In vitro inhibition of tumor growth by low-dose iron oxide nanoparticles activating macrophages.
Macrophages as immunocyte are attracting more and more attention in cancer therapy. Our previous study observed that dimercaptosuccinic acid (DMSA)-coated Fe3O4 magnetic nanoparticles triggered comprehensive immune responses of mouse macrophages (RAW264.7 cells) and induced production of many kinds of cytokines. This study investigated the effects of Fe3O4 magnetic nanoparticles on RAW264.7 cells proliferation, migration, and inhibition of tumor growth in vitro. Fe3O4 magnetic nanoparticles had an average size of about 11 nm with good dispersibility and uniformity. Fe3O4 magnetic nanoparticles internalized efficiently into RAW264.7 cells. Through Cell Counting Kit-8 (CCK-8) detection, the proliferation of RAW264.7 cells significantly increased by the low-dose Fe3O4 magnetic nanoparticles (50 µg/mL) treatment. The results of wound-healing and Transwell assays both displayed a significant promotion of the RAW264.7 cells migratory capability compared with control group ( P<0.01). It is interesting to find that a large number of proliferated RAW264.7 cells were activated to surround quickly and attack mouse liver cancer cell (Hepa1-6) cells by Fe3O4 magnetic nanoparticles. The growth of Hepa1-6 cells was effectively inhibited according to microscope imaging and flow cytometry analysis. The inhibition may be cooperative effects of RAW264.7 cells proliferation, migration, and immune activation. The results suggest potential clinical value of low-dose iron oxide nanomaterials in cancer therapy.


Developmental patterns of phenylpropylamino alkaloids accumulation in khat (Catha edulis, Forsk.).
Khat (Catha edulis Forsk., Celastraceae) is a perennial shrub that was introduced to Israel by Yemenite immigrants. Khat young leaves are chewed as a stimulant. The main stimulating active principles in this plant are the phenylpropylamino alkaloids (-)-cathinone [(S)-alpha-aminopropiophenone], (+)-cathine [(+)-norpseudoephedrine] and (-)-norephedrine. A novel GC-MS analysis method for the quantitative determination of phenylpropylamino alkaloids and their putative precursor 1-phenyl-1,2-propanedione in khat leaves was developed. We found a marked diversity in the phenylpropylamino alkaloids content and composition in 9 different accessions originated in seedlings and in the commercial cultivar "Mahanaim". The highest 1-phenyl-1,2-propanedione and (-)-cathinone levels occur in young leaves, the part traditionally chewed for its psycho-stimulating properties. Older leaves lack (-)-cathinone but contain the less active (+)-cathine and (-)-norephedrine. Young stems and flowers also contain 1-phenyl-1,2-propanedione, (-)-cathinone, (+)-cathine and (-)-norephedrine. We report the presence of a (-)-cathinone reductase in khat leaves capable of reducing (-)-cathinone to (+)-cathine in the presence of NADPH. We propose that (-)-cathinone is a biosynthetic precursor of (+)-cathine and (-)-norephedrine in khat leaves.


The contribution of species richness and composition to bacterial services.
Bacterial communities provide important services. They break down pollutants, municipal waste and ingested food, and they are the primary means by which organic matter is recycled to plants and other autotrophs. However, the processes that determine the rate at which these services are supplied are only starting to be identified. Biodiversity influences the way in which ecosystems function, but the form of the relationship between bacterial biodiversity and functioning remains poorly understood. Here we describe a manipulative experiment that measured how biodiversity affects the functioning of communities containing up to 72 bacterial species constructed from a collection of naturally occurring culturable bacteria. The experimental design allowed us to manipulate large numbers of bacterial species selected at random from those that were culturable. We demonstrate that there is a decelerating relationship between community respiration and increasing bacterial diversity. We also show that both synergistic interactions among bacterial species and the composition of the bacterial community are important in determining the level of ecosystem functioning.


Splenic lymphoma with villous lymphocytes in tropical West Africa.
Splenic lymphoma with villous lymphocytes (SLVL) is a monoclonal B-lymphoproliferative disorder characterised by splenomegaly and distinctive villous lymphocytes in the peripheral blood. It has not previously been reported from Africa, but we describe ten Ghanaian patients with SLVL seen at one hospital during a 4-year period. The clinical presentation is similar in Africa and in temperate regions, though the lymphocyte count is higher in African patients and the disorder predominantly affects middle-aged women rather than elderly men. It is likely that SLVL has previously been classified as splenic chronic lymphocytic leukaemia or hyper-reactive malarial splenomegaly.


A covariant change of the two highly conserved bases in the GTPase-associated center of 28 S rRNA in silkworms and other moths.
The GTPase-associated center in 23/28 S rRNA is one of the most conserved functional domains throughout all organisms. We detected a unique sequence of this domain in Bombyx mori species in which the bases at positions 1094 and 1098 (numbering from Escherichia coli 23 S rRNA) are C and G instead of the otherwise universally conserved bases U and A, respectively. These changes were also observed in four other species of moths, but not in organisms other than the moths. Characteristics of the B. mori rRNA domain were investigated by native polyacrylamide gel electrophoresis using RNA fragments containing residues 1030-1128. Although two bands of protein-free RNA appeared on gel, they shifted to a single band when bound to Bombyx ribosomal proteins Bm-L12 and Bm-P complex, equivalent to E. coli L11 and L8, respectively. Bombyx RNA showed lower binding capacity than rat RNA for the ribosomal proteins and anti-28 S autoantibody, specific for a folded structure of the eukaryotic GTPase-associated domain. When the C(1094)/G(1098) bases in Bombyx RNA were replaced by the conserved U/A bases, the protein-free RNA migrated as a single band, and the complex formation with Bm-L12, Bm-P complex, and anti-28 S autoantibody was comparable to that of rat RNA. The results suggest that the GTPase-associated domain of moth-type insects has a labile structural feature that is caused by an unusual covariant change of the U(1094)/A(1098) bases to C/G.


Reliability and Usefulness of Linear Sprint Testing in Adolescent Rugby Union and League Players.
The purpose of this study was to evaluate (a) whether there were differences in sprint times at 5, 10, 20, 30, and 40 m between rugby union and rugby league players, (b) determine the reliability and usefulness of linear sprint testing in adolescent rugby players. Data were collected on 28 rugby union and league academy players over 2 testing sessions, with 3-day rest between sessions. Rugby league players were faster at 5 m than rugby union players, with further difference unclear. Sprint time at 10, 20, 30, and 40 m was all reliable (coefficient of variation [CV] = 3.1, 1.8, 2.0, and 1.3%) but greater than the smallest worthwhile change (SWC [0.2 × between-subject SD]), rating the test as marginal for usefulness. Although the test was incapable of detecting the SWC, we recommend that practitioners and researchers use Hopkins' proposed method; whereby plotting the change score of the individual at each split (±typical error [TE] expressed as a CV) against the SWC and visually inspecting whether the TE crosses into the SWC are capable of identifying whether a change is both real (greater than the noise of the test, i.e., >TE) and of practical significance (>SWC). Researchers and practitioners can use the TE and SWC from this study to assess changes in performance of adolescent rugby players when using single beam timing gates.


