Home self-administration of vaginal misoprostol for medical abortion at 50-63 days compared with gestation of below 50 days.
Home use of misoprostol for termination of pregnancy is still controversial in many countries. Acceptability of home use of misoprostol has been investigated in pregnancies below 49 days gestation. In this study, we aimed to assess efficacy, feasibility and acceptability of home use of vaginal misoprostol for medical termination of pregnancy at 50-63 days compared with gestation of below 50 days among women who chose to administer misoprostol at home. In this prospective study, mifepristone 200 mg was given in hospital under nursing supervision in the university hospital outpatient family planning clinic. Women self-administered misoprostol 800 microg vaginally 36-48 h later at home. Follow-up was 2 weeks later. Women with gestation of 50-63 days on the day of mifepristone administration were compared with women with gestation of below 50 days. Efficacy and feasibility were assessed by review of patient records and questionnaires. Acceptability was assessed using questionnaires where women reported on future choice of abortion method were they to have another abortion. Among the 2992 women who had a medical abortion during the study period, 395 women chose to administer misoprostol at home and were included in the study. A total of 203 women were below 50 days gestation and 192 were between 50 and 63 days gestation. Efficacy was 97.5% and did not differ between the groups. Surgical intervention was needed in 10 patients, of whom four were in the lower gestational band (P = 0.36). No serious adverse events or blood transfusions were reported. Preference for home administration of misoprostol, were they to have another induced abortion in the future, was high, 92.3 and 86.6% respectively, and did not differ between the groups (P = 0.097). Need for extra analgesia significantly influenced women's experiences in both gestational groups. Medical abortion with mifepristone followed by home administration of vaginal misoprostol is safe and highly acceptable also to women with gestational length of 50-63 days as compared with shorter gestations. Efficacy, acceptability and preference for future place of administration of misoprostol, were women to have another abortion, did not differ between women with gestation below 50 days or between 50 and 63 days.


A novel cell wall-anchored peptidoglycan hydrolase (autolysin), IspC, essential for Listeria monocytogenes virulence: genetic and proteomic analysis.
We have recently concluded that a Listeria monocytogenes 86 kDa immunogenic surface protein, IspC, is a cell wall-anchored peptidoglycan hydrolase (autolysin), capable of degrading the cell wall peptidoglycan of the bacterium itself. To determine if this enzyme has any biological functions and/or plays a role in virulence, we in-frame-deleted the ispC gene from the L. monocytogenes chromosome. This DeltaispC mutant exhibited complete abrogation of expression of IspC and displayed no defects in in vitro growth, colony and microscopic morphologies, or biochemical characteristics. Lack of IspC led to attenuated virulence in mice, evidenced by a significant reduction in bacterial counts in livers and brains and no mortality compared with the wild-type. Furthermore, the data from assays using various eukaryotic cells for adhesion, invasion, actin tail formation, plaque formation and intracellular growth indicated that the mutant was severely attenuated in virulence in a cell culture model in a cell type-dependent manner. The findings that (i) the mutant was impaired for adhesion to certain eukaryotic cells, and (ii) both purified IspC and its C-terminal cell wall-binding domain were capable of binding sheep choroid plexus (SCP) epithelial cells and Vero cells, supported the role of IspC as an adhesin in virulence. The DeltaispC mutant exhibited a marked defect in adhesion to and invasion of SCP cells but not human brain microvascular endothelial cells (HBMEC), suggesting that IspC is necessary for crossing the blood-cerebrospinal fluid barrier. Proteomic and immunological analysis showed a reduced surface expression of some known or putative virulence factors (e.g. ActA, InlC2 and a flagellin homologue, FlaA) due to IspC deficiency. Altogether, this study demonstrates that IspC, expressed as a minor autolysin in vitro, is not important for cell division or separation but is essential for full virulence of L. monocytogenes in vivo.


Assessment of a Tele-education System to Enhance Retinopathy of Prematurity Training by International Ophthalmologists-in-Training in Mexico.
To evaluate a tele-education system developed to improve diagnostic competency in retinopathy of prematurity (ROP) by ophthalmologists-in-training in Mexico. Prospective, randomized cohort study. Fifty-eight ophthalmology residents and fellows from a training program in Mexico consented to participate. Twenty-nine of 58 trainees (50%) were randomized to the educational intervention (pretest, ROP tutorial, ROP educational chapters, and posttest), and 29 of 58 trainees (50%) were randomized to a control group (pretest and posttest only). A secure web-based educational system was created using clinical cases (20 pretest, 20 posttest, and 25 training chapter-based) developed from a repository of over 2500 unique image sets of ROP. For each image set used, a reference standard ROP diagnosis was established by combining the clinical diagnosis by indirect ophthalmoscope examination and image-based diagnosis by multiple experts. Trainees were presented with image-based clinical cases of ROP during a pretest, posttest, and training chapters. The accuracy of ROP diagnosis (e.g., plus disease, zone, stage, category) was determined using sensitivity and specificity calculations from the pretest and posttest results of the educational intervention group versus control group. The unweighted kappa statistic was used to analyze the intragrader agreement for ROP diagnosis by the ophthalmologists-in-training during the pretest and posttest for both groups. Trainees completing the tele-education system had statistically significant improvements (P < 0.01) in the accuracy of ROP diagnosis for plus disease, zone, stage, category, and aggressive posterior ROP (AP-ROP). Compared with the control group, trainees who completed the ROP tele-education system performed better on the posttest for accurately diagnosing plus disease (67% vs. 48%; P = 0.04) and the presence of ROP (96% vs. 91%; P < 0.01). The specificity for diagnosing AP-ROP (94% vs. 78%; P < 0.01), type 2 ROP or worse (92% vs. 84%; P = 0.04), and ROP requiring treatment (89% vs. 79%; P < 0.01) was better for the trainees completing the tele-education system compared with the control group. Intragrader agreement improved for identification of plus disease, zone, stage, and category of ROP after completion of the educational intervention. A tele-education system for ROP education was effective in improving the diagnostic accuracy of ROP by ophthalmologists-in-training in Mexico. This system has the potential to increase competency in ROP diagnosis and management for ophthalmologists-in-training from middle-income nations.


An Improved Boosting to Amplify Signal with Isobaric Labeling (iBASIL) Strategy for Precise Quantitative Single-cell Proteomics.
Mass spectrometry (MS)-based proteomics has great potential for overcoming the limitations of antibody-based immunoassays for antibody-independent, comprehensive, and quantitative proteomic analysis of single cells. Indeed, recent advances in nanoscale sample preparation have enabled effective processing of single cells. In particular, the concept of using boosting/carrier channels in isobaric labeling to increase the sensitivity in MS detection has also been increasingly used for quantitative proteomic analysis of small-sized samples including single cells. However, the full potential of such boosting/carrier approaches has not been significantly explored, nor has the resulting quantitation quality been carefully evaluated. Herein, we have further evaluated and optimized our recent boosting to amplify signal with isobaric labeling (BASIL) approach, originally developed for quantifying phosphorylation in small number of cells, for highly effective analysis of proteins in single cells. This improved BASIL (iBASIL) approach enables reliable quantitative single-cell proteomics analysis with greater proteome coverage by carefully controlling the boosting-to-sample ratio (e.g. in general <100×) and optimizing MS automatic gain control (AGC) and ion injection time settings in MS/MS analysis (e.g. 5E5 and 300 ms, respectively, which is significantly higher than that used in typical bulk analysis). By coupling with a nanodroplet-based single cell preparation (nanoPOTS) platform, iBASIL enabled identification of ∼2500 proteins and precise quantification of ∼1500 proteins in the analysis of 104 FACS-isolated single cells, with the resulting protein profiles robustly clustering the cells from three different acute myeloid leukemia cell lines. This study highlights the importance of carefully evaluating and optimizing the boosting ratios and MS data acquisition conditions for achieving robust, comprehensive proteomic analysis of single cells.


Tackling lipophilicity of peptide drugs: replacement of the backbone N-methyl group of cilengitide by N-oligoethylene glycol (N-OEG) chains.
Cilengitide is an RGD-peptide of sequence cyclo[RGDfNMeV] that was was developed as a highly active and selective ligand for the αvβ3 and αvβ5 integrin receptors. We describe the synthesis of three analogues of this peptide in which the N-Me group has been replaced by N-oligoethylene glycol (N-OEG) chains of increasing size: namely N-OEG2, N-OEG11, and N-OEG23, which are respectively composed of 2, 11, and 23 ethylene oxide monomer units. The different N-OEG cyclopeptides and the original peptide were compared with respect to lipophilicity and biological activity. The N-OEG2 analogue was straightforward to synthesize in solid phase using an Fmoc-N-OEG2 building block. The syntheses of the N-OEG11 and N-OEG23 cyclopeptides are hampered by the increased steric hindrance of the N-substituent, and could only be achieved by segment coupling, which takes place with epimerization and thus requires extensive product purification. All the N-OEG analogues were found to be more hydrophobic than the parent peptide, and their hydrophobicity was systematically enhanced upon increasing the length of the OEG chain. The N-OEG2 cyclopeptide displayed the same capacity as Cilengitide to inhibit the integrin-mediated adhesion of HUVEC endothelial, DAOY gliobastoma, and HT-29 colon cancer cells to their ligands vitronectin and fibrinogen. The N-OEG11 and N-OEG23 analogues also inhibited cell adhesion to these immobilized ligands, but their IC50 values dropped by 1 order of magnitude with respect to the parent peptide. These results indicate that replacement of the backbone N-Me group of Cilengitide by a short N-OEG chain provides a more lipophilic analogue with a similar biological activity. Upon increasing the size of the N-OEG chain, liophilicity is enhanced, but synthetic yields drop and the longer polymer chains may impede targeted binding.


