.
The purpose of this study was to investigate the applicability of BSID-II in diagnosing children with developmental delay in Kaohsuing area. Five hundred and forty-four children, all who were patients of Developmental Delay Clinic of Kaohsuing Medical University, participated in this study. The instrument of this study was the Bayley Scales of Infant Development--second edition (BSID-II), the primary value of which was in diagnosing developmental delay and planning intervention strategies. The standardization and statistical properties of BSID-II made it one of the best measures of infant development available. The findings as follows: (1) the alpha coefficients were between .95 and .99, which were higher than data on manual of BSID-II; (2) the reproducibilities, which were different with each examiner, were between .9503 and .9633, that were good enough to be a developmental scale; (3) Standard Errors of Measurement were between 2.8589 and 3.8206. It was a restricted sample so that these also were lower than the data on manual of BSID-II. This evidence shows BSID-II is a highly reliable instrument of developmental assessment at Kaohsuing area. A special norm for developmentally delayed children and quality control of examiners are suggested.


Case management of malaria: treatment and chemoprophylaxis.
Malaria case management is a vital component of programmatic strategies for malaria control and elimination. Malaria case management encompasses prompt and effective treatment to minimise morbidity and mortality, reduce transmission and prevent the emergence and spread of antimalarial drug resistance. Malaria is an acute illness that may progress rapidly to severe disease and death, especially in non-immune populations, if not diagnosed early and promptly treated with effective drugs. In this article, the focus is on malaria case management, addressing treatment, monitoring for parasite drug resistance, and the impact of drug resistance on treatment policies; it concludes with chemoprophylaxis and treatment strategies for malaria elimination in South Africa.


A systematic review of the computerized tools and digital techniques applied to fabricate nasal, auricular, orbital and ocular prostheses for facial defect rehabilitation.
A systematic review was conducted in early 2019 to evaluate the articles published that dealt with digital workflow, CAD, rapid prototyping and digital image processing in the rehabilitation by maxillofacial prosthetics. The objective of the review was to primarily identify the recorded cases of orofacial rehabilitation made by maxillofacial prosthetics using computer assisted 3D printing. Secondary objectives were to analyze the methods of data acquisition recorded with challenges and limitations documented with various software in the workflow. Articles were searched from Scopus, PubMed and Google Scholar based on the predetermined eligibility criteria. Thirty-nine selected papers from 1992 to 2019 were then read and categorized according to type of prosthesis described in the papers. For nasal prostheses, Common Methods of data acquisition mentioned were computed tomography, photogrammetry and laser scanners. After image processing, computer aided design (CAD) was used to design and merge the prosthesis to the peripheral healthy tissue. Designing and printing the mold was more preferred. Moisture and muscle movement affected the overall fit especially for prostheses directly designed and printed. For auricular prostheses, laser scanning was most preferred. For unilateral defects, CAD was used to mirror the healthy tissue over to the defect side. Authors emphasized on the need of digital library for prostheses selection, especially for bilateral defects. Printing the mold and conventionally creating the prosthesis was most preferred due to issues of proper fit and color matching. Orbital prostheses follow a similar workflow as auricular prosthesis. 3D photogrammetry and laser scans were more preferred and directly printing the prosthesis was favored in various instance. However, ocular prostheses fabrication was recorded to be a challenge due to difficulties in appropriate volume reconstruction and inability to mirror healthy globe. Only successful cases of digitally designed and printed iris were noted.


Catumaxomab: clinical development and future directions.
Catumaxomab, a monoclonal bispecific trifunctional antibody, was approved in the European Union in April 2009 for the intraperitoneal treatment of patients with malignant ascites. The marketing authorization holder Fresenius Biotech GmbH developed catumaxomab (Removab(®)) together with its partner TRION Pharma GmbH, Germany. It is the first substance worldwide with a regulatory label for the treatment of malignant ascites due to epithelial carcinomas. Since the peritoneum is of mesothelial origin and therefore lacks EpCAM expression, the intraperitoneal administration of catumaxomab is an attractive targeted immunotherapeutic approach. Catumaxomab is able to destroy EpCAM positive tumor cells in the peritoneal cavity known as the main cause of malignant ascites. In addition, catumaxomab is a potential therapeutic option for several primary tumors since the EpCAM molecule is expressed on the majority of epithelial carcinomas. This review focuses on the clinical development of catumaxomab and indicates future directions.


Genetic polymorphisms and non-small-cell lung cancer: future paradigms.
This article addresses some current issues about genetic polymorphisms studied in the non-small-cell lung cancer translational field. Furthermore, it discusses about new potential biomarkers regarding lung cancer risk and prognosis.


Influence of reflux and central obesity on intercellular space diameter of esophageal squamous epithelium.
While central obesity increases gastroesophageal reflux (GER) by mechanically disrupting the anti-reflux barrier, limited data exist on pathways by which central obesity may potentiate esophageal injury by non-mechanical means. Obesity has been associated with an impaired epithelial intestinal barrier. We aimed to assess the influence of central obesity and reflux on the squamous esophageal epithelial intercellular space diameter (ICSD). The ICSD was measured using electron microscopy in esophageal biopsies from individuals who underwent ambulatory pH monitoring and endoscopy. Anthropometric measurements were obtained on all participants. Participants were classified into four groups: with and without central obesity and reflux. Sixteen individuals were studied with four in each study group. The mean ICSD was almost three-fold greater (p < 0.001) in the group with central obesity without reflux, compared to controls without central obesity and reflux. It was also comparable to the ICSD in groups with acid reflux only and those with both reflux and central obesity. There is evidence of esophageal squamous ICSD increase in individuals with central obesity who do not have evidence of acid and nonacid reflux on ambulatory pH monitoring. This may reflect a mechanism by which central obesity potentiates reflux-induced esophageal injury and inflammation.


Doctor Chekhov's doctors.
Anton Chekhov (1860-1904) was both a writer and a doctor, as well as a patient. In spite of his literary success, he did not turn away from medicine until 1897, at the age of 37, when his tuberculosis became too serious. During his medical studies in Moscow, he wrote short stories, at night, under various pseudonyms to provide money for his family; all his life, Chekhov was his parents' financial support. It was Alexei Suvorin (1834-1912), the powerful director of Novoye Vremya (New Times), and the well-known writer Dimitry Grigorovich (1822-1899) who persuaded him that he had exceptional literary talent and requested him to abandon pseudonyms and sign his articles. So, for all his life, he practiced medicine as a district doctor and wrote plays and short stories. In each of his plays, except The Cherry Orchard, Chekhov introduced characters of doctors, principally Yevgeny Konstantinovich Lvov in Ivanov and Mikhail Lvovich Astrov in Uncle Vanya, as well as Khrushchev in The Wood Demon, Dorn in The Seagull, Tcheboutykin in The Three Sisters, and Triletski in Platonov. In his countless short stories, there are numerous doctors, for instance Professor Stepanovich (A Dreary Story), Doctors Kirilov (Enemies), Sobol (My Wife), Outchinnikov (An Inconvenience), Dymov (The Grasshopper), Startsvev (Ionitch), and others. Chekhov's main interest in psychiatry was clearly visible in The Nervous Breakdown, The Black Monk, The Man in a Case, A Doctor's Visit, and WardNo. 6 with Dr. Ragin. In his short stories as in his plays, Chekhov relied on his knowledge of provincial life; his doctor's characters were not professors, academicians, or Moscow's great physicians, but instead exhausted hard workers, with no effective diagnostic and therapeutic means, and poorly paid. Unlike himself, none of Chekhov's doctors was a writer or breadwinner, and Chekhov did not like to lay emphasis on the disease.


Up-regulation of yggG promotes the survival of Escherichia coli cells containing Era-1 mutant protein.
Era is a highly conserved GTPase essential for bacterial growth. Using a digoxigenin-labeled Era protein to screen a phage expression library of Escherichia coli genomic DNA, yggG, a gene that encodes a putative zinc metalloprotease was isolated and characterized. The deduced amino acid sequence of YggG showed high degrees of similarity to some reported heat shock proteins. In this study, the direct interaction between Era and YggG was confirmed, and it was found that the yggG gene, encoding a 25 kDa heat shock protein, was up-regulated at the mRNA level in partially defective Era GTPase mutants (era-1) and in E. coli cells overproducing Era-1. The delta yggG strain displayed the same growth rate as wild-type strain under normal growth conditions and after heat shock. Overexpression of Era-1 in the delta yggG strain resulted in a stronger growth-inhibitory effect than that in the wild-type strain, while coexpression of YggG partially restored the bacterial growth rate. The results indicated that YggG expression is significantly increased in response to stress caused by the Era-1 mutant protein in E. coli, thus promoting the growth of E. coli.