Severe leukopenia and liver necrosis in young African grey parrots (Psittacus erithacus erithacus) infected with psittacine circovirus.
This paper describes the signs, clinical pathology, and postmortem findings in 14 young African grey parrots (Psittacus erithacus erithacus) that were naturally infected with psittacine beak and feather disease (PBFD) virus (psittacine circovirus). All but two of the parrots had severe leukopenia at clinical presentation. Two other parrots also had severe anemia. All birds died within 3 wk after presentation. Postmortem examination documented liver necrosis in 11 of 14 birds and secondary bacterial or fungal infections in 9 of 14 birds. Tests for Chlamydia psittaci, polyomavirus, and Salmonella sp. were negative. PBFD viral infection could be demonstrated in all birds by polymerase chain reaction. Supporting evidence of PBFD viral infection was gathered by histologic examination of the bursa of Fabricius, electron microscopy, and DNA in situ hybridization. Electron microscopic examination of both the bursa of Fabricius and liver revealed virus particles resembling circovirus. DNA in situ hybridization of six liver tissue samples confirmed the presence of PBFD virus and excluded the presence of avian polyomavirus. Our findings suggest that a specific presentation of peracute PBFD viral infection, characterized by severe leukopenia, anemia, or pancytopenia and liver necrosis in the absence of feather and beak abnormalities, may occur in young African grey parrots.


Phosphoglycerate mutase in mammalian striated muscles: subcellular localization and binding partners.
Contrary to previously published data, we have found that in mammalian skeletal muscles, phosphoglycerate mutase (PGM) is organized in a regular, striated fashion within the sarcomere. In the absence of the enzyme effectors, PGM localizes mainly at the M-line, but under conditions typical for contracting muscle, the enzyme accumulates within the I-band of the sarcomere. Searching for muscle PGM binding partners, we have found that PGM interacts with several enzymes of triose phosphate metabolism. It might suggest that PGM is a central structural element of the muscle glycolytic complex located within the isotropic region of the sarcomere.


Down's syndrome: karyotypic stability of trisomy 21 in an established lympho-blastoid cell line.
A trisomic lymphoblastoid cell line derived from the peripheral blood of a patient with Down's syndrome was sequentially analyzed for chromosome constitution for 16.5 months of continuous culture in vitro. The cell line was found to maintain a modal chromosome number of 47 with trisomy 21. Parallel studies of modal chromosomes before and after banding procedures revealed no structural abnormalities except trisomy 21.


[Biologics register JuMBO. Long-term safety of biologic therapy of juvenile idiopathic arthritis].
In recent years the treatment of juvenile idiopathic arthritis (JIA) has changed dramatically. Nowadays one out of three children with polyarticular JIA is treated with a biologic drug; however, knowledge about the long-term safety of biologics is still limited. Information on drug safety is collected in the JIA biologic register (BiKeR) and the follow-up register juvenile arthritis methotrexate/biologics long-term observation (JuMBO). The latter currently includes information on more than 700 young adults most of whom were treated with etanercept and prospectively followed for more than 5 years. Preliminary data on the long-term safety of etanercept for JIA are therefore available. Over an observation period of 1,800 etanercept exposure-years, events of particular interest, such as malignancies, serious infections and new onset immune-mediated diseases have been recorded which occurred at rates of 0.1, 1.1 and 0.9/100 patient-years, respectively. Overall, new safety risks were not detected during long-term etanercept exposure. Moreover, JuMBO has also provided information on the long-term outcome of JIA and initial evidence suggests that JIA outcome, especially in functional aspects has improved in the biologic era. Data from BiKeR and JuMBO contribute to the risk-benefit assessment of biologic drugs which have been implemented in the routine treatment of JIA.


Activity of moxifloxacin against Bacteroides fragilis and Escherichia coli in an in vitro pharmacokinetic/pharmacodynamic model employing pure and mixed cultures.
The objective of this study was to determine the pharmacodynamic (PD) activity of moxifloxacin against four selected Bacteroides fragilis strains (three strains with low MICs and one strain with a high MIC) and two Escherichia coli strains (one strain with a low MIC and one strain with a high MIC) in a pharmacokinetic (PK) in vitro model in pure cultures as well as in mixed cultures. PK/PD assays of moxifloxacin were carried out with an initial maximum concentration of 4.0 mg l-1 and a half-life of 13 h. The E. coli strain with the low MIC was rapidly killed in both pure and mixed cultures in the in vitro PK/PD model, while the E. coli strain with the high MIC was not killed. None of the B. fragilis strains were rapidly killed in pure or mixed cultures. The bacterial numbers of the B. fragilis strains with low MICs were reduced by about one to two logs after 12 h in pure cultures. The presence of an E. coli strain with a low or a high MIC in the mixed culture reduced this effect even further.


[Intraocular hemorrhage in a goat with thrombocytopenia and metastasis of an adenocarcinoma in the iris].
This case report describes the findings in a 10-year-old goat with metastasis of an adenocarcinoma in the iris. Two weeks before admission, the owner had noticed blepharospasm of the left eye. Clinical examination by the referring veterinarian revealed unilateral intraocular hemorrhage. The goat was referred to our clinic for further work-up. The rectal temperature was 40 degrees C. The most important haematological result was severe thrombocytopenia. There was mild corneal oedema of the left eye. Approximately 75 per cent of the anterior chamber was filled with non-coagulated blood. The fluid in the anterior chamber dorsal to the blood was cloudy, and the corpora nigra could not be seen clearly. All other internal parts of the eye could not be seen. Ultrasonography of the left eye confirmed cloudiness of the anterior chamber and revealed moderate thickening of the iris. The right prescapular lymph node was markedly enlarged. Cytological examination of a fine needle aspirate of the lymph node showed a mixed population of neoplastic cells. Based on immunohistochemical evaluation of the cells metastasis of a carcinoma was diagnosed. The goat was subjected to euthanasia, and a postmortem examination was carried out. The anterior chamber of the left eye contained blood, and the iris was thicker than normal and adhered to the posterior surface of the cornea. There were neoplastic alterations in the iris, the oesophagus, the lung lobes, the liver, the kidney and in the prescapular, retropharyngeal, mediastinal and hepatic lymph nodes. Histologically, a diagnosis of carcinoma was confirmed, but the origin of the tumour could not be determined.


