Conformation determines the seeding potencies of native and recombinant Tau aggregates.
Intracellular Tau inclusions are a pathological hallmark of several neurodegenerative diseases, collectively known as the tauopathies. They include Alzheimer disease, tangle-only dementia, Pick disease, argyrophilic grain disease, chronic traumatic encephalopathy, progressive supranuclear palsy, and corticobasal degeneration. Tau pathology appears to spread through intercellular propagation, requiring the formation of assembled "prion-like" species. Several cell and animal models have been described that recapitulate aspects of this phenomenon. However, the molecular characteristics of seed-competent Tau remain unclear. Here, we have used a cell model to understand the relationships between Tau structure/phosphorylation and seeding by aggregated Tau species from the brains of mice transgenic for human mutant P301S Tau and full-length aggregated recombinant P301S Tau. Deletion of motifs (275)VQIINK(280) and (306)VQIVYK(311) abolished the seeding activity of recombinant full-length Tau, suggesting that its aggregation was necessary for seeding. We describe conformational differences between native and synthetic Tau aggregates that may account for the higher seeding activity of native assembled Tau. When added to aggregated Tau seeds from the brains of mice transgenic for P301S Tau, soluble recombinant Tau aggregated and acquired the molecular properties of aggregated Tau from transgenic mouse brain. We show that seeding is conferred by aggregated Tau that enters cells through macropinocytosis and seeds the assembly of endogenous Tau into filaments.


Postoperative Pain and Opioid Use in Children with Supracondylar Humeral Fractures: Balancing Analgesia and Opioid Stewardship.
Effective postoperative analgesia remains a priority in orthopaedic surgery, but concerns with regard to opioid diversion and misuse have brought overdue attention to improving opioid stewardship. Normative data for postoperative pain and opioid use are needed to guide and balance these dual priorities. We aimed to characterize postoperative pain and opioid use for an archetypal pediatric orthopaedic procedure: closed reduction and percutaneous pinning of a supracondylar humeral fracture. Children at a single pediatric trauma center who underwent closed reduction and percutaneous pinning of a supracondylar humeral fracture were enrolled and were prospectively followed. Validated pain scores (Wong-Baker FACES Pain Rating Scale) and opioid utilization data were collected using an automated text message-based protocol on postoperative days 1 to 7, 10, 14, and 21. Data were analyzed with descriptive and univariate statistics. Eighty-one patients with a mean age (and standard deviation) of 6.1 ± 2.1 years (62% of whom were male) were enrolled, including 53.1% who had Type-II fractures and 46.9% who had Type-III fractures. The mean pain ratings were highest on arrival to the emergency department (3.5 ± 3.5 points) and the morning of postoperative day 1 (3.5 ± 2.4 points). By postoperative day 3, the mean pain rating decreased to <2 (1.8 ± 1.8 points) and the mean opioid doses decreased to <1 dose (0.8 ± 1.2 doses). Postoperative opioid use decreased in parallel to reported pain (r = 0.972; p < 0.001). The interquartile range of opioid use was 1 to 7 doses, and patients used only 24.1% of the prescribed opioids (mean, 4.8 ± 5.6 doses used and 19.8 ± 7.1 doses prescribed). There was no significant difference (p > 0.05) in pain ratings or opioid use by fracture classification, age, or sex. Following closed reduction and percutaneous pinning for supracondylar humeral fracture, pain levels and opioid usage decrease to a clinically unimportant level by postoperative day 3. Patients who report pain scores of ≥6 points following discharge are outliers and should be screened for compartment syndrome or ischemia. Patients used <25% of prescribed opioid medication, suggesting the potential for overprescription and opioid diversion. A prescription for 7 opioid doses after discharge should allow adequate postoperative analgesia in the majority of patients while improving narcotic stewardship. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Orbital peripheral T-cell lymphoma in a child.
A 6-year-old boy with known peripheral T-cell lymphoma had progressive left periorbital swelling and CT findings consistent with abscess or necrosis. Biopsy revealed peripheral T-cell lymphoma and associated necrosis involving the lacrimal gland and surrounding orbital tissue. Immunohistochemical and T-cell receptor gene rearrangement studies confirmed the diagnosis. The patient responded to local radiation and systemic chemotherapy. This is the first pathologically confirmed case of orbital peripheral T-cell lymphoma with subpanniculitic features.


Properties of pacemaker potentials recorded from myenteric interstitial cells of Cajal distributed in the mouse small intestine.
Recording of electrical responses from isolated small intestine of mice using conventional microelectrodes revealed two types of potential, a pacemaker potential and a slow wave, both with rapid rising primary components and following plateau components. The rate of rise and peak amplitude were greater for pacemaker potentials than for slow waves, and the plateau component was smaller in slow waves than in pacemaker potentials. Both potentials oscillated at a similar frequency (20-30 min-1). Unitary potentials often discharged during the interval between pacemaker potentials. Infusion of Lucifer Yellow allowed visualization of the recorded cells; pacemaker potentials were recorded from myenteric interstitial cells of Cajal (ICC-MY) while slow waves were recorded from circular smooth muscle cells. Pacemaker potentials were characterized as follows: the primary component was inhibited by Ni2+, Ca2+-free solution or depolarization with high-K+ solution, the plateau component was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS), an inhibitor of Ca2+-activated Cl- channels, low [Cl-]o solution or Ca2+-free solution, and the generation of potentials was abolished by co-application of Ni2+and DIDS or by chelating intracellular Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM). These results indicate that in the mouse small intestine ICC-MY generate pacemaker potentials with two components in situ; the primary and plateau components may be generated by activation of voltage-dependent Ca2+-permeable channels and Ca2+-activated Cl- channels, respectively. Slow waves are generated in circular smooth muscles via electrotonic spread of pacemaker potentials. These properties of intestinal pacemaker potentials are considered essentially similar to those of gastric pacemaker potentials.


10-Hydroxy-2-decenoic acid, a natural product, improves hyperglycemia and insulin resistance in obese/diabetic KK-Ay mice, but does not prevent obesity.
10-Hydroxy-2-decenoic acid (10H2DA) is a fatty acid found in royal jelly (RJ). In healthy mice, it activates 5'-AMP-activated protein kinase (AMPK) and increases glucose transporter 4 (GLUT4) translocation. Therefore, we examined whether 10H2DA has a potential therapeutic effect against type 2 diabetes in obese/diabetic KK-Ay mice. 10H2DA (3 mg/kg body weight) was administered to female KK-Ay mice for 4 weeks by oral gavage. Phenotypes for body weight, plasma glucose by oral glucose tolerance test and insulin levels were measured. mRNA and protein levels were determined using qRT-PCR and Western blot analyses, respectively. Long-term administration of 10H2DA significantly improved hyperglycemia and insulin resistance in KK-Ay mice, but did not prevent obesity. 10H2DA increased the expression of phosphorylated AMPK (pAMPK) protein in skeletal muscles; however, this expression did not correlate with increased GLUT4 translocation. Furthermore, 10H2DA neither enhanced the expression of adiponectin receptor mRNA nor activated the insulin signaling cascade, such as GSK-3β phosphorylation, in the liver. We found that 10H2DA-treated mice had a significant increase in the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc-1α) mRNA in skeletal muscles compared with non-treated group (P=0.0024). These findings suggest that 10H2DA is involved in the improvement of type 2 diabetes, at least in part via activation of Pgc-1α expression, but does not prevent obesity.


Changes of phenolic profiles and antioxidant activity in canaryseed (Phalaris canariensis L.) during germination.
Canaryseed is an important cereal crop in western Canada. The changes of the total phenolic content (TPC), antioxidant activities, phenolic acid profiles (free and bound) of canaryseed during germination were investigated in the present study. The growth properties also were investigated. Fresh weight, shoot length and root length increased, whereas dry mass of canaryseed decreased during germination. A 22.3% loss of dry matter was observed at 120h of germination. The total phenolic content and antioxidant activities of free and bound extracts showed a general trend of germinated seeds>raw seeds>soaked seeds. Free, bound and total phenolic content significantly increased 1042%, 120% and 741% at the end of germination as compared to raw seeds (p<0.05). DPPH, ABTS and ORAC assays were employed to evaluate the antioxidant activity of canaryseed. There were high correlations between total phenolic content and antioxidant activities. TPC and ORAC values showed the highest correlation (r=0.9984). Six phenolic acids in free phenolic extracts and seven phenolic acids in bound phenolic extracts were detected, respectively. Bound ferulic acid, the dominant phenolic acid in canaryseed, significantly increased during germination (p<0.05). Study showed that germination provided a new approach to further develop canaryseed as a functional food for human consumption.


Occult foreign body simulating a choroidal melanoma with extrascleral extension.
A 62-year-old man was noted on routine examination to have a dark lesion in the peripheral fundus of the right eye and a corresponding dark scleral mass. The lesion was initially suspected to be a choroidal melanoma with extrascleral extension. The patient denied having ocular trauma. Orbital x-rays and ultrasonography, however, demonstrated the lesion to be an occult transcleral metallic foreign body. An occult foreign body should be considered in the differential diagnosis of a small choroidal or ciliary body melanoma with extrascleral extension.


Residue avoidance after topical application of veterinary drugs and parasiticides.
Deriving adequate withdrawal intervals for extralabel use of veterinary topical products is difficult because there are limited published data, and data for approved drugs and pesticides are usually proprietary. Where possible, approved products and doses labeled for the specific indication at hand should be used and label withdrawal times should be adhered to. When determining whether topical application of these chemicals may violate tolerance levels in meat and milk, the veterinarian often is limited to empirical data. In the decision-making process, factors, such as type of drug and pesticide formulations used, method of topical application, presence of hair or wool, environmental conditions, and animal species treated, should be considered. In many cases a conservative estimate for the slaughter withdrawal interval can be derived, despite the data gaps. Such recommendations should not be used for routine extralabel use, but are meant to apply to situations in which the drug or pesticide has been used, and human food safety concerns must be addressed.