Human papillomavirus and cervical cancer.
Cervical cancer is the second most common cancer in women worldwide, and knowledge regarding its cause and pathogenesis is expanding rapidly. Persistent infection with one of about 15 genotypes of carcinogenic human papillomavirus (HPV) causes almost all cases. There are four major steps in cervical cancer development: infection of metaplastic epithelium at the cervical transformation zone, viral persistence, progression of persistently infected epithelium to cervical precancer, and invasion through the basement membrane of the epithelium. Infection is extremely common in young women in their first decade of sexual activity. Persistent infections and precancer are established, typically within 5-10 years, from less than 10% of new infections. Invasive cancer arises over many years, even decades, in a minority of women with precancer, with a peak or plateau in risk at about 35-55 years of age. Each genotype of HPV acts as an independent infection, with differing carcinogenic risks linked to evolutionary species. Our understanding has led to improved prevention and clinical management strategies, including improved screening tests and vaccines. The new HPV-oriented model of cervical carcinogenesis should gradually replace older morphological models based only on cytology and histology. If applied wisely, HPV-related technology can minimise the incidence of cervical cancer, and the morbidity and mortality it causes, even in low-resource settings.


Brain Tumors in Adolescents and Young Adults: A Review.
Brain tumors account for the majority of cancer-related deaths in adolescents and young adults (AYAs), defined as individuals aged 15 to 39. AYAs constitute a distinct population in which both pediatric- and adult-type central nervous system (CNS) tumors can be observed. Clinical manifestations vary depending on tumor location and often include headaches, seizures, focal neurological deficits, and signs of increased intracranial pressure. With the publication of the updated World Health Organization CNS tumor classification in 2021, diagnoses have been redefined to emphasize key molecular alterations. Gliomas represent the majority of malignant brain tumors in this age group. Glioneuronal and neuronal tumors are associated with longstanding refractory epilepsy. The classification of ependymomas and medulloblastomas has been refined, enabling better identification of low-risk tumors that could benefit from treatment de-escalation strategies. Owing to their midline location, germ cell tumors often present with oculomotor and visual alterations as well as endocrinopathies. The management of CNS tumors in AYA is often extrapolated from pediatric and adult guidelines, and generally consists of a combination of surgical resection, radiation therapy, and systemic therapy. Ongoing research is investigating multiple agents targeting molecular alterations, including isocitrate dehydrogenase inhibitors, SHH pathway inhibitors, and BRAF inhibitors. AYA patients with CNS tumors should be managed by multidisciplinary teams and counselled regarding fertility preservation, psychosocial comorbidities, and risks of long-term comorbidities. There is a need for further efforts to design clinical trials targeting CNS tumors in the AYA population.


Photoelectrochemical Sensor with a Z-Scheme Fe2O3/CdS Heterostructure for Sensitive Detection of Mercury Ions.
Mercury (Hg2+) is a highly toxic element and can seriously affect human health. This work proposed a photoelectrochemical (PEC) sensor with a Z-scheme Fe2O3/CdS heterostructure and two thymine-rich DNA strands (DNA-1 and Au@DNA-2) for sensitive detection of Hg2+. The light excitation of the Fe2O3/CdS composite accelerated the electron transfer among Fe2O3, CdS, and the electrode to produce a stable photocurrent response. Upon the recognition of Hg2+ to thymine bases (T) in two DNA strands to form a stable T-Hg2+-T biomimetic structure, the photocurrent response increased with the increasing concentration of Hg2+ due to the opening of electronic transmission channels from Au nanoparticles to Fe2O3/CdS nanocomposite. Under the optimal conditions screened by the Box-Behnken experiments, the proposed PEC sensor showed excellent analytical performance for Hg2+ detection with high sensitivity, a detection limit of 0.20 pM at a signal-to-noise ratio of 3, high selectivity, a detectable concentration range of 1 pM-100 nM, and acceptable stability. The good recovery and low relative standard deviation for the analysis of Hg2+ in lake and tap water samples demonstrated the potential application of the designed Z-scheme Fe2O3/CdS heterostructure in the PEC detection of heavy metal ions.


Isolated and synchronous vulvar granular cell tumors: a clinicopathologic study of 17 cases in 13 patients.
Granular cell tumors (GCTs) are benign Schwann cell-derived neoplasms occurring throughout the body. Vulvar GCTs are usually isolated, but occasionally multifocal. On account of their anatomic location, surgical interventions aiming for negative resection margins can result in significant morbidity. We describe the clinicopathologic features of 17 vulvar GCTs in 13 patients followed for an average of 7 years. The average age at presentation was 46 years, and 84% of the patients were black. The tumors were multifocal in 3 (23%) patients, and all, either at presentation or subsequently also developed extravulvar foci. Patients with multifocal vulvar GCTs were nearly 10 years younger at presentation than patients in whom the disease was isolated. The most common complaint was a slow-enlarging mass occasionally associated with pruritus or overlying hyperpigmentation. Clinically, the tumors were subcutaneous, mobile, and nodular (2.1 cm on average), without overlying ulceration, and most often were found in the labia majora (6/17). The neoplasms were histologically heterogeneous, but exhibited either a predominantly nodular (3/17) or infiltrative (13/17) pattern of invasion. Cytologically, the tumors displayed round to polygonal cells with a granular cytoplasm, small hyperchromatic nuclei with minimal pleomorphism, and less than 2 mitoses per 10 high power fields. One tumor (1/17) consisted of cells with predominantly vesicular nuclei and prominent nucleoli and was classified as an atypical vulvar GCT. All tumors so examined were reactive for S-100 protein. Eight of 17 tumor excision specimens had positive margins. Of these, 5 tumors remained stable whereas the other 2 with follow-up progressed to require reexcisions after periods of 14 and 8.0 years, respectively. All patients with excisions with negative margins remained stable. Patients with multifocal tumors did not have a higher risk of recurrence per tumor, compared with patients with isolated disease, regardless of the margin status. No patient died from her disease. As granular cell neoplasms have such a low risk or recurrence and behave generally in an indolent manner, aggressive therapy is usually unwarranted.


Colonic Epithelial-Derived Selenoprotein P Is the Source for Antioxidant-Mediated Protection in Colitis-Associated Cancer.
Patients with inflammatory bowel disease (IBD) demonstrate nutritional selenium deficiencies and are at greater risk of developing colon cancer. Previously, we determined that global reduction of the secreted antioxidant selenium-containing protein, selenoprotein P (SELENOP), substantially increased tumor development in an experimental colitis-associated cancer (CAC) model. We next sought to delineate tissue-specific contributions of SELENOP to intestinal inflammatory carcinogenesis and define clinical context. Selenop floxed mice crossed with Cre driver lines to delete Selenop from the liver, myeloid lineages, or intestinal epithelium were placed on an azoxymethane/dextran sodium sulfate experimental CAC protocol. SELENOP loss was assessed in human ulcerative colitis (UC) organoids, and expression was queried in human and adult UC samples. Although large sources of SELENOP, both liver- and myeloid-specific Selenop deletion failed to modify azoxymethane/dextran sodium sulfate-mediated tumorigenesis. Instead, epithelial-specific deletion increased CAC tumorigenesis, likely due to elevated oxidative stress with a resulting increase in genomic instability and augmented tumor initiation. SELENOP was down-regulated in UC colon biopsies and levels were inversely correlated with endoscopic disease severity and tissue S100A8 (calprotectin) gene expression. Although global selenium status is typically assessed by measuring liver-derived plasma SELENOP levels, our results indicate that the peripheral SELENOP pool is dispensable for CAC. Colonic epithelial SELENOP is the main contributor to local antioxidant capabilities. Thus, colonic SELENOP is the most informative means to assess selenium levels and activity in IBD patients and may serve as a novel biomarker for UC disease severity and identify patients most predisposed to CAC development.


Treatment of "on-off effect" with a dopa decarboxylase inhibitor.
Irregularities in motor response after continuing levodopa therapy of Parkinson disease (the "on-off effect") were assessed with the addition of L-alpha-methyldopa hydrazine (carbidopa) in a double-blind study. Thirteen of 20 patients improved while receiving carbidopa and levodopa while only four of 17 patients improved while receiving placebo and levodopa. Twenty-three of 37 patients improved in a subsequent non-blind trial of carbidopa plus levodopa. Improvement was not dependent on an increase in dose or frequency of levodopa administration. Adverse effects included dyskinesia, imbalance, and confusion; nausea was eliminated. On patient died of glomerulonephritis that predated the drug trial, but worsened progressively during and after it. Carbidopa's suppression of the "on-off effect" suggests that extracerbral factors may be important in this phenomenon.