Cosecretion of protease inhibitor stabilizes antibodies produced by plant roots.
A plant-based system for continuous production of monoclonal antibodies based on the secretion of immunoglobulin complexes from plant roots into a hydroponic medium (rhizosecretion) was engineered to produce high levels of single-chain and full-size immunoglobulins. Replacing the original signal peptides of monoclonal antibodies with a plant-derived calreticulin signal increased the levels of antibody yield 2-fold. Cosecretion of Bowman-Birk Ser protease inhibitor reduced degradation of the immunoglobulin complexes in the default secretion pathway and further increased antibody production to 36.4 microg/g root dry weight per day for single-chain IgG1 and 21.8 microg/g root dry weight per day for full-size IgG4 antibodies. These results suggest that constitutive cosecretion of a protease inhibitor combined with the use of the plant signal peptide and the antibiotic marker-free transformation system offers a novel strategy to achieve high yields of complex therapeutic proteins secreted from plant roots.


Rising maternal circulating GH during murine pregnancy suggests placental regulation.
Placenta-derived hormones including growth hormone (GH) in humans contribute to maternal adaptation to pregnancy, and intermittent maternal GH administration increases foetal growth in several species. Both patterns and abundance of circulating GH are important for its activity, but their changes during pregnancy have only been reported in humans and rats. The aim of the present study was to characterise circulating profiles and secretory characteristics of GH in non-pregnant female mice and throughout murine pregnancy. Circulating GH concentrations were measured in whole blood (2 μL) collected every 10 min for 6 h in non-pregnant diestrus female C57Bl/6J mice (n = 9), and pregnant females at day 8.5-9.5 (early pregnancy, n = 8), day 12.5-13.5 (mid-pregnancy, n = 7) and day 17.5 after mating (late pregnancy, n = 7). Kinetics and secretory patterns of GH secretion were determined by deconvolution analysis, while orderliness and regularity of serial GH concentrations were calculated by approximate entropy analysis. Circulating GH was pulsatile in all groups. Mean circulating GH and total and basal GH secretion rates increased markedly from early to mid-pregnancy, and then remained elevated. Pulse frequency and pulsatile GH secretion rate were similar between groups. The irregularity of GH pulses was higher in all pregnant groups than that in non-pregnant mice. Increased circulating GH in murine pregnancy is consistent with an important role for this hormone in maternal adaptation to pregnancy and placental development. The timing of increased basal secretion from mid-pregnancy, concurrent with the formation of the chorioallantoic placenta and initiation of maternal blood flow through it, suggests regulation of pituitary secretion by placenta-derived factors.


Retinol esterification by mammary gland microsomes from the lactating rat.
Because vitamin A in milk is largely present as esterified retinol while blood plasma predominantly contains unesterified retinol, experiments were conducted to determine whether membranes from the lactating mammary gland are able to synthesize retinyl esters in vitro. When microsomes from rats lactating for 7 to 14 days were incubated with [(3)H]retinol dispersed in dimethylsulfoxide, some [(3)H]retinol esterification was observed (147 pmol/5 min per 0.5 mg protein). However, 3- to 7-fold increases in retinyl ester synthesis could be achieved by supplying either a fatty acyl CoA-generating system or preformed fatty acyl CoA thioesters; thus, the major activity in vitro has the characteristics of a fatty acyl CoA: retinol acyltransferase. Both long-chain and medium-chain fatty acyl CoA esters stimulated [(3)H]-labeled retinyl ester synthesis in vitro. Concordantly, analysis of the retinyl ester pattern of rat milk demonstrated the presence of eight different esters of retinol ranging in fatty acyl chain length from 8 to 18 carbons. Retinol esterification by microsomes was maximal at neutral pH (7.1) in the presence of approximately 50 micro M palmitoyl CoA, and was linear with time of incubation for at least 5 min. Retinyl ester synthesis increased with the apparent concentration of [(3)H]retinol to approximately 200 nmol/ml, but was also dependent on the ratio of retinol relative to total microsomal protein in the incubation mixture. These experiments demonstrate for the first time retinol esterification by mammary gland membranes and point to the hypothesis that free retinol from plasma is esterified in this organ before secretion of retinyl esters in milk.-Ross, A. C., Retinol esterification by mammary gland microsomes from the lactating rat.


Are we missing pancreatic exocrine insufficiency in 'at-risk' groups? Prospective assessment of the current practice and yield of faecal elastase testing in patients with diabetes mellitus, HIV and/or high alcohol intake.
There is cumulative evidence that pancreatic exocrine insufficiency (PEI) is under-recognised and can occur in patients with 'at-risk' conditions. Thus, we aimed to assess the current practice and yield of requesting faecal elastase (FEL-1), an indicator of PEI, in patients with 'at-risk' conditions. We prospectively recruited patients attending secondary care clinics with diabetes mellitus (DM), people living with HIV (PLHIV) and inpatients admitted to hospital with high alcohol intake (HAI). All patients underwent testing with FEL-1. Those patients with PEI (FEL-1 <200 μg/g) were contacted and offered a follow-up review in gastroenterology clinic. In total, 188 patients were recruited (HAI, n=78; DM, n=64; and PLHIV, n=46). Previous FEL-1 testing had not been performed in any of the patients. The return rate of samples was 67.9% for patients with HAI, 76.6% for those with DM and 56.5% for those with PLHIV. The presence of PEI was shown in 20.4% of patients with DM, 15.4% of patients with PLHIV and 22.6% in those with HAI. Diarrhoea and bloating were the most reported symptoms in followed-up patients with low FEL-1 (31.8% and 22.7% of patients, respectively). Follow-up computed tomography (CT) scans in those patients with PEI identified chronic pancreatitis changes in 13.6% and pancreatic atrophy in 31.8% of patients. These results suggest that there is a lack of testing for PEI in 'at-risk' groups. Our findings also suggest that using FEL-1 to test for PEI in patients with DM, PLHIV and HAI has a significant impact, although further studies are required to validate these findings.


Implantable left ventricular assist devices as initial therapy for refractory postmyocardial infarction cardiogenic shock.
Recently, the initial therapy for refractory cardiogenic shock has largely been based on use of short-term mechanical devices with later conversion to durable options. The premise is that such patients cannot tolerate cardiopulmonary bypass and the extended surgery needed for implantable left ventricular assist device (LVAD) placement. We have adopted an alternative strategy to implant long-term LVADs as the initial device therapy in such patients. Over a 3 year period, we used implantable LVADs (Jarvik 2000, one; Ventrassist, one; Heartmate XVE, two; and Heartmate II, nine) in 13 patients (11 men and two women; mean age 54 years) with postmyocardial infarction shock without prior use of a short-term LVAD. The median time interval from myocardial infarction to LVAD implantation was 3.5 days. Eight patients were on a ventilator, two had unknown neurological status and four had suffered cardiac arrest in the preceding 24 h. Two had prior coronary artery bypass graft. Nine had received dual antiplatelet therapy postmyocardial infarction. The mean laboratory value of creatinine was 1.5 mg/dl, alanine aminotransferase 748 U/l, international normalized ratio 1.5 and lactate 3.2 mmol/l. One procedure was carried out off pump; for the others, the mean cardiopulmonary bypass time was 72 min. Right ventricular assist devices were used in two cases and were later explanted. One patient died of progressive multiorgan failure. All others survived to hospital discharge. There were no re-explorations for bleeding or major infectious complications; two patients had perioperative stroke. The median duration of mechanical ventilation, intensive care unit stay and hospital stay was 3, 9 and 18 days, respectively. At 1 year, of the 12 survivors, eight have since had heart transplant, one patient underwent device explant, two remained alive on support and one died 7 months post-LVAD. Our data challenge the notion that patients in refractory cardiogenic shock are too ill to tolerate immediate placement of implantable LVADs. Despite the surgical challenges, a one-stop implantable LVAD approach for cardiogenic shock is feasible and may offer unique advantages over the bridge-to-bridge approach because it avoids the incremental costs, hospitalization and morbidity associated with repeated interventions.


An in vitro study into the efficacy of complex tooth alignment with conventional and self-ligating brackets.
To evaluate the efficacy of tooth alignment achieved by various small cross-section archwire/bracket combinations using the orthodontic measurement and simulation system. The study comprised three types of orthodontic brackets 1) conventional ligating (Victory Series and Mini-Taurus), 2) self-ligating (SmartClip a passive self-ligating bracket and Time3 an active self-ligating bracket), and 3) a conventional low-friction bracket (Synergy). All brackets had a nominal 0.022″ slot size. Brackets were combined with 1) 0.012″ stainless steel, 2) 0.012″ Orthonol, 3) 0.012″ Thermalloy, and 4) 0.0155″ coaxial archwires. Archwires were tied to the conventional brackets with stainless steel ligatures and elastomeric rings. The malocclusion simulated represented a central upper incisor displaced 2 mm gingivally (x-axis) and 2 mm labially (z-axis). The inciso-gingival correction achieved by the different archwire/bracket combinations ranged from 15 to 95%, while the labio-lingual correction ranged from 10 to 95%. The smallest correction was achieved by coaxial, Orthonol, and thermally archwires when ligated with the elastomeric rings to conventional brackets. Stainless steel archwires achieved from 65 to 90% of inciso-gingival correction and from 60 to 90% of labio-lingual correction. The resultant tooth alignment was the product of interaction between the archwire type, bracket type, and bracket design including ligature type. Small cross-sectional archwires might produce up to 95% correction if combined properly with the bracket system. Elastomeric rings when used with conventional brackets limit the efficacy of malalignment correction.


Maprotiline versus imipramine and placebo in neurotic depression.
The antidepressant effect of maprotiline, a tetracyclic compound, was compared with that of imipramine in a four-week, double-blind, placebo controlled study with neurotic depressives. On all factors of the Hamilton Depression Rating Scale and on most items of the Zung Self-Rating Scales for Depression and Anxiety, maprotiline appeared slightly more effective than imipramine and showed a faster onset of action. In addition, it appeared to cause fewer anticholinergic side effects.