Demonstration of insulin-like growth factor (IGF-I and -II) receptors and binding protein in human breast cancer cell lines.
The insulin like growth factors (IGFs), potent mitogens for a variety of normal and transformed cells, have been reported to be secreted by several human breast cancer cell lines (BC). We have investigated the binding characteristics of IGF-I and -II in four human BC: MCF-7, T-47D, MDA 231 and Hs578T. Binding studies in microsomal membrane preparations detected high specific binding for both IGF in all four BC studied. Cross-linking with 125I-IGF-I, followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) under reduced conditions, revealed the presence of an alpha subunit of apparent Mr = 130,000 in MCF-7, T-47D and MDA 213 cells. When 125I-IGF-II was cross-linked, a major band of apparent Mr = 260,000 was seen in all BC. This band was inhibited by IGF-II, but not by insulin. Cross-linking of 125I-IGF-I to conditioned media from BC demonstrated the presence of three binding proteins of apparent Mr = 45,000, 36,000 and 29,000 in all BC but T-47D, in which the 36,000 band was not seen. These data demonstrate that BC possess classical receptors for both IGF-I and -II and, furthermore, that BC produce specific binding proteins for these growth factors.


Prevalence of ventilator-associated pneumonia in a university hospital and prognosis for the patients affected.
To determine the prevalence of ventilator-associated pneumonia in an intensive care unit, as well as to identify related factors and characterize patient evolution. This study evaluated 278 patients on mechanical ventilation for more than 24 hours in a university hospital. Ventilator-associated pneumonia developed in 38.1% of the patients, translating to 35.7 cases/1000 ventilator-days: 45.3% were caused by gram-negative agents (Pseudomonas aeruginosa accounting for 22%); and multidrug resistant organisms were identified in 43.4%. In the ventilator-associated pneumonia group, time on mechanical ventilation, time to mechanical ventilation weaning, hospital stays and intensive care unit stays were all longer (p < 0.001). In addition, atelectasis, acute respiratory distress syndrome, pneumothorax, sinusitis, tracheobronchitis and infection with multidrug resistant organisms were more common in the ventilator-associated pneumonia group (p < 0.05). Mortality rates in the intensive care unit were comparable to those observed in the hospital infirmary. Associations between ventilator-associated pneumonia and various factors are expressed as odds ratios and 95% confidence intervals: acute sinusitis (38.8; 3.4-441); > 10 days on mechanical ventilation (7.7; 4.1-14.2); immunosuppression (4.3; 1.3-14.3); acute respiratory distress syndrome (3.5; 1.4-9.0); atelectasis (3.0; 1.2-7.3); cardiac arrest (0.18; 0.05-0.66); and upper gastrointestinal tract bleeding (0.07; 0.009-0.62). The variables found to be associated with in-hospital death were as follows: chronic renal failure (26.1; 1.9-350.7); previous intensive care unit admission (15.6; 1.6-152.0); simplified acute physiologic score II > 50 (11.9; 3.4-42.0); and age > 55 years (4.4; 1.6-12.3). Ventilator-associated pneumonia increased the time on mechanical ventilation and the number of complications, as well as the length of intensive care unit and hospital stays, but did not affect mortality rates.


Allele-specific targeting of hsa-miR-657 to human IGF2R creates a potential mechanism underlying the association of ACAA-insertion/deletion polymorphism with type 2 diabetes.
The biological mechanism of a recent discovered association of type 2 diabetes with the ACAA-insertion/deletion polymorphism at the 3'UTR of the IGF2R gene has remained unclear. A very recently emerging novel polymorphic control layer by microRNAs (miRNAs) makes it possible to elucidate this issue. In this study, a prediction by web tools MicroInspector and miRanda demonstrated that DNA sequence polymorphism (DSPs) ACAA-insertion/deletion in IGF2R 3'UTR is located within the hsa-miR-657 and hsa-miR-453 binding sites. And luciferase reporter assay revealed that hsa-miR-657 acts directly at the 3'UTR of the IGF2R. Furthermore, ACAA-deletion exerted a further repression compared with ACAA-insertion, indicating that hsa-miR-657 regulates IGF2R gene expression in a polymorphic control manner. Importantly, we also demonstrated that hsa-miR-657 can translationally regulate the IGF2R expression levels in Hep G2 cells. Thus, our findings testify the possibility that the ACAA-insertion/deletion polymorphism may result in the change of IGF2R expression levels at least in part by hsa-miR-657-mediated regulation, contributing to the elucidation for the pathogenesis of type 2 diabetes and raise the possibility that miRNAs or in combination with functional DNA sequence polymorphism may be valuable in the treatment of human type 2 diabetes.


Microbial transformation of androst-4-ene-3,17-dione by Beauveria bassiana.
The microbial transformation of androst-4-ene-3,17-dione (I) by the fungus Beauveria bassiana CCTCC AF206001 has been investigated using pH 6.0 and 7.0 media. Two hydroxylated metabolites were obtained with the pH 6.0 medium. The major product was 11alpha-hydroxyandrost-4-ene-3,17-dione (II) whereas the minor product was 6beta,11alpha-dihydroxyandrost-4-ene-3,17-dione (III). On the other hand, four hydroxylated and/or reduced metabolites were obtained with the pH 7.0 medium. The major product was 11alpha,17beta-dihydroxyandrost-ene-3-one (V) and the minor products were 17beta-hydroxyandrost-ene-3-one (IV), 6beta,11alpha,17beta-trihydroxyandrost-ene-3-one (VI) and 3alpha,11alpha,17beta-trihydroxy-5alpha-androstane (VII). The products were purified by chromatographic methods, and were identified on the basis of spectroscopic methods. This fungus strain is clearly an efficient biocatalyst for 11alpha-hydroxylation and reduction of the 17-carbonyl group.


A novel GATA4 loss-of-function mutation responsible for familial dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disorder and is associated with substantial morbidity and mortality. Increasing evidence suggests that genetic risk factors play an important role in the pathogenesis of idiopathic DCM. However, DCM is a genetically heterogeneous disease, and the genetic defects responsible for DCM in an overwhelming majority of cases remain to be identified. In the present study, the entire coding region and the splice junction sites of the GATA4 gene, which encodes a cardiac transcription factor essential for cardiogenesis, were sequenced in 150 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional characteristics of the mutant GATA4 were delineated in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.V291L, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes, and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the GATA4 mutant was associated with significantly diminished transcriptional activity. The findings expand the mutational spectrum of GATA4 linked to DCM and provide novel insight into the molecular etiology involved in DCM, suggesting the potential implications in the early prophylaxis and allele-specific treatment for this common type of cardiomyopathy.