Pigment epithelium-derived factor inhibits lysosomal degradation of Bcl-xL and apoptosis in HepG2 cells.
Pigment epithelium-derived factor (PEDF) has several biological actions on tumor cells, but its effects are cell-type dependent. The aim of this study was to examine the pathophysiological role of PEDF in hepatocellular carcinoma (HCC). PEDF expression was examined in various hepatoma cell lines and human HCC tissues, and was seen in various hepatoma cell lines including HepG2 cells. In human HCC tissues, PEDF expression was higher than in adjacent non-HCC tissues. In addition, serum PEDF levels were higher in HCC patients than in non-HCC patients, and curative treatment of HCC caused significant reductions in serum PEDF levels compared with pretreatment levels. In vitro experiments, camptothecin (CPT) was used to induce apoptosis and the effect of PEDF was investigated by knockdown of the PEDF gene in CPT-treated HepG2 cells. Knockdown of the PEDF gene enhanced CPT-induced apoptosis, simultaneously down-regulating Bcl-xL expression in HepG2 cells. Expression of apoptosis-related molecules and effects of bafilomycin A1 on CPT-induced apoptosis were also examined in PEDF gene knockdown HepG2 cells. Treatment with bafilomycin A1 suppressed CPT-induced decreases in Bcl-xL expression and increases in apoptosis in PEDF gene knockdown HepG2 cells. PEDF may, therefore, exert anti-apoptotic effects through inhibition of lysosomal degradation of Bcl-xL in CPT-treated HepG2 cells.


Intraoperative anesthetic consultation.
This article deals with consultation between anesthesiologists and urologic surgeons. Some of the subjects discussed represent problems that occur commonly, such as cardiac arrhythmias and intraoperative hypertension. Other subjects, though representing less common problems, have much more serious consequences and thus should be brought to the attention of surgeons. This latter group includes malignant hyperthermia, hyponatremia during transurethral prostatic resection, and cardiac arrest.


Two-dimensional polar harmonic transforms for invariant image representation.
This paper introduces a set of 2D transforms, based on a set of orthogonal projection bases, to generate a set of features which are invariant to rotation. We call these transforms Polar Harmonic Transforms (PHTs). Unlike the well-known Zernike and pseudo-Zernike moments, the kernel computation of PHTs is extremely simple and has no numerical stability issue whatsoever. This implies that PHTs encompass the orthogonality and invariance advantages of Zernike and pseudo-Zernike moments, but are free from their inherent limitations. This also means that PHTs are well suited for application where maximal discriminant information is needed. Furthermore, PHTs make available a large set of features for further feature selection in the process of seeking for the best discriminative or representative features for a particular application.


Perceptions of first-line nurse managers. What competencies are needed to fulfill this role?
First-line nurse managers have experienced an unprecedented shift in their roles and responsibilities as a result of health care reform. Consequently, there is a need to identify competencies required of first-line nurse managers in a changing health care environment. A descriptive, exploratory study of nurse managers in a western Canadian province was conducted using a combined quantitative and qualitative approach. The research instrument was comprised of three parts: a questionnaire that grouped five categories of competencies (technical, human, conceptual, leadership, and financial management); demographic data; and a critical incident technique that allowed the subjects to elaborate on a specific incident in their practice when they "performed at their best" as a manager. Findings revealed that nurse managers' need for knowledge and understanding was greater than their ability to implement managerial competencies. The exploration of competencies of first-line nurse managers has implications for curriculum development in leadership and management courses in nursing programs, as well as managerial development in health care agencies. Results will assist educators and administrators in addressing the changing needs of current and future nurse managers.


The effect of artemisinin combined with standard antimalarials against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro.
The activity of artemisinin (qinghaosu) in combination with some commonly-used antimalarial drugs was tested in vitro against a chloroquine-sensitive (NF54) and a chloroquine-resistant (K1) strain of Plasmodium falciparum. Both mefloquine and tetracycline showed marked potentiative synergism with artemisinin against both strains, whilst primaquine showed potentiation against K1. Combinations of artemisinin with pyrimethamine and with chloroquine were antagonistic. The results confirm observations on rodent malaria in vivo and indicate that the drug interactions seen were direct, through actions on the parasite, and not merely effects on drug distribution and metabolism in the mouse host.


Statins are diabetogenic--myth or reality?
Multiple clinical trials have demonstrated the beneficial effects of statins in lowering levels of low-density lipoprotein and in the prevention of cardiovascular disease. However, although statins have a good safety profile, a debate has been ongoing as to whether use of statins increases risk of new-onset diabetes. Recent large scale meta-analyses of statin trials support the concept of a diabetogenic effect of statins, as do some other small trials assessing changes in glycaemia parameters and insulin levels. However, a definitive mechanism of action has not yet been elucidated. Nevertheless, the level of evidence has been sufficient to lead the FDA to make a change to the labelling of statins. This review assesses the current available evidence and offers a clinical perspective.


Variations in the immune and metabolic response of proactive and reactive Sparus aurata under stimulation with Vibrio anguillarum vaccine.
Environmental insults, such as exposure to pathogens, modulate the behavioural coping style of animals to stressors, and repeated exposure to stressful environments may lead to species-specific infection phenotypes. To analyse the influence of stress behavioural phenotypes on immune and metabolic performance, gilthead sea bream (Sparus aurata L.) were first screened for proactive and reactive coping styles. Once characterized, both behavioural phenotypes fish groups were bath vaccinated with bacterin from Vibrio anguillarum, an opportunistic widespread pathogen of fish. Gills and liver were sampled at 0 (control group), 1, 3 and 7 days post-vaccination. Immune-, oxidative stress- and metabolic-related transcripts (il1β, tnfα, igm, gpx1, sod, cat, lpl, ghr1 and ghr2), metabolic endpoints (glucose, cholesterol and triglycerides), hepatic health indicators (aspartate aminotransferase, alanine transaminase and alkaline phosphatase), oxidative stress status (esterase activity, total antioxidant capacity and total oxidative status) and stress biomarkers (cortisol) were determined. Present results indicate that screening for coping styles in the gilthead sea bream segregated the two distinct phenotypes as expected: proactive and reactive. Results also indicate that under bath vaccination proactive fish show high immune response and lower metabolism, whereas reactive fish show low immune and higher metabolic responses.


Clonal heterogeneity of thymic B cells from early-onset myasthenia gravis patients with antibodies against the acetylcholine receptor.
Myasthenia gravis (MG) with antibodies against the acetylcholine receptor (AChR-MG) is considered as a prototypic autoimmune disease. The thymus is important in the pathophysiology of the disease since thymus hyperplasia is a characteristic of early-onset AChR-MG and patients often improve after thymectomy. We hypothesized that thymic B cell and antibody repertoires of AChR-MG patients differ intrinsically from those of control individuals. Using immortalization with Epstein-Barr Virus and Toll-like receptor 9 activation, we isolated and characterized monoclonal B cell lines from 5 MG patients and 8 controls. Only 2 of 570 immortalized B cell clones from MG patients produced antibodies against the AChR (both clones were from the same patient), suggesting that AChR-specific B cells are not enriched in the thymus. Surprisingly, many B cell lines from both AChR-MG and control thymus samples displayed reactivity against striated muscle proteins. Striational antibodies were produced by 15% of B cell clones from AChR-MG versus 6% in control thymus. The IgVH gene sequence analysis showed remarkable similarities, concerning VH family gene distribution, mutation frequency and CDR3 composition, between B cells of AChR-MG patients and controls. MG patients showed clear evidence of clonal B cell expansion in contrast to controls. In this latter aspect, MG resembles multiple sclerosis and clinically isolated syndrome, but differs from systemic lupus erythematosus. Our results support an antigen driven immune response in the MG thymus, but the paucity of AChR-specific B cells, in combination with the observed polyclonal expansions suggest a more diverse immune response than expected.


Laparoscopic paraesophageal hernia repair.
Paraesophageal hernias require surgery to avoid potentially serious complications. To evaluate paraesophageal hernia repair using the laparoscopic approach. Case series. University hospital and foregut testing laboratory. Sixty-five consecutive patients (mean age, 63.6 years; range, 26-90 years). Preoperative evaluation included barium esophagogram, endoscopy, esophageal manometry, and 24-hour pH monitoring. Operative complications, postoperative morbidity, follow-up symptoms (53 patients; mean, 18 months; range, 2-54 months) and barium esophagogram (46 patients). Fifty-six patients (86%) had a type III hernia and 9 (14%) had a type II hernia. Twenty (65%) of 31 patients who underwent pH monitoring had a positive 24-hour pH score, and 24 (56%) of 43 patients who underwent manometry had an incompetent lower esophageal sphincter. Four patients had a gastric volvulus and 21 patients had more than 50% of their stomach in the chest. All patients underwent hernia reduction, crural repair, and fundoplication (64 Nissen procedures and 1 Toupet procedure). The average duration of surgery was 2 hours. There were 2 conversions: gastric perforation and a difficult dissection because of a large fibrotic sac. Other complications, all managed intraoperatively, were 2 gastric perforations and bleeding in 6 patients. Average length of hospital stay was 2 days (range, 1-23 days). Early re-operation was required in 3 patients: slipped Nissen; small-bowel obstruction due to trocar-site hernia; and organo-axial rotation with gastroduodenal obstruction. Four patients required esophageal dilatation after surgery. Forty-nine of 53 patients available for long-term follow-up were satisfied with the results of surgery. Time to full recovery was 3 weeks (range, 1 week to 2 months). Seven of 46 patients experienced small type I hernias observed on routine follow-up esophagograms. Most paraesophageal hernias are type III. A concomitant antireflux procedure is recommended. Paraesophageal hernias can be managed successfully by the laparoscopic route with good outcome.