Pathogenic variations in Germ Cell Nuclear Acidic Peptidase (GCNA) are associated with human male infertility.
Infertility affects one in six couples, half of which are caused by a male factor. Male infertility can be caused by both, qualitative and quantitative defects, leading to Oligo- astheno-terato-zoospermia (OAT; impairment in ejaculate sperm cell concentration, motility and morphology). Azoospermia defined as complete absence of sperm cells in the ejaculation. While hundreds of genes are involved in spermatogenesis the genetic etiology of men's infertility remains incomplete.We identified a hemizygous stop gain pathogenic variation (PV) in the X-linked Germ Cell Nuclear Acidic Peptidase (GCNA), in an Azoospermic patient by exome sequencing. Assessment of the prevalence of pathogenic variations in this gene in infertile males by exome sequence data of 11 additional unrelated patients identified a probable hemizygous causative missense PV in GCNA in a severe OAT patient. Expression of GCNA in the patients' testes biopsies and the stage of spermatogonial developmental arrest were determined by immunofluorescence and immunohistochemistry. The Azoospermic patient presented spermatogenic maturation arrest with an almost complete absence of early and late primary spermatocytes and thus the complete absence of sperm. GCNA is critical for genome integrity and its loss results in genomic instability and infertility in Drosophila, C. elegans, zebrafish, and mouse. PVs in GCNA appear to be incompatible with male fertility in humans as well: A stop-gain PV caused Azoospermia and a missense PV caused severe OAT with very low fertilization rates and no pregnancy in numerous IVF treatments.


Expression of pY397-FAK and Its miR Regulators Drive Dedifferentiation in the Thyroid Neoplasia Spectrum.
Thyroid carcinomas are growing malignancies worldwide. They encompass several diagnostic categories with varying degrees of dedifferentiation. Focal adhesion kinase is involved in cellular communication and locomotion. It is regulated on a posttranscriptional level by miR-7, miR-135a, and miR-138 and on a posttranslational level by autophosphorylation at Y397 (pY397-FAK). We related regulators of FAK with histologic dedifferentiation, clinicopathological factors, and differential diagnosis in the thyroid neoplasia spectrum. We classified 82 cases into 5 groups with increasing aggressiveness: healthy tissue, follicular and classical variants of papillary thyroid carcinoma (PTC), dedifferentiated PTC, and anaplastic carcinoma. MiRs were analyzed by RT-qPCR. Protein expression of pY397-FAK was analyzed by immunohistochemistry (separately in the membrane, cytoplasm, and nuclear compartment) and Western blot. All three miRs were upregulated in healthy tissue compared to malignant, while pY397-FAK was downregulated. MiRs and pY397-FAK were not mutually correlated. MiR-135a-5p was decreasing while membranous and cytoplasmic pY397-FAK increased with dedifferentiation. Neither miR correlated with clinicopathological factors. MiR-135a-5p, miR-138-5p, and membranous and cytoplasmic pY397-FAK discriminated the follicular from the classical variant of PTC. Disturbances of FAK regulation on different levels contribute to neoplastic dedifferentiation. pY397-FAK exerts its oncogenic role in the membrane and cytoplasm. Diagnostically, miRs-135a-5p, miR-138-5p, and membranous and cytoplasmic pY397-FAK differentiated between classical and follicular PTC.


Integrated gut microbiota and fecal metabolome analyses of the effect of Lycium barbarum polysaccharide on D-galactose-induced premature ovarian insufficiency.
Premature ovarian insufficiency (POI) has become one of the greatest health threats to the reproduction of women during their fertile age. Lycium barbarum polysaccharides (LBPs) are known for anti-aging and reproductive protective functions. Here, we investigated the protective effect of LBP on POI mice and revealed its possible mechanism by a combination of 16S rRNA sequencing and metabolomics analysis. In the current study, female C57BL/6J mice treated with D-galactose were used as a model to investigate the reversal effect of LBP on the degenerative ovarian function. The ameliorative effect of LBP on POI was evaluated from the estrous cycle, ovarian reserve, serum sex hormone levels, and fertility testing. Additionally, 16S rRNA gene sequencing and untargeted metabolomics were integrated to analyze the effects of LBP on the gut microbiota and fecal metabolic profile in the POI mice. The results showed that LBP administration significantly increased the total number of follicles and the number of follicles at different developmental stages in the POI mice. In addition, LBP was effective in reducing the serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), regularizing the disordered estrous cycle, and increasing the number of offspring of the POI mice. The results from 16S rRNA sequencing showed that LBP had beneficial effects on the composition and structure of the gut microbiota in the POI mice. In a metabolomics study, a total of 23 metabolites were finally identified as potential biomarkers of POI, and multiple pathways were regulated after the treatment of LBP, especially the arginine biosynthesis, glycerophospholipid metabolism and steroid hormone biosynthesis pathways. Pearson's correlation analysis showed that the regulation effect of LBP on metabolites was closely related to Faecalibaculum, Bilophila and Anaerofustis in the gut microbiota. In summary, the results demonstrated that LBP could improve the ovarian reserve and provides evidence both on the gut microbiota and metabolism, which provide beneficial support for the applications of LBP in female ovarian function degeneration.


Case 266.
History A 1-year-old boy was referred for cochlear implant assessment after he received a diagnosis of bilateral profound sensorineural hearing loss at neonatal hearing screening shortly after birth. The child was born at term via uneventful delivery, and there was no history of familial hearing loss or maternal illness. Tympanic membranes were normal, and hearing loss was confirmed with auditory brainstem testing, which showed no response from either ear. Hearing aids were provided from 3 months of age, but no behavioral responses were noted when these were worn. He was also noted to have some mild developmental delay throughout his 1st year of life and was slow to crawl, roll over, and stand up. Physical examination showed no syndromic features or physical abnormalities. Ophthalmology confirmed normal vision and visual movements but bilateral anesthetic corneas. He had corneal abrasions due to minor repeated corneal trauma, and left-sided tarsorraphy was performed at 6 months. Facial nerve function, swallow, and voice quality were normal. To assess suitability for a cochlear implant, the patient underwent MRI of the temporal lobe and brain ( Figs 1 - 4 ) and thin-section CT of the temporal bones ( Figs 5 , 6 ). The patient subsequently underwent left cochlear implantation. Figure 1: Sagittal midline T1-weighted 1.5-T MR image (repetition time msec/echo time msec, 541/15). Figure 2: Axial T2-weighted MR image (6703/116, 4-mm section thickness) at the level of the pontomesencephalic junction. Figure 3: Axial T2-weighted MR image one level inferior to that shown in Figure 2 . Figure 4a: (a) Axial 1.5-T single-slab three-dimensional (3D) turbo spin-echo MR image (1200/271) at the level of the right internal auditory canal. (b) Corresponding axial 1.5-T single-slab 3D turbo spin-echo MR image at the level of the left internal auditory canal. Figure 4b: (a) Axial 1.5-T single-slab three-dimensional (3D) turbo spin-echo MR image (1200/271) at the level of the right internal auditory canal. (b) Corresponding axial 1.5-T single-slab 3D turbo spin-echo MR image at the level of the left internal auditory canal. Figure 5: Unenhanced axial thin-section (0.7-mm section thickness) CT image of the temporal bone at the level of the internal auditory canals and middle cochlear turns. Figure 6: Unenhanced axial thin-section (0.7-mm section thickness) CT image of the temporal bone at a level slightly inferior to that shown in Figure 5 .


Identification of salt-sensitive genes in the kidneys of Dahl rats.
Inherited differences in renal function underlie the effect of high salt diets on blood pressure in Dahl rats. We probed the kidneys of inbred Dahl SS/Jr and SR/Jr for anonymous and candidate genes whose expression was regulated by dietary sodium. mRNA quantitation of both candidate genes implicated in sodium excretion and anonymous gene products found by differential hybridization in the kidneys of salt-resistant (SR) and salt sensitive (SS) inbred Dahl rats on high and low salt diets for 21 days. Differential screening revealed a cDNA clone (H1) that showed increased dietary salt-dependent expression only in SS rats. Sequencing of the H1 cDNA showed it was the Dahl rat homologue to a perchloric acid soluble protein expressed in liver and kidney. Among candidate genes, transcript levels of arginosuccinate synthetase (AS) and arginosuccinate lyase (AL) were higher in SS on low salt diets, and AS mRNA increased in response to a high salt diet in SR. Renal mRNA for the ANP-A and the vasopressin type II receptors did not differ by strain or dietary conditions. Three new salt-sensitive genes were detected in the kidneys of inbred Dahl rats. Two genes encode enzymes in the biosynthesis of L-arginine. The upregulation of these genes by dietary salt indicates increased demand and biosynthesis of L-arginine in Dahl SS rats. A third gene encodes a small acid-soluble protein thought to influence the transcription/translation of numerous genes. Further studies will be needed to determine the nature of the association of these genes with salt-sensitivity and blood pressure.


The Cloke-Wilson rearrangement of aroyl-substituted donor-acceptor cylopropanes containing arylethyl donors.
The chemistry of donor-acceptor (D-A) cyclopropanes containing alkyl donors has been scantily investigated. In the present work, we have synthesized new D-A cyclopropanes containing arylethyl donors and explored their reactivity in the presence of Lewis acids. Upon treatment with SnCl4, these cyclopropanes underwent the Cloke-Wilson rearrangement to yield 3,4,5-trisubstituted γ-butyrolactones in good yields with high diastereoselectivity.


Efficiently harvesting excitons from electronic type-controlled semiconducting carbon nanotube films.
We have employed thin films of highly purified semiconducting carbon nanotubes as near-infrared optical absorbers in heterojunction photovoltaic and photodetector devices with the electron acceptor C(60). In comparison with previous implementations of more electrically heterogeneous carbon nanotube/C(60) devices, we have realized a 10× gain in zero-bias quantum efficiency (QE) and even more substantial gains in power conversion efficiency (η(p)). The semiconducting nanotube/C(60) heterojunctions are highly rectifying with a peak external QE, internal QE, and η(p) of 12.9 ± 1.3, 91 ± 22, and 0.6%, respectively, in the near-infrared. We show that the device efficiency is determined by the effective length scale for exciton migration in the nanotube films, confirm the high internal QE via photoluminescence quenching, and demonstrate that the driving force for exciton dissociation at the fullerene-fullerene heterointerface is optimized for diameters <1.0 nm. These results will guide the development of next-generation high-performance carbon nanotube-based solar cells and photosensitive devices.