Accuracy of oesophageal brush cytology: results of a prospective study and multicentre slide exchange.
The value of brush cytology has been assessed in the diagnosis of 101 oesophageal strictures in a department with no previous experience of oesophageal cytology. Cytological specimens obtained using a brush gave a correct diagnosis in 86 per cent of 36 malignant strictures with only 2 false negatives; when combined with biopsy, accuracy rose to 92 per cent. Of 65 benign strictures examined there were 3 false positives. In a series of test slides sent to 11 other hospitals the average false negative diagnosis was 4 per cent and false positive 3 per cent. Four of the centres had little previous experience and only two had extensive experience in oesophageal cytology. Therefore, brush cytology as a proved aid to the accurate diagnosis of oesophageal malignancy is within the capability of most pathology departments and should be used more widely.


Peptide backbone fragmentation initiated by side-chain loss at cysteine residue in matrix-assisted laser desorption/ionization in-source decay mass spectrometry.
Matrix-assisted laser desorption/ionization in-source decay (MALDI-ISD) is initiated by hydrogen transfer from matrix molecules to the carbonyl oxygen of peptide backbone with subsequent radical-induced cleavage leading to c'/z• fragments pair. MALDI-ISD is a very powerful method to obtain long sequence tags from proteins or to do de novo sequencing of peptides. Besides classical fragmentation, MALDI-ISD also shows specific fragments for which the mechanism of formation enlightened the MALDI-ISD process. In this study, the MALDI-ISD mechanism is reviewed, and a specific mechanism is studied in details: the N-terminal side of Cys residue (Xxx-Cys) is described to promote the generation of c' and w fragments in MALDI-ISD. Our data suggest that for sequences containing Xxx-Cys motifs, the N-Cα bond cleavage occurs following the hydrogen attachment to the thiol group of Cys side-chain. The c•/w fragments pair is formed by side-chain loss of the Cys residue with subsequent radical-induced cleavage at the N-Cα bond located at the left side (N-terminal direction) of the Cys residue. This fragmentation pathway preferentially occurs at free Cys residue and is suppressed when the cysteines are involved in disulfide bonds. Hydrogen attachment to alkylated Cys residues using iodoacetamide gives free Cys residue by the loss of •CH2CONH2 radical. The presence of alkylated Cys residue also suppress the formation of c•/w fragments pair via the (Cβ)-centered radical, whereas w fragment is still observed as intense signal. In this case, the z• fragment formed by hydrogen attachment of carbonyl oxygen followed side-chain loss at alkylated Cys leads to a w fragment. Hydrogen attachment on peptide backbone and side-chain of Cys residue occurs therefore competitively during MALDI-ISD process.


Bowl shaped deformation in a planar aromatic polycycle upon reduction. Li and Na separated dianions of the aromatic polycycle 5,6:11,12-di-o-phenylene-tetracene.
Herein we report the synthesis and crystal structures of three light alkali metal salts of the dianion of the polycyclic aromatic hydrocarbon 5,6:11,12-di-o-phenylenetetracene (LDOPT). The compounds are obtained by reaction of LDOPT with an excess of lithium or sodium metal in different O-donor solvents (DME, diglyme) and crystallize as naked, solvated-cation separated dianions exhibiting no interaction between the alkali metal ion and the aromatic π-system of LDOPT. Depending on the aprotic etheral solvent and the hardness of the alkaline metal agent a significant structural perturbation of the conjugated carbon framework of LDOPT is observed resulting in a bowl shaped curvature of the anionic π-perimeter, in contrast to its fully planar neutral state. Reduction of LDOPT with lithium in DME results in the formation of the solvent-separated molecular structure of {[(DME-κ2O)3Li+]2(LDOPT2-)}21 containing naked isolated units of dianionic LDOPT. A similar structural arrangement is observed for the corresponding sodium compound {[(DME-κ2O)3Na+]2(LDOPT2-)}22 in which, however, a lesser curvature of the isolated dianionic ligand skeleton compared to 1 is observed. In contrast to 1 and 2 reduction with sodium in diglyme results in the formation of {[(diglyme-κ3O)2Na+]2(LDOPT2-)}0.53. The deformation of the peripheric phenylene rings of [LDOPT2-] in 3 is not as pronounced as compared to 1 and 2. Nevertheless, molecular structures of 1-3 deviate from full-planarity as observed in the parent neutral LDOPT. No preferential endo- or exo-site coordination of the alkaline metal cations Li+ and Na+ on the curved dianionic π-perimeter is observed.


Iron balance and iron nutrition in infancy.
At birth, the total body iron content is approximately 75 mg/kg, twice that of an adult man in relation to weight. During the first 6 mo of life, total iron body content increases slightly and exclusive breastfeeding is sufficient to maintain an optimal iron balance. Thereafter, iron body content substantially increases and the infant becomes critically dependent on dietary iron, provided by complementary foods. Numerous factors may contribute to nutritional iron deficiency in infancy, the most important being low body iron content at birth, blood loss, high postnatal growth rate, and a low amount and/or bioavailability of dietary iron. We have documented that the prevalence of iron deficiency declined in Italy as iron nutrition improved and that early feeding on fresh cow's milk is the single most important determinant of iron deficiency in infancy. Healthy full-term infants should maintain optimal iron balance by consuming a good diet, which can be summarized as follows: breastfeeding should be continued exclusively for at least 5 mo and then together with complementary foods containing highly bioavailable iron; infants who are not breastfed or are partially breastfed should receive an iron-fortified formula, containing between 4.0 and 8.0 mg/L iron, from birth to 12 mo of age; fresh cow's milk should be avoided before 12 mo of age.


Role of the 5-HT receptor in neurogenic inflammation in Fisher 344 rat airways.
The increased plasma protein extravasation in the airways of Fisher 344 rats upon stimulation of sensory nerves is in part due to the degranulation of mast cells. In this study, we examined the role of 5-HT and histamine receptors in the capsaicin-induced increase in plasma protein extravasation in Fisher 344 rat airways, using Evans blue as an intravascular marker. We found that only 5-HT2 receptor agonists increased baseline plasma protein extravasation. Furthermore, the 5-HT2 receptor antagonist ketanserin reduced the capsaicin-induced increase in plasma protein extravasation. Combining ketanserin with the tachykinin NK1 receptor antagonist (+/-)-RP 67,580 ((3alphaR,7alphaR)-(7,7-diphenyl-2(1-imino-2-(2-methoxyph enylethyl)-perhydraisoinositol-4-one))) abolished the neurogenic increase in plasma protein extravasation. Finally, using selective receptor agonists and antagonists, we demonstrated that there was no modulation of the capsaicin-induced rise in plasma protein extravasation by stimulation of either histamine receptors or 5-HT1, 5-HT3 and 5-HT4 receptors. We conclude that, in the airways of Fisher 344 rats, the neurogenic increase in plasma protein extravasation is caused by activation of both tachykinin NK1 receptors and 5-HT2 receptors.