Alcohol Consumption Post-Liver Transplantation: A Cross-Sectional Study.
Listing patients with alcohol-associated liver disease (ALD) for liver transplant (LT) remains challenging especially due to the risk of alcohol resumption post-LT. We aimed to evaluate post-LT alcohol consumption at a Portuguese transplant center. We conducted a cross-sectional study including LT recipients from 2019 at Curry Cabral Hospital, Lisbon, Portugal. A pretested survey and a validated Portuguese translation of the Alcohol Use Disorder Identification Test (AUDIT) were applied via a telephone call. Alcohol consumption was defined by patients' self-reports or a positive AUDIT. In 2019, 122 patients underwent LT, and 99 patients answered the survey (June 2021). The mean (SD) age was 57 (10) years, 70 patients (70.7%) were males, and 49 (49.5%) underwent ALD-related LT. During a median (IQR) follow-up of 24 (20-26) months post-index LT, 22 (22.2%) recipients consumed any amount of alcohol: 14 had a drink monthly or less and 8 drank 2-4 times/month. On drinking days, 18 patients usually consumed 1-2 drinks and the remainder no more than 3-4 drinks. One patient reported having drunk ≥6 drinks on one occasion. All post-LT drinking recipients were considered low risk (score <8) as per the AUDIT score (median [IQR] of 1 [1-2]). No patient reported alcohol-related problems, whether self-inflicted or toward others. Drinking recipients were younger (53 vs. 59 years, p = 0.020), had more non-ALD-related LT (72.7 vs. 44.2%, p = 0.018) and active smoking (31.8 vs. 10.4%, p = 0.037) than abstinent ones. In our cohort, about a quarter of LT recipients consumed alcohol early posttransplant, all with a low-risk pattern according to the AUDIT score.


Variable stability of a selectable provirus after retroviral vector gene transfer into human cells.
Human lymphoblasts deficient in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) were infected with an amphotropic helper-free retroviral vector expressing human HPRT cDNA. The stability and expression of the HPRT provirus in five cell lines with different proviral integration sites were examined by determining HPRT mutation and reversion frequencies and by blot hybridization studies. Mutation to the HPRT-negative phenotype occurred at frequencies of approximately 4 X 10(-5) to 3 X 10(-6) per generation. Most mutations in each of the five cell lines were associated with partial or complete deletions or rearrangements of the provirus. Several mutants retained a grossly intact HPRT provirus, and in one such mutant HPRT shutdown resulted from a revertible epigenetic mechanism that was not associated with global changes in proviral methylation. Therefore, mutation and shutdown of the HPRT provirus in human lymphoblasts result from mechanisms similar to those reported for several other avian and mammalian replication-competent retroviruses.


PZT/PZT and PZT/BiT Composite Piezo-Sensors in Aerospace SHM Applications: Photochemical Metal Organic + Infiltration Deposition and Characterization.
The composition of fine-ground lead zirconate-titanate powder Pb(Zr0.52Ti0.48)O₃, suspended in PZT and bismuth titanate (BiT) solutions, is deposited on the curved surface of IN718 and IN738 nickel-based supper alloy substrates up to 100 µm thickness. Photochemical metal organic and infiltration techniques are implemented to produce smooth, semi-dense, and crack-free random orientated thick piezoelectric films as piezo-sensors, free of any dopants or thickening polymers. Every single layer of the deposited films is heated at 200 °C with 10 wt.% excess PbO, irradiated by ultraviolet lamp (365 nm, 6 watt) for 10 min, pyrolyzed at 400 °C, and subsequently annealed at 700 °C for one hour. This process is repeated successively until reaching the desired thickness. Au and Pt thin films are deposited as the bottom and top electrodes using evaporation and sputtering methods, respectively. PZT/PZT and PZT/BiT composite films are then characterized and compared to similar PZT and BiT thick films deposited on the similar substrates. The effect of the composition and deposition process is also investigated on the crystalline phase development and microstructure morphology as well as the dielectric, ferroelectric, and piezoelectric properties of piezo-films. The maximum remnant polarization of Pr = 22.37 ± 0.01, 30.01 ± 0.01 µC/cm², the permittivity of εr = 298 ± 3, 566 ± 5, and piezoelectric charge coefficient of d33 = 126, 148 m/V were measured versus the minimum coercive field of Ec = 50, 20 kV/cm for the PZT/PZT and PZT/BiT thick films, respectively. The thick film piezo-sensors are developed to be potentially used at frequency bandwidth of 1⁻5 MHz for rotary structural health monitoring and also in other industrial or medical applications as a transceiver.


Knowledge, Experiences and Training Needs of Health Professionals about Disaster Preparedness and Response in Southwest Ethiopia: a cross sectional study.
Over the past decade, the magnitude and intensity of disasters have been vividly rising globally due to the forces of nature or man. This study aimed at assessing the perceived knowledge, experiences and training needs of health professionals regarding disasters, their prevention and management in Jimma Zone, Southwest Ethiopia. An institution based cross-sectional survey was conducted on 377 health professionals taken from 9 randomly selected districts out of 18. All health professionals working at health offices, hospitals and health centers were included. Data were collected using a structured questionnaire which was developed by the investigators after reviewing the relevant literature in the field. Data were coded and entered into SPSS 20 software for cleaning and analysis. Descriptive and logistic regression analyses were done. The majority (85.1%) of the participants were able to define the concept of disaster from various perspectives; 9.7% did not know about it at all and 5.2% could describe the concept partially or misconceived it. The majority (84.3%) agreed that disaster has direct public health consequences on humans. The main public health consequence of disaster the participants mentioned was environmental pollution (65.8%). Malaria, measles and diarrhoeal diseases accounted for 35.5%, 33.1% and 10.5% of the epidemics, respectively. Only 20.6% of the respondents were trained on disaster related topics in the last two years. The majority felt that they had poor knowledge on early warning indicators of drought (48.0%) and flood (48.0%). Simialry, 50.8%, 47.7%, 51.1% and 42.6% of the participants had poor knowledge on preparedness to drought, preparedness to flood, response to drought, response to flood. On composite scale, they generally perceived to have adequate (29.4%), moderate (32.4%) and poor (38.2%) knowledge about early warning information bout, preparedness for and response to common disasters. A vast majority (92.8%) reported that they need training on disaster preparedness, management and response. A considerable number of professionals had limited understanding about the concept of disaster and response to certain specific disasters. They also had limited opportunities for training, despite their felt needs. Therefore, training should be provided focusing on the specific gaps identified.


Glucarpidase for the management of elevated methotrexate levels in patients with impaired renal function.
The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage, administration, and current role in therapy of a recently approved agent for controlling methotrexate toxicity are reviewed. Glucarpidase is a bacterial enzyme useful in reversing toxicity induced by the widely used antineoplastic agent methotrexate. Glucarpidase gained U.S. marketing approval in 2012 for reducing serum methotrexate concentrations greater than 1 μM/L in patients with delayed methotrexate clearance due to impaired renal function. In clinical trials, glucarpidase has been administered to a total of 3887 patients receiving high-dose methotrexate (i.e., doses of ≥500 mg/m(2)), including pediatric patients. Patients treated with glucarpidase in addition to standard supportive care (hydration, urinary alkalization, leucovorin rescue, and, in some cases, hemodialysis) had a mean reduction in serum methotrexate levels of greater than 88%, with reductions occurring in a median of 15 minutes; however, up to 4.4% of adult patients and up to 6% of pediatric patients in clinical trial cohorts died despite glucarpidase use, suggesting the agent might not confer a survival advantage over supportive care alone. Glucarpidase is well tolerated; the most common adverse effects are flushing, nausea, vomiting, hypotension, and headache, which are typically grade 1 or 2 in severity and resolve without intervention. Glucarpidase is a well-tolerated and effective treatment for reducing serum methotrexate concentrations greater than 1 μM/L in patients with impaired renal function. While there are few adverse effects associated with treatment, there may be little or no impact on methotrexate-associated mortality.


Shifting evaluation windows: predictable forward primes with long SOAs eliminate the impact of backward primes.
Recent work suggests that people evaluate target stimuli within short and flexible time periods called evaluation windows. Stimuli that briefly precede a target (forward primes) or briefly succeed a target (backward primes) are often included in the target's evaluation. In this article, the authors propose that predictable forward primes act as "go" signals that prepare target processing, such that earlier forward primes pull the evaluation windows forward in time. Earlier forward primes may thus reduce the impact of backward primes. This shifting evaluation windows hypothesis was tested in two experiments using an evaluative decision task with predictable (vs. unpredictable) forward and backward primes. As expected, a longer time interval between a predictable forward prime and a target eliminated backward priming. In contrast, the time interval between an unpredictable forward primes and a target had no effects on backward priming. These findings suggest that predictable features of dynamic stimuli can shape target extraction by determining which information is included (or excluded) in rapid evaluation processes.