Identification and Genetic Characterization of Blastocystis Species in Patients from Makkah, Saudi Arabia.
Blastocystis species (sp.) are gastrointestinal protozoan parasites with high prevalence rates worldwide. Blastocystis sp. show extensive genetic diversity with 17 different subtypes (STs) described to date. A few studies have investigated the prevalence and STs of Blastocystis sp. in Makkah, Saudi Arabia. Therefore, we aimed in this study to identify and characterize subtypes of Blastocystis sp. in the City of Makkah, Saudi Arabia. Stool samples were collected from 140 patients who presented to King Abdulaziz Hospital, Hera General Hospital and Modern Medical Center in Saudi Arabia. Different microscopic examination methods of patients' stools and molecular analyses (using primers targeting SSU rRNA gene) were performed to identify and characterize STs of Blastocystis sp. Our microscopic examination of stool samples showed that 96/140 patients (68.6%) had Blastocystis sp. infection. Clinical examination of infected patients revealed that 81 patients were symptomatic, whereas 15 were asymptomatic. Next, we isolated DNA from Blastocystis sp.-positive stool samples followed by PCR amplification of small-subunit ribosomal RNA (SSU rRNA) gene and sequence analysis. Our sequence analysis showed that subtype 3 (ST3) was the most prevalent (53.13%) followed by subtype 1 (ST1) (45.83%), whereas subtype 2 (ST2) was the least prevalent (1.04%). Moreover, our results showed that all three STs resulted in more symptomatic than asymptomatic cases. Finally, we identified novel haplotypes which comprised of 8 ST3, 6 ST1, and one ST2 haplotypes. Our identification of several haplotypes in patients' stools confirms the genetic diversity of Blastocystis sp. and may explain the reported low host specificity and differential pathogenicity of Blastocystis sp. We believe that additional molecular epidemiological and genomic studies are needed to understand the prevalence and pathogenicity of different subtypes in humans and animal hosts.


Clinical applications of mesenchymal stem cells in chronic lung diseases.
Mesenchymal stem (stromal) cells (MSCs) are multipotent stromal cells that have the ability to modulate immune response to tissue injury and promote repair in vivo. The therapeutic potential of ex vivo expanded MSCs are currently under investigation for a variety of chronic and acute lung diseases. This review summarizes the encouraging results regarding the safety of MSCs administration from recent and current clinical trials for idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and chronic obstructive pulmonary disease. It also reviews the early preliminary data extracted by the same trials regarding the efficacy of MSCs in the aforementioned lung diseases.


Are proton pump inhibitors associated with the development of community-acquired pneumonia? A meta-analysis.
This study was presented at the American College of Chest Physicians meeting in Pittsburgh (PA, USA) in October 2011. The study objective was to evaluate the association of proton pump inhibitors (PPIs) and community-acquired pneumonia (CAP). The design was a meta-analysis of nine case-controlled and cohort studies. 120,863 pneumonia cases from 1987 to 2006 were included in the meta-analysis. PubMed and Ovid Medline were searched from inception through May 2011 by two investigators independently using keywords: PPI, pneumonia, CAP, anti-ulcer, antacid, omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. This meta-analysis only included case-controlled and cohort studies that were published in full in English and evaluated PPI use and CAP incidence. Studies were excluded if they included the following patients: pediatric, Helicobacter pylori treatment and critically ill. Bibliographies of recent review articles and systematic reviews were hand-searched. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Two investigators independently extracted data into standardized data collection forms that were confirmed by a third investigator. Data were analyzed based on current use of PPIs, duration of PPI use (<30 days or >180 days) and PPI dose (high vs low). Overall association of PPI and CAP was analyzed using the random effects model (Comprehensive Meta analysis(®) Version 2.0). Nine studies met all criteria for the primary outcome. Newcastle-Ottawa Quality Assessment Scale scores ranged from 4 to 8 out of 9. Current use of PPIs (odds ratio [OR]: 1.39; 95% CI: 1.09-1.76), PPI use <30 days (OR: 1.65; 95% CI: 1.25-2.19), PPI high dose (OR: 1.50; 95% CI: 1.33-1.68) and PPI low dose (OR: 1.17; 95% CI: 1.11-1.24) were significantly associated with CAP. There was no association between CAP and PPI use >180 days (OR: 1.10; 95% CI: 1.00-1.21). In conclusion, patients currently receiving PPIs, particularly <30 days or high dose, showed an association with CAP. Practitioners need to be vigilant about adverse effects of PPIs and consider alternative therapies.


Leu M1 and peanut agglutinin stain the neoplastic cells of Hodgkin's disease.
It has been suggested that the malignant cells of Hodgkin's disease (HD), Reed-Sternberg cells, and their mononuclear variants may be related to cells of the monocyte-histiocyte system. To test this hypothesis, 20 cases of HD were tested with nine antibodies, monoclonal or polyclonal, that normally react with cells of monocytic/histiocytic/granulocytic lineages, as well as PNA, which binds to histiocytes directly. Only two reagents, Leu M1 and PNA bound to the neoplastic cells in 20/22 and 13/22 cases tested, respectively. Leu M1 was the most sensitive reagent and was negative in only two cases of lymphocyte predominant HD. Leu M1 also could be employed in routinely fixed and processed formalin or B5-fixed tissue. This antibody, which was negative in 27 cases of non-Hodgkin's lymphoma, including 12 peripheral T-cell lymphomas, should prove to be of value in differential diagnosis of HD and morphologically similar reactive and neoplastic lymphoid lesions.


Destabilization of the non-pathogenic, cellular prion-protein by a small molecular drug.
The presence of the normal cellular prion-protein (PrPc) is a prerequisite for the development of fatal, neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). We discovered a new biological activity of the well-known coumarin antibiotic novobiocin; the treatment of eukaryotic cells with novobiocin induces the rapid depletion of PrPc. This activity is shared by coumermycin A1, another coumarin with a related molecular structure. Novobiocin's effects on the prion-protein are time- and dose-dependent. No permanent damage to the treated cells was observed, which continue to proliferate after cessation of drug exposure. Most of the cellular proteins are unaffected by novobiocin treatment. Pretreatment with geldanamycin, an inhibitor of the aminoterminal ATPase of heat-shock protein 90 (Hsp90) partially antagonizes novobiocin's depletory activity. Concurrent treatment with the protease inhibitor chymostatin completely prevents PrPc loss. Here we show that the stability of the normal cellular prion-protein may be targeted pharmacologically. These findings open up a hitherto unknown avenue to the study of TSEs in general and may have therapeutic implications.


Comparison of methods of plasma volume determination for dose calculation of factor VIII in patients with classic haemophilia.
Plasma volumes have been measured in 12 patients with moderate or severe haemophilia A and compared with plasma volumes derived by calculation using a variety of commonly recommended formulae based on body weight with or without a correction for haematocrit. The mean plasma volume by measurement was 47 ml/kg. A calculated plasma volume using 42 ml/kg and a correction for haematocrit most closely approximated the measured results. The correlation coefficient was 0.9. Ex vivo factor VIII recoveries, following infusion of either lyophilised cryoprecipitate or NZFVIII (controlled pore glass preparation), were then determined based on the observed/expected response assuming different values for plasma volume. Mean recoveries of approximately 100% were associated with a 2.4% FVIII rise per unit/kg administered using cryoprecipitate. Ex vivo recoveries following NZFVIII exceeded 100% with mean values, depending on the technique used for plasma volume determination, up to 131%. Recoveries were not significantly affected by the plasma volume method used and all methods indicated that the labelled potency of NZFVIII is currently being underestimated by at least 20-30%.


Somatosensory evoked potential identification of sensorimotor cortex in removal of intracranial neoplasms.
To assess the ease and reliability of routine use of somatosensory evoked potentials (SSEPs) for identification of sensorimotor cortex in brain tumour removal and to document its influence on the performance and outcome of surgery. SSEPs in response to contralateral median nerve stimulation were recorded from the cortical surface by means of a four lead electrode strip. Polarity reversal of short latency SSEP waves was used to identify the position of the central sulcus in 46 consecutive craniotomies for removal of metastases, gliomas, or meningiomas located in, near, or overlying sensorimotor cortex. SSEPs were successfully recorded in 43/46 cases (94%) with demonstration of polarity reversal in 42/43 (98%). SSEP localization led to modification of 14/42 (33%) procedures, most frequently because of either displacement or involvement of sensorimotor cortex by tumour. Six patients (14%) developed new neurological deficits but none of these was attributable to incorrect identification of sensorimotor cortex. SSEP polarity reversal is a simple, reliable, accurate, and inexpensive method of localizing sensorimotor cortex under general anaesthesia. Correct identification is possible when sensorimotor cortex is displaced or when surface anatomy is obscured by tumour. Routine use of this technique should be considered in all procedures for lesions located near the central sulcus.


Discovery of talatisamine as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons.
Blocking specific K+ channels has been proposed as a promising strategy for the treatment of neurodegenerative diseases. Using a computational virtual screening approach and electrophysiological testing, we found four Aconitum alkaloids are potent blockers of the delayed rectifier K+ channel in rat hippocampal neurons. In the present study, we first tested the action of the four alkaloids on the voltage-gated K+, Na+ and Ca2+ currents in rat hippocampal neurons, and then identified that talatisamine is a specific blocker for the delayed rectifier K+ channel. External application of talatisamine reversibly inhibited the delayed rectifier K+ current (IK) with an IC50 value of 146.0+/-5.8 microM in a voltage-dependent manner, but exhibited very slight blocking effect on the voltage-gated Na+ and Ca2+ currents even at the high concentration of 1-3 mM. Moreover, talatisamine exerted a significant hyperpolarizing shift of the steady-state activation, but did not influence the steady state inactivation of IK and its recovery from inactivation, suggesting that talatisamine had no allosteric action on IK channel and was a pure blocker binding to the external pore entry of the channel. Our present study made the first discovery of potent and specific IK channel blocker from Aconitum alkaloids. It has been argued that suppressing K+ efflux by blocking IK channel may be favorable for Alzheimer's disease therapy. Talatisamine can therefore be considered as a leading compound worthy of further investigations.


[Percutaneous endoscopic cholangioscopy (percutaneous cholangioscopy)].
The aim of this paper is to present the percutaneous cholangioscopic method, objectives, indications, technique and advantages of this method in exploration and treatment of common bile duct disease. Percutaneous cholangioscopy is a complementary mini-invasive method, which is associated to classic or laparoscopic surgical procedures on common bile duct disorder. This method has the main characteristic intraductal approach, which is made via an external preformed fistula derived from an anterior surgical open or mini-invasive interventional procedures performed on the common bile duct. Percutaneous cholangioscopy is very performing in early or differential diagnosis determination of common bile duct malignant tumors and is a valuable method for mini-invasive intraductal treatment that can be performed by this method, avoiding another interventional surgical or endoscopical procedure on common bile duct.


Studies on metabolism of vitamin A. Absorption of retinal (vitamin A aldehyde) in rats.
1. Young rats with low reserves of vitamin A were dosed with retinal in groundnut oil, and the stomach, the contents, mucosa and muscles of small intestine, the blood and the liver were analysed at periods up to 24hr. after dosing. 2. Up to 6hr. after the dose, retinal was present in high concentrations in the contents, mucosa and muscles of the intestine. Small but significant amounts were present in blood and liver at all times. 3. The intestinal mucosa and muscles always contained small amounts of retinol and its esters. 4. A study of the distribution of the three forms of the vitamin within the mucosal cell showed that most of the mucosal retinal enters the cell unchanged. 5. When protein-depleted rats were similarly given retinal, the rate of reduction of the aldehyde, and the consequent deposition in the liver of retinol and its esters, progressively decreased with reduced protein intake.