Eye and foot checks in patients with diabetes on haemodialysis: Are they done, and who does them?
To determine if retinal and foot checks are carried out on patients with diabetes receiving haemodialysis. Eighty-four patients with diabetes receiving haemodialysis were asked if they recalled having eye and foot screening in the last year, and if so, by whom was the check done. Seventy-seven (91.7%) patients recalled having an eye check in the preceding 12 mo. Of these, 52 (67.5%) did so in an ophthalmology clinic, 17 (22%) in retinal screening, three (3.9%) in an optician clinic. Three patients (3.9%) went to both ophthalmology and retinal screening, and two (2.6%) attended an ophthalmology and optician. Seventy (83.3%) patients recalled having a foot check in the preceding 12 mo. Of these, 33 (47.1%) were done by practice nurse, 14 (20%) by a diabetes nurse, 11 (15.7%) by a general practitioner, eight (11.4%) by a chiropodist, and four (5.7%) were each checked by renal nurse, diabetes consultant, junior doctor, or unknown person at a foot clinic. Most patients with diabetes on haemodialysis are able to recall having an eye check in the last year, although 8.3% could not. A significant proportion of patients could not recall having a foot check (16.7%) in the last year. This baseline audit suggests that an improvement in the rate of foot screening is important to achieve in patients with diabetes on haemodialysis in our unit.


Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen.
Lung cancer is becoming increasingly common in women and in the United States accounts for more female cancer deaths annually than breast cancer. Many epidemiological studies have provided evidence that women are more susceptible than men to the adverse effects of tobacco smoke. These observations suggest the possible role of estrogens in lung carcinogenesis. We report here the expression of mRNA for estrogen receptor alpha (ERalpha) and beta (ERbeta) in cultured human non-small cell lung cancer cells, cultured lung fibroblasts, and primary cultures of normal bronchial epithelium. Western analysis of ERalpha suggested that the main protein expressed in lung tumor cells is a variant, probably attributable to alternative splicing. Protein for ERbeta was found to be a mixture of full-length as well as alternatively spliced variants. beta-Estradiol produced a proliferative response in vitro in both normal lung fibroblasts and cultured non-small cell lung tumor cells. This effect was also observed in vivo. In this regard, beta-estradiol stimulated growth of the non-small cell lung tumor line, H23, grown as tumor xenografts in SCID mice. This effect was blocked by fluvestrant (ICI 182,780). In paraffin sections of non-small cell lung tumors, ERbeta immunoreactivity was localized to the nucleus, whereas ERalpha immunoreactivity was mainly localized to the cytoplasm, suggesting that both nuclear and cytoplasmic signaling may be involved in estrogenic responses in the lung. To show that the ERs found in the lung are functional, we demonstrated that beta-estradiol stimulated transcription of an estrogen response element-luciferase construct transfected in non-small cell lung tumor cell lines. Antiestrogens blocked this effect. Treatment of lung fibroblasts with beta-estradiol also increased secretion of hepatocyte growth factor by 2-fold. These results suggest that estrogen signaling plays a biological role in both the epithelium and the mesenchyme in the lung and that estrogens could potentially promote lung cancer, either through direct actions on preneoplastic or neoplastic cells or through indirect actions on lung fibroblasts. Additionally, it is possible that antiestrogens may have therapeutic value to treat or prevent lung cancer.


Comparison of amphetamine metabolism using isolated hepatocytes from five species including human.
Isolated hepatocyte suspensions from rat, rabbit, dog, squirrel monkey and human livers were used to study the metabolism of amphetamine (AMP), a drug for which species-dependent differences in metabolism have been demonstrated in vivo. Hepatocytes were isolated by perfusion of the whole liver or of biopsy specimens. In general, the metabolite profile of hepatocytes from each species corresponded to the profile of urinary metabolites identified previously. Rat hepatocytes primarily metabolized AMP by aromatic hydroxylation to p-hydroxyamphetamine. Rabbit hepatocytes converted AMP almost exclusively to products of the oxidative deamination pathway. Metabolism by hepatocytes from the other three species was mixed, but oxidative deamination was somewhat more active than aromatic hydroxylation in dog, squirrel monkey and human hepatocytes. The overall rate of AMP metabolism differed significantly among the species; the half-life in the hepatocyte suspensions varied about 70-fold, with rabbit less than rat less than dog less than squirrel monkey = human. Metabolism of AMP by human hepatocytes mare closely resembled metabolism by squirrel monkey liver cells than the other species in terms of metabolite profile and rate. However, the disposition of phenylacetone, a product of oxidative deamination of AMP, varied in hepatocytes from the two primate species. Thus, the metabolism of AMP by isolated hepatocytes was unique for each species examined. These studies demonstrate the applicability of isolated hepatocytes to the study of interspecies differences in hepatic xenobiotic metabolism, providing an in vitro technique that can be readily adapted to human liver tissue.


Thyroid hormones in generalized scleroderma. A controlled study.
Parameters of thyroid metabolism were analysed in 42 patients with generalized scleroderma and healthy individuals matched with respect to sex and age for comparison. Decreased free thyroxine (p less than 0.01), decreased free triiodothyronine (p less than 0.001), and increased thyroid-stimulating hormone (p less than 0.001) evidenced an associated state of myxoedema in scleroderma. Total thyroxine was normal, and total triiodothyronine was increased (p less than 0.01) probably reflecting binding to abnormal serum proteins in scleroderma. Normal concentrations of reverse triiodothyronine indicated a normal peripheral metabolism of thyroid hormones. Thyroid-stimulating immunoglobulins also analysed were within normal range. Changes in free thyroxine, free triiodothyronine, and thyroid-stimulating hormone were quantitatively small with mean values within normal ranges. In conclusion, this study evidenced a mild associating myxoedema state in generalized scleroderma. Probably, this reflected slight and subclinical affection of the thyroid.


Patch Testing to Paraphenylenediamine: The North American Contact Dermatitis Group Experience (1994-2018).
Background/Objectives: Paraphenylenediamine (PPD) is an aromatic amine dye that may cause allergic contact dermatitis. This study examines the epidemiology of allergic patch test reactions to PPD. Methods: This retrospective analysis characterizes individuals tested to PPD (1% petrolatum) by the North American Contact Dermatitis Group (1994-2018). Demographics and dermatitis site(s) were compared between PPD-allergic and PPD-negative patients. PPD reactions were analyzed by reaction strength, clinical relevance, occupational relatedness, and source as well as coreactivity with structurally related compounds. Results: Of 54,917 patients tested to PPD, 3095 (5.6%) had an allergic patch test reaction. Compared with PPD-negative patients, PPD-allergic patients had significantly greater odds of age >40 years (odds ratio [OR] 1.55 [95% confidence interval; CI 1.43-1.69]) and female gender (OR 1.52 [95% CI 1.41-1.66]), but lower odds of being White (OR 0.66 [95% CI 0.60-0.71]). The most common primary anatomic sites of dermatitis were face (25.5%), hands (21.9%), and scattered/generalized pattern (15.5%). Over half (55.3%) of PPD reactions were ++ or +++ at the final reading and 60.9% were currently relevant. Common exposure sources included hair dye (73.5%) and clothing/shoes/apparel (3.9%). Occupationally related reactions occurred in 8.3%, most commonly in hairdressers/cosmetologists (72.8%). The most common coreactions were benzocaine (11.3%), N-isopropyl-N'-phenyl-p-phenylenediamine (6.7%), disperse dye mix (6.5%), and black rubber mix (5.1%). Conclusions: The 24-year percentage of allergic reactions to PPD was 5.6%. PPD allergy was associated with female gender and age >40 years. PPD allergic patients were less likely to be White. Allergic reactions were usually clinically relevant and hair dye was the most frequently identified source.


Long non-coding RNA NNT-AS1 functions as an oncogenic gene through modulating miR-485/BCL9 in cholangiocarcinoma.
Growing evidence suggests that long non-coding RNAs (lncRNAs) could function as important regulators in carcinogenesis and cancer progression. Nicotinamide nucleotide transhydrogenase antisense RNA 1 (lncRNA NNT-AS1) is up-regulated in some human tumors and functions as a tumor promoter. This study aimed to detect the effect of NNT-AS1 on cholangiocarcinoma (CCA) prognosis. In this study, we detected NNT-AS1 expression in CCA tissue samples and cell lines, and analyzed the association between NNT-AS1 expression levels and clinical parameters of CCA patients. Moreover, we conducted loss-of-function studies in CCA cancer cells to explore the biological function and molecular mechanism of NNT-AS1. NNT-AS1 was downregulated by using RNAi technology. Cell proliferation was examined by CCK8 and clone formation assays. Cell migration and invasion were determined by wound healing and transwell assays. Western blot assays were used to explore protein expression. In this study, NNT-AS1 was expressed at high levels in CCA and closely associated with poor prognosis of patients with CCA. NNT-AS1 knockdown impaired cell proliferation, suppressed CCA cell migration and invasion, and restrained tumor growth in vitro. Moreover, NNT-AS1 directly bounded to miR-485 and further regulated BCL9. Finally, rescue assays verified that NNT-AS1 modulated the tumorigenesis of CCA by regulating miR-485. Taken together, NNT-AS1 played a critical biological role in the development of CCA. Our results elucidated NNT-AS1/miR-485/BCL9 axis might lead to a further understanding of the molecular mechanism of CCA.


An implantable and versatile piezoresistive sensor for the monitoring of human-machine interface interactions and the dynamical process of nerve repair.
Flexible wearable and implantable piezoresistive sensors have attracted lots of attention in the applications of healthcare monitoring, disease diagnostics, and human-machine interactions. However, the restricted sensing range, low sensing sensitivity at small strains, limited mechanical stability at high strains, and sophisticated fabrication processes restrict the far-reaching applications of these sensors for ultrasensitive full-range healthcare monitoring. In this work, an implantable and versatile piezoresistive sensor was developed from a series of conductive composites. The conductive composites, hydroxyethyl cellulose (HEC)/soy protein isolate (SPI)/polyaniline (PANI) sponges (HSPSs), were prepared by lyophilization of HEC/SPI solution and then in situ polymerization of aniline. The sensitivity, response time, and mechanical robustness of the HSPS sensors were characterized, and they can achieve a gauge factor of -0.29, a response time of 0.14 s, and sensing stability for at least 100 cycles. The HSPS sensors could efficiently work in vivo for 4 weeks for the measurement of stimuli, without severe inflammatory reaction. When the versatile HSPS sensors were attached to different parts of the human body, they could detect a variety of human motions including coughing, bending of fingers and elbow, abdominal breathing and walking. Notably, the HSPS sensors could be used to monitor the nerve repair in rats and the results are highly consistent with the electrophysiological data. At the same time a new score system was developed to evaluate rat nerve repair. These results indicate that the HSPS sensors exhibit good biocompatibility, sensitivity, sensing stability and fast response time. The HSPS sensors can be used not only as implantable sensors in vivo but also for analyzing human body motions. Furthermore, they provide an effective sensor device and a real-time, dynamic method for evaluating nerve repair without damage and death of animals. Hence, HSPSs might have great potential in in vivo detection, monitoring of human-machine interfacing interactions and the nerve tissue engineering field.


NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin.
Loss of expression of the cell-cell adhesion molecule E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) in development and in the progression from epithelial tumours to invasive and metastatic cancers. Here, we demonstrate that the loss of E-cadherin function upregulates expression of the neuronal cell adhesion molecule (NCAM). Subsequently, a subset of NCAM translocates from fibroblast growth factor receptor (FGFR) complexes outside lipid rafts into lipid rafts where it stimulates the non-receptor tyrosine kinase p59(Fyn) leading to the phosphorylation and activation of focal adhesion kinase and the assembly of integrin-mediated focal adhesions. Ablation of NCAM expression during EMT inhibits focal adhesion assembly, cell spreading and EMT. Conversely, forced expression of NCAM induces epithelial cell delamination and migration, and high NCAM expression correlates with tumour invasion. These results establish a mechanistic link between the loss of E-cadherin expression, NCAM function, focal adhesion assembly and cell migration and invasion.


Sedimentation Pulse in the NE Gulf of Mexico following the 2010 DWH Blowout.
The objective of this study was to investigate the impacts of the Deepwater Horizon (DWH) oil discharge at the seafloor as recorded in bottom sediments of the DeSoto Canyon region in the northeastern Gulf of Mexico. Through a close coupling of sedimentological, geochemical, and biological approaches, multiple independent lines of evidence from 11 sites sampled in November/December 2010 revealed that the upper ~1 cm depth interval is distinct from underlying sediments and results indicate that particles originated at the sea surface. Consistent dissimilarities in grain size over the surficial ~1 cm of sediments correspond to excess (234)Th depths, which indicates a lack of vertical mixing (bioturbation), suggesting the entire layer was deposited within a 4-5 month period. Further, a time series from four deep-sea sites sampled up to three additional times over the following two years revealed that excess (234)Th depths, accumulation rates, and (234)Th inventories decreased rapidly, within a few to several months after initial coring. The interpretation of a rapid sedimentation pulse is corroborated by stratification in solid phase Mn, which is linked to diagenesis and redox change, and the dramatic decrease in benthic formanifera density that was recorded in surficial sediments. Results are consistent with a brief depositional pulse that was also reported in previous studies of sediments, and marine snow formation in surface waters closer to the wellhead during the summer and fall of 2010. Although sediment input from the Mississippi River and advective transport may influence sedimentation on the seafloor in the DeSoto Canyon region, we conclude based on multidisciplinary evidence that the sedimentation pulse in late 2010 is the product of marine snow formation and is likely linked to the DWH discharge.


Towards automated segmentation of cells and cell nuclei in nonlinear optical microscopy.
Nonlinear optical (NLO) imaging techniques based e.g. on coherent anti-Stokes Raman scattering (CARS) or two photon excited fluorescence (TPEF) show great potential for biomedical imaging. In order to facilitate the diagnostic process based on NLO imaging, there is need for an automated calculation of quantitative values such as cell density, nucleus-to-cytoplasm ratio, average nuclear size. Extraction of these parameters is helpful for the histological assessment in general and specifically e.g. for the determination of tumor grades. This requires an accurate image segmentation and detection of locations and boundaries of cells and nuclei. Here we present an image processing approach for the detection of nuclei and cells in co-registered TPEF and CARS images. The algorithm developed utilizes the gray-scale information for the detection of the nuclei locations and the gradient information for the delineation of the nuclear and cellular boundaries. The approach reported is capable for an automated segmentation of cells and nuclei in multimodal TPEF-CARS images of human brain tumor samples. The results are important for the development of NLO microscopy into a clinically relevant diagnostic tool.


Effect of Poloxamer 188 on Collateral Blood Flow, Myocardial Infarct Size, and Left Ventricular Function in a Canine Model of Prolonged (3-Hour) Coronary Occlusion and Reperfusion.
Poloxamer 188 is a surfactant with hemorheological, antithrombotic, and neutrophil-inhibitory properties. This agent has been demonstrated to reduce infarct size and to improve left ventricular function in animal models of myocardial infarction and reperfusion, and recently in a randomized trial of patients receiving thrombolytic therapy for acute myocardial infarction. In addition to reducing reperfusion injury, poloxamer 188 might be beneficial by increasing collateral blood flow. The purpose of this study was to determine the effect of poloxamer 188 on collateral blood flow, myocardial infarct size, and left ventricular function in a canine model of prolonged (3 hours) coronary occlusion and reperfusion. Closed-chest dogs (n = 21) underwent a 3-hour coronary occlusion and 3 hours of reperfusion. At 1 hour of occlusion, dogs received poloxamer 188, 75 mg/kg IV bolus, followed by 150 mg/kg/h IV for the final 2 hours of coronary occlusion and throughout reperfusion, or a saline placebo. Regional myocardial blood flow was measured using colored microspheres. Myocardial infarct size and area at risk were determined by postmortem histochemical staining. Compared with controls, poloxamer 188-treated dogs showed no significant increase in collateral blood flow during the final 2 hours of a 3-hour coronary artery occlusion. In addition, poloxamer 188 treatment had no beneficial effect on infarct size or left ventricular function in this model. Increased collateral blood flow is unlikely to be a beneficial mechanism of poloxamer 188 in myocardial infarction. These data also question the benefit of this agent to reduce reperfusion injury in the setting of more prolonged (3-hour) coronary occlusion.


Cardiovascular conditioning in individuals with diabetic retinopathy.
The benefit of exercise for individuals with diabetes mellitus and high-risk complications of retinopathy has been questioned. Thirty-nine individuals with diabetes and visual impairment completed a 12-wk rehabilitation program that included cardiovascular conditioning. Pre- and postprogram assessment of exercise training in 30 subjects included a graded stress test with a bicycle ergometer. There were improvements in exercise tolerance as measured by the work load achieved (from 248 +/- 27 to 303 +/- 31 kilopond meter [kpm], P less than .05). There was a trend toward improvement in METS achieved (from 3.3 +/- 0.2 to 3.8 +/- 0.3, P = .06). There was no correlation of improvement in exercise tolerance with improvements in glycemic control, lipoprotein balance, and change in body weight. Individuals with diabetic retinopathy may be given the option of entering cardiovascular training programs with appropriate modifications to fit specific needs.


Common inheritance of chromosome Ia associated with clonal expansion of Toxoplasma gondii.
Toxoplasma gondii is a globally distributed protozoan parasite that can infect virtually all warm-blooded animals and humans. Despite the existence of a sexual phase in the life cycle, T. gondii has an unusual population structure dominated by three clonal lineages that predominate in North America and Europe, (Types I, II, and III). These lineages were founded by common ancestors approximately10,000 yr ago. The recent origin and widespread distribution of the clonal lineages is attributed to the circumvention of the sexual cycle by a new mode of transmission-asexual transmission between intermediate hosts. Asexual transmission appears to be multigenic and although the specific genes mediating this trait are unknown, it is predicted that all members of the clonal lineages should share the same alleles. Genetic mapping studies suggested that chromosome Ia was unusually monomorphic compared with the rest of the genome. To investigate this further, we sequenced chromosome Ia and chromosome Ib in the Type I strain, RH, and the Type II strain, ME49. Comparative genome analyses of the two chromosomal sequences revealed that the same copy of chromosome Ia was inherited in each lineage, whereas chromosome Ib maintained the same high frequency of between-strain polymorphism as the rest of the genome. Sampling of chromosome Ia sequence in seven additional representative strains from the three clonal lineages supports a monomorphic inheritance, which is unique within the genome. Taken together, our observations implicate a specific combination of alleles on chromosome Ia in the recent origin and widespread success of the clonal lineages of T. gondii.


Design, analysis, and implementation of a parallel tree search algorithm.
The alpha-beta algorithm for searching decision trees is adapted to allow parallel activity in different parts of a tree during the search. The algorithm has been implemented in a procedural simulation language (GASP IV). The simulation environment provides the illusion of multiple software processes and multiple hardware processors. A number of preliminary experiments have been done to gather statistics on run time, nodes scored, and nodes visited. Results indicate that a substantial reduction in time of search occurs because of the use of parallelism. An analytic expression for the storage requirements of the algorithm is derived. The analysis provides an example of the classical tradeoff between time and storage.


Is it possible to create magnetic semiconductors that function at room temperature?
As electronic devices continue to shrink to just a few nanometers, enabling the integration of billions of devices in computers, power consumption has surged beyond control, exceeding thermal limits and leading to failure. To address this issue, researchers are exploring an alternative to conventional electronics by harnessing the property of "spin" rather than "charge." This emerging field, known as spintronics, compared to its counterpart electronics, holds the promise of more energy-efficient quantum computing and data storage, and beyond. Recent successes with van der Waals (vdW)-layered diluted magnetic chalcogenide semiconductors (dMCSs) are promising and have sparked a vibrant research community. This field is still in its infancy on the path to realizing the ultimate spintronics. But it is highly likely that the remaining scientific challenges can be overcome within the next decade or so.


