Successful treatment using immunotherapy in combination with chemotherapy for metastatic squamous cell carcinoma of unknown primary origin with bulky abdominal mass: A case report.
Cancer of unknown primary (CUP) means that the primary focus cannot be found after preliminary clinical evaluation. It accounts for 2.3% to 5% of newly diagnosed cancer cases. Due to the lack of standard treatment, CUP is usually associated with poor prognosis and is the third to fourth most common cause of cancer-related deaths. We report the case of a 42-year-old female patient who was admitted to the hospital for intermittent right abdominal pain and abdominal distension. Abdominal computed tomography (CT) showed a large abdominal mass of unknown origin, which was difficult to resect due to its close relationship with surrounding tissues. Twenty days later, the patient had enlarged left supraclavicular lymph nodes, and percutaneous biopsy revealed squamous cell carcinoma. In addition, next-generation sequencing (NGS) of tissue and blood samples showed immune-related mutations and PD-L1 expression. The patient was diagnosed with metastatic squamous cell carcinoma of unknown primary origin, with a bulky abdominal mass. The patient was treated with carboplatin, albumin-binding paclitaxel, and immune checkpoint inhibitor (carilizumab). After 6 cycles, the patient was switched to maintenance treatment with carilizumab. The general condition of the patient improved, and the lesion was significantly reduced. The treatment efficacy was assessed as partial remission according to Response Evaluation Criteria in Solid Tumors. The patient benefited from immunotherapy combined with chemotherapy. There is no recommended standard treatment for most CUPs, which leads to their poor prognoses. By performing NGS for patients and targeting immune-related positive predictors, immunotherapy combined with chemotherapy may prolong the overall survival of patients. This case report suggests that immunotherapy combined with chemotherapy is feasible and effective in patients with CUP.


Dopaminergic neuronal survival and the effects of bFGF in explant, three dimensional and monolayer cultures of embryonic rat ventral mesencephalon.
Embryonic substantia nigra cells when transplanted into the striatum can reverse many of the defects of Parkinson's disease. The efficacy of such grafts is compromised by the poor survival of grafted dopaminergic neurones; typically, 3-10% survive transplantation. We used three tissue culture models to identify stages in the procedure for the preparation and insertion of grafts which might be responsible for this cell death and to identify environments in which survival is optimised. (1) The ventral mesencephalon was dissected from the donor brain, then placed immediately into culture contained in a collagen gel. (2) The dissected tissue fragments were enzymatically dissociated, then the cells placed into monolayer culture. (3) Enzymatically dissociated tissue was packed into 0.5-mm-diameter porous tubes, to simulate the compaction of cells into a graft deposit in the host brain. Dissociation of the tissue by itself caused the death of approximately 30% of dopaminergic neurones, as judged by the difference in cell counts between the intact embryonic day 14 (E14) mesencephalon, and cells dissociated then packed into tubes. Of the dissociated neurones approximately 60% died during the first 24 h and 87% during the first 3 days in monolayer culture, while only 7% of dopaminergic neurones in three-dimensional cultures and 11% of neurones in explant cultures died over the first 3 days. Embryonic dopaminergic neurones are clearly very vulnerable to adverse conditions during the first days after their removal from the donor brain. The excellent survival of neurones in three-dimensional and explant cultures indicates that close association with other cells, which may provide greatly improved access to trophic factors, can enable the cells to survive this period of vulnerability. In contrast to its effects in monolayer cultures, bFGF had no effect on dopaminergic neuronal survival in either explant or three-dimensional cultures.


HIV-1 envelope protein evokes intracellular calcium oscillations in rat hippocampal neurons.
Treatment of single rat hippocampal neurons with 200 pM recombinant HIV-1 envelope glycoprotein, gp120, resulted in large increases in the intracellular free calcium concentration ([Ca2+]i) as measured with indo-1-based microfluorimetry. Three patterns of [Ca2+]i increases were observed: in one pattern the [Ca2+]i rose rapidly and transiently as a single peak, in a second pattern gp120 induced [Ca2+]i oscillations that subsided when the protein was removed, and in a third pattern the oscillations continued long after washout of gp120. Both single peak and oscillatory [Ca2+]i increases were completely blocked by the Ca2+ channel blocker nitrendipine (1 microM). The sustained oscillatory responses were also blocked completely and reversibly by the N-methyl-D-aspartate (NMDA) receptor antagonist CGS19755 (10 microM) and the Na+ channel blocker tetrodotoxin (1 microM). Complete block by antagonists of Ca2+, Na+, and NMDA-gated ion channels suggests that at least two cells are required to maintain the [Ca2+]i oscillations. We hypothesize that gp120 acts as an excitotoxin by increasing synaptic activity in the network of neurons established in primary culture.


Timing of bilateral cerebellar output evoked by unilateral vestibular stimulation in the frog.
Electrical stimulation of one VIIIth nerve evoked simple spike activity in Purkinje cells located on either side of the cerebellum. This cellebullar output was delayed by ca. 10 ms with respect to its mossy fiber-parallel fiber input. The onset of the cerebellar output occurs on the average simultaneously on either side of the corpus cerebelli. The delay is explained by slowly rising EPSPs in PC induced by primary afferent and by second and higher order vestibular fibers. The latter inputs are stronger and terminate ipsi- and contralaterally in the granular layer.


Analysis of dietary patterns and nutritional adequacy in lactating women: a multicentre European cohort (ATLAS study).
Eating habits of lactating women can influence the nutrient composition of human milk, which in turn influences nutrient intake of breastfed infants. The aim of the present study was to identify food patterns and nutritional adequacy among lactating women in Europe. Data from a multicentre European longitudinal cohort (ATLAS study) were analysed to identify dietary patterns using cluster analysis. Dietary information from 180 lactating women was obtained using 3-d food diaries over the first 4 months of lactation. Four dietary patterns were identified: 'vege-oils', 'fish-poultry', 'confectionery-salads' and 'mixed dishes'. Nutrition adequacy was not significantly different between clusters, but the 'vege-oils' cluster tended to yield the highest nutrition adequacy measured by Mean Adequacy Ratio. Compared with European dietary reference values (DRVs) for lactating women, women in all clusters had inadequate intakes of energy, pantothenic acid, folate, vitamin C, vitamin A, vitamin D, zinc, iodine, potassium and linoleic acid. Adequate intake for fibre and α-linolenic acid was only achieved in the 'vege-oils' cluster. Overall, fat intake was above DRVs. The present study showed that various dietary patterns do not adequately supply all nutrients, indicating a need to promote overall healthy dietary habits for European lactating women.


Neural associative memories and sparse coding.
The theoretical, practical and technical development of neural associative memories during the last 40 years is described. The importance of sparse coding of associative memory patterns is pointed out. The use of associative memory networks for large scale brain modeling is also mentioned.


Nonrandom X Chromosome Inactivation Detection.
X chromosome inactivation patterns may be clinically useful in assessing tumor clonality, determining carrier status for certain X-linked disorders, and evaluating the pathogenicity of a genetic variant identified in an X-linked gene. The protocols in this article utilize the highly polymorphic trinucleotide repeat within the first exon of the human androgen receptor gene (AR) and the methylation-sensitive restriction enzyme HpaII to distinguish between the maternal and paternal alleles and simultaneously determine their methylation status. The data obtained from these protocols can be used to calculate the ratio of inactivation between the two alleles that ultimately reflects whether a female has a random or nonrandom pattern of X chromosome inactivation. © 2023 Wiley Periodicals LLC. Basic Protocol 1: X chromosome inactivation assay Basic Protocol 2: PCR amplification and labeling of digested and undigested DNA templates.


Thymoma: prognostic factors.
The relative importance of factors influencing prognosis and survival in the treatment of thymoma is still controversial. Fifty-three patients operated on for thymoma from 1966 to 1990 were evaluated, 14 with myasthenia gravis and 39 without. Survival was analyzed as it related to associated disease, gross invasion by the tumor and the predominant cell type. Follow-up information was obtained in all cases (mean observation time: 11.2 years). A high proportion (51%) of our patients had invasive forms (stages III and IV). The overall 5-, 10- and 20-year survival rates were 52%, 46% and 21%, respectively. Factors indicating a poor prognosis included local invasion (P < 0.0001), predominantly, epithelial histologic features (P = 0.002), tumor-related symptoms and the type of surgical procedure. Myasthenia gravis was not an adverse factor for survival. The degree of tumor invasion was the main prognostic factor and treatment should be planned accordingly.


Excitation-contraction coupling: effects of "zero"-Ca2+ medium.
Frog sartorius muscles, exposed for up to 15--20 min to media containing ethylene glycol bis (beta-aminoethyl ether) - N, N'-tetraacetic acid and thus having free Ca2+ concentration less than 10(-8) M, produce isometric contractions with basically normal but speedier latency relaxation and earliest tension development. The excitation-contraction coupling is thus also basically normal, but speedier evidently in respect to release of activator Ca2+ from the sarcoplasmic reticulum.


In vivo toxicity evaluation of biologically synthesized silver nanoparticles and gold nanoparticles on adult zebrafish: a comparative study.
In this study, toxicity of biologically synthesized silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs) was compared using zebrafish as a model organism. At 96 h, LC50 of AgNPs and AuNPs was found to be 24.5 µg/L and 41 mg/L, respectively. Following the LC50 determination, half of the LC50 of AgNPs (12.25 µg/L) and AuNPs (20.5 mg/L) was exposed to adult zebrafishes for 14 days. Morphological changes, liver marker enzymes, reactive oxygen species (ROS) generation, genotoxic effects and mRNA expression levels of oxidative stress and innate immune response related genes were studied using nanoparticle treated gill, liver and blood cells. In this study, AgNP-treated gill and liver tissues showed a number of morphological changes such as cell membrane damage, irregular cell outlines, pyknotic nuclei and complete disruption of gill and liver cells; on the contrary, AuNPs treated liver tissues alone showed such changes. The levels of liver marker enzymes such as alanine aminotransferase and aspartate aminotransferase were increased after AgNPs treatment when compared to AuNPs treatment. AgNP-treated liver cells showed higher levels of ROS generation than the control; on the other hand, AuNPs treatment exhibited lower levels of ROS generation than the control. Interestingly, AgNP-treated blood cells showed micronuclei formation and nuclear abnormalities, while AuNPs treatment did not show such effects. Based on these observations, it is clear that AgNPs may cause oxidative stress and immunotoxicity to adult zebrafish than the AuNPs. However, these results clearly reveal the significance of relatively safe and less toxic bionanomaterials for possible biomedical applications.