Construction of Porous Aromatic Frameworks with Exceptional Porosity via Building Unit Engineering.
The construction of excellent porous organic frameworks (POFs) with high surface areas and stability is always a tremendous challenge in synthetic chemistry. The geometric configuration and reactive group of building unit are crucial factors to influence the structure and porosity of the resulting product. Herein, the design, synthesis, and characterization of two porous aromatic framework (PAF) materials, named PAF-100 and PAF-101, are reported via a strategy of building unit engineering. PAF-100 and PAF-101 present high Brunauer-Emmett-Teller surface areas exceeding 5000 m2 g-1 and uniform pore size distributions. Furthermore, PAF-100 and PAF-101 show high methane uptake with value of 742 and 622 cm3 g-1 , respectively, at 298 K and 70 bar. The successful synthesis of PAFs with exceptional porosity from engineered building unit is powerful for constructing highly porous POFs.


Discharge patterns after radical prostatectomy in the United States of America.
Discharge patterns, including prolonged length of stay (LOS) and adverse discharge disposition (ADD), are important clinical indicators of quality of care. We examined the effect of several indicators on discharge patterns after radical prostatectomy (RP). Within the Nationwide Inpatient Sample, we focused on RPs performed between 2001 and 2007. Multivariable logistic regression analyses predicting the likelihood of prolonged LOS and ADD were performed. Overall, 89,883 eligible RPs were identified, yielding a weighted national estimate of 442,400 eligible RPs. The rates of prolonged LOS decreased from 28.9 in the early period (2001-2003) to 14.4% in the late period (2006-2007) (P < 0.001). Similarly, the rates of ADD decreased from 7.4 in the early period to 5.0% in the late period (P < 0.001). In multivariable analyses adjusted for clustering, both annual hospital caseload (AHC) and insurance status were independent predictors of prolonged LOS and ADD. For example, RP performed at low AHC hospitals were more frequently associated with prolonged LOS than intermediate (OR = 0.45, P < 0.001) and high (OR = 0.21, P < 0.001) AHC hospitals. Similarly, RP performed at low AHC hospitals were more frequently associated with ADD than intermediate (OR = 0.54, P < 0.001) and high (OR = 0.63, P < 0.001) AHC hospitals. An improving temporal trend in discharge patterns was recorded in patients undergoing RP, with significant reductions in the rates of prolonged LOS and ADD. Nonetheless, important disparities were recorded when discharge patterns were stratified according to insurance status and AHC. Specifically, shorter LOS and lower rates of ADD should be expected in patients with private insurance and/or treated at high AHC institutions.


Culture, context, and innovation: a Kiwi Canuck perspective.
This commentary lends a global practitioner perspective on the utility of this volume to the efforts of mentors and mentees and mentoring program developers. Dave Marshall and Karen Shaver, of Big Brothers Big Sisters New Zealand and Canada, respectively, offer keen insights into the value of creating a shared language for discussing mentoring relationship development, while at the same time acknowledging the specific impact that cultural differences play in helping to shape mentoring processes.


Eliminating the Simon effect by instruction.
A growing body of research demonstrates that instructions can elicit automatic response activations. The results of the present study indicate that instruction-based response activations can also counteract automatic response activations based on long-term associations. To this end, we focused on the Simon effect, which is the observation that responding to a nonspatial feature of a stimulus (e.g., color) is faster and more accurate when the task-irrelevant stimulus position matches the spatial position of the correct response. The Simon effect can be eliminated or even reversed when combining a Simon task with an incompatible position task (e.g., press right for left stimuli; press left for right stimuli). The present study demonstrates that the Simon effect is eliminated even after presenting only the instructions of an incompatible position task, without participants having the opportunity to practice that task. Moderate practice of the incompatible task did not add anything to the effect of the instructions. Finally, the instructions of a compatible spatial stimulus-response task did not affect the Simon effect. The present results converge with previous findings indicating that the Simon effect is highly malleable and suggest that stimulus-response associations formed on the basis of instructions can counteract effects of long-term stimulus-response associations.


Different effect of beta-carotene on proliferation of prostate cancer cells.
It was shown that high doses of beta-carotene (>30 microM) decrease proliferation of prostate cancer cells in vitro. However, it is rather doubtful whether such concentration of beta-carotene is really accessible at cellular level. We studied the effect of 3 and 10 microM beta-carotene on proliferation and gene expression in LNCaP and PC-3 prostate cancer cell lines. Beta-carotene--more efficiently absorbed from medium by androgen-sensitive LNCaP cells--increased proliferation of LNCaP cells whereas it had weaker effect on PC-3 cells. Initial global analysis of expression of genes in both cell lines treated with 10 microM beta-carotene (Affymetrix HG-U133A) showed remarkable differences in number of responsive genes. Their recognition allows for conclusion that differences between prostate cancer cell lines in response to beta-carotene treatment are due to various androgen sensitivities of LNCaP and PC-3 cells. Detailed analysis of expression of selected genes in beta-carotene treated LNCaP cells at the level of mRNA and protein indicated that the observed increase of proliferation could have been the result of slight induction of a few genes affecting proliferation (c-myc, c-jun) and apoptosis (bcl-2) with no significant effect on major cell cycle control genes (cdk2, RB, E2F-1).


Surface microstructural features of scales in relation to toxic stress of Basic Violet-1.
The present work deals with scanning electron microscopic (SEM) studies of the scales of Labeo rohita on exposure to lethal and sublethal doses of Basic Violet-1 (an important textile and hair colorant). The dye induced loosening of the scales and caused breakage and disorganization of lepidonts. Erosion of lepidonts occurred mostly in the fish exposed to 0.20 and 0.40 mg/L dye, during acute exposure and to 0.0225 and 0.045 mg/L dye, during the subchronic exposure. However, lepidonts were sloughed off from their sockets in 0.60 and 0.80 mg/L dye during acute exposure and in 0.09 mg/L dye during the subchronic exposure. Circuli, the base that provides anchorage to the lepidonts, got damaged, and tubercles responsible for coloration of a fish became atrophied with an increase in the duration of exposure. The results of the present investigation clearly indicated that exposure to Basic Violet-1 (BV-1) even at a concentration as low as 0.0225 mg was responsible for deleterious changes in the scale morphology of the test fish after 150 days of exposure. Similar changes were observed in the scales of the dead fish also. It can thus be suggested that this noninvasive technique is very helpful for evaluating the health status of an aquatic body. At the same time, the changes in ultramorphology of scales can act as an early indicator of the stress of very minute doses of dyes and even the scales of a dead fish can act as indicators of the untoward changes that would have occurred in the environment of the fish before death.