Effect of gemfibrozil on cardiotoxicity induced by doxorubicin in male experimental rats.
Cardiotoxicity is an adverse effect of the anticancer drug doxorubicin (DOX). Gemfibrozil (GEM) is a lipid-lowering drug with a number of biological properties such as anti-inflammatory and antioxidant activities. Therefore, we decided to investigate the effect of GEM on DOX-induced cardiotoxicity in rats. Twenty-eight adult male Wistar rats were divided into four experimental groups as follows: Group I received normal saline (2 ml/kg) orally for 14 days, group II received DOX (2.5 mg/kg; in six injections; accumulative dose: 15 mg/kg) intraperitonially for 14 days, group III received DOX + GEM (100 mg/kg) orally for 14 days concomitantly with DOX administration, and group IV received GEM orally for 14 days. Lipid panel, various biochemical biomarkers, and histological observations were evaluated in serum and heart samples. According to our results, DOX significantly increased the levels of lipid panel (triglycerides, total cholesterol, and low-density lipoproteins cholesterol) as well as markers of cardiac dysfunction (Aspartate aminotransferase, Creatine kinase-muscle/brain, Lactate dehydrogenase and Cardiac Troponin I). Moreover, DOX significantly increased malondialdehyde and nitric oxide levels in cardiac tissue. Furthermore, administration of DOX reduced the level of glutathione as well as the superoxide dismutase, catalase, and Glutathione peroxidase activities. DOX-treated rats showed significantly higher tumor necrosis factor-α and interleukin-1β. GEM administration significantly attenuated the lipid panel and biochemical biomarkers in DOX-treated rats. Our results were confirmed by histopathological evaluations of the heart. Based on our findings, GEM is a promising cardioprotective agent in patients treated with DOX through mitigative effects on biochemical markers and oxidative stress indices.


Repeated Pap smear screening among Mexican-American women.
The factors that influence repeated cervical cancer screening among Latina women are not well understood. Studies of compliance in this population over-emphasize initial or recent screening and under-emphasize how this practice is repeated over time. The purpose of this study was to identify the demographic and psychosocial factors associated with repeated Pap smear screening among low-income Mexican-American women living in two urban communities in Texas. A total of 1804 Mexican-American women were interviewed as part of a community survey. Multiple regression results indicate that demographic characteristics such as age, marital status, level of acculturation and health insurance were associated with the total number of Pap smears reported for the 5 years prior to the interview. Pap smear beliefs were the strongest predictor of repeated screening, while global beliefs about cancer did not significantly explain the results. Health promotion interventions should take into consideration the cultural and psychosocial needs of Mexican-American women, placing emphasis on their specific screening-related beliefs, if they are to succeed in promoting repeated compliance with Pap smear screening guidelines.


Respiratory sinus arrhythmia in man: relation to cardiovascular pressures.
The relationship of repiratory sinus arrhythmia (RSA) to the accompanying oscillations of cardiovascular pressures has been studied in five healthy subjects. Tidal volumes (VT) of 1.0, 1.5, and 2.0 1 at a breathing rate of 6 c-min(-1) were used as reference. With identical VT, oesophageal pressure was varied by negative inspiratory pressure (NIP) and intermittent positive-pressure ventilation (IPPV). Compared with control, NIP with 1.01 significantly increased RSA, the oscillations of brachial artery pressures (PBA), and the net filling pressures of the ventricles. IPPV did not significantly change the variations of PBA but reduced RSA and the repiratory variations of the right ventricular end-diastolic net pressure. During control breathing and with NIP the acceleration of heart rate during inspiration was associated with rising PBA and rising net filling pressures of both ventricles. The results indicate that RSA may be elicited by cardiovascular reflexes due to changes in venous filling of the heart rather than by the variations in systemic arterial pressure.


Uncovering cis regulatory codes using synthetic promoter shuffling.
Revealing the spectrum of combinatorial regulation of transcription at individual promoters is essential for understanding the complex structure of biological networks. However, the computations represented by the integration of various molecular signals at complex promoters are difficult to decipher in the absence of simple cis regulatory codes. Here we synthetically shuffle the regulatory architecture--operator sequences binding activators and repressors--of a canonical bacterial promoter. The resulting library of complex promoters allows for rapid exploration of promoter encoded logic regulation. Among all possible logic functions, NOR and ANDN promoter encoded logics predominate. A simple transcriptional cis regulatory code determines both logics, establishing a straightforward map between promoter structure and logic phenotype. The regulatory code is determined solely by the type of transcriptional regulation combinations: two repressors generate a NOR: NOT (a OR b) whereas a repressor and an activator generate an ANDN: a AND NOT b. Three-input versions of both logics, having an additional repressor as an input, are also present in the library. The resulting complex promoters cover a wide dynamic range of transcriptional strengths. Synthetic promoter shuffling represents a fast and efficient method for exploring the spectrum of complex regulatory functions that can be encoded by complex promoters. From an engineering point of view, synthetic promoter shuffling enables the experimental testing of the functional properties of complex promoters that cannot necessarily be inferred ab initio from the known properties of the individual genetic components. Synthetic promoter shuffling may provide a useful experimental tool for studying naturally occurring promoter shuffling.


Modern surgery for global cataract blindness: preliminary considerations.
Unoperated cataract in the developing world remains ophthalmology's major unsolved problem. Recent developments have brought into question the assumptions of those who have thought that extracapsular surgery with implantation of a posterior chamber intraocular lens is an unrealistic approach to the treatment of global cataract blindness. High-quality 1-piece posterior chamber intraocular lenses are being manufactured locally for approximately $10 each. Most ophthalmologists can be trained to perform extracapsular surgery in a 1-month course. This process is particularly effective if outstanding local surgeons receive intensive training to become instructors. While the incidence and treatment of posterior capsule opacification requires further study, the development of a low-cost YAG laser may be a solution. Imaginative ways to recover costs will need to be developed if the staggering prevalence of cataract blindness is to be effectively addressed. The improved result of modern surgery may make patients more willing to pay for their operation.


A randomized controlled evaluation of absorption of silver with the use of silver alginate (Algidex) patches in very low birth weight (VLBW) infants with central lines.
To measure systemic silver absorption when using silver-impregnated alginate central catheter dressings in very low birth weight (VLBW) neonates and to monitor blood stream infection. Fifty infants were enrolled in a prospective, randomized controlled trial lasting 28 days. Each patient was assigned to standard dressing or silver alginate (Algidex) group. Serum silver concentrations were obtained on day 1, 7, and 28. Significant differences in mean serum silver concentrations for the treatment versus standard dressing group were observed using student's t-test analysis. The silver alginate group had a 45.8% reduction in infection/1000 line days, although too few patients were enrolled to draw meaningful efficacy conclusions about prevention of blood stream infection. Mean serum silver concentrations in the treatment group were significantly higher than controls although below levels anticipated to result in toxicity. A large study evaluating reduced blood stream infections in VLBW infants is warranted.


Daily physical activity and physical function in adult maintenance hemodialysis patients.
Maintenance hemodialysis (MHD) patients reportedly display reduced daily physical activity (DPA) and physical performance. Low daily physical activity and decreased physical performance are each associated with worse outcomes in chronic kidney disease patients. Although daily physical activity and physical performance might be expected to be related, few studies have examined such relationships in MHD patients, and methods for examining daily physical activity often utilized questionnaires rather than activity monitors. We hypothesized that daily physical activity and physical performance are reduced and correlated with each other even in relatively healthier MHD patients. Daily physical activity, 6-min walk distance (6-MWT), sit-to-stand, and stair-climbing tests were measured in 72 MHD patients (32 % diabetics) with limited comorbidities and 39 normal adults of similar age and gender mix. Daily physical activity was examined by a physical activity monitor. The human activity profile was also employed. Daily physical activity with the activity monitor, time-averaged over 7 days, and all three physical performance tests were impaired in MHD patients, to about 60-70 % of normal values (p < 0.0001 for each measurement). Human activity profile scores were also impaired (p < 0.0001). MHD patients spent more time sleeping or in marked physical inactivity (p < 0.0001) and less time in ≥ moderate activity (p < 0.0001). These findings persisted when comparisons to normals were restricted to men or women separately. After adjustment, daily physical activity correlated with 6-MWT but not the two other physical performance tests. Human activity profile scores correlated more closely with all three performance tests than did DPA. Even in relatively healthy MHD patients, daily physical activity and physical performance are substantially impaired and correlated. Whether training that increases daily physical activity or physical performance will improve clinical outcome in MHD patients needs to be examined.


Long-Term Results of Crossover Bypass for Iliac Atherosclerotic Lesions in the Era of Endovascular Treatment: The Re-ACTION Study (Retrospective Assessment of Crossover Bypass as a Treatment for Iliac LesiONs).
Objective: The aim of this study was to elucidate the long-term results of crossover bypass (CB) for iliac atherosclerotic lesions in the era of endovascular treatment (EVT). Methods: A retrospective multicenter cohort study was performed. CB was performed in 242 patients between 2003 and 2014 by vascular surgeons at multiple medical centers in Japan. Results: Perioperative mortality was 1.7%. Primary patency rates were 86% at 5 years and 82% at 8 years. Univariate analysis showed that critical limb ischemia (Rutherford class 4-6), vein graft, and superficial femoral artery occlusion were significantly associated with low primary patency. In multivariate analysis, only critical limb ischemia influenced primary patency. The secondary patency rate was 87% at both 5 and 8 years. The limb salvage rate was 98% at both 5 and 8 years. The overall survival rates were 71% at 5 years and 49% at 8 years. Conclusion: The long-term results of CB were good in our study, compared with previous reports. Our results suggest that CB remains an option for the arterial reconstruction in unilateral iliac occlusive disease after EVT failed.


Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma.
Interferon-alpha (IFN-alpha) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-alpha and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-alpha2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-alpha2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-alpha2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy x 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-alpha2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-alpha2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-alpha and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-alpha2a and radiation therapy in a previous trial. In the high-risk group of patients in the present study, concurrent treatment with IFN-alpha2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-alpha2a, or compared with radiation therapy alone in other trials.


Temporal dynamics and statistical characteristics of the microfluctuations of accommodation: dependence on the mean accommodative effort.
Microfluctuations of accommodation have been the subject of many studies. New technological developments now permit us to study the dynamics of the microfluctuations with unprecedented resolution and accuracy. We aim to characterise their temporal statistics for different levels of accommodative effort, using a custom-built aberrometer. We conducted 46 s long measurements on the dominant eye of 9 young, healthy subjects. The ocular wavefront was sampled every 250 microm across the 3.9 mm measured pupil, at a frame rate of 173 Hz. This enabled us to obtain high resolution estimates of the Power Spectral Density (PSD). Results show that the shape of the estimated PSD for a 4 D effort is distinct from the shape for the two extrema of the accommodation range. The autocorrelation function of the increments of the accommodation signal is also affected by the level of effort, regardless of the refractive error of the subject.