Crosslinking of ribosomal proteins S4, S5, S7, S8, S11, S12 and S18 to domains 1 and 2 of 16S rRNA in the Escherichia coli 30S particle.
RNA-protein crosslinks were introduced into Escherichia coli 30S ribosomal subunits by treatment with 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDC). Complexes of 16S rRNA cross-linked to 30S ribosomal proteins were isolated and hybridized with a series of single-stranded bacteriophage M13-rDNA probes. These probes, each carrying an inserted rDNA fragment, were used to select contiguous 16S rRNA sections covering all of domain 1 and the major part of domain 2 (starting at the 5'-P terminus and ending at nucleotide 869) and the proteins covalently linked to each of these sections were identified by 2-dimensional polyacrylamide gel electrophoresis. This procedure identified proteins S4, S5, S7, S8, S11, S12, and S18 as the species most efficiently crosslinked to domains 1 and 2 of 16S rRNA. These results are discussed in the light of current knowledge of the tertiary structure of 16S rRNA in the E. coli 30S ribosomal subunit.


Design and development of novel series of indole-3-sulfonamide ureido derivatives as selective carbonic anhydrase II inhibitors.
Indole is a privileged moiety with a wide range of bioactivities, making it a popular scaffold in drug design and development studies as well as in synthetic chemistry. Here, novel urea derivatives of indole, containing sulfonamide at position-3 of indole, were synthesized using a well-known tail approach, as carbonic anhydrases (CAs; EC 220.127.116.11) inhibitors. All the newly synthesized molecules were screened for their CA-inhibitory activity against four clinically relevant isoforms of human-origin carbonic anhydrase (hCA), that is, hCA I, hCA II, hCA IX, and hCA XII. These compounds were specifically active against hCA II, more than against hCA I, hCA IX, and hCA XII. Derivative 6l was found to be most active, with a Ki value of 7.7 µM against hCA II.


Tumors, cysts and allied lesions of the jaws and oral mucosa in Lagos, Nigeria, 1969-74.
Tumors, tumor-like lesions and cysts of the oral cavity and jaw bones seen over a 5-year period, 1969-1974, in the Department of Oral Surgery and Pathology, Lagos University Teaching Hospital, Lagos, Nigeria, are reviewed using the World Health Organization's guidelines for histologic classifications. The histopathologic distribution of the 286 lesions seen over this period was as follows: tumors of non-odontogenic tissues, 180 cases (62.9%); tumors of odontogenic tissue, 37 cases (12.9%); cysts and periapical granulomas, 67 cases (23.4%) and tumors of debatable odontogenic origin, two cases (0.8%). On the strength of available evidence, this report does not share the view that jaw tumors are more common among Africans; instead, the report's conclusion agrees with the "harvesting" theory: that jaw tumors, which are generally slow-growing, painless and non life-threatening, are "showing up" more at treatment centres throughout Africa, thus giving a clinician the chance to see many cases of jaw lesions over a relatively short time.


Cutting edge: IL-1β processing during Pseudomonas aeruginosa infection is mediated by neutrophil serine proteases and is independent of NLRC4 and caspase-1.
To examine the role of caspase-1 and the NLRC4 inflammasome during bacterial infection, C57BL/6, IL-1β(-/-), caspase-1(-/-), and NLRC4(-/-) mouse corneas were infected with ExoS/T- or ExoU-expressing Pseudomonas aeruginosa. We found that IL-1β was essential for neutrophil recruitment and bacterial clearance and was produced by myeloid cells rather than resident cells. In addition, neutrophils were found to be the primary source of mature IL-1β during infection, and there was no significant difference in IL-1β processing between C57BL/6 and caspase-1(-/-) or NLRC4(-/-) infected corneas. IL-1β cleavage by human and mouse neutrophils was blocked by serine protease inhibitors and was impaired in infected neutrophil elastase (NE)(-/-) corneas. NE(-/-) mice also had an impaired ability to clear the infection. Together, these results demonstrate that during P. aeruginosa infection, neutrophils are the primary source of mature IL-1β and that IL-1β processing is dependent on serine proteases and not NLRC4 or caspase-1.


Novel Heteroleptic Tin(II) Complexes Capable of Forming SnO and SnO2 Thin Films Depending on Conditions Using Chemical Solution Deposition.
A new heteroleptic complex series of tin was synthesized by the salt metathesis reaction of SnX2 (X = Cl, Br, and I) with aminoalkoxide and various N-alkoxy-functionalized carboxamide ligands. The complexes, [ClSn(dmamp)]2 (1), [BrSn(dmamp)]2 (2), and [ISn(dmamp)]2 (3), were prepared from the salt metathesis reaction of SnX2 with one equivalent of dmamp; [Sn(dmamp)(empa)]2 (4), [Sn(dmamp)(mdpa)]2 (5), and [Sn(dmamp)(edpa)]2 (6) were prepared via the salt metathesis reaction using complex 2 with one equivalent of N-alkoxy-functionalized carboxamide ligand. Complexes 1-5 displayed dimeric molecular structures with tin metal centers interconnected by μ2-O bonding via the alkoxy oxygen atom. The molecular structures of complexes 1-5 showed distorted trigonal bipyramidal geometries with lone pair electrons in the equatorial position. Using complex 6 as a tin precursor, SnO x films were deposited by chemical solution deposition (CSD) and subsequent post-deposition annealing (PDA) at high temperatures. SnO and SnO2 films were selectively obtained under controlled PDA atmospheres of argon and oxygen, respectively. The SnO films featured a tetragonal romarchite structure with high crystallinity and a preferred growth orientation along the (101) plane. They also exhibited a lower transmittance of >52% at 400 nm due to an optical band gap of 2.9 eV. In contrast, the SnO2 films exhibited a tetragonal cassiterite crystal structure and an extremely high transmittance of >97% at 400 nm was observed with an optical band gap of 3.6 eV.


Jugular venous pulse recording in a patient without a tricuspid valve.
The unusual contour of the jugular venous pulse tracing (JVPT) in a patient whose tricuspid valve was excised is described. The appearance of an early positive systolic wave (SW) followed by a prominent "V" wave and a delayed deep "Y" descent were noted.


Regional mRNA expression of the endogenous opioid and dopaminergic systems in brains of C57BL/6J and 129P3/J mice: strain and heroin effects.
We have previously shown strain and dose differences in heroin-induced behavior, reward and regional expression of somatostatin receptor mRNAs in C57BL/6J and 129P3/J mice. Using Real Time PCR we examined the effects of five doses of heroin on the levels of the transcripts of endogenous opioid peptides and their receptors and dopaminergic receptors in the mesocorticolimbic and nigrostriatal pathways in these same mice. Compared to C57BL/6J animals, 129P3/J mice had higher mRNA levels of Oprk1 in the nucleus accumbens and of Oprd1 in the nucleus accumbens and a region containing both the substantia nigra and ventral tegmental area (SN/VTA). In the cortex of 129P3/J mice, lower levels of both Oprk1 and Oprd1 mRNAs were observed. Pdyn mRNA was also lower in the caudate putamen of 129P3/J mice. Strain differences were not found in the levels of Oprm1, Penk or Pomc mRNAs in any region examined. Within strains, complex patterns of heroin dose-dependent changes in the levels of Oprm1, Oprk1 and Oprd1 mRNAs were observed in the SN/VTA. Additionally, Oprd1 mRNA was dose-dependently elevated in the hypothalamus. Also in the hypothalamus, we found higher levels of Drd1a mRNA in C57BL/6J mice than in 129P3/J animals and higher levels of DAT (Slc6a3) mRNA in the caudate putamen of C57BL/6J animals than in 129P3/J counterparts. Heroin had dose-related effects on Drd1a mRNA in the hypothalamus and on Drd2 mRNA in the caudate putamen.


GENETICS OF STERILITY IN HYBRIDS BETWEEN TWO SUBSPECIES OF DROSOPHILA.
Hybrids between D. pseudoobscura bogotana and D. pseudoobscura pseudoobscura are fertile except for males produced in one of the two reciprocal crosses. As there is no premating isolation between these subspecies, nonreciprocal male sterility represents the first step in speciation. Genetic analysis reveals two causes of hybrid F1 sterility: a maternal effect and incompatibilities between chromosomes within males. The maternal effect appears to play the greatest role in hybrid sterility. The X chromosome has the largest effect on fertility of any chromosome, a ubiquitous result in analyses of hybrid sterility and inviability in Drosophila. This effect is entirely attributable to a region comprising less than 30% of the X chromosome. These results are compared to those from a similar study of D. pseudoobscura-D. persimilis hybrids, an older and more reproductively isolated species pair in the same lineage. Such comparisons may allow one to identify the genetic changes characterizing the early versus late stages of speciation.


Identification of transmembrane tryptic peptides of rhodopsin using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
The application of mass spectrometry for determining the topography of integral membrane proteins has focused primarily on the mass determination of fragments that do not reside in the lipid bilayer. In this work, we present the accurate mass determination of transmembrane tryptic peptides of bovine rhodopsin using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The ability to determine the accurate mass of hydrophobic transmembrane peptides will facilitate the mapping of ligand binding sites in membrane receptors. It will also augment the determination of membrane spanning regions from integral membrane proteins digested in lipid bilayers. Affinity-purified rhodopsin in detergent and rhodopsin in retinal rod membranes were digested with trypsin. Tryptic peptides were separated using reverse-phase, high-performance liquid chromatography at 55 degrees C with the detergent octyl-beta-glucoside in the mobile phase. Four of the six transmembrane tryptic peptides of rhodopsin were identified, ranging in mass from 3,260 Da to 6,528 Da. The identities of the peptides were confirmed by Edman microsequencing. In addition, heterogeneity in the glycosylation of the N-terminal tryptic peptide of rhodopsin was identified by MALDI MS, without modifying the carbohydrate prior to analysis.