Formation and persistence of specific purine DNA adducts by 32P-postlabelling in target and non-target organs of rats treated with aristolochic acid I.
Binding of the naturally occurring carcinogen, aristolochic acid I (AAI), to DNA in male Wistar rats has been examined. Rats were treated orally with a single dose (13.8 mmol) of AAI and sacrificed 1 day and 1, 2, 4, 16 and 36 weeks after treatment. The formation and persistence of two specific purine AAI-DNA adducts were studied utilizing the nuclease P1 enhancement method of the 32P-postlabelling assay. Both adducts, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI) and 7-(deoxyguanosin-N2-yl)-aristolactam I (dG-AAI), were detectable for up to 36 weeks in all target (forestomach) and non-target (glandular stomach, liver, lung, urinary bladder) organs and showed differential rates of removal and persistence. In all organs, dA-AAI was the major adduct present. In the target organ (forestomach), both adducts were removed rapidly within the first two weeks; thereafter, extensive removal of dG-AAI continued, whereas dA-AAI attained constant levels (4-36 weeks). Of interest was the marked decrease of both adducts in glandular stomach, the neighbouring non-target tissue to the forestomach. These results suggest that the persistence of a specific AAI-DNA adduct, namely dA-AAI, in the target organ may be the critical lesion responsible for initiation of carcinogenesis by AAI.


Solid-state NMR on a large multidomain integral membrane protein: the outer membrane protein assembly factor BamA.
Multidomain proteins constitute a large part of prokaryotic and eukaryotic proteomes and play fundamental roles in various physiological processes. However, their structural characterization is challenging because of their large size and intrinsic flexibility. We show here that motional-filtered high-resolution solid-state NMR (ssNMR) experiments allow for the observation and structural analysis of very large multidomain membrane proteins that are characterized by different motional time scales. This approach was used to probe the folding of the 790-residue membrane protein BamA, which is the core component of the Escherichia coli outer membrane protein assembly machinery. A combination of dipolar- and scalar-based two-dimensional ssNMR experiments applied to two uniformly (13)C,(15)N-labeled BamA variants revealed characteristic secondary structure elements and distinct dynamics within the BamA transmembrane protein segment and the periplasmic POTRA domains. This approach hence provides a general strategy for collecting atomic-scale structural information on multidomain (membrane) proteins in a native-like environment.


The service and educational contributions of a general medicine consultation service.
General medicine consultation services (GMCS) are perceived as providing routine services in perioperative patient management for referring surgeons. Their potential contributions to improving patient care and resident education have not been well defined. Review of the first year of GMCS in a university teaching hospital showed that only 57% of the consultations were for routine perioperative management of surgical patients. The consultations presented a broad range of medical problems, especially cardiovascular disease (35% of all consultations). Consulting physicians made 2.2 new diagnoses per consult, and 16% of patients required transfer to other services. A GMCS may improve patient care by uncovering new diagnoses, and, by offering them exposure to a variety of medical problems, can improve the consultation skills of students and residents.


Binding affinities to rat brain synaptosomes--synthesis of biotinylated analogues of Substance P.
The synthesis of four biotinylated analogues of Substance P is described. The affinities of these analogues and of their complexes with avidin for the 125I-Bolton Hunter Substance P binding sites on rat brain synaptosomes were determined. While these biotinylated peptides complexed to avidin retain a good biological activity on the guinea-pig ileum bioassay, we observe a net decrease in their binding affinities in the central nervous system. The present study confirms that in the central nervous system the higher affinity is related to the N-terminal tetrapeptide and establishes that the free amino group (N-alpha-Arg and N-epsilon-Lys) are not essential in the binding.


Prevalence of psychiatric disorder: with and without psychosocial impairment.
To identify rates of psychiatric disorder in a representative sample of primary school children in a North of England city. The study obtained multi-criterion screen data on a representative one-in-three sample of 7- and 8-year-old children in Newcastle upon Tyne. It also obtained psychiatric interview data for screen-positive and a proportion of screen negative children. In addition the clinically trained interviewers rated psychiatric impairment. Estimated rates of disorder with impairment, calibrated to be equivalent to that of children attending local child psychiatric clinics, were 1.2% for emotional disorder, 5.6% for disruptive behaviour disorder and 6.7% for any disorder. These findings are consistent with other contemporary studies using similar impairment criteria.


Domoic acid and human exposure risks: a review.
Domoic acid is a potent neurotoxin that is naturally produced by several diatom species of the genus Pseudo-nitzschia. The toxin acts as a glutamate agonist and is excitotoxic in the vertebrate central nervous system and other glutamate receptor-rich organs. Human exposure to domoic acid occurs via the consumption of contaminated shellfish that have accumulated the toxin while filter feeding on toxigenic phytoplankton during blooms. The first reported human domoic acid poisoning event occurred in Canada in 1987 during which clinical signs of acute toxicity such as gastrointestinal distress, confusion, disorientation, memory loss, coma and death were observed. The illness was named amnesic shellfish poisoning (ASP) and due to effective seafood monitoring programs there have been no documented ASP cases since 1987. However, domoic acid poisoning has a significant effect on marine wildlife and multiple poisoning events have occurred in marine birds and mammals over the last few decades. Currently, domoic acid producing diatom blooms are thought to be increasing in frequency world wide, posing an increasing threat to wildlife and human health. Of particular concern are the potential impacts of long-term low-level exposure in "at risk" human populations. The impacts of repetitive low-level domoic acid exposure are currently unknown. This review provides a basic description of the mechanism of action of domoic acid as well as a synthesis of information pertaining to domoic acid exposure routes, toxin susceptibility, and the importance of effective monitoring programs. The importance of investigating the potential human health impacts of long-term low-level domoic acid exposure in "at risk" human populations is also discussed.


Herbacetin, a constituent of ephedrae herba, suppresses the HGF-induced motility of human breast cancer MDA-MB-231 cells by inhibiting c-Met and Akt phosphorylation.
Ephedrae herba suppresses hepatocyte growth factor-induced cancer cell motility by inhibiting tyrosine phosphorylation of the hepatocyte growth factor receptor, c-Met, and the PI3K/Akt pathway. Moreover, Ephedrae herba directly inhibits the tyrosine-kinase activity of c-Met. Ephedrine-type alkaloids, which are the active component of Ephedrae herba, do not affect hepatocyte growth factor-c-Met-Akt signalling, prompting us to study other active molecules in the herb. We recently discovered herbacetin glycosides and found that their aglycon, herbacetin, inhibits hepatocyte growth factor-c-Met-Akt signalling. This study revealed a novel biological activity of herbacetin. Herbacetin suppressed hepatocyte growth factor-induced motility in human breast cancer MDA-MB-231 cells by inhibiting c-Met and Akt phosphorylation and directly inhibiting c-Met tyrosine kinase activity. The effects of herbacetin were compared to those of kaempferol, apigenin, and isoscutellarein, all of which have similar structures. Herbacetin inhibition of hepatocyte growth factor-induced motility was the strongest of those for the tested flavonols, and only herbacetin inhibited the hepatocyte growth factor-induced phosphorylation of c-Met. These data suggest that herbacetin is a novel Met inhibitor with a potential utility in cancer therapeutics.