Imaging the brain activity changes underlying impaired visuospatial judgments: simultaneous FMRI, TMS, and behavioral studies.
Damage to parietal cortex impairs visuospatial judgments. However, it is currently unknown how this damage may affect or indeed be caused by functional changes in remote but interconnected brain regions. Here, we applied transcranial magnetic stimulation (TMS) to the parietal cortices during functional magnetic resonance imaging (fMRI) while participants were solving visuospatial tasks. This allowed us to observe both the behavioral and the neural effects of transient parietal activity disruption in the active healthy human brain. Our results show that right, but not left, parietal TMS impairs visuospatial judgment, induces neural activity changes in a specific right-hemispheric network of frontoparietal regions, and shows significant correlations between the induced behavioral impairment and neural activity changes in both the directly stimulated parietal and remote ipsilateral frontal brain regions. The revealed right-hemispheric neural network effect of parietal TMS represents the same brain areas that are functionally connected during the execution of visuospatial judgments. This corroborates the notion that visuospatial deficits following parietal damage are brought about by a perturbation of activity across a specific frontoparietal network, rather than the lesioned parietal site alone. Our experiments furthermore show how concurrent fMRI and magnetic brain stimulation during active task execution hold the potential to identify and visualize networks of brain areas that are functionally related to specific cognitive processes.


Vestibular function in children with vestibulocochlear nerve aplasia/hypoplasia.
Infants and young children with vestibulocochlear nerve (VCN) hypoplasia/aplasia present with severe hearing loss and are candidates for cochlear implantation (CI). It is unknown whether vestibular function is related to CI outcome and if vestibular tests can guide the operation decision. Our aim was to describe the vestibular function in patients with VCN hypoplasia/aplasia before a possible CI. Forty-two ears in 23 patients were tested between 2019 and 2022 with bone-conducted cervical vestibular evoked myogenic potentials (BCcVEMP), video head impulse test (vHIT) and miniice-water caloric test (mIWC). All ears could be tested with at least one vestibular test and 83% could be tested with more than one method. Twenty-nine ears (61%) showed normal function with at least one method. The presence of a normal response to any test doubled the likelihood of a measured hearing threshold after CI, the best predictors being the BCcVEMP and vHIT (p < 0.05). Canal function may represent a predictor of auditive pathway integrity with a possible favourable audiological outcome after CI operation. Our results demonstrate high vestibular response rates suggesting a functioning pathway despite the radiological diagnosis.


Juxtafacet cysts of the cervical spine.
We report a retrospective series of 13 patients who presented with symptoms and signs caused by cervical juxtafacet cysts. Clinical findings, radiographic features, surgical management strategies, and possible causes are reported and discussed. We reviewed clinical histories, radiographic studies, surgical notes, and pathological records of all 13 patients who underwent surgery for subaxial cervical juxtafacet cysts from 1984 to 1997 at the Mayo Clinic in Rochester, MN. During the summer of 1997, surgical outcomes were assessed by direct or telephone interview. Nine patients were men and four were women. The average age at the time of presentation was 66 years. One patient had undergone a previous anterior cervical fusion below the level of the cyst. Ten patients presented with radiculopathies. Two patients presented with myeloradiculopathies. One patient presented with a cervical myelopathy. Computed tomographic myelography and magnetic resonance imaging were essential in establishing a preoperative diagnosis. The cysts were located at C7-T1 in nine patients, at C4-C5 in two patients, at C6-C7 in one patient, and at C3-C4 in one patient. All patients underwent posterior laminectomy or hemilaminectomy, excision of the cyst, and decompression of the thecal sac and/or nerve root. Two patients underwent concurrent posterior fusion procedures for instability. All patients experienced good to excellent relief of their radicular pain. All three myelopathies stabilized after surgery. There were no major complications or recurrences. Juxtafacet cysts seem to be a degenerative change of the cervical spine rather than a traumatic event. Similar to their counterparts in the lumbar spine, they tend to arise in segments with increased mobility. Surgical treatment is effective.


Differences in Sole Carbon Source Utilization of the Dental Plaque Microbiota Between Caries-Free and Caries-Affected Children.
Increasing lines of evidence indicate that while microbial profile might vary, community-level metabolic potential is often more stably correlated with healthy and diseased states. Here, we investigated the community-level metabolic diversity of dental plaque microbiota from caries-free (CF) and caries-affected (CA) children by measuring their sole carbon source utilization using a Biolog assay. The dietary habits of 32 CF and 31 CA children were recorded by a questionnaire. Supragingival plaque samples were collected and inoculated into Biolog AN Microplates to assess the metabolism of sole carbon sources by plaque bacteria. The results revealed significant differences in dietary habits between CF and CA children. Meanwhile, Biolog assay showed consistently higher, albeit not statistically significant, overall metabolic activity as measured by average well color development (AWCD) value in the plaque microbiota from CA group than CF group. Most importantly, the CA group had more than twice as many core-positive carbon sources (defined as being utilized by >90% of plaque microbiota from subjects within the group) as that of the CF group (31 vs. 14), including CA group-specific, cariogenic core-positive carbon sources such as sucrose, glucose and raffinose. Furthermore, CF and CA groups could be well distinguished by cluster and principle component analyses based on the types of sole carbon sources significantly differentially utilized by the two groups. Our results indicate that plaque communities associated with caries state are more metabolically versatile than those associated with healthy state, which could contribute to differential clinical caries states. Meanwhile, Biolog could be an effective tool in revealing the community-level physiological profiles of microbiota associated with different caries states.


Repriming of delayed potassium conductance in frog skeletal muscle.
A dissection of the semitendinosus muscle from Rana pipiens was developed for three-microelectrode voltage-clamp studies of the delayed potassium-selective conductance system. The delayed conductance inactivates in muscles bathed in high concentrations of potassium or rubidium, but can be reprimed by hyperpolarizing voltage pulses to membrane potentials beyond -80 mV. The repriming time-course was studied by measuring the delayed conductance that coulde be activated following hyperpolarizing pulses of varying duration. Responses following 20-100 s pulses to potentials between -90 and -140 mV could not be reconciled with an exponential approach to the conductance present in normally polarized fibres. The sigmoid appearance of the early (< 25 s) time course was exaggerated by cooling from 20 to 10 degrees C. This effect was described by a sequential model invoking two inactivated states with different temperature dependences. An explanation is suggested for differences in the kinetics and voltage dependence of repriming between briefly and chronically depolarized muscle cells.


Evaluation of irreversible compression of digitized posterior-anterior chest radiographs.
The purpose of this article is to assess lossy image compression of digitized chest radiographs using radiologist assessment of anatomic structures and numerical measurements of image accuracy. Forty posterior-anterior (PA) chest radiographs were digitized and compressed using an irreversible wavelet technique at 10, 20, 40, and 80:1. These were presented in a blinded fashion with an uncompressed image for A-B comparison of 11 anatomic structures as well as overall quality assessments. Mean error, root-mean square (RMS) error, maximum pixel error, and number of pixels within 1% of original value were also computed for compression ratios from ratios from 5:1 to 80:1. We found that at low compression (10:1) there was a slight preference for compressed images. There was no significant difference at 20:1 and 40:1. There was a slight preference on some structures for the original compared with 80:1 compressed images. Numerical measures showed high image faithfulness, both in terms of number of pixels that were within 1% of their original value, and by the average error for all pixels. Our findings suggest that lossy compression at 40:1 or more can be used without perceptible loss in the representation of anatomic structures. On this finding, we will do a receiver-operator characteristic (ROC) analysis of nodule detection in lossy compressed images using 40:1 compression.


Superior Stability Secured by a Four-Phase Cathode Electrolyte Interface on a Ni-Rich Cathode for Lithium Ion Batteries.
A multifunctional coating with high ionic and electronic conductivity is constructed on the surface of LiNi0.8Co0.1Mn0.1O2 (NCM) to boost the battery stability upon cycling and during storage as well. Phosphoric acid reacts with residual lithium species on the pristine NCM to form a Li3PO4 coating with extra carbon nanotubes (CNTs) penetrating through, which shows high ionic and electronic conductivity. NCM, Li3PO4, CNTs, and the electrolyte jointly form a four-phase cathode electrolyte interface, which plays a key role in the great enhancement of capacity retention, from 50.3% for pristine NCM to 84.8% for the modified one after 500 cycles at 0.5C at room temperature. The modified NCM also delivers superior electrochemical performances at a high cut-off voltage (4.5 V), high temperature (55 °C), and high rate (10C). Furthermore, it can deliver 154.2 mA h g-1 at the 500th cycle after exposed to air with high humidity for 2 weeks. These results demonstrate that the well-constructed multifunctional coating can remarkably enhance the chemical and electrochemical performances of NCM. The improved cycling, storage, and rate performance are attributed to the four-phase cathode electrolyte interface delivering high electron and ionic conductivity and securing the cathode against attack. This work broadens the horizon for constructing effective electrode/electrolyte interfaces for electrochemical energy storage and conversion.


Safety of serotonin (5-HT3) receptor antagonists in patients undergoing surgery and chemotherapy: protocol for a systematic review and network meta-analysis.
Serotonin (5-HT3) receptor antagonists are a class of antiemetic medications often used to prevent nausea and vomiting among patients undergoing chemotherapy, radiotherapy or surgery. However, recent studies suggest that these agents might be associated with increased cardiac harm. To examine this further, we are proposing to conduct a systematic review and network meta-analysis on the comparative safety of 5-HT3 receptor antagonists among patients undergoing chemotherapy or surgery. Studies reporting one or more safety outcomes of interest for 5-HT3 receptor antagonists compared with each other, placebo, and/or other anti-emetic agents (for example, benzamides, phenothiazines, butyrophenones, antihistamines, and anticholinergics) among children and adult patients undergoing surgery or chemotherapy will be included. Our primary outcome of interest is arrhythmia. Our secondary outcomes include cardiac death, QT prolongation, PR prolongation, all-cause mortality, nausea, and vomiting. We will include experimental studies, quasi-experimental studies (namely controlled before-after and interrupted time series), and observational studies (namely cohort studies). We will not limit inclusion by publication status, time period, duration of follow-up or language of dissemination.Electronic databases (for example, MEDLINE, EMBASE) will be searched from inception onwards. These main searches will be supplemented by searching for difficult to locate and unpublished studies, such as dissertations, and governmental reports. The eligibility criteria will be pilot-tested and subsequently used to screen the literature search results by two reviewers in duplicate. A similar process will be followed for full-text screening, data abstraction, and risk of bias/methodological quality appraisal. The Cochrane Risk of Bias tool will be used to appraise experimental and quasi-experimental studies, and cohort studies will be assessed using the Newcastle Ottawa Scale. If the data allows, random effects meta-analysis and a network (that is, mixed treatment comparisons) meta-analysis will be conducted. All analyses will be conducted separately for different study designs, patient populations (for example, children and adults), and reason for administering 5-HT3 receptor antagonists (for example, post-surgery and chemotherapy). Our results will help inform patients, clinicians, and health policy-makers about the potential safety concerns, as well as the comparative safety, of using these antiemetic agents. PROSPERO registry number:CRD42013003564.