Copy number variation and neuropsychiatric illness.
Copy number variants (CNVs) at specific loci have been identified as important risk factors for several neuropsychiatric disorders, such as schizophrenia, autism spectrum disorder, intellectual disability (ID) and depression. These CNVs are individually rare (<0.5% frequency), have high effect sizes, and show pleiotropic effects for multiple neuropsychiatric disorders, which implies a shared aetiology. Neuropsychiatric CNVs are also associated with cognitive impairment and other medical morbidities, such as heart defects and obesity. As most neuropsychiatric CNVs are multigenic, it has been challenging to map their effects onto specific biological processes, although gene-set analyses have implicated genes related to the synapse and chromatin regulation. However, future whole-genome sequencing studies have potential for identifying novel single-gene CNV associations, which could provide insights into the pathophysiology underlying neuropsychiatric disorders.


Assessment of ordered and complementary pore volumes in polymer-templated mesoporous silicas and organosilicas.
A method to determine the volumes of ordered mesopores and complementary small pores in polymer-templated ordered mesoporous silicas and organosilicas is proposed on the basis of the existing relation between the pore width and unit cell values obtained by the XRD structure modeling and the adsorption pore volume.


Examining dopamine D3 receptor occupancy by antipsychotic drugs via [3H]7-OH-DPAT ex vivo autoradiography and its cross-validation via c-fos immunohistochemistry in the rat brain.
Dopamine D3 receptors are a major target for drug discovery programs related to psychiatric disorders such as schizophrenia. The ability of a compound to occupy significant levels of D3 receptors is important for achieving therapeutic efficacy in both pre-clinical and clinical settings. Here we attempt to characterise antipsychotic drug-effects at D3 receptors by measuring receptor occupancy via ex-vivo [3H]7-OH-DPAT autoradiography, and further validating this outcome via analysis of Fos-like immunoreactivity (Fos-LI) in the rat major islands of Calleja (ICjM), a brain structure with high D3 expression. Rats were treated subcutaneously with haloperidol (0.04 mg/kg), clozapine (20 mg/kg) and olanzapine (0.63 mg/kg), the selective D2 antagonist L-741626 (2.5 mg/kg) and the selective D3 antagonist SB-277011-A (10 mg/kg). Doses were based on levels of D2 occupancy considered clinically relevant (60-80%). When measuring D3 occupancy, clozapine and SB-277011-A displayed meaningful levels of occupancy (60% and 77%, respectively), haloperidol and olanzapine showed limited occupancy (16% and 27%, respectively), whereas L-741626 showed no occupancy. There were no significant changes in ICjM Fos-LI after L-741626 and haloperidol treatment, minor but significant increases after olanzapine treatment, whereas highly significant increases were seen with SB-277011-A and clozapine. Additionally, pre-treating clozapine with the D1 antagonist SCH23390 caused a significant, albeit non-complete, reduction in Fos-LI, highlighting the D1 agonist property of clozapine. In conclusion, it appears that drugs occupying >50% D3 receptors produce robust increases in ICjM Fos-LI. This study may help to identify the appropriate D3 receptor antagonists that have the potential to be tested in the clinic.


Clinical Assessments of Hand Function in First Carpometacarpal Osteoarthritis Do Not Appear to Correlate with Radiographic Findings.
Thumb carpometacarpal (first CMC) osteoarthritis (OA), a degenerative process affecting hand use, is typically assessed by clinical examination and radiographs. This assessment determines treatment, but it may not reflect functional limitations. We aimed to explore the relationship between measures of hand function and radiographs in individuals with and without first CMC OA. We designed a cross-sectional, observational pilot study, enrolling five patients with first CMC OA (nine thumbs with modified Eaton-Littler grades ranging from 1 to 4, using retrospective radiographic data) and nine healthy controls. They underwent evaluation of hand function using four patient-reported outcome measures (PROMs)-the Patient-Specific Functional Scale (PSFS); the Patient-Rated Wrist/Hand Evaluation (PRWHE); the Disabilities of the Arm, Shoulder, and Hand (DASH); and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH)-and one performance measure, the Arthritis Hand Function Test (AHFT). Spearman's ρ with 95% subject clustered bootstrapped confidence intervals was calculated to assess for correlations between radiographic findings and measures of hand function. Only the DASH work score showed strong positive correlation with radiographic OA grade, with PSFS, PRWHE, M-SACRAH, and AHFT scores demonstrating low to moderate correlations. Notable differences were found between patients and control subjects in median scores of the DASH, PSFS, PRWHE, and M-SACRAH, as well as in the grip, pinch, and button scores of the AHFT. While only the DASH work score strongly correlated with radiographic grade of first CMC OA, several measures detected considerable differences in functional hand use between patients and control subjects. The findings of this pilot study suggest that hand function scores be considered in addition to radiographs when determining severity of first CMC OA. The findings can also inform the design of a larger, powered study.


Epilepsy self-management behaviors among African Americans with epilepsy.
Although self-management practices are heavily studied in the general population of adults with epilepsy, African American people with epilepsy (PWE) have been understudied. Improving understanding about epilepsy self-management among African Americans is warrantedbecause of the significantly greater mortality rates among this population compared withPWE from other racial/ethnic groups. The purpose of this study was to assess the reliability and validity of the Adult Epilepsy Self-Management Measurement Instrument (AESMMI) for Black/African American adults and describe their self-management behaviors. This study was a cross-sectional survey of self-identified Black/African American adults who reported that a health provider diagnosed them as having epilepsy or a seizure disorder. Participants completed a cross-sectional survey between spring 2017 and fall 2018. The survey measured self-management behaviors (65-itemAESMMI), quality of life, depression, seizure severity, epilepsy history, and demographics. We ran descriptive analyses, computed scales, and ran reliability statistics for the AESMMI. Correlations were run between total AESMMI score and depression symptoms and quality of life to assess construct validity. Generally, participants (N = 114) were male (58.6%), from urban/suburban settings (90.5%), at least high school graduates (86.4%), and of lowerincome (90.3%). Their ages ranged from 19 to 64 years with a mean age of 53 years (standard deviation [SD] = 10.9). Participants had general (72.8%) and focal seizures (55.3%) primarily. Many were diagnosed at a young age (M = 10.9), were on antiepileptic medications (91.2%), and had seen a primary care doctor (68.4%) or general neurologist for treatment (54.4%). Sixty percent had visited a neurologist in the past year. African American participants had a low score on quality of life (Quality of Life in Epilepsy [QOLIE], M = 1.86) and low depression symptoms (Patient Health Questionnaire [PHQ-8], M = 3.13). Participants reported conducting self-management behaviors in the following domains more frequently: proactivity (M = 4.11), medication adherence (M = 3.92), healthcare communications (M = 3.91), and social support (M = 3.90). In contrast, they performed self-management behaviors related to treatment (M = 3.34), stress management (M = 3.56), and safety (M = 3.58) less frequently. The overall reliability of the AESMMI was 0.88. Adult Epilepsy Self-Management Measurement Instrument score was correlated with quality of life (r = 0.151). Findings are clinically relevant as knowing patients'self-management behaviors enables healthcare clinicians to support and encourage adults to improve the management of their epilepsy. Services or interventions related to coping with stress, safety, and adherence with treatment and medication may be warranted for African Americans with epilepsy.


Treatment of Adolescent e-Cigarette Use: Limitations of Existing Nicotine Use Disorder Treatment and Future Directions for e-Cigarette Use Cessation.
Electronic cigarette use ("vaping") has surged in the United States since the mid-2010s. From 2011 to 2018, current e-cigarette use among high school students escalated from 1.5% to 20.8% (∼3.05 million youths),1 countering downward trends in combustible nicotine product use (21.8% in 2011 to 13.9% in 2018).1 Although preventing the initial uptake of vaping is crucial, for the millions of adolescents who have taken up this behavior-many of whom express interest in quitting (eg, 44.5% of current, adolescent non-light e-cigarette users in one US national representative sample)2-it is critically important to help them quit vaping so as to curtail future substance use disorders and other health consequences. Here, we discuss several challenges around adolescent vaping treatment, and highlight research areas in urgent need of attention.


The detection and quantification of Bacillus thuringiensis spores from soil and swabs using quantitative PCR as a model system for routine diagnostics of Bacillus anthracis.
To optimize the DNA isolation for the routine detection and quantification of bacillary spores in soil and swabs. The procedure is primarily intended for diagnostics of Bacillus anthracis spores, but due to its high pathogenicity, B. thuringiensis served as its surrogate organism. Various commercial kits for soils and swabs in combination with quantitative PCR were tested with different results. The PowerSoil DNA kit and the Ultra Clean Microbial DNA kit gave the best results for the extraction from soil and swabs, respectively. Extra beating led to considerably higher yields of DNA. The effectiveness of isolation reached 23% for DNA isolation from soil and 13% from swabs. The limit of detection was assessed to be 8·85 × 103 from 250 mg of soil and 2·79 × 103 from a swab inoculated with 100 μl of spore suspension. The optimized protocol is suitable for direct isolation and quantification of bacillary spores without any previous culturing. In contrast to previous studies, the isolation and quantification of spores was performed directly from the sample, without previous culture of spores on plates. Therefore, the method is suitable for such conditions where previous culturing is not possible, such as in military installations under field conditions.


Comparative Efficacy and Safety of Various Anti-Microbials in Patients of Acute Rhinosinusitis at Tertiary-Care Hospital in Uttarakhand (UK).
To compare the efficacy of gatifloxacin, azithromycin with amoxicillin as positive control for the treatment of Acute rhinosinusitis (ARS). To monitor adverse drug reaction profile of amoxicillin, azithromycin and gatifloxacin in patient of ARS. An open randomized trial of comparative efficacy and safety of amoxicillin, azithromycin and gatifloxacin in patients with ARS. Patients were randomized into three groups as under: group 1: patients on oral amoxicillin 500 mg TDS for 10 days; group 2: patients on oral azithromycin 500 mg OD for 5 days; group 3: patients on oral gatifloxacin 400 mg OD for 10 days. Patients were evaluated for signs and symptoms at day 1, day 7 (for group 2), on day 12 (for group 1, 3) as primary end points and 28 days after post therapy as secondary end point. All the three antimicrobial drugs i.e., amoxicillin, azithromycin and gatifloxacin were effective in reducing symptoms of acute sinusitis on visual analogue scale scoring. Azithromycin showed significant improvement radiographically on day 7 (P < 0.01) and on day 35 (P < 0.01). Gatifloxacin elicited very highly significant improvement radiographically on day 40 (P < 0.001) and significant improvement on day 12 (P < 0.01) when compared with amoxicillin. Azithromycin, the ketolide was associated with lesser adverse effects as compared to amoxicillin. All the three antimicrobial drugs i.e., amoxicillin, azithromycin and gatifloxacin were effective in reducing symptoms of acute sinusitis on visual analogue scale scoring. Gatifloxacin was found to be most effective drug both in terms of improvement in signs and symptoms on visual analogue scale and radiographic scoring and was associated with least adverse events in comparison to rest of two drugs under study.