SuFExable polymers with helical structures derived from thionyl tetrafluoride.
Sulfur(VI) fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulfur(VI) connective hubs. The efficiency of SuFEx and the stability of the resulting bonds have led to polymer chemistry applications. Now, we report the SuFEx click chemistry synthesis of several structurally diverse SOF4-derived copolymers based on the polymerization of bis(iminosulfur oxydifluorides) and bis(aryl silyl ethers). This polymer class presents two key characteristics. First, the [-N=S(=O)F-O-] polymer backbone linkages are themselves SuFExable and undergo precise SuFEx-based post-modification with phenols or amines to yield branched functional polymers. Second, studies of individual polymer chains of several of these new materials indicate helical polymer structures. The robust nature of SuFEx click chemistry offers the potential for post-polymerization modification, enabling the synthesis of materials with control over composition and conformation.


The Burden of Digestive Diseases in the United States Population.
Digestive diseases are common and lead to significant morbidity, mortality, and health care utilization. We used national survey and claims databases to expand on earlier findings and investigate current trends in the digestive disease burden in the United States. The National Ambulatory Medical Care Survey, Nationwide Emergency Department Sample, National Inpatient Sample, Vital Statistics of the U.S., Surveillance, Epidemiology, and End Results Program, Optum Clinformatics® Data Mart, and Centers for Medicare and Medicaid Services Medicare 5% Sample databases were used to estimate medical care, mortality, cancer incidence, and claims-based prevalence with a digestive disease diagnosis. Rates were age-adjusted (for national databases) and shown per 100,000 population. For all digestive diseases, prevalence (claims-based, all-listed diagnoses) was 30.5% among commercial insurance enrollees (2020) and 53.1% among Medicare beneficiaries (2019). In the U.S. population, digestive diseases contributed to approximately 126 million ambulatory care visits (2015), 41 million emergency department visits (2018), 16 million hospital discharges (2018), and 472,000 deaths (2019) annually. Prevalence, medical care, and mortality rates with a digestive disease diagnosis were higher among children and younger adults (except for emergency department visits) and then increased with age. Women had higher prevalence and medical care rates with a digestive disease diagnosis, but mortality rates were higher among men. Prevalence and medical care rates with a digestive disease diagnosis were higher among Blacks, followed by Whites, then Hispanics, and lowest among Asians. Mortality rates were higher among Blacks compared with Whites and lower among Hispanics compared with non-Hispanics. Between 2004 and the most recent year, ambulatory care visit rates with a digestive disease diagnosis increased by 4%, hospital discharge rates decreased by 3%, and mortality rates decreased by 7%. Among commercial insurance enrollees, rates were higher compared with national data for ambulatory care visits and hospital discharges, but lower for emergency department visits. The medical care use and mortality burdens varied among individual digestive diseases. The digestive disease burden in the United States is substantial, particularly among Blacks and older adults.


Ovarian morphology and internal vis-à-vis non internal laying in relation to triacylglycerol, hormones and their receptors concentration around the age of sexual maturity in broiler breeder hens.
1. Ovarian morphology, serum hormone concentrations of 17-β-estradiol, progesterone, testosterone, tri-iodothyronine (T3), thyroxine (T4) and triacylglycerol (TAG) were investigated at 23 and 26 weeks of age in broiler breeder hens provided with ad libitum access to feed. Progesterone, oestrogen-β, thyroid-α and -β receptor mRNAs were also quantified in the infundibulum at the same ages. 2. A large variation in the ovarian morphology was observed at 23 weeks of age including hens with undeveloped ovaries, non-laying hens with post ovulatory follicles (POF) and a predominance of non-laying hens without a POF. 3. Serum concentrations of triglyceride, 17-β-estradiol and progesterone at 23 weeks of age were lower in hens with an undeveloped ovary compared with other groups of hens, whereas testosterone, triiodothyronine and thyroxin were higher. 4. At 26 weeks of age, the average number of hierarchical yellow follicles in normal layers was 7.64 ± 0·41 whereas in internal layers, the follicular numbers were significantly greater at 8.66 ± 0·53. The higher follicular numbers in internal layers were associated with higher serum triglyceride and progesterone concentrations. 5. Oestrogen receptor-β and thyroid receptor-β mRNA was up regulated in the infundibulum of internal layers compared with normal laying hens at 26 weeks of age.


Measuring User Experience With 3, 5, 7, or 11 Points : Does It Matter?
To assess versions of the shorter form variant of Usability Metric for User Experience (UMUX-LITE) questionnaire differing in the number of response options for the items (3, 5, 7, and 11). The UMUX-LITE is an efficient (two-item) standardized questionnaire that measures perceived usability. A growing body of evidence shows it closely corresponds to one of the most widely used standardized usability questionnaires, the System Usability Scale (SUS), with regard to both correlation and magnitude of concurrently collected means. Although the "standard" version of the UMUX-LITE uses items with seven response options, there is some variance in practice. Members of a corporate user experience panel (n = 242) completed surveys rating a recent Web site experience with the SUS and UMUX-LITE, also providing ratings of overall experience and likelihood-to-recommend. Scale reliabilities were acceptable (coefficient α >.70) with the exception of UMUX-LITE with three response options. All UMUX-LITE correlations with SUS, overall experience, and likelihood-to-recommend were highly significant. For likelihood-to-recommend, there was a significant difference in the magnitude of correlations, with 11 response options higher than three. Although some statistically significant differences were observed in correspondence between SUS and UMUX-LITE scores, these did not seem to translate to practically significant differences. The number of UMUX-LITE response options does not matter much, especially in practice. Because the version with three response options showed some weakness with regard to reliability and correlation with likelihood-to-recommend, practitioners should avoid it. Unless there is a strong reason to do otherwise, use the "standard" version with seven response options.


Insulin-like growth factor I action on rat anterior pituitary cells: suppression of growth hormone secretion and messenger ribonucleic acid levels.
Somatomedin preparations have previously been shown to suppress GH release. The effects of a synthetic recombinant human insulin-like growth factor analog (IGF-I; Thr 59) were, therefore, tested on long term GH secretion by male rat pituitary monolayer cell cultures grown in serum-free defined medium. IGF-I (3.25 nM) maximally suppressed basal GH secretion for up to 72 h by 66%, with an ED50 of 0.1 nM. Human pancreatic GRF-(1-44) (GHRH; 1 nM) stimulated GH secretion by 230% during 72 h. IGF-I (0.13 nM) suppressed GHRH-stimulated GH secretion by 30% (P less than 0.005). IGF-I (0.625 nM) completely abolished stimulation of GH by GHRH (1 nM), while higher doses of IGF-I (up to 6.5 nM) actually suppressed GH secretion even in the presence of GHRH (up to 1 nM). The depletion of intracellular GH levels in GHRH-treated cells was reversed by IGF-I (3.25 nM). PRL secretion was not altered in the same cells by IGF-I. Equivalent doses of epidermal growth factor and fibroblast growth factor did not alter basal or GHRH-stimulated GH secretion. Nitrocellulose dot hybridization of immobilized pituitary cell RNA extracts with rat GH [32P]cDNA showed that cellular GH mRNA levels were lowered in IGF-I-treated cells in a dose-dependent manner. Maximal suppression of GH mRNA was achieved with 0.65 nM IGF-I. IGF-I also inhibited the 3-fold stimulation of GH mRNA induced by 1 nM GHRH. The data show that IGF-I directly modulates GH gene expression at the level of the somatotroph by inhibiting basal and GHRH-stimulated GH secretion and GH mRNA levels during 72 h. These effects may occur at different postranscriptional sites. Alternatively, they may result from a direct inhibition of IGF-I on GH gene transcription.


[Submacular hemorrhage following photodynamic therapy in the treatment of choroidal neovascularization].
To describe the incidence, clinical features and evolution of submacular hemorrhage (SMH) occurring after photodynamic therapy (PDT) with verteporfin in the treatment of choroidal neovascularization (CNV). A retrospective analysis of the patients treated with PDT in our hospital between July 2002 and May 2005 was undertaken. 8 out of 504 eyes treated with PDT (1.58%) developed SMH; 4 of them (0.79%) required surgical attack. The incidence of SMH for every application of PDT was 0.65% (8/1221). The underlying disorder defined was age-related macular degeneration (AMD) in 7 cases (87.5%), and high myopia in one case (12.5%). Regarding the type of lesion, 5 were occult (62.5%; p=0.01), 1 predominantly classic, 1 minimally classic, and the last one was not classified. The average final visual acuity (VA) was 0.057, with 25% of patients having a VA >or= 0.1. Patients lost 4 Snellen lines on average. SMH after PDT was an event of unknown etiology and low frequency. The incidence in our series (1.58%) was comparable with that described in the world literature (0.24-9.0%). The greatest incidence of AMD was in the occult group with no classic type of CNV, suggesting a possible higher risk for SMH in this type of lesion. It is mandatory to inform patients of the possibility of this complication, which can compromise the visual result of the PDT, and sometimes require surgery. The low risk of SMH related to the PDT justifies its application when it is indicated.


Evaluation of Vancoplus versus ceftriaxone against cephalosporin resistance MRSA strain in experimental meningitis model.
The aim of this study was to compare the efficacy of ceftriaxone plus vancomycin (Vancoplus) versus ceftriaxone alone against cephalosporin resistant methicillin-resistant Staphylococcus aureus (MRSA) strain by using meningitis mice model. The MRSA strain ATCC 43300 was used to induce meningitis in mice. The mice were fed standard pelleted diet and water ad libitum. The test room was air conditioned with temperature 23 +/- 2 degrees C, humidity 65+/- 5% and with artificial fluorescent light 10-14 hrs. of light and dark, respectively. Twenty four mice were divided into four group containing six rats in each group. The ceftriaxone group received 28.57 mg/Kg body weight/day and the vancoplus group received 42.8 mg/Kg body weight/day and control as well as infected group received normal saline. The bacterial susceptibility test in CSF was performed for cephalosporin resistance MRSA strain by determining the lytic zone for the vancoplus and ceftriaxone antibiotic. The lytic zone was more in vancoplus as compared to ceftriaxone. It was also found that activities of antioxidant enzymes such as catalase were significantly increased (p<0.001) along with decreased (p<0.001) in lipid peroxidation (malonaldialdehyde) level in CSF of vancoplus treated group as compared to infected as well as ceftriaxone resistance group and come back to normal level. It was concluded that vancoplus beneficial for the patients who suffered from cephalosporin resistant MRSA bacterial strain.