Adverse Childhood Experiences Distinguish Violent Juvenile Sexual Offenders' Victim Typologies.
Juvenile perpetrators account for over 25% of all sexual offenses, and over one-third of such offenses are against victims under the age of 18. Given empirical connections between adverse childhood experience (ACE) exposure and perpetration of violence, we create victim typologies based on the juveniles' relationship to their victims among 5539 justice-involved adolescents who have committed violent against-person sexual felonies. Multinomial logistic regression is used to assess which covariates, including individual ACE exposures and cumulative traumatic exposures, are associated with victim typologies. This approach allows for better targeting of violence prevention efforts, as a more nuanced understanding of the increased likelihood to victimize specific victim groups lends to potential differences in treatment provision, beyond simplistic findings regarding ACE exposure increasing offending. Results indicate five classes of victim types, ranging from a low of 6.4%, with primarily strangers as victims, to 31.3%, with predominately acquaintances as victims, and only 12.9% with a diverse array of relationships to victims. Importantly, many demographic and individual risk factors, and specific traumatic exposures were related to victimizing one's sibling, while cumulative trauma as measured by an ACE score decreased the likelihood of victimizing classmates, while increasing the likelihood of victimizing siblings and other relatives compared to victimizing acquaintances.


Development of an Effective and Stable Genotype-Matched Live Attenuated Newcastle Disease Virus Vaccine Based on a Novel Naturally Recombinant Malaysian Isolate Using Reverse Genetics.
Genotype VII Newcastle disease viruses are associated with huge economic losses in the global poultry industry. Despite the intensive applications of vaccines, disease outbreaks caused by those viruses continue to occur frequently even among the vaccinated poultry farms. An important factor in the suboptimal protective efficacy of the current vaccines is the genetic mismatch between the prevalent strains and the vaccine strains. Therefore, in the present study, an effective and stable genotype-matched live attenuated Newcastle disease virus (NDV) vaccine was developed using reverse genetics, based on a recently isolated virulent naturally recombinant NDV IBS025/13 Malaysian strain. First of all, the sequence encoding the fusion protein (F) cleavage site of the virus was modified in silico from virulent polybasic (RRQKRF) to avirulent monobasic (GRQGRL) motif. The entire modified sequence was then chemically synthesized and inserted into pOLTV5 transcription vector for virus rescue. A recombinant virus termed mIBS025 was successfully recovered and shown to be highly attenuated based on OIE recommended pathogenicity assessment indices. Furthermore, the virus was shown to remain stably attenuated and retain the avirulent monobasic F cleavage site after 15 consecutive passages in specific-pathogen-free embryonated eggs and 12 passages in one-day-old chicks. More so, the recombinant virus induced a significantly higher hemagglutination inhibition antibody titre than LaSota although both vaccines fully protected chicken against genotype VII NDV induced mortality and morbidity. Finally, mIBS025 was shown to significantly reduce both the duration and quantity of cloacal and oropharyngeal shedding of the challenged genotype VII virus compared to the LaSota vaccine. These findings collectively indicate that mIBS025 provides a better protective efficacy than LaSota and therefore can be used as a promising vaccine candidate against genotype VII NDV strains.


Coffee and alcohol consumption and bladder cancer.
Epidemiological studies on coffee, alcohol and bladder cancer risk published up to 2007 were reviewed. Coffee drinkers have a moderately higher relative risk of bladder cancer compared to non-drinkers. The association may partly be due to residual confounding by smoking or dietary factors, but the interpretation remains open to discussion, although the absence of dose and duration-risk relations weighs against the presence of a causal association. Most studies of alcohol and bladder cancer found no association, with some studies finding a direct and other an inverse one. This again may be due to differential confounding effect of tobacco smoking--the major risk factor for bladder cancer--in various populations. Thus, epidemiological findings on the relation between alcohol drinking and bladder cancer exclude any meaningful association.


Domain-Specific Programming Languages for Computational Nucleic Acid Systems.
The construction of models of system behavior is of great importance throughout science and engineering. In bioengineering and bionanotechnology, these often take the form of dynamic models that specify the evolution of different species over time. To ensure that scientific observations and conclusions are consistent and that systems can be reliably engineered on the basis of model predictions, it is important that models of biomolecular systems can be constructed in a reliable, principled, and efficient manner. This review focuses on efforts to address this need by using domain-specific programming languages as the basis for custom design tools for researchers working on computational nucleic acid devices, where a domain-specific language is simply a programming language tailored to a particular application domain. The underlying thesis of our review is that there is a continuum of practical implementation strategies for computational nucleic acid systems, which can all benefit from appropriate domain-specific languages and software design tools. We emphasize the need for specialized yet flexible tools that can be realized using domain-specific languages that compile to more general-purpose representations.


[Biomechanical properties of the cribriform lamina in glaucoma-induced atrophy of the optic nerve and after decompression operations on the scleral canal].
The authors made a mathematical and clinical analysis of the cribriform lamina (CL) of the optic nerve and nerve fiber bundles passing through its foramens in glaucoma-induced optic neuropathy. It was shown that in elevated intraocular pressure, there was a significant CL deformity leading to the compression and deformity of nerve fibers. The important biomechanical characteristic of CL deformity is the tangent of the angle between the longitudinal axis of the scleral canal and the perpendicular to the CL surface. An increase in the inner radius of the scleral canal of the optic nerve due to its dissection at decompression surgery is one of the ways of diminishing CL flexure and nerve fiber deformity. A small increase in the scleral canal radius (by approximately 10%) was demonstrated to eliminate significant CL flexure.


Pathological signaling via platelet-derived growth factor receptor {alpha} involves chronic activation of Akt and suppression of p53.
In contrast to direct activation of platelet-derived growth factor (PDGF) receptor α (PDGFRα) via PDGF, indirect activation via growth factors outside the PDGF family failed to induce dimerization, internalization, and degradation of PDGFRα. Chronically activated, monomeric PDGFRα induced prolonged activation of Akt and suppressed the level of p53. These events were sufficient to promote both cellular responses (proliferation, survival, and contraction) that are intrinsic to proliferative vitreoretinopathy (PVR) and induce the disease itself. This signature signaling pathway appeared to extend beyond PVR since deregulating PDGFRα in ways that promote solid tumors also resulted in chronic activation of Akt and a decline in the level of p53.


[Spectrum of neuropsychological changes in multiple sclerosis].
Early disability of patients with multiple sclerosis at the able-bodied age is often caused by both a neurological disorder and the difficulties of their social and psychological adaptation that is aggravated significantly by higher cortical dysfunctions and by behavioral problems. The paper presents the results of the dynamic neuropsychological observation of 124 patients with multiple sclerosis and of their first degree relatives. Even at the early stage of the disease there were some cognitive disorders as worse transitent verbal, semantic, visual memory active attention and slower sensomotor reactions; difficulties in conceptual mentality. The cognitive functions, the activity of the disease, an actual psychological state, depression for example, and the expression of brain atrophy and the localization of the foci are bound by the certain way. The personality traits of patients and their close relatives testified a possible psychosomatic nature of this disease.


Quantification of nasal airflow resistance in English bulldogs using computed tomography and computational fluid dynamics.
Stenotic nares, edematous intranasal turbinates, mucosal swelling, and an elongated, thickened soft palate are common sources of airflow resistance for dogs with brachycephalic airway syndrome. Surgery has focused on enlarging the nasal apertures and reducing tissue of the soft palate. However, objective measures of surgical efficacy are lacking. Twenty-one English bulldogs without previous surgery were recruited for this prospective, pilot study. Computed tomography was performed using conscious sedation and without endotracheal intubation using a 128 multidetector computed tomography scanner. Raw multidetector computed tomography data were rendered to create a three-dimensional surface mesh model by automatic segmentation of the air-filled nasal passage from the nares to the caudal soft palate. Three-dimensional surface models were used to construct computational fluid dynamics models of nasal airflow resistance from the nares to the caudal aspect of the soft palate. The computational fluid dynamics models were used to simulate airflow in each dog and airway resistance varied widely with a median 36.46 (Pa/mm)/(l/s) and an interquartile range of 19.84 to 90.74 (Pa/mm)/(/s). In 19/21 dogs, the rostral third of the nasal passage exhibited a larger airflow resistance than the caudal and middle regions of the nasal passage. In addition, computational fluid dynamics data indicated that overall measures of airflow resistance may significantly underestimate the maximum local resistance. We conclude that computational fluid dynamics models derived from nasal multidetector computed tomography can quantify airway resistance in brachycephalic dogs. This methodology represents a novel approach to noninvasively quantify airflow resistance and may have utility for objectively studying effects of surgical interventions in canine brachycephalic airway syndrome.


A comparison of health information on Florida's free-nets.
In the popular rush to provide electronic consumer health information, particularly via the Internet, one system has been largely overlooked-the free-net. Free-nets are often text-based systems from which users choose topics from "menus." While the World Wide Web can be more graphically appealing, it can also be overwhelming. Medical information resources are available to diverse populations through free-nets, which are convenient, free services. The amount of information and range of topics they offer are vast. A study of Florida's free-nets during a six-month period involved five free-net systems. Survey items included user demographics, interlibrary loan services, attitudes toward providing medical advice, and availability of medical librarian expertise. Comparisons include the number of user queries on medical and health-related free-net menus, user-friendliness, and the type of health information provided.