Identification of a luminescent platinum(II) complex with BODIPY derivative as novel photodynamic therapy agent for triple negative breast cancer cells.
Triple-negative breast cancer (TNBC) is one of the most malignant breast tumors for its poor prognosis and high tumor recurrence. It is urgent to develop new strategy or effective agents to overcome resistance and improve therapeutic effectiveness. Boron-dipyrromethene (BODIPY) based photosensitizers possess exciting photophysical features suitable for theranostic applications, namely, photodynamic therapy (PDT). We have designed a luminescent monofunctional platinum(II) complex with BODIPY derivative, namely I2BC-Pt, as novel high PDT agent against triple negative breast cancer (TNBC). The di-iodinated BODIPY complex I2BC-Pt showed excellent PDT effect against TNBC cells in green light (520 nm) giving IC50 values of 0.11-0.13 μM in MDA-MB-231 and MDA-MB-468 cells. I2BC-Pt predominately aggregated in the mitochondria of MDA-MB-231 cells and emitted green fluorescence. Besides, the anticancer mechanism studies demonstrated that I2BC-Pt could help DNA repair through attenuating RAD51, FoxM1 and BRCA1/2, and induce p53-mediated apoptosis of TNBC cells. Taken together, I2BC-Pt could be potentially developed as a BODIPY-based photosensitizers for TNBC therapy.


Cytology of the respiratory tract.
Cytology can be a rewarding diagnostic technique in equine practice. The respiratory tract readily lends itself to sampling for cytologic evaluation from the upper to lower regions of the system. This article discusses preservation and staining techniques that will allow the practitioner to present satisfactory samples to the laboratory. General considerations for cytologic analysis are discussed as well as the specific findings for individual disorders of the respiratory tract. The proper use of cytologic findings in conjunction with other diagnostic techniques for the respiratory tract are also discussed.


A retrospective comparison for prediction of optimal length of right subclavian vein catheterization in infants: landmark-based estimation vs. linear regression model.
The optimal insertion length for right subclavian vein catheterization in infants has not been determined. This study retrospectively compared landmark-based and linear regression model-based estimation of optimal insertion length for right subclavian vein catheterization in pediatric patients of corrected age < 1 year. Fifty catheterizations of the right subclavian vein were analyzed. The landmark related distances were: from the needle insertion point (I) to the tip of the sternal head of the right clavicle (A) and from A to the midpoint (B) of the perpendicular line drawn from the sternal head of the right clavicle to the line connecting the nipples. The optimal length of insertion was retrospectively determined by reviewing post-procedural chest radiographs. Estimates using a landmark-based equation (IA + AB - intercept) and a linear regression model were compared with the optimal length of insertion. A landmark-based equation was determined as IA + AB - 5. The mean difference between the landmark-based estimate and the optimal insertion length was 1.0 mm (95% limits of agreement -18.2 to 20.3 mm). The mean difference between the linear regression model (26.681 - 4.014 × weight + 0.576 × IA + 0.537 × AB - 0.482 × postmenstrual age) and the optimal insertion length was 0 mm (95% limits of agreement -16.7 to 16.7 mm). The difference between the estimates using these two methods was not significant. A simple landmark-based equation may be useful for estimating optimal insertion length in pediatric patients of corrected age < 1 year undergoing right subclavian vein catheterization.


Eating behaviors, nutritional status, and menstrual function in elite female adolescent volleyball players.
Nutritional status, eating behaviors and menstrual function was examined in 23 nationally ranked female adolescent volleyball players using a health/weight/ dieting/menstrual history questionnaire, the Eating Disorder Inventory (EDI), and the Body Shape Questionnaire (BSQ). Nutrient and energy intakes (El) and energy expenditure (EE) were determined by 3-d weighed food records and activity logs. Iron (Fe), vitamins C, B12, and Folate status were assessed using serum and whole blood. Mean El (2248 +/- 414 kcal/d) was less than EE (2815 +/- 306 kcal/d). Mean carbohydrate (5.4 +/-1.0g/kg/d) and protein (1.1+/-0.3g/kg/d) intakes were below recommended levels for highly active women. Mean intakes for folate, Fe, Ca, Mg, and Zn were less than the respective RDAs/DRIs and almost 50% of the athletes were consuming less than the RDAs/DRIs for the B-complex vitamins and vitamin C. Three athletes presented with Fe deficiency anemia (Hb <12 mg/dL), while marginal vitamin B12 status (<200 pg/ml) and vitamin C status (<28 mmol/L) were found in 1 and 4 athletes, respectively. Approximately 1/2 of the athletes reported actively "dieting". Mean BSQ and EDI subscales scores were within the normal ranges; yet, elevated scores on these scales were reported by 26% and 35% of athletes, respectively. Past or present amenorrhea was reported by 17% of the athletes and 13% and 48%, reported past or present oligomenorrhea and "irregular" menstrual cycles, respectively. These results indicate that elite adolescent volleyball players are at risk for menstrual dysfunction and have energy and nutrient intakes that place them at risk for nutritional deficiencies and compromised performance.


An Arthrobacter citreus strain suitable for degrading ε-caprolactam in polyamide waste and accumulation of glutamic acid.
ε-Caprolactam-a toxic xenobiotic compound present in industrial polyamide waste was found to be degraded by caprolactam-degrading bacteria. Arthrobacter citreus was able to utilize up to 20 g ε-caprolactam/l as the sole source of carbon more efficiently as compared to the other Gram positive caprolactam-degrading bacteria Rhodococcus rhodochrous and Bacillus sphaericus. The cells of A. citreus remained viable in medium up to 40 g caprolactam/l. The degradation of 10 g caprolactam/l by A. citreus, when supplied as the sole source of carbon and nitrogen lead to the formation of 6-aminocaproic acid which was detected in broth and there was also an increase in the ammonium content. One of the other metabolites found to consistently accumulate in extracellular medium during the utilization of caprolactam by A. citreus was glutamic acid, though not reported in case of other caprolactam-degrading bacteria. A. citreus could metabolise caprolactam to form non toxic products such as 6-aminocaproic acid and glutamic acid which are amino acids of physiological and commercial importance. In the presence of 6-aminocaproic acid, the rate of caprolactam utilization by A. citreus was decreased but not inhibited and the viable count of cells was found to increase using both the substrates simultaneously. A. citreus was also suitable for degradation of caprolactam in presence of low phosphate as prevalent in soil, and in sterile soil without the supplementation of any other carbon or nitrogen, as well as in native non sterile soil where other microorganisms are present.


Traumatic life-events and alcohol and drug use disorders among Mexican adolescents: Bidirectional associations over 8 years.
Most research linking type of traumatic events to the incidence of alcohol and drug use disorders among adolescents are cross-sectional and no longitudinal research exists in low/middle income countries where violence is common. Studies on bidirectional associations are infrequent. We estimated prospective associations of 7 types of events and new occurrence of DSM-IV alcohol use disorders (AUD) and drug use disorders (DUD), as well as prospective associations between DSM-IV AUD, DUD and the new onset of 7 types of traumatic events, from a follow-up conducted in 2013 (n = 1071; ages 19-26) of the original Mexican Adolescent Mental Health Survey conducted in 2005 (ages 12-17), by using Relative Ratios (RR) and Hazard Ratios (HR) estimates. After adjustments for mental disorders and demographics, "any traumatic event" increased the RR and HR of a new AUD and any substance use disorder (SUD). In HR estimates, bidirectional associations were found between "Ever committed or witnessed violence" and "Ever beaten up by spouse…" and AUD, DUD and SUD. DUD disorder increased HR for several events. Our sample is representative of the largest metropolitan area in Mexico but does not include other cities and other age groups that may differ in risk factors. Corrections for multiple tests suggests caution. We found partial support for the self-medication hypothesis and weaker support for the risky behavior hypothesis, and only two traumatic events ("Ever beaten up by spouse, partner…" and "Ever committed or witnessed violence") showed evidence of a bidirectional association.


Listening to music with personal listening devices: monitoring the noise dose using a smartphone application.
To monitor listening habits to personal listening devices (PLDs) using a smartphone application and to compare actual listening habits to self-report data. Two stages: self-report listening habits questionnaire, and real-time monitoring of listening habits through a smartphone application. Overall 117 participants aged 18-34 years (mean 25.5 years) completed the questionnaire, and of them, 40 participants (mean age: 25.2 years) were monitored for listening habits during two weeks. Questionnaire main findings indicated that most of the participants reported listening for 4-7 days a week, for at least 30 min at high listening levels with volume control settings at 75-100%. Monitored data showed that actual listening days per week were 1.5-6.5 d, with mean continuous time of 1.56 h, and mean volume control setting of 7.39 (on a scale of 1-15). Eight participants (22%) were found to exceed the 100% noise dose at least once during the monitoring period. One participant (2.7%) exceeded the weekly 100% daily noise dose. Correlations between actual measurements and self-report data were low to moderate. Results confirmed the feasibility of monitoring listening habits by a smartphone application, and underscore the need for such a tool to enable safe listening behaviour.


LncRNA-MEG3 protects against ganglion cell dysplasia in congenital intestinal atresia through directly regulating miR-211-5p/GDNF axis.
Background LncRNAs are known to take part in normal brain functions and nervous system diseases. Little evidence has pointed to the dysregulation of lncRNAs in congenital intestinal atresia. We aimed to investigate the underlying molecular mechanism of congenital intestinal atresia that involves in lncRNA-MEG3. Materials and methods The expressions of LncRNA-MEG3, miR-211-5p and GDNF were determined by the qRT-PCR and Western blot assay when appropriate. The results were verified in intestinal atresia Wistar rat model and bone marrow derived stem cell (BMSCs)-derived into intestinal ganglion cells. RNA immunoprecipitation and RNA pull-down assays were performed to analyze the regulatory mechanism between MEG3 and miR-211-5p. The effects of MEG3 on the cell proliferation and apoptosis of isolated intestinal ganglion cells were detected with an MTT assay and flow cytometry, respectively. Results The expression of MEG3 was detected to be declined in congenital intestinal atresia tissues at clinic and animal levels. MEG3 promoted the differentiation of BMSCs into intestinal ganglion cells and regulated GDNF expression in retinal ganglion cells (RGC-5 cells) via targeting miR-211-5p. Hypoxia induced the apoptosis of intestinal ganglion cells via MEG3/miR-211-5p/GDNF axis. Conclusion MEG3 promoted the differentiation of BMSCs into intestinal ganglion cells and inhibited the apoptosis of intestinal ganglion cells under the exposure of hypoxia to protect against CIA injury via directly regulating miR-211-5p/GDNF axis.