[Hypotensive effect of long-acting garlic tablets allicor (a double-blind placebo-controlled trial)].
To evaluate a hypotensive action of long-acting garlic powder tablets allicor in patients with mild or moderate hypertension and to compare allicor effects with those of foreign analog--kwai garlic tablets. A double-blind, randomized and placebo-controlled study enrolled 85 patients with mild or moderate hypertension. The patients were divided into 4 groups: group 1 received allicor in a dose 600 mg/day, group 2--2400 mg/day, group 3--kwai in a dose 900 mg/day, group 4--placebo. Allicor produced reaction in both systolic and diastolic pressure. An increase of allicor daily dose to 2400 mg does not provide an additional hypotensive effect. Kwai results in only systolic but not diastolic arterial pressure lowering. Allicor is more effective than kwai in reduction of diastolic blood pressure. It can be recommended as a hypotensive treatment in mild and moderate arterial hypertension.


Consensus on Diagnostic Criteria of Idiopathic Orbital Inflammation Using a Modified Delphi Approach.
Current practice to diagnose idiopathic orbital inflammation (IOI) is inconsistent, leading to frequent misdiagnosis of other orbital entities, including cancer. By specifying criteria, diagnosis of orbital inflammation will be improved. To define a set of criteria specific for the diagnosis of IOI. A 3-round modified Delphi process with an expert panel was conducted from June 8, 2015, to January 25, 2016. Fifty-three orbital scientist experts, identified through membership in the Orbital Society, were invited to participate in on online survey and they scored, using 5-point Likert scales, items that are eligible as diagnostic criteria from the literature and from personal experience. The items were clustered around the anatomic subtypes of IOI: idiopathic dacryoadenitis and idiopathic orbital fat inflammation (2 nonmyositic IOIs), and idiopathic orbital myositis (myositic IOI). Items with dissensus were rescored in the second round, and all items with consensus (median, ≥4; interquartile range, ≤1) were ranked by importance in the third round. Consensus on items to be included in the criteria. Of the 53 experts invited to participate, a multinational panel of 35 (66%) individuals with a mean (SD) years of experience of 31 (11) years were included. Consensus was achieved on 7 of 14 clinical and radiologic items and 5 of 7 pathologic items related to diagnosis of nonmyositic IOI, and 11 of 14 clinical and radiologic items and 1 of 5 pathologic items for myositic IOI. There was agreement among panelists to focus on surgical tissue biopsy results in the diagnosis of nonmyositic IOI and on a trial with systemic corticosteroids in myositic IOI. Panelists agreed that a maximum number of 30 IgG4-positive plasma cells per high-power field in the orbital tissue is compatible with the diagnosis of IOI. An international panel of experts endorsed consensus diagnostic criteria of IOI. These criteria define a level of exclusion suggested for diagnosis and include tissue biopsy for lesions not confined to the extraocular muscles. This consensus is a step toward developing guidelines for the management of IOI, which needs to be followed by validation studies of the criteria.


Crystallization Caught in the Act with Terahertz Spectroscopy: Non-Classical Pathway for l-(+)-Tartaric Acid.
Crystal formation is a highly debated problem. This report shows that the crystallization of l-(+)-tartaric acid from water follows a non-classical path involving intermediate hydrated states. Analytical ultracentrifugation indicates solution clusters of the initial stages aggregate to form an early intermediate. Terahertz spectroscopy performed during water evaporation highlights a transient increase in the absorption during nucleation; this indicates the recurrence of water molecules that are expelled from the intermediate phase. Besides, a transient resonance at 750 GHz, which can be assigned to a natural vibration of large hydrated aggregates, vanishes after the final crystal has formed. Furthermore, THz data reveal the vibration of nanosized clusters in the dilute solution indicated by analytical ultracentrifugation. Infrared spectroscopy and wide-angle X-ray scattering highlight that the intermediate is not a crystalline hydrate. These results demonstrate that nanoscopic intermediate units assemble to form the first solvent-free crystalline nuclei upon dehydration.


Mixed diboration of alkenes in a metal-free context.
Experimental and theoretical rationalization on regioselective mixed diboration of alkenes, with the unsymmetrical diboron reagent Bpin-Bdan, providing the protecting Bdan moiety in the internal position.


Lymphocytic choriomeningitis virus infection induced by percutaneous exposure.
We report a case of acquired lymphocytic choriomeningitis virus (LCMV) infection due to an accidental percutaneous inoculation of LCMV at work. The injured worker developed a flu-like syndrome, followed by pericarditis and meningoencephalitis. Seroconversion was confirmed by ELISA. The patient made a complete recovery. We review measures undertaken to prevent a similar event and propose a follow-up protocol in the event of accidental LCMV exposure.


Effect of renal nerve stimulation on the activity of the tubuloglomerular feedback mechanism.
The influence of renal nerve stimulation on the tubuloglomerular feedback mechanism was studied on anaesthetized rats. The analyses was made by comparing the single-glomerular filtration rate (SNGFR) measured from late proximal tubules with SNGFR measured from distal tubules in the same nephron. In the former situation the flow to the macula densa cells is interrupted and in the latter the macula densa is influenced by the flow passing by. In the control situation the SNGFR measured proximally was 47.7 +/- 2.2 nl . min-1 (mean +/- SE) and 40.1 +/- 1.8 measured distally indicating an activated tubuloglomerular feedback. During renal nerve stimulation (2-3 Hz), the SNGFR fell to 38.5 +/- 2.3 and 33.5 4/- 1.7 when measured proximally and distally, respectively. The results indicate that the tubuloglomerular feedback mechanism is unaffected by renal nerve stimulation.


A randomised study on the clinical progress of high-risk elective major gastrointestinal surgery patients treated with olive oil-based parenteral nutrition with or without a fish oil supplement.
n-3 Fatty acids have clinical benefits. The primary aim of the present study was the assessment of infection in patients who underwent major high-risk elective gastrointestinal surgery receiving postoperatively fish oil (FO)-supplemented parenteral nutrition (PN), compared with those receiving a standard olive oil (OO) emulsion. The secondary aims were the assessment of anti-inflammatory response and evaluation of tolerance and safety of these emulsions. A prospective, randomised, double-blind study was performed in patients requiring at least 5 d of PN. An isoenergetic and isoproteic formula was administered: group A received OO alone, while group B received OO that was partially replaced with FO (16.6 %, w/w). End points were outcome measures (mortality, sepsis, infection, hospitalisation days and PN duration), inflammatory response (C-reactive protein (CRP), prealbumin and leucocytes) and safety (TAG and glucose metabolism, and liver and kidney function). Statistical analysis was done using Student's t test and Fisher's exact test (P < 0.05). Twenty-seven patients were evaluated, with thirteen patients receiving FO. In this group, a significantly lower incidence of infections was found (23.1 v. 78.6 %, P = 0.007). CRP, prealbumin and leucocytes were not significantly different between the groups. There were no differences in safety parameters. We conclude that high-risk surgical patients receiving FO-supplemented PN for 5 d present a lower incidence of infection. Emulsions were safe and well tolerated.


A Novel Approach to Assess Motor Outcome of Deep Brain Stimulation Effects in the Hemiparkinsonian Rat: Staircase and Cylinder Test.
Deep brain stimulation of the subthalamic nucleus is an effective treatment option for Parkinson's disease. In our lab we established a protocol to screen different neurostimulation patterns in hemiparkinsonian (unilateral lesioned) rats. It consists of creating a unilateral Parkinson's lesion by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle, implanting chronic stimulation electrodes into the subthalamic nucleus and evaluating motor outcomes at the end of 24 hr periods of cable-bound external neurostimulation. The stimulation was conducted with constant current stimulation. The amplitude was set 20% below the individual threshold for side effects. The motor outcome evaluation was done by the assessment of spontaneous paw use in the cylinder test according to Shallert and by the assessment of skilled reaching in the staircase test according to Montoya. This protocol describes in detail the training in the staircase box, the cylinder test, as well as the use of both in hemiparkinsonian rats. The use of both tests is necessary, because the staircase test seems to be more sensitive for fine motor skill impairment and exhibits greater sensitivity to change during neurostimulation. The combination of the unilateral Parkinson model and the two behavioral tests allows the assessment of different stimulation parameters in a standardized way.


Heterostructured TiO2/NiTiO3 Nanorod Arrays for Inorganic Sensitized Solar Cells with Significantly Enhanced Photovoltaic Performance and Stability.
Organic dyes used in the conventional dye-sensitized solar cells (DSSCs) suffer from poor light stability and high cost. In this work, we demonstrate a new inorganic sensitized solar cell based on ordered one-dimensional semiconductor nanorod arrays of TiO2/NiTiO3 (NTO) heterostructures prepared via a facile two-step hydrothermal approach. The semiconductor heterostructure arrays are highly desirable and promising for DSSCs because of their direct charge transport capability and slow charge recombination rate. The low-cost NTO inorganic semiconductor possesses an appropriate band gap that matches well with TiO2, which behaves like a "dye" to enable efficient light harvesting and fast electron-hole separation. The solar cells constructed by the ordered TiO2/NTO heterostructure photoanodes show a significantly improved power conversion efficiency, high fill factor, and more promising, outstanding life stability. The present work will open up an avenue to design heterostructured inorganics for high-performance solar cells.


Can Elevated Pretreatment Serum Carcinoembryonic Antigen Levels Serve as a Potential Biomarker Guiding Adjuvant Chemotherapy in Rectal Cancer Patients With ypTis-3N0 After Neoadjuvant Radiotherapy and Surgery?
Survival benefit of adjuvant chemotherapy (ACT) remained controversial in patients with stage II/III rectal cancer (RC) who received neoadjuvant therapy and surgery. This study aimed to investigate the guiding role of elevated pretreatment serum carcinoembryonic antigen (CEA) levels for receiving ACT in yield pathological Tis-3N0 (ypTis-3N0) RC patients after neoadjuvant radiotherapy and surgery. Between 2004 and 2015, 10,973 RC patients with ypTis-3N0 who received neoadjuvant radiotherapy and radical surgery were retrospectively analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. Compared with CEA-normal group, elevated-CEA patients had worse 5-year CSS rate (90.1 vs 83.5%). The 5-year CSS rates were 86.3 and 87.4% for ypTis-3N0M0 patients with or without ACT, respectively. Patients receiving ACT had a comparable 5-year CSS rate compared to those who did not regardless of CEA levels in ypTis-3N0M0 RC patients (CEA elevation group: 76.4 vs. 83.5%, P = 0.305; CEA normal group: 90.0 vs. 90.1%, P = 0.943). Intriguingly, ypT3N0M0 RC patients with elevated CEA levels may benefit from ACT (5-year CSS: 69.1 vs. 82.9%, P = 0.045), while those with normal CEA levels did not (5-year CSS: 89.3 vs. 89.3%, P = 0.885). Multivariate Cox analysis demonstrated that ACT tended to be a protective factor in elevated-CEA ypT3N0M0 RC patients (HR = 0.633, 95% CI = 0.344-1.164, P = 0.141), while ACT was not associated with improved CSS in normal-CEA ypT3N0M0 RC patients (HR = 1.035, 95% CI = 0.487-2.202, P = 0.928). Elevated pretreatment serum CEA levels may serve as a promising biomarker guiding ACT in rectal cancer patients with ypT3N0M0.