STAT3 inhibition in prostate and pancreatic cancer lines by STAT3 binding sequence oligonucleotides: differential activity between 5' and 3' ends.
Signal transducers and activators of transcription (STAT) were originally discovered as components of signal transduction pathways. Persistent aberrant activation of STAT3 is a feature of many malignancies including prostate cancer and pancreatic cancer. One consequence of persistently activated STAT3 in malignant cells is that they depend on it for survival; thus, STAT3 is an excellent molecular target for therapy. Previously, we reported that single-stranded oligonucleotides containing consensus STAT3 binding sequences (13410 and 13411) were more effective for inducing apoptosis in prostate cancer cells than antisense STAT3 oligonucleotides. Control oligonucleotides (scrambled sequences) had no effect. Here, we report that authentic STAT3 binding sequences, identified from published literature, were more effective for inducing apoptosis in prostate cancer cells and pancreatic cancer cells than was oligonucleotide 13410. Moreover, the authentic STAT3 binding sequences showed differing efficacies in the malignant cell lines depending on whether the canonical STAT3 binding sequence was truncated at the 5' or the 3' end. Finally, expression of one STAT3-regulated gene was decreased following treatment, suggesting that STAT3 may regulate the same set of genes in the two types of cancer. We conclude that truncating the 5' end left intact enough of the canonical STAT3 binding site for effective hybridization to the genome, whereas truncation of the 3' end, which is outside the canonical binding site, may have affected binding of required cofactors essential for STAT3 activity, thereby reducing the capacity of this modified oligonucleotide to induce apoptosis. Additional experiments to answer this hypothesis are under way.


Prospective randomized study of therapy in cerebrospinal fluid shunt infection.
Thirty patients who met the rigid criteria for a prospective randomized study of cerebrospinal fluid (CSF) shunt infections underwent therapy with the three currently advocated treatment modalities to determine the efficacy of each form of therapy. Ten patients (Group A) underwent shunt removal and, in addition to receiving systemic antibiotics, were treated by either external ventricular drainage or intermittent ventricular taps for decompression and antibiotic administration; 10 patients (Group B) were treated by removal and immediate replacement of the shunt and intrashunt antibiotic therapy; and 10 patients (Group C) received antibiotics without removal or replacement of the shunt. All patients were given intravenous and intraventricular antibiotics as follows: in Group A, antibiotics were given by both the intravenous and the intraventricular routes for a minimal period of 7 days; in Group B, intravenous antibiotics were administered for a minimal period of 3 weeks and twice daily intraventricular antibiotics were given for a minimal period of 2 weeks; in Group C, intravenous antibiotics were administered for a minimal period of 3 weeks and twice daily intraventricular antibiotics were given for a minimal period of 2 weeks. In all patients, CSF was obtained from the shunt and cultured 48 hours after the cessation of antibiotic therapy, and the cultures were repeated within 4 months of the completion of treatment. All patients in Group A and 9 of 10 patients in Group B were treated successfully. They were clinically asymptomatic, and cultures after treatment were sterile. However, only 3 patients in Group C responded to treatment. The remaining patients of Group C had persistent infections requiring additional therapy. The mean follow-up of the study group was 23 +/- 14 (SD) months. The mean hospitalization time for the study group was 33 +/- 21 days; the hospitalization time was 24.7 +/- 17 days for Group A alone, 32.7 +/- 8 days for Group B, and 47 +/- 37 days Group C.


Three-dimensional structure of N5-carboxyaminoimidazole ribonucleotide synthetase: a member of the ATP grasp protein superfamily.
Escherichia coli PurK, a dimeric N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) synthetase, catalyzes the conversion of 5-aminoimidazole ribonucleotide (AIR), ATP, and bicarbonate to N5-CAIR, ADP, and Pi. Crystallization of both a sulfate-liganded and the MgADP-liganded E. coli PurK has resulted in structures at 2.1 and 2.5 A resolution, respectively. PurK belongs to the ATP grasp superfamily of C-N ligase enzymes. Each subunit of PurK is composed of three domains (A, B, and C). The B domain contains a flexible, glycine-rich loop (B loop, T123-G130) that is disordered in the sulfate-PurK structure and becomes ordered in the MgADP-PurK structure. MgADP is wedged between the B and C domains, as with all members of the ATP grasp superfamily. Other enzymes in this superfamily contain a conserved Omega loop proposed to interact with the B loop, define the specificity of their nonnucleotide substrate, and protect the acyl phosphate intermediate formed from this substrate. PurK contains a minimal Omega loop without conserved residues. In the reaction catalyzed by PurK, carboxyphosphate is the putative acyl phosphate intermediate. The sulfate of the sulfate ion-liganded PurK interacts electrostatically with Arg 242 and the backbone amide group of Asn 245, components of the J loop of the C domain. This sulfate may reveal the location of the carboxyphosphate binding site. Conserved residues within the C-terminus of the C domain define a pocket that is proposed to bind AIR in collaboration with an N-terminal strand loop helix motif in the A domain (P loop, G8-L1). The P loop is proposed to bind the phosphate of AIR on the basis of similar binding sites observed in PurN and PurE and proposed in PurD and PurT, four other enzymes in the purine pathway.


Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast.
An association has been reported between consumption of a high soy diet and a low incidence of breast cancer within populations of Southeast Asia. Phytoestrogens present in soy act as partial estrogen agonists or antagonists and can inhibit breast cancer cell proliferation in vitro. The effect of 14-day dietary soy supplementation with 60 g (45 mg isoflavones) on the normal breast of 84 premenopausal patients was determined. Serum concentrations of the isoflavanoids, genistein, daidzein, and equol, were raised in patients after soy supplementation (P < or = 0.025). Nipple aspirate (NA) levels of genistein and daidzein were higher than paired serum levels, both before (P < 0.001 and P = 0.001, respectively) and after soy supplementation (P < 0.001 and P = 0.049, respectively); however, there was no significant increase in NA isoflavone levels in response to soy. NA levels of apolipoprotein D were significantly lowered and pS2 levels raised in response to soy supplementation (P < or = 0.002), indicative of an estrogenic stimulus. No effect of soy supplementation on breast epithelial cell proliferation, estrogen and progesterone receptor status, apoptosis, mitosis, or Bcl-2 expression was detected. In conclusion, short term dietary soy has a weak estrogenic response on the breast, as measured by nipple aspirate apolipoprotein D and pS2 expression. No antiestrogenic effect of soy on the breast was detected.


Characterizing and inferring quantitative cell cycle phase in single-cell RNA-seq data analysis.
Cellular heterogeneity in gene expression is driven by cellular processes, such as cell cycle and cell-type identity, and cellular environment such as spatial location. The cell cycle, in particular, is thought to be a key driver of cell-to-cell heterogeneity in gene expression, even in otherwise homogeneous cell populations. Recent advances in single-cell RNA-sequencing (scRNA-seq) facilitate detailed characterization of gene expression heterogeneity and can thus shed new light on the processes driving heterogeneity. Here, we combined fluorescence imaging with scRNA-seq to measure cell cycle phase and gene expression levels in human induced pluripotent stem cells (iPSCs). By using these data, we developed a novel approach to characterize cell cycle progression. Although standard methods assign cells to discrete cell cycle stages, our method goes beyond this and quantifies cell cycle progression on a continuum. We found that, on average, scRNA-seq data from only five genes predicted a cell's position on the cell cycle continuum to within 14% of the entire cycle and that using more genes did not improve this accuracy. Our data and predictor of cell cycle phase can directly help future studies to account for cell cycle-related heterogeneity in iPSCs. Our results and methods also provide a foundation for future work to characterize the effects of the cell cycle on expression heterogeneity in other cell types.