Synthesis of 4-trifluoromethyl-2H-chromenes via the reaction of 2-(trifluoroacetyl)phenols with vinyltriphenylphosphonium chloride.
Substituted on the benzene ring 4-CF3-2H-chromenes have been prepared from substituted 2-(trifluoroacetyl)phenols and vinyltriphenylphosphonium chloride according to the Schweizer protocol in moderate to excellent yields. The influence of the type and the position of aromatic ring substituents on yields of 4-CF3-2H-chromenes have been investigated. It has been shown that 4-CF3-2H-chromenes are convenient precursors to 4-CF3-coumarins.


Can trifluoperazine protect mitochondria against reactive oxygen species-induced damage?
Trifluoperazine (TFP) (35 microM) prevents mitochondrial transmembrane potential (delta psi) collapse and swelling induced by 10 microM Ca2+ plus oxyradicals generated from delta-aminolevulinic acid autoxidation. In contrast with EGTA, TFP cannot restore the totally collapsed delta psi. So, TFP might not remove Ca2+ from its 'harmful site', but could impair the ROS-driven cross-linking between membrane-SH proteins. Our data are correlated with the protective uses of TFP against oxidative processes promoted by oxyradicals plus Ca2+.


Human gut microbiota and endocrinology: paradigm shift from genome to its regulation.
Over the last two decades, it has become clear that the human gut microbiota, a complex community of bacteria, archaea, fungi, and viruses, are a critical determinant of human health and disease. Microbiota-derived metabolites provide the host with energy, protect against pathogens, modulate immune and endocrine systems as well as the level of reactive oxygen species in the gut. It has come with no surprise that the human gut microbiota is also linked to the production, utilisation, and regulation of host hormones. This implies that the gut microbiota is capable of influencing human behaviour, appetite regulation, and metabolism as well as development and immunity. Many of the advances in the field of crosstalk between the gut microbiota and host health, disease and behaviours are generally based on DNA analyses of microbial populations and transplantation of monocultured commensal species to germ-free animals. Recent reports on the activity of the gut microbiota in gastrointestinal diseases such as IBD and CRC have highlighted two important points. Firstly, microbial DNA-based abundance does not always correlate with their level of activity and secondly, that metabolism of the complex gut microbiota is regulated by host health status, including the production and metabolism of several human hormones. In this review, we will discuss the lessons learnt from studying the activity and metabolism of the human gut microbiota in health and across gastrointestinal diseases, and how these findings can shape future research on the microbiome-gut-endocrine axis.


An Incidental Finding at Transplant Assessment: Case Report.
A 43-year-old woman with chronic hypersensitivity pneumonitis was referred for lung transplant assessment. An echocardiogram as part of her work-up revealed a large left atrial myxoma, presenting a conundrum on how best to manage her combined pathology. Because of the level of pulmonary disease, early intervention to remove the myxoma was not thought be viable without postoperative support. Use of extracorporeal membrane oxygenation to bridge patients for lung transplant is feasible, yet risks increased perioperative mortality. We present the first reported case of simultaneous cardiac myxoma removal and lung transplant.


In vitro selection of translational regulatory elements.
Untranslated regions (UTRs) of mRNAs carry various kinds of translational regulatory elements; however, our knowledge of them is still limited. We created an in vitro selection system that allows us to make a systematic enrichment of the sequences that alter translation efficiency (SESTRE) in any given mRNA and translation system. This method consists of the introduction of random nucleotide sequences into the UTRs of given mRNAs, followed by translation, size fractionation of the polyribosomes, and reverse transcription and PCR amplification (RT-PCR), with repeated cycles of these steps to enrich highly or poorly translatable mRNAs. With this experimental method, we examined how and where translational enhancer motifs emerge on mRNAs using the in vitro translation systems of wheat germ extract. The results indicate that the translational enhancers differentially emerge in response to the presence or absence of the 5' cap. Interestingly, the translational enhancers that activate cap-independent translation evolved more readily in the 3' UTR than in the 5' UTR in wheat germ extract. This SESTRE method should be a powerful tool with which to improve the translational efficiency of given mRNAs in given translation systems and to investigate the structure-function relationship of eukaryotic mRNAs underlying translational control.


Pressure-flow relationships of the canine iliac periphery and systemic hemodynamics: effects of sodiumnitroprusside and adenosine.
It has been reported that sodiumnitroprusside (SNP) decreases mean systemic pressure and simultaneously increases pressure pulse amplification towards the iliac periphery (Kenner and van Zwieten 1982). This unexpected finding was suggested to be due to a decrease in iliac peripheral resistance but an increase in iliac differential resistance. In order to investigate this apparent contradiction, the iliac periphery was hemodynamically isolated from the rest of the circulation and perfused with the dog's own blood by means of a pump. Perfusion pressure (P) and flow (F), femoral venous pressure (Pv), systemic pressure (Ps) and cardiac output (CO) were measured. Steady state pressure-flow relations of the isolated bed were obtained during control and during various i.v. infusion rates of SNP and adenosine (ADS) and were found to be straight (mean r = 0.99). Their slope (delta P/delta F) was defined as differential resistance (Rd). Peripheral resistance (Rp) of the iliac bed was defined as Rp = (P-Pv)/F, calculated at the flow value where perfusion pressure equalled the prevailing systemic pressure. Total peripheral resistance (TPR) was defined as TPR = Ps/CO. The changes of Rd, Rp, Ps, CO and TPR with respect to control show that during low SNP infusion rates Rd and Rp were both increased while TPR was decreased. During all infusion rates of SNP CO did not change while Ps decreased. During low infusion rates of adenosine CO increased while Ps, Rd and Rp did not change and TPR decreased.(ABSTRACT TRUNCATED AT 250 WORDS)


Colony-forming ability of ultraviolet-irradiated xeroderma pigmentosum fibroblasts from different DNA repair complementation groups.
Patients with xeroderma pigmentosum develop severe sunlight-induced damage, including malignant neoplasms, on sun-exposed skin. Some patients also have neurological abnormalities. Xeroderma pigmentosum cells are known to have impaired ability to repair ultraviolet light- or chemical mutagen-induced damage to their DNA, and cell-fusion studies have shown five complementation groups among the DNA excision repair-deficient strains. All xeroderma pigmentosum fibroblast strains we tested had lower colony-forming abilities after ultraviolet irradiation than normal strains. Furthermore, we have found that strains from different complementation groups can have different post-ultraviolet colony-forming abilities and that strains from patients with neurological abnormalities are the most sensitive to ultraviolet light. These results suggest that extremely ineffective repair of damaged DNA in central nervous system neurons may be the cause of the neurological abnormalities.


Detection of sub-critical arterial stenoses by hyperaemic Doppler.
This study assessed the potential of hyperaemic Doppler to detect sub-critical stenoses using a flowrig model. Pulsatile flow of a blood substitute was produced in a compliant circuit. A cadaver carotid artery, constricted by a silk suture produced a variable, focal stenosis. Forty-seven stenoses were created in five arteries. Pressure gradients and Doppler measurements were recorded simultaneously across each stenosis at low (200 ml/min) and high (400 ml/min) flow rates. The change in peak velocities between the arterial segment 2cm proximal to the stenosis (V1), and the stenotic jet (V2) were used to calculate three Doppler indices: (i) V2/V1 ratio, (ii) V2-V1 difference, (iii) a modified 'Bernoulli' value. A high flow pressure gradient of > or = 15% of the resting distal pressure (% delta P), represented a significant stenosis. There was improved correlation between Doppler indices and % delta P at high flow (r = 0.87 to 0.88) compared to low flow rates (r = 0.81 to 0.84). Optimum V2/V1 cut off values were determined by received operator characteristics (ROC) curve analysis. At low flow five sub-critical stenoses were not detected (sensitivity 82.8%) yet all but one of these lesions were identified at high flow (sensitivity of 96.6%). The V2-V1 and Bernoulli indices did not improve on the discriminant ability of the V2/V1 ratio. The V2/V1 ratio is sensitive to haemodynamic changes at enhanced flow rates across ideal arterial stenoses. The potential of hyperaemic Doppler to detect sub-critical lesions and so avoid intraarterial pressure measurements deserves further in vivo study.


Castleman disease and TAFRO syndrome: To improve the diagnostic consciousness is the key.
Castleman disease (CD) and TAFRO syndrome are very rare in clinical practice. Most clinicians, especially non-hematological clinicians, do not know enough about the two diseases, so it often leads to misdiagnosis or missed diagnosis. To explore the clinical features and diagnosis of CD and TAFRO syndrome. We retrospectively collected the clinical and laboratory data of 39 patients who were diagnosed with CD from a single medical center. Clinical classification identified 18 patients (46.15%) with unicentric Castleman disease (UCD) and 21 patients (53.85%) with multicentric Castleman disease (MCD), the latter is further divided into 13 patients (33.33%) with idiopathic multicentric Castleman disease-not otherwise specified (iMCD-NOS) and 8 patients (20.51%) with TAFRO syndrome. UCD and iMCD are significantly different in clinical manifestations, treatment, and prognosis. However, a few patients with MCD were diagnosed as UCD in their early stage. There was a correlation between two of Thrombocytopenia, anasarca and elevated creatinine, which were important components of TAFRO syndrome. In UCD group, the pathologies of lymph modes were mostly hyaline vascular type (13/18, 72.22%), however plasma cell type or mixed type could also appear. In iMCD-NOS group and TAFRO syndrome group, the pathologies of lymph mode shown polarity of plasma cell type and hyaline vascular type respectively. Compared with patients with TAFRO syndrome, patients with iMCD-NOS were diagnosed more difficultly. The clinical and pathological types of CD are not completely separate, there is an intermediate situation or mixed characteristics between two ends of clinical and pathological types. The clinical manifestations of patients with CD are determined by their pathological type. TAFRO syndrome is a special subtype of iMCD with unique clinical manifestations.