Treatment of superficial thrombophlebitis. A comparative trial between placebo, Hirudoid cream and piroxicam gel.
A prospective randomized trial on the treatment of superficial thrombophlebitis has been performed in 68 patients randomized to either Hirudoid cream, piroxicam gel or placebo. Both spontaneous and infusion thrombophlebitis were included. Treatment effect was evaluated using the status of thrombophlebitis, the thrombophlebitic area, pain intensity with a visual analogue scale, and side effects were registered. Both in the treatment groups and the placebo group there was a significant decrease of signs and symptoms during the treatment period. There was no statistical difference between the treatment groups and no difference between spontaneous and infusion thrombophlebitis.


Comparison of MRI graded cartilage and MRI based volume measurement in knee osteoarthritis.
The aim of this study was to investigate the relationship between the femoral, tibial and patellar cartilage volume and MRI grading of the articular cartilage in patients with knee OA. Articular cartilage volumes of 65 postmenopausal women were determined by processing images acquired in the sagittal plane using a fast spin echo proton density-weighted sequence. The articular cartilages were divided into 5 compartments including lateral and medial tibial, lateral and medial femoral and patellar compartments. The articular cartilages were graded using a modified Outerbridge classification. Grade 0 indicated intact cartilage, grade 1 chondral softening with normal contour, grade 2 superficial fraying, grade 3 surface irregularity and thinning and grade 4 full thickness cartilage loss. The grades of articular cartilage were compared with cartilage volume measurements. In medial femoral cartilage, grade 1 had more volume compared to grade 0 cartilage (p: 0.017). In medial tibial cartilage, grade 1 had more volume compared to grade 0 and grade 2 cartilage (p: 0.045 and p: 0.027, respectively). In patellar cartilage, grade 1 cartilage had significantly more volume than grade 0 cartilage (p: 0.007). In lateral tibial and femoral cartilages, no significant difference was observed between grade 0 and grade 1 cartilage. Cartilage volume correlates well with MR grading of articular cartilage. The higher the grade of the cartilage the less the volume, with the exception of grade 1 lesions. Grade 1, reflects oedema in the cartilage and has a conflicting effect on volume measurement. The combination of MRI based volume measurement and grading of articular cartilage may provide an accurate method for the non-invasive evaluation and follow-up of articular cartilage.


Efficacy of imidacloprid, imidacloprid/permethrin and phoxim for flea control in the Mustelidae (ferrets, mink).
Farmed mink (Mustela vison), a close relative of the domestic ferret (Mustela putorius furo), naturally infested with the squirrel flea (Ceratophyllus sciurorum) were included in a study to investigate three compounds for flea control. The test products were imidacloprid in a 10% (w/v) solution, an imidacloprid 10% (w/v)/permethrin 50% (w/v) solution, and phoxim; all three are well-known compounds for the control of different ectoparasites in a wide range of animals. Two groups of mink received 0.1 ml per animal of the imidacloprid or the imidacloprid/permethrin combination at days 0 and 28, respectively. Two groups of mink were sprayed with 25 ml of a 0.1% phoxim solution at day 0 and either 1x25 ml or 2x25 ml, respectively, of a 0.05% phoxim solution at day 28. One group of mink served as an untreated control. At assessment on day 56 the efficacy was 91.9% in the imidacloprid group, 89.3% in the imidacloprid/permethrin group, 92.2% in the phoxim 1x25-ml group and 99.3% in the phoxim 2x25 ml group, respectively. In the untreated control group an average of 757 fleas per mink nesting material was recorded.


[Medical application of the art of supplication before the Tang dynasty].
Ample materials on diseases treated with supplication were seen on excavated texts, medical works from ancient time, and religious works before the Tang dynasty (including Tang dynasty). Since the breaking up of witchcraft from medicine, there are still supplication applied in the treatment and prevention of diseases, including those of internal medicine, external medicine, women's and children's diseases, disease of the sense organs, and infections. There are dual reasons for this phenomena, one being the diseases caused by spirit and ghostss; and the other being certain effectiveness of this art on some diseases not cured by other regular treatments, hence, its acceptance by secular people.


Biosynthesis of fluorothreonine and fluoroacetic acid by the thienamycin producer, Streptomyces cattleya.
An antimetabolite, THX, was isolated from fermentation broths of the thienamycin producer, Streptomyces cattleya, when the organism was grown in the presence of a fluorine-containing substrate. THX was subsequently identified as one of the four possible stereoisomers of 4-fluorothreonine. Inorganic fluoride or any one of a number of organofluorine compounds can be used as precursors of 4-fluorothreonine. In addition, 19F NMR has provided evidence that the organism synthesizes fluoroacetate under the same fermentation conditions. The in vitro antibacterial spectrum of 4-fluorothreonine is also presented.


Web-Based Benefit-Finding Writing for Adults with Type 1 or Type 2 Diabetes: Preliminary Randomized Controlled Trial.
The high prevalence of diabetes distress and subclinical depression in adults with type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively) indicates the need for low-intensity self-help interventions that can be used in a stepped care approach to address some of their psychological needs. However, people with diabetes can be reluctant to engage in mental health care. Benefit-finding writing (BFW) is a brief intervention that involves writing about any positive thoughts and feelings concerning a stressful experience such as an illness, avoiding potential mental health stigma. It has been associated with increases in positive affect and positive growth and has demonstrated promising results in trials in other clinical populations. However, BFW has not been examined in people with diabetes. This study aimed to evaluate the efficacy of a Web-based BFW intervention for reducing diabetes distress and increasing benefit finding in diabetic adults with T1DM or T2DM compared to a control writing condition. Adults with T1DM or T2DM and diabetes distress were recruited online through the open access Writing for Health program. After completing baseline questionnaires, they were randomly allocated to receive online BFW or an active control condition of online writing about the use of time (CW). Both groups completed 15-minute online writing sessions, once per day, for 3 consecutive days. Online measures were administered at baseline, 1 month, and 3 months postintervention. Participants were also asked to rate their current mood immediately prior to and following each writing session. Seventy-two adults with T1DM or T2DM were recruited and randomly allocated to receive BFW (n=24) or CW (n=48). Participants adhered to the BFW regimen. Greater increases in positive affect immediately postwriting were found in the BFW group than in the CW group. However, there were no significant group-by-time interactions (indicating intervention effects) for benefit finding or diabetes distress at either the 1-month or 3-month follow-up. Both the BFW and CW groups demonstrated small, significant decreases in diabetes distress over time. BFW was well tolerated by adults with diabetes in this study but did not demonstrate efficacy in improving diabetes distress or benefit finding compared to an active control writing condition. However, due to recruitment difficulties, the study was underpowered and the sample was skewed to individuals with minimal diabetes distress and none to minimal depression and anxiety at baseline. Future research should continue to investigate the efficacy of variants of therapeutic writing for adults with T1DM or T2DM, using larger samples of participants with elevated diabetes distress. Australiand New Zealand Clinical Trials Registry ACTRN12615000241538; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368146.


Sand Barriers around Latrine Pits Reduce Fecal Bacterial Leaching into Shallow Groundwater: A Randomized Controlled Trial in Coastal Bangladesh.
We evaluated the effectiveness of a sand barrier around latrine pits in reducing fecal indicator bacteria (FIB) leaching into shallow groundwater. We constructed 68 new offset single pit pour flush latrines in the Galachipa subdistrict of coastal Bangladesh. We randomly assigned 34 latrines to include a 50 cm thick sand barrier under and around the pit and 34 received no sand barrier. Four monitoring wells were constructed around each pit to collect water samples at baseline and subsequent nine follow-up visits over 24 months. Samples were tested using the IDEXX Colilert method to enumerate E. coli and thermotolerant coliforms most probable number (MPN). We determined the difference in mean log10MPN FIB counts/100 mL in monitoring well samples between latrines with and without a sand barrier using multilevel linear models and reported cluster robust standard error. The sand barrier latrine monitoring well samples had 0.38 mean log10MPN fewer E. coli (95% CI: 0.16, 0.59; p = 0.001) and 0.38 mean log10MPN fewer thermotolerant coliforms (95% CI: 0.14, 0.62; p = 0.002), compared to latrines without sand barriers, a reduction of 27% E. coli and 24% thermotolerant coliforms mean counts. A sand barrier can modestly reduce the risk presented by pit leaching.


ERCC1 and ERCC2 polymorphisms and adult glioma.
ERCC2 and ERCC1 are important in DNA nucleotide excision repair and lie on chromosome 19q13.3 near a putative glioma suppressor region. We genotyped constitutive variants ERCC1 C8092A and ERCC2 K751Q and R156R in approximately 450 adults with glioma and 500 controls from two independent population-based series, uniformly reviewed patients' tumors to determine histopathologic category, and determined a variety of tumor markers among astrocytic tumors. Odds ratios (ORs) for glioblastoma for those carrying two ERCC1 A alleles versus none or one were 1.67 in series 1 and 1.64 in series 2, which yielded a combined OR of 1.67 (95% CI, 0.93-3.02; P = 0.09), adjusted for age, gender, ethnicity, and series. Odds ratios for the ERCC2 variants were not consistently elevated or reduced for the two series in all cases versus controls. However, among whites, for those with ERCC2 K751Q genotype QQ versus QK/KK, the OR for nonglioblastoma histologies versus controls was 1.82 (95% CI, 0.97-3.44; P = 0.06). Also, among whites, glioma patients were significantly more likely than controls to be homozygous for variants in both ERCC1 C8092A and ERCC2 K751Q (OR, 3.2; 95% CI, 1.1-9.3). Given the numbers of comparisons made, these findings could be due to chance. However, the results might warrant clarification in additional series in conjunction with the nearby putative glioma suppressor genes (GLTSCR1 and GLTSCR2).