The influence of plasma concentrations of tri-iodothyronine on the acute increases in insulin and muscle protein synthesis in the refed fasted rat.
To examine whether the low plasma levels of triiodothyronine (T3) in fasted rats might limit the recovery of muscle protein synthesis on refeeding, rats were fasted for either 3 or 4 days and refed with or without pretreatment with thyroid hormones. Fasting suppressed T3 levels, plasma insulin and the rate of the translational phase of muscle protein synthesis (KRNA; the rate per unit RNA), especially after the 4-day fast. On refeeding, plasma T3 levels remained low for more than 3 h after the 3-day fast and for more than 8 h after the 4-day fast. Insulin concentrations increased within the first hour of refeeding, eventually achieving supranormal concentrations after the 3-day fast. The KRNA increased within the first hour of refeeding, achieving well-fed control values by 3 h after the 3-day fast or 24 h after the 4-day fast. The increases in KRNA were significantly correlated with the increases in insulin at low insulin concentrations, achieving a plateau value at 150 pmol/l, so that further increases in insulin were not associated with any further increases in protein synthesis. Pretreatment with thyroid hormone induced increased T3 levels which were maintained for up to 8 h of refeeding. This had no effect on the responses of either insulin or protein synthesis to refeeding after the 3-day fast, but did result in an acceleration of the recovery in the KRNA and plasma insulin levels in the rats fasted for 4 days. Analysis of the insulin-KRNA relationship showed no evidence for any increase in the insulin sensitivity of muscle protein synthesis with thyroid pretreatment, the initial stimulation of protein synthesis on refeeding the rats fasted for 4 days reflecting increased insulin secretion. Since in the untreated animals, insulin secretion on refeeding was also correlated with T3 levels, these results are consistent with the previously reported thyroidal dependence of insulin secretion.


An Antarctic hot spot for fungi at Shackleton's historic hut on Cape Royds.
The historic expedition huts located in the Ross Sea Region of the Antarctic and the thousands of artifacts left behind by the early explorers represent important cultural heritage from the "Heroic Era" of Polar exploration. The hut at Cape Royds built by Ernest Shackleton and members of the 1907-1908 British Antarctic Expedition has survived the extreme Antarctic environment for over 100 years, but recent studies have shown many forms of deterioration are causing serious problems, and microbial degradation is evident in the historic wood. Conservation work to reduce moisture at the hut required removal of fodder, wood, and many different types of organic materials from the stables area on the north side of the structure allowing large numbers of samples to be obtained for these investigations. In addition, wood from historic food storage boxes exposed in a ravine adjacent to the hut were also sampled. Fungi were cultured on several different media, and pure cultures were obtained and identified by sequencing of the internal transcribed spacer region of rDNA. From the 69 cultures of filamentous fungi obtained, the most predominant genera were Cadophora (44%) followed by Thielavia (17%) and Geomyces (15%). Other fungi found included Cladosporium, Chaetomium, and isolates identified as being in Pezizomycotina, Onygenales, Nectriaceae, and others. No filamentous basidiomycetes were found. Phylogenetic analyses of the Cadophora species showed great species diversity present revealing Cadophora malorum, Cadophora luteo-olivacea, Cadophora fastigiata, as well as Cadophora sp. 4E71-1, a C. malorum-like species, and Cadophora sp. 7R16-1, a C. fastigiata-like species. Scanning electron microscopy showed extensive decay was present in the wood samples with type 1 and type 2 forms of soft rot evident in pine and birch wood, respectively. Fungi causing decay in the historic wooden structures and artifacts are of great concern, and this investigation provides insight into the identity and species diversity of fungi found at the site. The historic woods and other organic materials at this site represent a large input of carbon into the Antarctic environment. This as well as nutrient additions from the nearby Adélie penguin (Pygoscelis adeliae) colony and favorable conditions for fungal growth at Cape Royds appear responsible for the significant fungal diversity, and where extensive decay is taking place in wood in contact with the ground.


Priming problem solving with conceptual processing of relevant objects.
In the present study, the author explored the effect of processing relevant information on producing solutions to brief insight problems. She hypothesized that the conceptual processing of objects relevant to the target solution would facilitate that solution relative to unrelated objects or the shallow processing of words. The author also explored the effect of knowledge of the relationship between the initial object-processing task and the problem-solving task. The results showed that participants who conceptually processed objects related to the target solution (Experiment 1), but not those who shallowly processed words related to the target solution (Experiment 2), were more likely to produce the solution relative to the control; and knowledge of the relationship between objects and solutions made no difference in the frequency of target solutions produced. The results of Experiment 3 showed that conceptual processing of an object could prime a nondominant solution for an ambiguously worded problem. Taken together, the results of the studies supported the effect of conceptual processing on facilitating insight in problem solving.


Tissue engineering.
Tissue engineering concepts will enter the clinical arena in thoracic and cardiovascular surgery soon and at high speed, replacing many procedures currently in practice. Drivers for change are suboptimal implants (heart valves) and missing implants (heart muscle). Medical device industry has to include these new concepts into their future perspectives.


Diagnostic accuracy and microbial profiles of tuberculous pleurisy: a comparative study of metagenomic next generation sequencing and GeneXpert Mycobacterium tuberculosis.
There is a clinical challenge in diagnosing tuberculous pleurisy accurately and promptly, highlighting the urgent need for a rapid and sensitive diagnostic method. This study aimed to evaluate the diagnostic accuracy of metagenomic next-generation sequencing (mNGS) and GeneXpert Mycobacterium tuberculosis (MTB) for identifying tuberculous pleurisy and analyzing the microbial profiles of both tuberculous and non-tuberculous pleural effusions. The study enrolled 31 patients with suspected tuberculous pleurisy, of which 15 were confirmed to have tuberculous pleurisy and subsequently allocated to the tuberculous pleurisy group (TP group), while the remaining 16 individuals were assigned to the non-tuberculous pleurisy group (NTP group). mNGS and GeneXpert MTB were performed on pleural effusion samples, and the diagnostic accuracy of both tests was compared. We employed established formulas to compute crucial indicators, including sensitivity, specificity, missed diagnosis rate, misdiagnosed rate, positive predictive value (PPV), and negative predictive value (NPV). The results showed that both tests had high specificity (100%) and positive predictive value (100%) for detecting tuberculous pleurisy, along with comparable sensitivity (46.67% for mNGS and 40.0% for GeneXpert MTB). Further analysis of the combined efficacy of mNGS and GeneXpert MTB showed that the combined test had a sensitivity of 66.67% and a specificity of 100%. mNGS analysis revealed that MTB was detected in 7 out of 15 patients with tuberculous pleural effusions, while non-tuberculous pleural effusions were associated with a diverse range of microbial genera and species. The most frequently detected genera at the microbial genus level in the NTP group were Microbacterium spp. (6/16), Prevotella spp. (5/16), and Campylobacter spp. (5/16). These findings suggest that mNGS and GeneXpert MTB are useful diagnostic tools for identifying patients with tuberculous pleurisy, and mNGS can provide valuable insights into the microbial profiles of both tuberculous and non-tuberculous pleural effusions.


Faster cognitive decline in the years prior to MR imaging is associated with smaller hippocampal volumes in cognitively healthy older persons.
Early identification of persons at risk for cognitive decline in aging is critical to optimizing treatment to delay or avoid a clinical diagnosis of mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD). To accomplish early identification, it is essential that trajectories of cognitive change be characterized and associations with established biomarkers of MCI and AD be examined during the phase in which older persons are considered cognitively healthy. Here we examined the association of rate of cognitive decline in the years leading up to structural magnetic resonance imaging with an established biomarker, hippocampal volume. The sample comprised 211 participants of the Rush Memory and Aging Project who had an average of 5.5 years of cognitive data prior to structural scanning. Results showed that there was significant variability in the trajectories of cognitive change prior to imaging and that faster cognitive decline was associated with smaller hippocampal volumes. Domain-specific analyses suggested that this association was primarily driven by decline in working memory. The results emphasize the importance of closely examining cognitive change and its association with brain structure during the years in which older persons are considered cognitively healthy.


Role of complement component C1q in the IgG-independent opsonophagocytosis of group B streptococcus.
We investigated the role of complement component C1q in the IgG-independent opsonophagocytosis of type III group B Streptococcus (GBS) by peripheral blood leukocytes. We report that C1q binds to type III GBS both in normal human serum deficient in IgG specific for type III capsular polysaccharide and in a low-ionic strength buffer. The dissociation constant Kd ranged from 2.0 to 5.5 nM, and the number of binding sites Bmax ranged from 630 to 1360 molecules of C1q per bacterium (CFU). An acapsular mutant strain of GBS bound C1q even better than the wild type, indicating that the polysaccharide capsule is not the receptor for C1q. In serum, binding of C1q to GBS was associated with activation of the classical complement pathway. However, normal human serum retained significant opsonic activity after complete depletion of C1q, suggesting that the serum contains a molecule that is able to replace C1q in opsonization and/or complement activation. Mannan-binding lectin, known to share some functions with C1q, appeared not to be involved, since its depletion from serum had little effect on opsonic activity. Excess soluble C1q or its collagen-like fragment inhibited phagocytosis mediated by normal human serum, suggesting that C1q may compete with other opsonins for binding to receptor(s) on phagocytes. We conclude that, although C1q binds directly to GBS, C1q binding is neither necessary nor sufficient for IgG-independent opsonophagocytosis. The results raise the possibility that additional unknown serum factor(s) may contribute to opsonization of GBS directly or via a novel mechanism of complement activation.