Assessing suffering in advanced cancer patients using Pictorial Representation of Illness and Self-Measure (PRISM), preliminary validation of the Spanish version in a Latin American population.
This study aims to adapt the Pictorial Representation of Illness and Self-Measure (PRISM), a practical, nonverbal method with strong psychometric properties, to Spanish and to explore its criterion validity in advanced cancer and palliative care (PC). Of the consecutive advanced cancer patients attending a palliative care consultation, 209 were invited to participate. To examine criterion validity, correlations were calculated between the PRISM, the Detection of Emotional Distress scale (DED), the Edmonton Symptom Assessment System (ESAS), the Structured Interview of Symptoms and Concerns (SISC), and the suffering visual analogue scale (VAS). Ninety-eight patients fulfilled inclusion criteria (mean age, 60 years; SD, 14.25; 57 % female). The most frequent types of cancer were lung, breast, and colorectal. Average time since diagnosis was 30 months (2.5 years). PRISM significantly correlated with the Suffering VAS, the DED, and the SISC. It also showed significant correlations with psychosocial factors such as emotional distress, anxiety, loss of control, and perceived coping and spiritual distress items such as loss of dignity and hopelessness, but not with items examining physical symptoms. The PRISM is a valid measure of suffering in advanced cancer patients. Its Spanish version fits adequately with current definitions and conceptualizations of suffering and may be used in PC settings. Further analysis of other psychometric properties in Spanish-speaking settings is recommended.


BDNF-Induced potentiation of spontaneous twitching in innervated myocytes requires calcium release from intracellular stores.
Brain-derived neurotrophic factor (BDNF) can potentiate synaptic release at newly developed frog neuromuscular junctions. Although this potentiation depends on extracellular Ca(2+) and reflects changes in acetylcholine release, little is known about the intracellular transduction or calcium signaling pathways. We have developed a video assay for neurotrophin-induced potentiation of myocyte twitching as a measure of potentiation of synaptic activity. We use this assay to show that BDNF-induced synaptic potentiation is not blocked by cadmium, indicating that Ca(2+) influx through voltage-gated Ca(2+) channels is not required. TrkB autophosphorylation is not blocked in Ca(2+)-free conditions, indicating that TrkB activity is not Ca(2+) dependent. Additionally, an inhibitor of phospholipase C interferes with BDNF-induced potentiation. These results suggest that activation of the TrkB receptor activates phospholipase C to initiate intracellular Ca(2+) release from stores which subsequently potentiates transmitter release.


Nasal discharge cytology an important diagnostic method for allergic fungal sinusitis: report of three cases.
Allergic fungal sinusitis (AFS) is a distinct clinicopathological entity. It occurs in immunocompetent individuals with history of atopy, increased IgE levels and peripheral eosinophilia and causes noninvasive pansinusitis. It is histologically characterised by the presence of 'allergic mucin' with clusters of eosinophils, charcot - Leyden crystals and scattered fungal hyphae. AFS is an immunological reaction to fungal deposits. As AFS is noninvasive, fungal hyphae can be demonstrated in nasal secretions on cytology. Etiological agent of AFS is Aspergillus or pigmented dematiaceous family. Special stains are helpful for identification. We came across three cases of age group ranging from 26 to 60-year of recurrent rhinitis with nasal discharge. The nasal secretions were collected by nasal swabs onto the glass slide and stained with Giemsa and silver stains. Smears revealed fungal hyphae amidst inflammatory cells with occasional Charcot-Leyden crystals. Nasal secretion cytology plays an important role in diagnosis and can be used for preoperative as well as intraoperative diagnosis of AFS and can be used as an additional diagnostic tool.


AIDS and cerebrovascular disease.
Although neurological complications of human immunodeficiency virus (HIV) infection are common, the presence of cerebrovascular disease (CVD) has been seldom reported. The purpose of this report is to review available data on the association between stroke and acquired immunodeficiency syndrome (AIDS). A review of all literature published between mid-1976 and December 1994 was performed through a MEDLINE search with the following key words: AIDS, CVD, human T-cell lymphotropic virus type III, and HIV-1. Only reports of clinical stroke in patients with AIDS or HIV infection and autopsy series with stroke findings were selected. The type of study, population, number of stroke patients, subtype and etiology of stroke, and associated AIDS conditions were described. Six clinical series and 11 autopsy series were found, with a total of 1885 cases with AIDS, AIDS-related complex, and HIV carriers. Forty percent had a neurological complication, but only 1.3% had a stroke syndrome. Ischemic infarcts were more common than intracerebral hemorrhages. Cerebral infarcts were generally due to nonbacterial thrombotic endocarditis or concomitant opportunistic central nervous system infection, and intracerebral hemorrhages were usually associated with thrombocytopenia, primary central nervous system lymphoma, and metastatic Kaposi's sarcoma. Autopsy findings of CVD were generally not related with clinical stroke before death. Data are not available to determine the role of risk factors for AIDS in CVD. Because of limitations of the available data, it is still not clear whether there is an association between AIDS and stroke. Further studies are needed to better define the epidemiology of CVD in association with AIDS.


Evidence for direct non-genomic effects of triiodothyronine on bone rudiments in rats: stimulation of the inositol phosphate second messenger system.
Thyroid hormones increase cytosolic free calcium by binding to plasma membrane receptors in several tissues. This calcium increase appears to initiate extranuclear effects in these tissues. Increases in cytosolic calcium are often a consequence of stimulation of inositol phosphate second messenger pathway. Several calcemic hormones act via this signal transduction route. Therefore we investigated the effects of the metabolically active T3 and the inactive analogues 3,5-diiodotyrosine and rT3 on the inositol phosphate pathway in fetal rat limb bone cultures prelabeled with [3H]myoinositol. Labelled inositol and inositol phosphates were separated by HPLC. There was a significant increase in the radioactivity in inositol bis- and trisphosphates after 1 min of exposure to 10(-7) mol/l T3. Stimulation was also observed at 10(-6) mol/l T3, but not at 10(-5) mol/l. Time course studies demonstrated a rapid effect of T3 on inositol phosphates within 30 seconds that lasted through 5 min. After 20 min incubation with T3, no increase was observed in inositol mono- and bisphosphates, and a decrease was seen in inositol trisphosphate. Pretreatment with indomethacin prevented these effects of T3. 3,5-diiodotyrosine and rT3 did not affect inositol phosphate metabolism. These results suggest the existence of plasma membrane-associated receptors for T3 in bone, in addition to the nuclear receptors demonstrated previously. The role of these receptors in the effects of thyroid hormones on bone remains to be established.


Genomic organization and linkage via a bidirectional promoter of the AP-3 (adaptor protein-3) mu3A and AK (adenosine kinase) genes: deletion mutants of AK in Chinese hamster cells extend into the AP-3 mu3A gene.
The cDNA and genomic DNA for the mu3A subunit of the AP-3 (adaptor protein-3) complex were cloned from Chinese hamster cells. The AP-3 mu3A genes in Chinese hamster, human and mouse each comprise nine exons and eight introns, with all introns located in identical positions in the species studied. The AP-3 mu3A genes in these species are linked in a head-to-head fashion with the gene for the purine salvage pathway enzyme AK (adenosine kinase). These genes share the first exon, and a 512 bp fragment covering the intervening untranslated sequence has the characteristic of a CpG island promoter, and it effectively carried out transcription in both directions. Deletion studies indicate that this region contains both positive and negative regulatory elements affecting transcription of these genes. In comparison with the AP-3 mu3A gene (27 kb), the AK gene in human is very large (558 kb), with average exon and intron lengths of approx. 100 bp and 55.7 kb respectively. The ratio of non-coding to coding sequence in the human AK gene is >550, which is the highest reported for any gene. We also present evidence that a number of AK- mutants of Chinese hamster ovary cells contain large deletions that affect both of these genes. In addition to lacking part of the AK gene, two of these mutants also lacked all of the exons and introns corresponding to the AP-3 mu3A gene. These mutants should prove useful in elucidating the role of AP-3 mu3A in vesicle-mediated protein sorting--a process that is altered in Hermansky-Pudlak syndrome. Detailed phylogenetic analysis of the micro family of proteins presented here also provides insight into how different AP complexes are related and may have evolved.


MicroRNA-374b inhibits migration and invasion of glioma cells by targeting EGFR.
To investigate the expression level of microRNA-374b in glioma tissues and its influence on the invasive ability of glioma cells. Meanwhile, the regulatory mechanism of microRNA-374b in glioma was also explored. The expression level of microRNA-374b in 32 glioma tissues and para-cancerous tissues were detected by quantitative Real-time polymerase chain reaction (qRT-PCR). The relationship between microRNA-374b expression and clinical indicators of glioma was analyzed. Meanwhile, the expression of microRNA-374b in glioma cells was verified by qRT-PCR as well. Subsequently, microRNA-374b over-expression model was constructed in glioma cell lines, including U251 and U87. Next, the effect of microRNA-374b on cellular biological functions was analyzed using cell counting kit-8 (CCK-8) assay, Wound healing test and transwell invasion assay, respectively. Finally, the relationship between miRNA and epidermal growth factor receptor (EGFR) was explored. QRT-PCR results showed that the expression level of microRNA-374b in glioma was significantly lower than that of adjacent tissues, and the difference was statistically significant. Compared with patients with higher expression of microRNA-374b, the occurrence rate of lymph node or distant metastasis was significantly higher in those with lower microRNA-374b expression. In addition, compared with NC group, the proliferation, invasion and migration abilities of cells in microRNA-374b mimics group was significantly decreased. Subsequently, results demonstrated that the expression of EGFR was significantly increased in glioma cells and tissues, which was negatively correlated with microRNA-374b expression. Subsequent cell recovery experiment indicated that microRNA-374b and EGFR had a mutual regulation and could affect the malignant progression of glioma all together. MicroRNA-374b could inhibit the invasion and migration of glioma by regulating EGFR. Moreover, the expression of microRNA-374b was significantly associated with lymph node metastasis, distant metastasis and poor prognosis.