Insulin resistance in the spontaneously hypertensive rat.
To determine experimentally if insulin resistance is associated with spontaneously occurring hypertension, insulin-stimulated glucose metabolism was studied in an animal model of genetic hypertension. The spontaneously hypertensive rat (SHR) and its genetic control, the Wistar-Kyoto strain (WKY) were studied with the euglycemic hyperinsulinemic clamp technique. Clamp studies demonstrated reduced insulin-stimulated glucose uptake in SHR (P less than .001). These data indicate that SHR is insulin-resistant when compared with WKY. A reduction of insulin-stimulated glucose metabolism occurred in older animals of both strains, providing evidence of an aging effect on insulin-stimulated glucose metabolism. However, the reduction of insulin-stimulated glucose metabolism was more pronounced in the hypertensive animals. This study demonstrates the presence of peripheral (skeletal muscle) insulin resistance in the SHR.


Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications.
Superparamagnetic iron oxide nanoparticles can provide multiple benefits for biomedical applications in aqueous environments such as magnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles' surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality water-dispersible nanoparticles around 10 nm in size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11051-012-1100-5) contains supplementary material, which is available to authorized users.


13.4 % Efficiency from All-Small-Molecule Organic Solar Cells Based on a Crystalline Donor with Chlorine and Trialkylsilyl Substitutions.
How to simultaneously achieve both high open-circuit voltage (Voc ) and high short-circuit current density (Jsc ) is a big challenge for realising high power conversion efficiency (PCE) in all-small-molecule organic solar cells (all-SM OSCs). Herein, a novel small molecule (SM)-donor, namely FYSM-SiCl, with trialkylsilyl and chlorine substitutions was designed and synthesized. Compared to the original SM-donor FYSM-H, FYSM-Si with trialkylsilyl substitution showed a decreased crystallinity and lower highest occupied molecular orbital (HOMO) level, while FYSM-SiCl had an improved crystallinity, more ordered packing arrangement, significantly lower HOMO level, and predominant "face-on" orientation. Matched with a SM-acceptor Y6, the FYSM-SiCl-based all-SM OSCs exhibited both high Voc of 0.85 V and high Jsc of 23.7 mA cm-2 , which is rare for all-SM OSCs and could be attributed to the low HOMO level of FYSM-SiCl donor and the delicate balance between high crystallinity and suitable blend morphology. As a result, FYSM-SiCl achieved a high PCE of 13.4 % in all-SM OSCs, which was much higher than those of the FYSM-H- (10.9 %) and FYSM-Si-based devices (12.2 %). This work demonstrated a promising method for the design of efficient SM-donors by a side-chain engineering strategy via the introduction of trialkylsilyl and chlorine substitutions.


THE EFFECT OF RIGHT VENTRICULAR PACEMAKER LEAD POSITION ON FUNCTIONAL STATUS IN PATIENTS WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION.
The study was aimed at assessing the difference between the right ventricle apex versus the right ventricular outflow tract lead position in functional capacity in the patients with the preserved left ventricular ejection fraction after 12 months of pacemaker stimulation. This was a prospective, randomized, follow-up study, which lasted for 12 months. The study sample included 132 consecutive patients who were implanted with permanent anti-bradicardiac pacemaker. Regarding the right ventricular lead position the patients were divided into two groups: the right ventricle apex group consisting of 61 patients with right ventricular apex lead position. The right ventricular outflow tract group included 71 patients with right ventricular outflow tract lead position. Functional capacity was assessed by Minnesota Living With Heart Failure score, New York Heart Association class and Six Minute Walk Test. Left ventricular ejection fraction was assessed by echocardiography. Minnesota Living With Heart Failure score and New York Heart Association class had a statistically significant improvement in both study groups. The patients from right ventricle apex group walked 20.95% (p=O.03) more in comparison to starting values. The patients from right ventricular outflow tract group walked only 13.63% (p=0.09) longer distance than the startingoneConclusion. Analysis of tests of functional status New York Heart Association class and Minnesota Living With Heart Failure questionnaire showed an even improvement in the right ventricle apex and right ventricular outflow tract groups. Analysis of 6 minute walk test showed that only the patients with the preserved left ventricular ejection fraction from the right ventricle apex group had a significant improvement after 12 months of pacemaker stimulation..


Control of mouse limb initiation and antero-posterior patterning by Meis transcription factors.
Meis1 and Meis2 are homeodomain transcription factors that regulate organogenesis through cooperation with Hox proteins. Elimination of Meis genes after limb induction has shown their role in limb proximo-distal patterning; however, limb development in the complete absence of Meis function has not been studied. Here, we report that Meis1/2 inactivation in the lateral plate mesoderm of mouse embryos leads to limb agenesis. Meis and Tbx factors converge in this function, extensively co-binding with Tbx to genomic sites and co-regulating enhancers of Fgf10, a critical factor in limb initiation. Limbs with three deleted Meis alleles show proximal-specific skeletal hypoplasia and agenesis of posterior skeletal elements. This failure in posterior specification results from an early role of Meis factors in establishing the limb antero-posterior prepattern required for Shh activation. Our results demonstrate roles for Meis transcription factors in early limb development and identify their involvement in previously undescribed interaction networks that regulate organogenesis.


Smooth dissection of ligamentum flavum for lumbar microdiscectomy. Preliminary report of this personal technique.
A newly designed technique for preservation of the ligamentum flavum (LF) during the lumbar discectomy is presented. This technique allows the evacuation of the lumbar herniated disk, without removal or laminar disinsertion of the LF. This ligament is smoothly dissected longitudinally in its more lateral portion, obtaining, after discectomy, the contact of the 2 margins with restoration of its functional integrity. Forty-five patients were operated on with this technique. We feel that this technique could offer advantages in reduction of epidural fibrosis and of decreased risk of dural injury, and is helpful to the surgeon in the case of recurrence of discal herniation.


Self-sample HPV tests as an intervention for nonattendees of cervical cancer screening in Finland: a randomized trial.
Attendance in screening is an important determinant of cervical cancer. Previous experience on high-risk human papillomavirus (hrHPV) DNA testing on patient-obtained samples suggests a good effect among nonattendees of screening. We assessed the effects of self-sampling on attendance in the Finnish screening program. Nonattendees after the primary invitation in one municipality (Espoo) were randomized to receive either a self-sampling kit (2,397 women) or an extra invitation (6,302 women). One fourth (1,315 women) of reminder letter arm nonattendees also received a self-sampling kit as a third intervention. Main outcomes were increases in screening attendance and coverage. The adjusted relative risk for participation by self-sampling as a second intervention in comparison to a reminder letter arm was 1.21 (95% CI: 1.13-1.30). Total attendance increased from 65% to 76% by self-sampling and from 65% to 74% with a reminder letter. Combining the interventions (reminder letter and then self-sampling) increased total attendance from 63% to 78%. One fifth of the participants in all three groups increased screening coverage (previous Pap smear ≥5 years ago or never). Self-obtained samples were more often HPV positive than provider-obtained ones (participants after primary invitation and reminder letter), 12% to 13% versus 7%. Self-sampling is a feasible option in enhancing the attendance at organized screening, particularly as an addition to a reminder letter. If self-sampling is used as a third intervention after two written invitations, the overall attendance in Finland could most likely reach the desired 80% to 85%.


Female migrants, family members and community socio-demographic characteristics influence facility delivery in Rufiji, Tanzania.
Health professionals and public health experts in maternal and newborn health encourage women to deliver at health facilities in an effort to reduce maternal and newborn mortality. In the existing literature, there is scant information on how migration, family members and community influence facility delivery. This study addresses this knowledge gap using 10 years of longitudinal surveillance data from a rural district of Tanzania. Multilevel logistic regression was used to quantify the influence of hypothesized migration, family and community-level factors on facility delivery while adjusting for known confounders identified in the literature. We report adjusted odds ratios (AOR). Overall, there has been an increase of 14% in facility delivery over the ten years, from 63% in 2001 to 77% in 2010 (p < .001). Women residing in households with female migrants from outside their community were more likely to give birth in a facility AOR = 1.2 (95% CI 1.11-1.29). Furthermore, the previous facility delivery of sisters and sisters-in-law has a significant influence on women's facility delivery; AOR = 1.29, 95% CI 1.15-1.45 and AOR = 1.7, 95% CI 1.35-2.13 respectively. Community level characteristics play a role as well; women in communities with higher socioeconomic status and older women of reproductive age had increased odds of facility delivery; AOR = 2.37, 95% CI 1.88-2.98 and AOR = 1.17, 95% CI 1.03-1.32 respectively. Although there has been an increase in facility delivery over the last decade in Rufiji, this study underscores the importance of female migrants, family members and community in influencing women's place of delivery. The findings of this study suggest that future interventions designed to increase facility delivery must integrate person-to-person facility delivery promotion, especially through women of the community and within families. Furthermore, the results suggest that investment in formal education of the community and increased community socio-economic status may increase facility delivery.


Intelligent quantitative recognition of sulfide using machine learning-based ratiometric fluorescence probe of metal-organic framework UiO-66-NH2/Ppix.
Sulfides possess either high toxicity or play crucial physiological role such as gas transmitter dependent upon dosage, hence the significant for their rapid sensitive and selective concentration determination. Herein, a machine learning enhanced ratiometric fluorescence sensor was engineered for sulfide determination by incorporating the nanometal-organic framework (UiO-66-NH2) along with protoporphyrin IX (Ppix). The blue fluorescence at 431 nm originated from the moiety of UiO-66-NH2 by 365 nm excitation serves as an internal calibration reference signal, while the red fluorescence at 629 nm from the moiety of Ppix serves as the analytical signal, and the intensity is correlated to the amount of sulfides. The fluorescence color of the sensor gradually varies from blue to red upon sequential addition of copper and sulfide ions, resulting in RGB (Red, Green, Blue) feature values for corresponding sulfide concentrations, which facilities the advanced data processing techniques using machine learning algorithms. On the basis of fluorescence image fingerprint extraction and machine learning algorithms, an online data analysis model was developed to improve the precision and accuracy of sulfide determination. The established model employed Linear Discriminant Analysis (LDA) and was subjected to rigorous cross-validation to ensure its robustness. By analyzing the correlation between RGB feature values and sulfide concentrations, the study highlighted a significant positive relationship between the red feature values and sulfide concentrations. The application of machine learning techniques on the ratiometric fluorescence signal of the UiO-66-NH2/Ppix probe demonstrated its potential for intelligent quantitative determination of sulfides, offering a valuable and efficient tool for pollution detection and real-time rapid environmental monitoring.