Sharpening the focus on populations: an intentional community health nursing approach. Part II.
An interpretive study conducted in a Midwestern metropolitan area was designed to examine expertise in everyday community health nursing (CHN) practice. Twenty-five nurses from three practice areas (traditional, nontraditional, and program development) participated in group and individual interviews and field observations, sharing stories of their practice. Transcribed interviews and field observation notes were analyzed as a text. One of the major findings of the study focused on experiences of the nurses as they developed the population aspects of their everyday practice. Part I describes the natural development of a population focus of CHN generalists whose care most often targeted individuals and families. The stories of how their practices evolved and were supported by their institutions provided insights into how nurses develop a broad population-focused practice perspective. Part II examines the practice of those CHN specialists who nurse their target populations from an intentional perspective. Their population-focused practice, in which they repeatedly displayed what the research team terms multilingual and multiperspectival skills, was solidly based in their prior individual and family-focused experience and expertise in program planning and evaluation.


Efficacy and safety profile of the novel antimicrobial peptide PXL150 in a mouse model of infected burn wounds.
The urgent need to develop novel antimicrobial therapies has stimulated interest in antimicrobial peptides as therapeutic candidates for the treatment of infectious diseases. The aim of this study was to evaluate the anti-infectious effect of the synthetic antimicrobial peptide PXL150, formulated in hydroxypropyl cellulose (HPC) gel, on Pseudomonas aeruginosa in vitro and in an in vivo mouse model of infected burn wounds as well as to assess the in vivo safety profile of PXL150 in rats and rabbits. Minimal microbicidal concentration analysis showed prominent efficacy of PXL150 against P. aeruginosa in vitro, which was further enhanced in formulating the peptide in HPC gel. Application of 1.25, 2.5, 5, 10 and 20mg/g PXL150 in HPC gel twice daily for four consecutive days significantly reduced bacterial counts in the burn wounds compared with non-treated or placebo-treated controls. Continuous bioluminescence measurements of the bacteria revealed a pronounced anti-infective effect already at the first day post infection by PXL150 in concentrations of ≥2.5mg/g. In the non-clinical safety studies, PXL150 showed a favourable safety profile following repeated administration systemically and locally in rats and rabbits, respectively. In conclusion, these data support that PXL150 has the potential to be an effective and safe drug candidate for the treatment of infected burn wounds. The findings encourage the progression of PXL150 as a novel topical treatment of microbial infections.


Does despotic behavior or food search explain the occurrence of problem brown bears in Europe?
Bears foraging near human developments are often presumed to be responding to food shortage, but this explanation ignores social factors, in particular despotism in bears. We analyzed the age distribution and body condition index (BCI) of shot brown bears in relation to densities of bears and people, and whether the shot bears were killed by managers (i.e., problem bears; n = 149), in self-defense (n = 51), or were hunter-killed nonproblem bears (n = 1,896) during 1990-2010. We compared patterns between areas with (Slovenia) and without supplemental feeding (Sweden) of bears relative to 2 hypotheses. The food-search/food-competition hypothesis predicts that problem bears should have a higher BCI (e.g., exploiting easily accessible and/or nutritious human-derived foods) or lower BCI (e.g., because of food shortage) than nonproblem bears, that BCI and human density should have a positive correlation, and problem bear occurrence and seasonal mean BCI of nonproblem bears should have a negative correlation (i.e., more problem bears during years of low food availability). Food competition among bears additionally predicts an inverse relationship between BCI and bear density. The safety-search/naivety hypothesis (i.e., avoiding other bears or lack of human experience) predicts no relationship between BCI and human density, provided no dietary differences due to spatiotemporal habitat use among bears, no relationship between problem bear occurrence and seasonal mean BCI of nonproblem bears, and does not necessarily predict a difference between BCI for problem/nonproblem bears. If food competition or predation avoidance explained bear occurrence near settlements, we predicted younger problem than nonproblem bears and a negative correlation between age and human density. However, if only food search explained bear occurrence near settlements, we predicted no relation between age and problem or nonproblem bear status, or between age and human density. We found no difference in BCI or its variability between problem and nonproblem bears, no relation between BCI and human density, and no correlation between numbers of problem bears shot and seasonal mean BCI for either country. The peak of shot problem bears occurred from April to June in Slovenia and in June in Sweden (i.e., during the mating period when most intraspecific predation occurs and before fall hyperphagia). Problem bears were younger than nonproblem bears, and both problem and nonproblem bears were younger in areas of higher human density. These age differences, in combination with similarities in BCI between problem and nonproblem bears and lack of correlation between BCI and human density, suggested safety-search and naïve dispersal to be the primary mechanisms responsible for bear occurrence near settlements. Younger bears are less competitive, more vulnerable to intraspecific predation, and lack human experience, compared to adults. Body condition was inversely related to the bear density index in Sweden, whereas we found no correlation in Slovenia, suggesting that supplemental feeding may have reduced food competition, in combination with high bear harvest rates. Bears shot in self-defense were older and their BCI did not differ from that of nonproblem bears. Reasons other than food shortage apparently explained why most bears were involved in encounters with people or viewed as problematic near settlements in our study.


Noun-phrase anaphors and focus: the informational load hypothesis.
The processing of noun-phrase (NP) anaphors in discourse is argued to reflect constraints on the activation and processing of semantic information in working memory. The proposed theory views NP anaphor processing as an optimization process that is based on the principle that processing cost, defined in terms of activating semantic information, should serve some discourse function--identifying the antecedent, adding new information, or both. In a series of 5 self-paced reading experiments, anaphors' functionality was manipulated by changing the discourse focus, and their cost was manipulated by changing the semantic relation between the anaphors and their antecedents. The results show that reading times of NP anaphors reflect their functional justification: Anaphors were read faster when their cost had a better functional justification. These results are incompatible with any theory that treats NP anaphors as one homogeneous class regardless of discourse function and processing cost.


HinCyc: a knowledge base of the complete genome and metabolic pathways of H. influenzae.
We present a methodology for predicting the metabolic pathways of an organism from its genomic sequence by reference to a knowledge base of known metabolic pathways. We applied these techniques to the genome of H. influenzae by reference to the EcoCyc knowledge base to predict which of 81 metabolic pathways of E. coli are found in H. influenzae. The resulting prediction is a complex hypothesis that is presented in computer form as HinCyc: an electronic encyclopedia of the genes and metabolic pathways of H. influenzae. HinCyc connects the predicted genes, enzymes, enzyme-catalyzed reactions, and biochemical pathways in a WWW-accessible knowledge base to allow scientists to explore this complex hypothesis.


Natural language processor as a tool to assess heparin induced thrombocytopenia awareness.
The life-threatening consequences of heparin induced thrombocytopenia (HIT) may be prevented with early recognition, prompt heparin withdrawal and direct thrombin inhibitor use. To determine the level of HIT awareness, electronic term recognition software can be used to query the electronic medical record (EMR) to assess the thought process and test ordering behavior of health care providers confronted with falling platelet counts. We sought to assess the awareness of HIT in a large teaching institution using these tools. Mayo Clinic databases were queried to identify a cohort of hospitalized adults receiving heparin (06/1/08-06/1/09). Serial platelet counts for each patient were scrutinized for a 50% decrement from baseline. "Clinician awareness" was defined by mention of HIT (determined by electronic term recognition software) within the hospital record by any member of the healthcare team or requisition of platelet factor 4/heparin antibody testing. During this time period, 34,694 adults were hospitalized and 24,956 received heparin. Only 3,239 (13%) patients had more than 1 platelet count during the hospital stay. Of 199 patients (6.1%) with ≥50% platelet count drop, clinician awareness was 36%. The absolute platelet count was the only independent variable associated with HIT awareness (P < 0.001). Both appropriate platelet count monitoring and HIT awareness are low at this large teaching institution. Software tools for monitoring awareness and providing realtime alerts of significant platelet count decrements may be useful.


Probing and trapping a sensitive conformation: amyloid-β fibrils, oligomers, and dimers.
Alzheimer's disease (AD) is a devastating neurodegenerative disease with pathological misfolding of amyloid-β protein (Aβ). The recent interest in Aβ misfolding intermediates necessitates development of novel detection methods and ability to trap these intermediates. We speculated that two regions of Aβ may allow for detection of specific Aβ species: the N-terminal and 22-35, both likely important in oligomer interaction and formation. We determined via epitomics, proteomic assays, and electron microscopy that the Aβ(42) species (wild type, ΔE22, and MetOx) predominantly formed fibrils, oligomers, or dimers, respectively. The 2H4 antibody to the N-terminal of Aβ, in the presence of 2% SDS, primarily detected fibrils, and an antibody to the 22-35 region detected low molecular weight Aβ species. Simulated molecular modeling provided insight into these SDS-induced structural changes. We next determined if these methods could be used to screen anti-Aβ drugs as well as identify compounds that trap Aβ in various conformations. Immunoblot assays determined that taurine, homotaurine (Tramiprosate), myoinositol, methylene blue, and curcumin did not prevent Aβ aggregation. However, calmidazolium chloride trapped Aβ at oligomers, and berberine reduced oligomer formation. Finally, pretreatment of AD brain tissues with SDS enhanced 2H4 antibody immunostaining of fibrillar Aβ. Thus we identified and characterized Aβs that adopt specific predominant conformations (modified Aβ or via interactions with compounds), developed a novel assay for aggregated Aβ, and applied it to drug screening and immunohistochemistry. In summary, our novel approach facilitates drug screening, increases the probability of success of antibody therapeutics, and improves antibody-based detection and identification of different conformations of Aβ.