The optical convolution of time functions.
The ease with which an optical system can achieve an extremely large time-bandwidth product makes optical filters and cross-correlation function generators attractive for signal detection and parameter estimation when signal-to-noise ratios are very low. The principles of a new optical filter that overcomes the sometimes severe positioning requirements of conventional optical filters are described. The relationship between the signal amplitude and matched-filter impulse response amplitude is discussed, and a method for reducing a noise component that is common to all optical filters is given. A matched filter was constructed and used to detect a radar-like pulse when the signal-to-noise ratio was -40 dB. A digital computer may be used with an optical system to filter time signals with an accuracy that potentially is as good as the accuracy of an all-digital system, but with a significant reduction in computation. The theory of an optical digital filter is presented.


Potential sexual function improvement by using transanal mesorectal approach for laparoscopic low rectal cancer excision.
Preliminary results of the transanal approach for low rectal cancer suggest better oncological outcomes than the conventional laparoscopic approach. We currently report the functional results. From 2008 to 2012, 100 patients with low rectal cancer and suitable for sphincter-saving resection were randomized between transanal and laparoscopic low rectal dissection. Patients derived from this randomized trial were enrolled for functional assessment. End points were bowel function (LARS bowel and Wexner continence scores) and urogenital function (IPSS, IIEF-5 and FSFI-6 scores) obtained by questionnaires sent to patients with a follow-up more than 12 months. Overall, 76 patients were eligible and 72 responded to the questionnaire: 38 in the transanal group and 34 in the laparoscopic group. The bowel function did not differ between the transanal and the laparoscopic groups: LARS 36 versus 37 (p = 0.941) and Wexner 9 versus 10 (p = 0.786). The urologic function was also similar between the two groups: IPSS 5.5 versus 3.5 (p = 0.821). Among sexually active patients before surgery, 20 of 28 (71 %) patients in the transanal group and 9 of 23 (39 %) in the laparoscopic group maintained an activity after surgery (p = 0.02). Erectile function was also better in men after transanal compared to laparoscopic low rectal dissection: IIEF 17 versus 7 (p = 0.119). Transanal approach for low rectal cancer did not change bowel and urologic functions compared to the conventional laparoscopic approach. However, there was a trend to a better erectile function with a significantly higher rate of sexual activity in the transanal group.


TNFalpha, IFNgamma and IL-10 gene polymorphisms in a sample of Sicilian patients with coeliac disease.
Coeliac disease is associated with DQ2 and DQ8 alleles, but other genes also confer an additional genetic risk. Defining whether the genetic profiles of interleukin-10, tumour necrosis factor alpha and interferon gamma are associated with an increased coeliac disease risk. The functionally gene polymorphisms of tumour necrosis factor alpha (-308G/A), interferon gamma (+874T/A) and interleukin-10 (-1082G/A) were typed using sequence specific primer-polymerase chain reaction in 110 Sicilian coeliac disease patients and in 220 Sicilian healthy controls. No differences in genotype frequencies of interleukin-10 polymorphisms were found between coeliac disease patients and healthy controls. A significant increase of -308A (p<0.033; OR: 1.72; CI: 1.27-2.33) and of +874T (p: 0.0045; OR: 3.02; CI: 1.47-6.21) allele frequencies, both in hetero- and homozygosis, was observed in coeliac patients in comparison with healthy controls. In addition, simultaneous significant higher percentages of -308A and +874T alleles (p: 0.0066; OR: 2.33; CI: 1.42-3.82) as well as simultaneous significant lower percentages of -308A and +874T alleles (p: 0.003; OR: 0.23; CI: 0.10-0.60) were observed in coeliac patients compared with healthy controls. Genetically determined higher frequencies of -308A tumour necrosis factor alpha and +874T interferon gamma alleles, both in hetero and in homozygosis and mostly whether simultaneous, may play a role in predisposing to gluten intolerance. Subjects positive for -308A tumour necrosis factor alpha and +874T interferon gamma alleles have an increased risk for coeliac disease.


Chest radiographic staging in allergic bronchopulmonary aspergillosis: relationship with immunological findings.
The question of whether a chest radiographic severity staging system could be correlated with standard blood/serum diagnostic indices in allergic bronchopulmonary aspergillosis (ABPA) was addressed in 41 patients. Asthma and positive Aspergillus fumigatus (AF) serology were considered essential diagnostic inclusion criteria. Eosinophil count, serum immunoglobulin (Ig)E and immediate skin hypersensitivity were also tested to grade patients as "definite" or "likely" ABPA. Definite cases had all five of these factors present, whereas likely cases had three or more. Chest radiographs were examined by experienced radiologists blinded to the clinical data. The six-stage radiographic score (0-5) was based on the severity and duration of changes seen: stage 0: normal; stage 1: transient hyperinflation; stage 2: transient minor changes; stage 3: transient major changes; stage 4: permanent minor changes; and stage 5: permanent major changes. Significant positive correlations (p<0.05) were observed between peak AF titres (expressed as an index), peak eosinophil count and radiographic severity stage. When considered as subgroups, these correlations approached, but did not reach, significance for the group with "likely" ABPA (n=28), but in the group with definite ABPA (n=13), there was a high correlation between radiographic score and peak AF index (r=0.59), as well as peak eosinophil count (r=0.62). This study suggests that the peak Aspergillus fumigatus index and eosinophil counts correlate best with the severity of radiographic stages in allergic bronchopulmonary aspergillosis. This chest radiographic staging system may be useful in the clinical assessment and management of patients with allergic bronchopulmonary aspergillosis, particularly in those patients with more severe radiographic stages.


[Birthweight curves: a review of the literature].
There are many birthweight reference curves in the literature. This study reviews birthweight curves that are commonly used in France as well as references that provide birthweight by sex. The 19 curves selected for review were published between 1971 and 2001 using samples of between 300 to 3 million newborns in Europe, Australia and North America. Our objective was to summarize their main characteristics and to provide guidelines for analysis by explaining which factors are responsible for differences between curves, and discussing the methods used to construct them. The characteristics of the population must be taken into account and study samples must be recent and representative. The sample size must be sufficient to ensure stable estimates for premature infants. It is preferable to use different curves for boys and girls because sex is a key determinant of birth weight. The choice of appropriate birth weight reference remains difficult in some countries, in France particularly, and the use of individual customised birth weight curves provides an interesting alternative.