The RS4939827 polymorphism in the SMAD7 GENE and its association with Mediterranean diet in colorectal carcinogenesis.
The objective of our investigation is to study the relationship between the rs4939827 SNP in the SMAD7 gene, Mediterranean diet pattern and the risk of colorectal cancer. We examined 1087 cases of colorectal cancer and 2409 population controls with available DNA samples from the MCC-Spain study, 2008-2012. Descriptive statistical analyses, and multivariate logistic mixed models were performed. The potential synergistic effect of rs4939827 and the Mediterranean diet pattern was evaluated with logistic regression in different strata of of adherence to the Mediterranean diet and the genotype. High adherence to Mediterrenean diet was statistically significantly associated with colorectal cancer risk. A decreased risk for CRC cancer was observed for the CC compared to the TT genotype (OR = 0.65 and 95% CI = 0.51-0.81) of the rs4939827 SNP Also, we could show an association between the Mediterranean diet pattern (protective factor) and rs4939827. Although the decreased risk for the CC genotype was slightly more pronounced in subjects with high adherence to Mediterrenean diet, there was no statistically significant synergistic effect between genotype CC and adherence to the Mediterranean dietary pattern factors. The SMAD7 gene and specifically the allele C could be protective for colorectal cancer. An independent protective association was also observed between high adherence Mediterranean diet pattern and CRC risk. Findings form this study indicate that high adherence to Mediterranean diet pattern has a protective role for CRC cancer probably involving the Tumor Growth Factor- β pathway in this cancer.


[Colorectal polyposis syndrome: a guide to diagnosis].
Biopsies and resection specimens of the gastrointestinal tract are a major part of the routine workload in many histopathology departments, whereby polypoid lesions are generally the main focus. In addition to distinguishing non-neoplastic from neoplastic polyps and evaluating the grade of dysplasia of the latter, the pathologist should always consider the possibility of an underlying polyposis syndrome. Not only have additional hereditary polyposis syndromes been identified in recent years due to a better understanding of their genetic and epigenetic alterations but also knowledge on well known polyposes has improved, leading to subtyping of various forms according to their different genotype. It is essential for the histopathologist to understand that the conventional histomorphology of individual polyps combined with information on the number and distribution of these lesions and clinical data can provide clues regarding a possible hereditary background. Therefore, the correct histological assessment of polyps is not just about getting the diagnosis right, it might also lead to genetic screening of family members and spouses.


Primary cell culture of meningothelial cells--a new model to study the arachnoid in glaucomatous optic neuropathy.
In a previous report, we found that the occurrence and amount of meningothelial cell nests in the subarachnoid space are significantly increased in glaucomatous optic nerves compared to normals. In order to allow research into the role of meningothelial cells during diseases of the optic nerve, an in vitro model is necessary. For this purpose, we developed a culture method for porcine meningothelial cells from the arachnoid layer covering the optic nerve. Meningothelial cells were scraped from the arachnoid layer of porcine optic nerves and cultured for 2-3 weeks until the cells formed a monolayer. To eliminate contaminating fibroblasts from the culture, cells were negatively selected using magnetic anti-fibroblast beads after the first passage. Cells were detached using 0.05% Trypsin-EDTA, incubated with anti-fibroblast beads, separated using a magnetic column and the flow-through was collected. The purified primary meningothelial cells were characterized by electron microscopy and immunocytochemistry using anti-glial fibrillary acidic protein (GFAP) and anti-keratan sulfate antibodies. Primary cells grew out after dissection and formed a monolayer within 2-3 weeks, which was composed of two morphologically different cell types, flattened cells with round nuclei and fibroblast-like cells with long processes. The fibroblast-like cells in the culture could be labelled and selected using anti-fibroblast microbeads. The second cell type did not bind to the anti-fibroblast beads, and upon immunocytochemistry showed a marked expression of both GFAP and keratan sulphate. In addition, examination of these cells by electron microscopy revealed morphological characteristics of meningothelial cells, including hemidesmosomes and cytoplasmatic filaments. The technique described in this paper for the primary culture of meningothelial cells from the subarachnoid space of the optic nerve and using magnetic beads for the removal of fibroblasts is effective in obtaining a highly enriched meningothelial cell culture.


[Localization and identification of the LH-RF center in the brain of the toad, Bufo vulgaris Laur].
Using indirect immunofluorescence procedure with an anti-synthetic LHRF serum, pericarya of neurons producing LHRF or an LHRF-like substance were revealed in hypophysectomized Bufo vulgaris. They are localized principally in the forebrain near the posterior end of the first and second ventricles. The fluorescent axons coming from these pericarya are visible on their pathway to a region near tha pars tuberalis and to the median eminence.


JTZ-951, an HIF prolyl hydroxylase inhibitor, suppresses renal interstitial fibroblast transformation and expression of fibrosis-related factors.
Some preceding studies have provided evidence that hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) inhibitors have therapeutic potential against tubular interstitial fibrosis (TIF). Recently, transformation of renal interstitial fibroblasts (RIFs) into α-smooth muscle actin-positive myofibroblasts with loss of their hypoxia-inducible erythropoietin (EPO) expression has been hypothesized as the central mechanism responsible for TIF with renal anemia (the RIF hypothesis). These reports have suggested that HIF-PH inhibitors may suppress TIF via suppressing transformation of RIFs. However, the direct effect of HIF-PH inhibitors on transformation of RIFs has not been demonstrated because there has been no appropriate assay system. Here, we established a novel in vitro model of the transformation of RIFs. This model expresses key phenotypic changes such as transformation of RIFs accompanied by loss of their hypoxia-inducible EPO expression, as proposed by the RIF hypothesis. Using this model, we demonstrated that JTZ-951, a newly developed HIF-PH inhibitor, stabilized HIF protein in RIFs, suppressed transformation of RIFs, and maintained their hypoxia-inducible EPO expression. JTZ-951 also suppressed the expression of FGF2, FGF7, and FGF18, which are upregulated during transformation of RIFs. Furthermore, expression of Fgf2, Fgf7, and Fgf18 was correlated with TIF in an animal model of TIF. We also demonstrated that not only FGF2, which is a well-known growth-promoting factor, but also FGF18 promoted proliferation of RIFs. These data suggest that JTZ-951 has therapeutic potential against TIF with renal anemia. Furthermore, FGF2, FGF7, and FGF18, which faithfully reflect the anti-TIF effects of JTZ-951, have potential as TIF biomarkers.


Pharmacodynamic monitoring of cyclosporin.
The efficacy of cyclosporin as an immunosuppressive agent is largely based on clinical indicators such as graft survival, rejection or nephrotoxicity. Therapeutic monitoring is necessary to evaluate the efficacy of cyclosporin therapy. The most widely used method for monitoring cyclosporin therapy is the measurement of predose through blood concentrations of the drug. The relationship of a single or multiple blood cyclosporin concentration to slowly evolving outcomes is difficult to establish. Some investigators have found a good correlation between cyclosporin trough concentrations on the one hand and cyclosporin toxicity and rejection on the other, but others have not. Therapeutic monitoring of cyclosporin may be enhanced using some biological assays for immunosuppression (pharmacodynamic monitoring) in addition to cyclosporin trough concentrations (pharmacokinetic monitoring). However, direct monitoring of the immune response to cyclosporin therapy using a clinically applicable biological assay is difficult. Some pharmacodynamic parameters have been suggested as biological markers in the clinical monitoring of cyclosporin.


A novel surgical training simulator for transanal total mesorectal excision.
The transanal total mesorectal excision (TaTME) approach for rectal cancer has been gaining popularity. Although TaTME requires specific training, the opportunity to obtain this training is limited. We developed the first dry simulator that includes some important structural landmarks to provide training that includes all the procedural steps of TaTME. The model was structured based on a computed tomography scan data. The simulator mimics the rectum and surrounding key anatomical structures. All material components were made of polyvinyl alcohol and stained with various colors to easily identify these anatomical structures while undergoing the training. Our simulator is compact in its size and can be easily packed, stacked, and stored. The materials mimic the real one and the model allows us to perform the entire step-by-step TaTME procedures with genuine clinical devices from the attachment of operative platform to the anastomosis. We have held the course 24 times to date, with more than 200 surgeons participating not only from domestic hospitals but also from other countries. The result of the satisfaction survey from 65 participants, which was rated from 0 to 10 points, was an average score of 8.6 (± 1.4) points. We present the world's first TaTME simulator and believe that it will play an important role for the safe spread of TaTME surgery.


Optically-driven collapse of a plasmonic nanogap self-monitored by optical frequency mixing.
A nanoparticle separated from a metallic surface by a few-nanometer thick polymer layer forms a nanoscale junction, or nanogap. Illuminating this structure with ultrashort optical pulses, exciting the plasmon resonance, results in a continuous, monitorable collapse of the nanogap. The four-wave mixing signal generated by this illumination of the nanogap provides a simultaneous monitoring of the collapse, increasing dramatically upon gap closure. Collapse is irreversible, occurring with simultaneous ablation of the dielectric from the junction.


The effects of hemicholinium-3 (Hc-3) during tetanic (TP) and posttetanic potentiation (PTP) on sympathetic ganglion.
An electrophysiological analysis has been made of the synaptic plasticity in the eighth sympathetic ganglion of the toad. The mean amplitude of Compound Action Potential (CAP) recorded extracellularly was taken as a measure of the synaptic transmission. Repetitive stimulation of the preganglionic axonal fibers at 50 Hz for 40 seconds in the presence of Hc-3 led to facilitatory and depressant actions on ganglionic synaptic transmission. Hc-3 in the presence of elevated extracellular Ca2+ concentration (5.4 mM) increased Tetanic Potentiation (TP) and Posttetanic Potentiation (PTP) on eighth sympathetic ganglion. Hc-3 plus 3,4-diaminopyridine (3,4-DAP) increased synaptic transmission, TP, and PTP from postganglionic CAP responses to supramaximal preganglionic stimulation.