Intradiploic hematoma in an infant: case report and literature review.
Intradiploic hematoma is extremely rare, especially in infant patients. Less than 15 cases were reported in English literature up to now. Here, we presented another intradiploic hematoma in an infant boy without coagulopathy. A left parietal craniotomy was performed. Post-operative CT showed well-reconstructed skull.


Pregnancy Epigenetic Signature in T Helper 17 and T Regulatory Cells in Multiple Sclerosis.
Increasing evidence supports the anti-inflammatory role of estrogens in Multiple Sclerosis (MS), originating from the observation of reduction in relapse rates among women with MS during pregnancy, but the molecular mechanisms are still not completely understood. Using an integrative data analysis, we identified T helper (Th) 17 and T regulatory (Treg) cell-type-specific regulatory regions (CSR) regulated by estrogen receptor alpha (ERα). These CSRs were validated in polarized Th17 from healthy donors (HD) and in peripheral blood mononuclear cells, Th17 and Treg cells from relapsing remitting (RR) MS patients and HD during pregnancy. 17β-estradiol induces active histone marks enrichment at Forkhead Box P3 (FOXP3)-CSRs and repressive histone marks enrichment at RAR related orphan receptor C (RORC)-CSRs in polarized Th17 cells. A disease-associated epigenetic profile was found in RRMS patients during pregnancy, suggesting a FOXP3 positive regulation and a RORC negative regulation in the third trimester of pregnancy. Altogether, these data indicate that estrogens act as immunomodulatory factors on the epigenomes of CD4+ T cells in RRMS; the identified CSRs may represent potential biomarkers for monitoring disease progression or new potential therapeutic targets.


Intrahepatic calculi: imaging by MR.
The magnetic resonance (MR) examinations of six patients with intrahepatic calculi were reviewed retrospectively to 1) determine the ability of MR to demonstrate intrahepatic calculi and 2) assess the MR appearance of the stones. In five out of six cases, MRI demonstrated intrahepatic calculi. In three cases, stones exhibited a low intensity signal on the different spin echo (SE) sequences, as previously described by in vitro and in vivo studies. However in two other cases, a significant signal with short T1 and relatively long T2 relaxation times was noticed. These different features are discussed in relation to chemical and physical differences in intrahepatic calculi and compared with variable CT attenuation values of stones. MRI seems to provide complementary information concerning intrahepatic calculi.


Chronic mild stress exacerbates severity of experimental autoimmune encephalomyelitis in association with altered non-coding RNA and metabolic biomarkers.
The causal factors determining the onset and severity of multiple sclerosis (MS) are not well understood. Here, we investigated the influence of chronic stress on clinical symptoms, metabolic and epigenetic manifestations of experimental autoimmune encephalomyelitis (EAE), a common animal model of MS. Lewis rats were immunized for monophasic EAE with MBP69-88 and were exposed to chronic stress for 37days starting 7days prior to immunization. The exposure to stress accelerated and exacerbated the clinical symptoms of EAE. Both stress and EAE also disrupted metabolic status as indicated by trace elemental analysis in body hair. Stress particularly exacerbated chlorine deposition in EAE animals. Moreover, deep sequencing revealed a considerable impact of stress on microRNA expression in EAE. EAE by itself upregulated microRNA expression in lumbar spinal cord, including miR-21, miR-142-3p, miR-142-5p, miR-146a, and miR-155. Stress in EAE further up-regulated miR-16, miR-146a and miR-155 levels. The latter two microRNAs are recognized biomarkers of human MS. Thus, stress may synergistically exacerbate severity of EAE by altering epigenetic regulatory pathways. The findings suggest that stress may represent a significant risk factor for symptomatic deterioration in MS. Stress-related metabolic and microRNA signatures support their value as biomarkers for predicting the risk and severity of MS.


A ray of light about frozen embryos.
The Tennessee Supreme Court's decision in Davis v. Davis, a case that raises the question of how to allocate frozen embryos in the event of divorce, addresses many of the legal issues posed by in vitro fertilization. The decision considers the interests of the progenitors as well as of the children who may result. For example, the court held that gamete providers' discretion regarding the disposition of embryos can be limited only when their decisions would harm the children who might be born. The court also made clear that efforts to seek genetic parenthood are protected only when accompanied by a desire to raise the resulting children, a conclusion that also affects other reproductive technologies. In addition to elaborating an analytic framework, the court set guidelines for resolving disputes when the couples had made no prior agreements, including holding that while the embryos are ex-utero the desire to avoid genetic parenthood almost always trumps the wish to become a parent. The well-reasoned analysis in Davis v. Davis should help shape legal and ethical discussion regarding the use of in vitro fertilization for many years to come.


[Pelvic lymph node dissection (extended vs standard) and prostate cancer].
The role and the potential benefit, if any, of pelvic lymphadenectomy in prostate cancer are still controversially discussed. It is generally accepted that PLND at time of radical prostatectomy is the only reliable diagnostic procedure to achieve as much individual histological staging information as possible to trigger postoperative adjuvant management. However, the extent of pelvic lymph node dissection (limited vs. extended) and the most suitable candidates for this procedure are still a matter of intense debate. The aim of this review is to critically evaluate the current status on lymph node dissection in prostate cancer.


Current and future funding sources for specialty mental health and substance abuse treatment providers.
Goals were to describe funding for specialty behavioral health providers in 1986 and 2005 and examine how the recession, parity law, and Affordable Care Act (ACA) may affect future funding. Numerous public data sets and actuarial methods were used to estimate spending for services from specialty behavioral health providers (general hospital specialty units; specialty hospitals; psychiatrists; other behavioral health professionals; and specialty mental health and substance abuse treatment centers). Between 1986 and 2005, hospitals-which had received the largest share of behavioral health spending-declined in importance, and spending shares trended away from specialty hospitals that were largely funded by state and local governments. Hospitals' share of funding from private insurance decreased from 25% in 1986 to 12% in 2005, and the Medicaid share increased from 11% to 23%. Office-based specialty providers continued to be largely dependent on private insurance and out-of-pocket payments, with psychiatrists receiving increased Medicaid funding. Specialty centers received increased funding shares from Medicaid (from 11% to 29%), and shares from other state and local government sources fell (from 64% to 46%). With ACA's full implementation, spending on behavioral health will likely increase under private insurance and Medicaid. Parity in private plans will also push a larger share of payments for office-based professionals from out-of-pocket payments to private insurance. As ACA provides insurance for formerly uninsured individuals, funding by state behavioral health authorities of center-based treatment will likely refocus on recovery and support services. Federal Medicaid rules will increase in importance as more people needing behavioral health treatment become covered.


Pontine Infarction and Vertebral Artery Dissecting Aneurysm as the First Presentation of Behçet's Disease: A Case Report.
Behçet's disease (BD) is a systemic disease of inflammatory origin that appears most often in the third or fourth decade of life. Behçet's disease is hallmarked predominantly by mucocutaneous lesions and ocular involvement. Vertebral artery dissection and neurological manifestations are rare complications in Behçet's disease. We examine the case of a medically free 33-year-old male who was admitted to the emergency department complaining of sudden-onset dizziness, vomiting, and tinnitus. Neurological examination revealed fluctuating consciousness, multiple gaze nystagmus, motor deficit in the upper and lower limbs, bilateral Babinski sign, and truncal ataxia. Magnetic resonance imaging (MRI) showed a right pontine hyperintense lesion on T2-weighted images (T2WI). A right vertebral angiogram four months after the incident showed a dissection in the mid-cervical third of an anomalous duplicated origin arm of the right vertebral artery. This case describes an uncommon form of initial presentation of Behçet's disease via a pontine infarction triggered by a dissecting aneurysm in an anatomically rare variant of the vertebral artery.


Non-contraceptive benefits of intrauterine levonorgestrel administration: why not?
Levonorgestrel intrauterine systems (LNG-IUS) represent a modern therapy for an array of preexisting gynecological conditions, though they were first marketed in Finland in 1990. However, there are countries in which their use is extremely limited by social and cultural factors. This manuscript describes the possible reasons for this misuse, taking in consideration the clinical noncontraceptive benefits of intrauterine levonorgestrel in routinary practice. Medical diseases in which LNG-IUS represent a treatment include abnormal uterine bleeding, iron-deficiency anemia, endometrial hyperplasia, uterine fibroids, adenomyosis, endometriosis, and coagulopathies. The advantage of reducing the need for more radical treatments such as surgery or hysterectomy is well demonstrated, with remarkable benefits for patients. However, in many countries, surgery is still used as a first-line treatment and there is a need to define who could benefit from a less invasive option. It seems clear that such a reduced use of LNG-IUS depends on factors that imply both patients and practitioners, and that the role of counseling is becoming a key component in the decision-making process to reach the ultimate goal of compliance.


Food advertising and self-regulation: a view from the trenches.
This study assessed the logic of arguments advanced when the New Zealand advertising self-regulation complaints board adjudicated a complaint about a food product; in addition, it compared these arguments and the complainant's experience of the process to international best practice criteria relating to independence. Documents relating to a complaint about chicken nuggets were analysed. Shuy's logical framework was used to analyse the arguments advanced; the case was subsequently compared to the best practice criteria advanced in the Madelin (2006) report. Even a well-informed and expert complainant found the system difficult to use and biased in favour of the advertiser. Analysis of rhetorical strategies used to respond to the complaint reveal use of fallacious reasoning, including ad hominem, to which the complainant was unable to respond. In the case reviewed, the New Zealand self-regulatory system did not meet the level of openness, independence or transparency that the complainant expected and that are listed as "best practice" criteria in the Madelin Report. A regulatory system run by a government agency could afford greater protection to complainants and consumers and offer a more balanced adjudication process. As the prevalence of obesity increases, governments are examining how effectively regulation controls marketing activities that encourage consumption of energy dense, nutrient poor foods. This paper raises timely and important questions about the balance and fairness of self-regulation as experienced by a complainant.


Primary leiomyosarcoma of thyroid gland: the youngest case.
Primary leiomyosarcomas of the thyroid gland are extremely rare. We report a case of a 32 year-old women with a multinodular goiter. She underwent total thyroidectomy. The tumor histology showed spindle-shaped cells that expressed desmine, caldesmone and smooth muscle actine but were negative cytokeratins.