The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis.
Liver-specific overexpression of the insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IGF2BP2-2 induces a fatty liver, which highly expresses IGF2 Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These findings underline the detrimental role of p62 in liver disease.


Usefulness of the Polish versions of the Montreal Cognitive Assessment 7.2 and the Mini-Mental State Examination as screening instruments for the detection of mild neurocognitive disorder.
Screening tests are a key step in the diagnosis of dementia and should therefore be highly sensitive to the detection of mild neurocognitive disorders (NCD). The Mini Mental State Examination (MMSE) is the most commonly used screening method. The Montreal Cognitive Assessment (MoCA) is a newer and less well-known screening tool, which has none of the limitations of the MMSE. The aim of this study was to analyse the reliability of the Polish versions of MoCA 7.2 vs MMSE in the detection of mild NCD among people aged over 60. The study was carried out at the Department and Clinic of Geriatrics from September 2014 to March 2017. The study included 281 participants, 91 of whom were assigned to the group without NCD. The other 190 had been diagnosed with mild NCD. In the analysis of the ROC curve of the MoCA 7.2 results, the AUC was 0.925 (p < 0.001). The optimal cut-off point for mild NCD was 23/24 points, with sensitivity and specificity of 83.2% and 79.1%. In the ROC curve of MMSE results, the AUC was 0.847 (p < 0.001). The optimal cut-off point for mild NCD was 27/28 points, with sensitivity and specificity of 75.8% and 66.7%. The difference between AUC MoCA 7.2 and MMSE was 0.078 (p = 0.036). MoCA 7.2 detects mild NCD with more sensitivity than MMSE. We recommend using the cut-off point for MoCA of 23/24 points, because this is characterised by a higher sensitivity than the previously recommended cut-off point of 25/26 points. For the MMSE, the recommended cut-off point should be 27/28, which gives greater diagnostic accuracy than the previously recommended 25/26 points.


Vestibulospinal and Corticospinal Modulation of Lumbosacral Network Excitability in Human Subjects.
As part of a project aimed to develop a novel, non-invasive techniques for comprehensive assessment of supraspinal-spinal connectivity in humans, the present study sought to explore the convergence of descending vestibulospinal and corticospinal pathways onto lumbosacral motor pools. Transcutaneous electrical spinal stimulation-evoked motor potentials were recorded from knee and ankle flexors and extensors in resting neurologically intact participants. Descending influences on lumbosacral motor neurons were studied using galvanic vestibular (GVS) or transcranial magnetic stimulation (TMS) to elicit descending vestibulospinal or corticospinal volleys, respectively. Facilitatory conditioning effects of descending corticospinal volleys were manifested by a significant increase of spinally evoked motor potentials in recorded knee and ankle muscles bilaterally, and were observed at the 10-30 ms conditioning-test intervals (CTIs); whereas, facilitatory conditioning effects of vestibulospinal volleys manifested at longer latencies (CTIs of 90 and 110 ms), and lasted up to 250 ms. TMS mediated volleys revealed the conditioning effects at both short and long latencies, suggestive of both direct and indirect influence. In contrast, vestibulospinally mediated conditioning effects occurred at longer latencies, consistent with this pathway's known anatomical and functional interfaces with other descending systems including the reticulospinal pathway and, suggestively, propriospinal interneurons. Our work demonstrates the utility and sensitivity of transcutaneous spinal stimulation in human neurophysiological studies as a technique for quantitative characterization of excitatory conditioning effects in multiple lumbosacral motor pools, obtained through descending pathways. This characterization becomes critical in understanding the neuroplasticity in the central nervous system during motor learning and neurological recovery.


Using detergent-enhanced LAMP for African trypanosome detection in human cerebrospinal fluid and implications for disease staging.
Where human African trypanosomiasis (HAT) patients are seen, failure to microscopically diagnose infections by Trypanosoma brucei gambiense in blood smears and/or cerebrospinal fluid (CSF) in the critical early stages of the disease is the single most important factor in treatment failure, a result of delayed treatment onset or its absence. We hypothesized that the enhanced sensitivity of detergent-enhanced loop-mediated isothermal amplification (LAMP) will allow for point of care (POC) detection of African trypanosomes in the CSF of HAT patients where the probability for detecting a single parasite or parasite DNA molecule in 1 μL of CSF sample is negligible by current methods. We used LAMP targeting the multicopy pan-T. brucei repetitive insertion mobile element (RIME LAMP) and the Trypanosoma brucei gambiense 5.8S rRNA-internal transcribed spacer 2 gene (TBG1 LAMP). We tested 1 μL out of 20 μL sham or Triton X-100 treated CSFs from 73 stage-1 and 77 stage-2 HAT patients from the Central African Republic and 100 CSF negative controls. Under sham conditions, parasite DNA was detected by RIME and TBG1 LAMP in 1.4% of the stage-1 and stage-2 gambiense HAT CSF samples tested. After sample incubation with detergent, the number of LAMP parasite positive stage-2 CSF's increased to 26%, a value which included the 2 of the 4 CSF samples where trypanosomes were identified microscopically. Unexpected was the 41% increase in parasite positive stage-1 CSF's detected by LAMP. Cohen's kappa coefficients for RIME versus TBG1 LAMP of 0.92 (95%CI: 0.82-1.00) for stage-1 and 0.90 (95%CI: 0.80-1.00) for stage-2 reflected a high level of agreement between the data sets indicating that the results were not due to amplicon contamination, data confirmed in χ2 tests (p<0.001) and Fisher's exact probability test (p = 4.7e-13). This study detected genomic trypanosome DNA in the CSF independent of the HAT stage and may be consistent with early CNS entry and other scenarios that identify critical knowledge gaps for future studies. Detergent-enhanced LAMP could be applicable for non-invasive African trypanosome detection in human skin and saliva or as an epidemiologic tool for the determination of human (or animal) African trypanosome prevalence in areas where chronically low parasitemias are present.


Reactive muscle firing of anterior cruciate ligament-injured females during functional activities.
The high incidence of noncontact anterior cruciate ligament (ACL) injuries in females has attracted research to investigate the capacity of muscles to reflexively protect the knee joint from capsuloligamentous injury. Numerous reflex pathways link mechanoreceptors in the ACL with contractile fibers in the quadriceps and hamstring muscles. Loads placed on the ACL modify reactive muscle activity through the feed-back process of neuromuscular control and are critical for dynamic muscular stabilization. Noncontact ACL injuries may be the result of aberrations in reactive muscle firing patterns. Therefore, compensatory muscle activation strategies must be employed if functional stability is to be restored after injury or surgical reconstruction. The purpose of our study was to compare the amplitude of reactive muscle activity in females with ACL-deficient (ACLD), ACL-reconstructed (ACLR), and control knees during functional activities. Female volunteer subjects were stratified into groups based on the status of their ACLs. Each subject performed 4 functional activities, bilaterally, during a single test session. Twenty-four female subjects participated in this study (ACLD = 6, ACLR = 12, control = 6). Integrated electromyographic (IEMG) data were collected with surface electrodes from the vastus medialis, vastus lateralis, medial hamstring, and lateral hamstring during downhill walking (15 degrees , 0.92 m/s), level running (2.08 m/s), and hopping and landing from a jump (20.3 cm). IEMG was normalized to the mean amplitude of 3 to 6 consecutive test repetitions. The mean area and peak IEMG of a 250-millisecond period after ground contact was used to represent reactive muscle activity. Side-to-side differences were determined using dependent t tests, and group differences were determined using a one-way analysis of variance. During running, the ACLD group demonstrated significantly greater area and peak IEMG activity in the medial hamstring in comparison with the ACLR group and greater peak activity in the lateral hamstring when compared with the control group. The ACLD group also demonstrated greater peak activity in the vastus medialis and a smaller area of IEMG activity in the lateral hamstring than the control group during running. During landing, the ACLD group demonstrated significantly less area of IEMG activity in the vastus lateralis when compared with the control group. No significant differences were identified between the ACLR and control groups, nor were side-to side differences revealed. Our results suggest that adaptations occur in the reactive muscle activity of ACLD females during functional activities. Strategies to minimize the anterior tibial translation in response to joint loading included increased hamstring activity and quadriceps inhibition. The reactive muscle activity exhibited in ACLD subjects is presumably an attempt to regain functional stability through the dynamic restraint mechanism. The absence of side-to-side differences suggests that these adaptations occur bilaterally after ACL injury.