Using food fortification to improve vitamin D bioaccessibility and intakes.
Vitamin D intakes and status are low in many countries due to seasonal UVB exposure variation and the fact that few foods are naturally vitamin D rich. Data modelling studies show that vitamin D intakes increase with food fortification, and countries with mandatory fortification policies have higher vitamin D intakes and status compared to countries without. While many foods can be vitamin D fortified, vitamin D bioavailability differs depending on fortification methods, food structure and composition. Randomised controlled trials (RCT) report that vitamin D2 bioavailability varies between foods, whereas vitamin D3 is bioavailable from many foods. In vitro studies suggest that altering the lipid composition of fortified foods increases vitamin D3 absorption. Olive oil increased vitamin D3 absorption during in vitro digestion compared to other dietary oils. Additionally, when vitamin D3 was incorporated into micelles formed from in vitro digestion of olive oil, more vitamin D3 was absorbed compared to other dietary oils. However, in a human postprandial study, a preformed vitamin D3 micelle dairy drink did not increase vitamin D3 absorption, and a vitamin D3 olive dairy drink increased vitamin D3 absorption in vitamin D insufficient participants only. Action is urgently needed to improve vitamin D intakes and status worldwide. Food fortification improves vitamin D intakes; however, fortification strategies unique to each country are needed. This review will synthesise the literature describing data modelling and intervention trials that assess the safety and efficacy of vitamin D fortification strategies, and those manipulating food composition to alter vitamin D bioavailability from fortified foods. Additionally, RCT examining the impact of vitamin D fortification strategies on vitamin D intakes and status over time are reviewed.


Comparison of barium and diatrizoate bowel labelling agents in computed tomography.
A new suspension of barium sulphate, E-Z-CAT, for use as a bowel labelling agent in computed tomography (CT) of the abdomen and pelvis, has been compared with diatrizoate (Gastrografin) in 111 patients. The E-Z-CAT labelled the duodenum more efficiently and patients preferred its taste. Both substances are satisfactory bowel-labelling agents.


Lack of sensitive period for lead-induced behavioral impairment on a spatial delayed alternation task in monkeys.
A total of 52 monkeys (Macaca fascicularis) were dosed orally with vehicle or 1.5 mg/kg/day of lead on one of four dosing regimens (13 monkeys/group): vehicle only; dosed with lead from birth onward; dosed with lead from birth to 400 days of age and vehicle thereafter; dosed with vehicle from birth to 300 days of age and lead thereafter. Blood lead concentrations averaged 3-6 micrograms/dl when monkeys were not being dosed with lead, 32-36 micrograms/dl when being dosed with lead and having access to infant formula, and 19-26 micrograms/dl when being dosed with lead after weaning from infant formula. When monkeys were 6-7 years old, they were tested on a spatial delayed alternation task. The task required the monkey to alternate responses between two push buttons. The initial delay was 0.10 sec and was increased in steps to 15 sec by the end of the experiment. All three treated groups were impaired to approximately an equal degree. Deficits were observed in the initial training procedure, and at the longer delay values. These results suggest that there is not an early critical period for lead-induced impairment on this task and that exposure only during infancy results in impairment comparable to ongoing exposure beginning at birth. These results are in contrast to previous findings on a series of nonspatial discrimination reversal tasks, in which the group exposed early in life only was unimpaired, while the group exposed beginning after infancy was less impaired that the group exposed continuously from birth.


Brugia malayi: rat cell interactions with infective larvae mediated by complement.
Albino rat macrophages and neutrophils, in the presence of fresh normal rat serum as a source of complement, adhered to and promoted killing of Brugia malayi infective larvae in vitro. Eosinophils, by themselves, were marginally cytotoxic at a high cell-target ratio but promoted cytotoxicity when mixed with macrophages. Eosinophil culture supernatants enhanced the macrophage mediated killing of infective larvae. The complement of fresh normal rat serum was found to act by the alternate pathway. Fresh normal rat serum depleted of alternate pathway complement activity by treatment with zymosan A, or of Factor B by heating at 50 C for 20 min, or of Factor D by passing through Sephadex G75 column, failed to promote cell adherence to the parasite. C3 molecules were detected on the surface of infective larvae by immunofluorescence. There was a significant consumption of complement when Brugia malayi infective larvae were incubated in fresh normal rat serum. Albino rat cells were more potent in inducing cytotoxicity to infective larvae in vitro than those from jird or Mastomys natalensis, which may reflect the greater resistance offered by the rat to B. malayi infection. There was much less cellular infiltration on introduction of Brugia malayi infective larvae into the peritoneal cavity of jirds compared to rats and Mastomys natalensis indicating the greater susceptibility of jirds to intraperitoneally induced infections.


Electron ultra-high dose rate FLASH irradiation study using a clinical linac: Linac modification, dosimetry, and radiobiological outcome.
Ultra-high dose rate FLASH irradiation (FLASH-IR) has been shown to cause less normal tissue damage compared with conventional irradiation (CONV-IR), this is known as the "FLASH effect." It has attracted immense research interest because its underlying mechanism is scarcely known. The purpose of this study was to determine whether FLASH-IR and CONV-IR induce differential inflammatory cytokine expression using a modified clinical linac. An Elekta Synergy linac was used to deliver 6 MeV CONV-IR and modified to deliver FLASH-IR. Female FvB mice were randomly assigned to three different groups: a non-irradiated control, CONV-IR, or FLASH-IR. The FLASH-IR beam was produced by single pulses repeated manually with a 20-s interval (Strategy 1), or single-trigger multiple pulses with a 10 ms interval (Strategy 2). Mice were immobilized in the prone position in a custom-designed applicator with Gafchromic films positioned under the body. The prescribed doses for the mice were 6 to 18 Gy and verified using Gafchromic films. Cytokine expression of three pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], interleukin-6 [IL-6]) and one anti-inflammatory cytokine (IL-10) in serum samples and skin tissue were examined within 1 month post-IR. The modified linac delivered radiation at an intra-pulse dose rate of around 1 × 106 Gy/s and a dose per pulse over 2 Gy at a source-to-surface distance (SSD) of 13 to 15 cm. The achieved dose coverage was 90%-105% of the maximum dose within -20 to 20 mm in the X direction and 95% within -30 to 30 mm in the Y direction. The absolute deviations between the prescribed dose and the actual dose were 2.21%, 6.04%, 2.09%, and 2.73% for 6, 9, 12, and 15 Gy as measured by EBT3 films, respectively; and 4.00%, 4.49%, and 2.30% for 10, 14, and 18 Gy as measured by the EBT XD films, respectively. The reductions in the CONV-IR versus the FLASH-IR group were 4.89%, 10.28%, -7.8%, and -22.17% for TNF-α, IFN-γ, IL-6, and IL-10 in the serum on D6, respectively; 37.26%, 67.16%, 56.68%, and -18.95% in the serum on D31, respectively; and 62.67%, 35.65%, 37.75%, and -12.20% for TNF-α, IFN-γ, IL-6, and IL-10 in the skin tissue, respectively. Ultra-high dose rate electron FLASH caused lower pro-inflammatory cytokine levels in serum and skin tissue which might mediate differential tissue damage between FLASH-IR and CONV-IR.


A case of lymphomatoid granulomatosis with central nervous system involvement successfully treated with IFNα.
Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease affecting mainly extranodal sites such as the lung, central nervous system (CNS), skin, kidney, and liver. We report a case of low-grade LYG involving the CNS that was successfully treated with interferon alpha (IFNα). A 69-year-old woman developed necrotic erythema of the skin and was initially diagnosed with pyoderma gangrenosum based on skin biopsy. She showed a limited response to prednisolone. Approximately 6 months after the initial onset, low-grade LYG was diagnosed after detection of CNS lesions on brain biopsy. The whole blood EBV-DNA load determined by real-time polymerase chain reaction was slightly elevated. Two months into IFNα therapy, skin and CNS lesions had responded favorably and the EBV-DNA load decreased. IFNα plays an important role in treatment of LYG through its antiproliferative, immunomodulatory, and anti-EBV effects. To our knowledge, this is the first case report of successful treatment with IFNα in Japan. Further investigation is necessary to determine optimal use of IFNα for LYG.


Female Sexual Dysfunction.
Female sexual dysfunction is an umbrella term that encompasses several facets of sexuality in terms of desire, arousal, orgasm, and/or sexual pain. Persistent, recurrent problems with sexual arousal, desire, orgasm, or pain that distress the patient or strain the relationship with their partner are known as sexual dysfunction. Female sexual dysfunction can occur at any stage of life and can drastically curtail quality of life for many women. It is reasonable that all physicians, surgeons, and health care professionals have basic education and tools available to guide patients and to assist clinicians of possible causes and treatment strategies.


Improving Data Collection in Pregnancy Safety Studies: Towards Standardisation of Data Elements in Pregnancy Reports from Public and Private Partners, A Contribution from the ConcePTION Project.
The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible.


User stories as lightweight requirements for agile clinical decision support development.
We sought to demonstrate applicability of user stories, progressively elaborated by testable acceptance criteria, as lightweight requirements for agile development of clinical decision support (CDS). User stories employed the template: As a [type of user], I want [some goal] so that [some reason]. From the "so that" section, CDS benefit measures were derived. Detailed acceptance criteria were elaborated through ensuing conversations. We estimated user story size with "story points," and depicted multiple user stories with a use case diagram or feature breakdown structure. Large user stories were split to fit into 2-week iterations. One example user story was: As a rheumatologist, I want to be advised if my patient with rheumatoid arthritis is not on a disease-modifying anti-rheumatic drug (DMARD), so that they receive optimal therapy and can experience symptom improvement. This yielded a process measure (DMARD use), and an outcome measure (Clinical Disease Activity Index). Following implementation, the DMARD nonuse rate decreased from 3.7% to 1.4%. Patients with a high Clinical Disease Activity Index improved from 13.7% to 7%. For a thromboembolism prevention CDS project, diagrams organized multiple user stories. User stories written in the clinician's voice aid CDS governance and lead naturally to measures of CDS effectiveness. Estimation of relative story size helps plan CDS delivery dates. User stories prove to be practical even on larger projects. User stories concisely communicate the who, what, and why of a CDS request, and serve as lightweight requirements for agile development to meet the demand for increasingly diverse CDS.