Skin and bones: the contribution of skin tone and facial structure to racial prototypicality ratings.
Previous research reveals that a more 'African' appearance has significant social consequences, yielding more negative first impressions and harsher criminal sentencing of Black or White individuals. This study is the first to systematically assess the relative contribution of skin tone and facial metrics to White, Black, and Korean perceivers' ratings of the racial prototypicality of faces from the same three groups. Our results revealed that the relative contribution of metrics and skin tone depended on both perceiver race and face race. White perceivers' racial prototypicality ratings were less responsive to variations in skin tone than were Black or Korean perceivers' ratings. White perceivers ratings' also were more responsive to facial metrics than to skin tone, while the reverse was true for Black perceivers. Additionally, across all perceiver groups, skin tone had a more consistent impact than metrics on racial prototypicality ratings of White faces, with the reverse for Korean faces. For Black faces, the relative impact varied with perceiver race: skin tone had a more consistent impact than metrics for Black and Korean perceivers, with the reverse for White perceivers. These results have significant implications for predicting who will experience racial prototypicality biases and from whom.


The role of polymer spacers in specific adhesion.
We study the role of flexible spacers in specific adhesion from the point of view of polymer reaction--diffusion theory. By assuming that the interactions between complementary adhesion moieties occur on a length scale much smaller than the size of the polymer spacer, we describe in detail binding and rupture between two opposing surfaces. Predictions are given for the physical properties of interest such as the time evolution of bond density and the ranges of attraction and unbinding. We also discuss the dynamic crossover between reversible and irreversible bridging.


Real-time volumetric relative dosimetry for magnetic resonance-image-guided radiation therapy (MR-IGRT).
The integration of magnetic resonance imaging (MRI) with linear accelerators (linac) has enabled the use of 3D MR-visible gel dosimeters for real-time verification of volumetric dose distributions. Several iron-based radiochromic 3D gels were created in-house then imaged and irradiated in a pre-clinical 1.5 T-7 MV MR-Linac. MR images were acquired using a range of balanced-fast field echo (b-FFE) sequences during irradiation to assess the contrast and dose response in irradiated regions and to minimize the presence of MR artifacts. Out of four radiochromic 3D gel formulations, the FOX 3D gel was found to provide superior MR contrast in the irradiated regions. The FOX gels responded linearly with respect to real-time dose and the signal remained stable post-irradiation for at least 20 min. The response of the FOX gel also was found to be unaffected by the radiofrequency and gradient fields created by the b-FFE sequence during irradiation. A reusable version of the FOX gel was used for b-FFE sequence optimization to reduce artifacts by increasing the number of averages at the expense of temporal resolution. Regardless of the real-time MR sequence used, the FOX 3D gels responded linearly to dose with minimal magnetic field effects due to the strong 1.5 T field or gradient fields present during imaging. These gels can easily be made in-house using non-reusable and reusable formulations depending on the needs of the clinic, and the results of this study encourage further applications of 3D gels for MR-IGRT applications.


Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma.
Unresectable biliary tract carcinoma (BTC) is associated with a very poor prognosis. To improve efficacy and tolerance of the 5-fluorouracil (5-FU)/cisplatin combination in BTC, we designed a new therapeutic schedule, the LV5FU2-P regimen. Twenty-nine patients with advanced or metastatic BTC were prospectively enrolled in the study. The treatment (LV5FU2-P regimen) consisted of a biweekly administration of a 2-h infusion of leucovorin 200 mg/m(2), a 400 mg/m(2) bolus of 5-FU followed by a 22-h continuous infusion of 600 mg/m(2) 5-FU on two consecutive days and cisplatin 50 mg/m(2) on day 2. Clinical symptoms, performance and weight changes were monitored. Objective responses were observed in 10 patients (34%) (95% confidence interval 23% to 45%) including one complete response and nine partial responses (stabilization 38%, progression 28%). Median progression-free survival and overall survival were 6.5 and 9.5 months, respectively. Weight gain was observed in 45% of patients and performance status improved in 60%. One patient had a grade 4 thrombocytopenia, and grade 3 toxicity occurred in 41% of patients. There were no treatment-related deaths. This study, one of the largest phase II trials performed for this disease, shows that the LV5FU2-P regimen is an active and well-tolerated chemotherapy for advanced and metastatic BTC.


Animal models of MEN1.
Animal models of cancer have been instrumental in advancing our understanding of the biology of tumor initiation and progression, in studying gene function and in performing preclinical studies aimed at testing novel therapies. Several animal models of the MEN1 syndrome have been generated in different organisms by introducing loss-of-function mutations in the orthologues of the human MEN1 gene. In this review, we will discuss MEN1 and MEN1-like models in Drosophila, mice and rats. These model systems with their specific advantages and limitations have contributed to elucidate the function of Menin in tumorigenesis, which turned out to be remarkably conserved from flies to mammals, as well as the biology of the disease. Mouse models of MEN1 closely resemble the human disease in terms of tumor spectrum and associated hormonal changes, although individual tumor frequencies are variable. Rats affected by the MENX (MEN1-like) syndrome share some features with MEN1 patients albeit they bear a germline mutation in Cdkn1b (p27) and not in Men1 Both Men1-knockout mice and MENX rats have been exploited for therapy-response studies testing novel drugs for efficacy against neuroendocrine tumors (NETs) and have provided promising leads for novel therapies. In addition to presenting well-established models of MEN1, we also discuss potential models which, if implemented, might broaden even further our knowledge of neuroendocrine tumorigenesis. In the future, patient-derived xenografts in zebrafish or mice might allow us to expand the tool-box currently available for preclinical studies of MEN1-associated tumors.


Development and Validation of a Persian Version of Dichotic Emotional Word Test.
Emotional words in comparison with neutral words have different hemispheric specialization. It is assumed that the right hemisphere has a role in processing every kind of emotional word. The objective of the present study was the development of a Persian version of the dichotic emotional word test and evaluate its validation among adult Persian speakers. The present study was done on 60 adults, with the age ranging from 18-30 years for both genders, who had no history of neurological disorders with normal hearing. The developed test included eight main lists; each had several dichotic emotional/ neutral pairs of words. Participants were asked to recall as many words in each list as they could after they listened to them. A content validity index was used to analyze the validity of the test. The mean content validity index score was 0.94. The findings showed that in the left ear, emotional words were remembered more than neutral ones (P=0.007). While in the right ear, neutral words were remembered more (P=0.009). There were no significant differences in male and female scores. Dichotic emotional word test has a high content validity. The ability to remember emotional words better in the left ear supports the dominant role of the right hemisphere in emotional word perception.


Suvorexant in the Treatment of Difficulty Falling and Staying Asleep (Insomnia).
Insomnia affects more than 10% of the population and causes significant discomfort and disability. Suvorexant is an orexin receptor antagonist that specifically targets the wake-sleep cycle. This review summarizes recent and seminal evidence in the biological and physiological evidence of insomnia, the mechanism of action of suvorexant in treating insomnia, and clinical evidence regarding its use. There is no single clear diagnosis for insomnia, and thus prevalence is not entirely clear, but it is estimated to affect 10%-30% of the adult population. Comorbidities include obesity, diabetes, and various psychiatric conditions, and insomnia likely has a contributing role in these conditions. Insomnia, by definition, impacts sleep quality and also wakefulness, including academic success and work efficiency. Insomnia is likely related to genetic susceptibility and a triggering event, leading to hyper-arousal states and functional brain disturbances. This leads to hyperactivity of the hypothalamic-pituitary-adrenal axis, over-secretion of corticotropin-releasing factor, and aberrancy in neurotransmitter release. Though several pharmacological options exist for the treatment of insomnia, there is equivocal data regarding their efficacy or limits to their use due to side effects and contraindications. Suvorexant is a novel dual orexin receptor antagonist, which is shown to improve sleep by reducing arousals. Unlike classical therapeutics, suvorexant does not alter the sleep profile; it prolongs the time spent in each sleep state. Though it may cause some somnolence, it is milder than reported with other drugs. Multiple clinical studies support the use of suvorexant in insomnia. In primary insomnia, suvorexant is effective (over placebo), as measured by polysomnography and reported by patients, in both attaining and maintaining sleep. Similar, albeit to a smaller degree, results were found in secondary insomnia. Suvorexant carries two significant advantages over existing therapies; it has a much better safety profile in approved doses, and it preserves natural sleep architecture, thus promoting more restful sleep and recovery. Unfortunately, data exists mostly for suvorexant versus placebo, and head-to-head trials with common hypnotics are needed to assess the true efficacy of suvorexant over the alternatives. And while tolerance is less likely to develop, close monitoring of post-marketing data is required to evaluate for long term adverse events and efficacy.


Optimization of Neferine Purification Based on Response Surface Methodology and Its Anti-Metastasis Mechanism on HepG2 Cells.
Liver cancer continues to be a focus of scientific research due to its low five-year survival rate. One of its main core issues is the high metastasis of cells, for which there is no effective treatment. Neferine was originally isolated from Plumula nelumbinis and demonstrated to have a good antitumor effect. In order to extract high-purity Neferine in a more efficient and environmentally friendly manner, response surface methodology (RSM) was used to optimize the isolation and purification procedures in this study. The extract conditions of a 7:3 ratio for the eluent of dichloromethane: methanol, 1:60 for the mass ratio of the extract amount: silica gel, and 3 mL/min of the elution flow rate were shown to be the optimal conditions. These conditions resulted in the highest yield of 6.13 mg per 66.60 mg of starting material, with productivity of 8.76% and purity of 87.04%. Compared with the previous methods, this method can prepare Neferine in large quantities more quickly. We subsequently evaluated the antitumor activity of the purified Neferine against HepG2 hepatic cancer cells. The purified Neferine was found to inhibit the proliferation of HepG2 cells through the CCK-8 assay, with an IC50 of 33.80 μM in 24 h, 29.47 μM in 48 h, 24.35 μM in 72 h and 2.78 μM in 96 h of treatment. Neferine at a concentration of 3 μM could significantly inhibit the migration and invasion abilities of the HepG2 cells in vitro. We also explored the mechanism of action of Neferine via Western blot. We showed that Neferine could reduce RhoA expression by effectively inhibiting the phosphorylation of MYPT1, thereby effectively exerting anti-metastasis activity against HepG2 cells. Thus, we have optimized the isolation procedures for highly pure Neferine by response surface methodology (RSM) in this study, and purified Neferine is shown to play an essential role in the anti-metastasis process of liver cancer cells. The Neferine purification procedure may make a wide contribution to the follow-up development of other anti-metastasis lead compounds.


History of medicine. Alphonse Loewenthal (1903-1983)--the uncrowned king of dermatology in Africa.
The career and achievements of Dr L. J. A. Loewenthal, M.D., F.R.C.P., as a dermatologist in Africa are sketched. He made notable contributions to local dermatology. Starting in 1931 in Uganda with studies on tropical ulcer and vitamin A deficiency, he ended his career in Johannesburg 40 years later with investigations on the skin of miners. Over this period it is doubtful whether any dermatologist on the African continent equalled his accomplishments.