Percutaneous nephrostomy: current indications and potential uses in obstetrics and gynecology. Literature review and report of a case.
Percutaneous nephrostomy offers a rapid and relatively safe means of short- or long-term management of urinary obstruction, irrespective of the underlying cause. It is particularly useful in patients who cannot undergo general anesthesia or surgery because of potential major risks. At present, the most common indication for percutaneous nephrostomy in OB/GYN is probably urinary tract obstruction secondary to pelvic malignancy. It is not indicated in terminal patients, but can be used to temporize renal function to allow palliative therapy and to assess the residual functional capacity of the obstructed kidney. Percutaneous nephrostomy will most likely be used even more frequently in the future as current roles are expanded particularly in areas such as perinatology.


A comparison of the effects of 2 mandibular anchorage systems used with a 3-dimensional bimetric maxillary distalizing arch.
The purpose of this study was to compare the effects of 2 mandibular anchorage systems used with a 3-dimensional bimetric maxillary distalizing arch. The Wilson rapid molar distalization appliance for Class II molar correction was used with 26 patients; two groups of 13 patients each were formed. In the first group (9 girls, 4 boys with a mean age 11 years 5 months), mandibular anchorage was gained by a modified lip bumper with a standard lingual arch of 0.9-mm stainless steel. The second group (7 girls, 6 boys, with a mean age of 13 years) had a 0.016 x 0.016-inch utility arch, with a 3-dimensional lingual arch for anchorage. Cephalometric radiographs were taken before and after maxillary first molar distalization. The treatment results showed that the extrusion of the mandibular first molar was statistically significant in both the modified lip bumper and utility arch groups (P < .01 and P <.05, respectively). The incisal edge of the mandibular incisor moved forward significantly in the modified lip bumper and utility arch groups (P < .05 and P < .01, respectively); however, the protrusion in the utility arch group was significantly greater than in the lip bumper group (P <.05). In both groups, significant proclination of the mandibular incisor was observed (P < .01). Comparison of the anchor units showed that there was significantly greater proclination in the utility arch group than in the modified lip bumper group (P < .05). Both anchor units similarly enhanced the mandibular first molar anchorage. However, particularly in the utility group, mandibular incisor anchorage control seemed to be inadequate.


Effects of spinal health educational programs for elementary school children.
This study examined the effects of spinal health educational programs. A nonequivalent control-group pretest-posttest design was used. Participants were 88 fifth-grade elementary schoolchildren. Three groups were compared: a Web-based program group, a traditional face-to-face program group, and a control group. In both intervention groups, the changes for spinal health knowledge and self-efficacy were significantly higher than those of the control group. However, the changes of spinal health practices were not significantly different. A Web-based spinal health education program is a convenient and flexible health educational approach that was as effective in this study as traditional face-to-face instruction.


Alopecia areata: alterations in the hair growth cycle and correlation with the follicular pathology.
A histopathological study was performed in 17 patients with alopecia areata to elucidate the changes in hair cycle dynamics. The findings confirm the view that the initial event in alopecia areata is the premature entry of anagen follicles into telogen, although some follicles survive for a time in a dystrophic anagen state. However, after re-entry into anagen takes place, growth appears to be halted in anagen III rather than anagen IV, as has previously been suggested. Follicles then return prematurely to telogen and these truncated cycles are repeated until the disease activity subsides. A new pathogenic hypothesis is presented which relates alterations in hair cycle dynamics to pathological changes within the anagen follicle and also provides an explanation for the formation of exclamation mark hairs and the non-destructive nature of the disease.


Dopaminergic modulation of low-Mg²⁺-induced epileptiform activity in the intact hippocampus of the newborn mouse in vitro.
To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (<0.3 μM) attenuated epileptiform activity, whereas >3 μM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 μM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 μM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 μM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 μM) or the D2-like antagonist sulpiride (10 μM), whereas the D2 antagonist L-741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 μM) were without effect. The anticonvulsive effect of 0.1 μM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 μM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect.


[Antibacterial activities of cefetamet against clinically isolated strains from community acquired respiratory tract infections (II)].
Antibacterial activities of cefetamet (CEMT) against clinically isolated strains from patients with community acquired respiratory tract infections were compared to those of other oral beta-lactam antibiotics in the period from January to March 1994. The following results were obtained. 1. CEMT showed strong antibacterial activities against three major pathogens causing community acquired respiratory tract infections, Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae. However, antibacterial activities of CEMT against benzylpenicillin (PCG)-insensitive S. pneumoniae (PISP) and PCG-resistant S. pneumoniae (PRSP) were slightly weaker than of those of some the reference antibiotics. 2. No MIC value changes of CEMT were observed from year to year against Moraxella subgenus Branhamella catarrhalis and Klebsiella pneumoniae.


Evaluating deciduous tree leaves as biomonitors for ambient particulate matter pollution in Pittsburgh, PA, USA.
Fine particulate matter (PM2.5) air pollution varies spatially and temporally in concentration and composition and has been shown to cause or exacerbate adverse effects on human and ecological health. Biomonitoring using airborne tree leaf deposition as a proxy for particulate matter (PM) pollution has been explored using a variety of study designs, tree species, sampling strategies, and analytical methods. In the USA, relatively few have applied these methods using co-located fine particulate measurements for comparison and relying on one tree species with extensive spatial coverage, to capture spatial variation in ambient air pollution across an urban area. Here, we evaluate the utility of this approach, using a spatial saturation design and pairing tree leaf samples with filter-based PM2.5 across Pittsburgh, Pennsylvania, with the goal of distinguishing mobile and stationary sources using PM2.5 composition. Co-located filter and leaf-based measurements revealed some significant associations with traffic and roadway proximity indicators. We compared filter and leaf samples with differing protection from the elements (e.g., meteorology) and PM collection time, which may account for some variance in PM source and/or particle size capture between samples. To our knowledge, this study is among the first to use deciduous tree leaves from a single tree species as biomonitors for urban PM2.5 pollution in the northeastern USA.


[Treatment of multiple sclerosis--2. Application of a new immunological basic research is close].
Based on continuous advances in our knowledge of the pathophysiological mechanisms involved in the development of multiple sclerosis and other putatively autoimmune diseases, several new immunological treatment strategies are currently being tested in different parts of the world. In principle, these strategies are designed to interfere with three steps in the presumed pathogenic immunological process: inhibition of lymphocyte recruitment to inflammatory foci in the central nervous system; blocking of antigen-specific activation; and interference with immunological effector mechanisms. Preliminary results are available for some of these treatment strategies.


Cervical spondylotic amyotrophy with intramedullary cavity formation.
A case report. To show that an intramedullary lesion was the cause of cervical spondylotic amyotrophy. Cervical spondylotic amyotrophy is the clinical syndrome characterized by muscle wasting and weakness in the upper extremities without a remarkable sensory loss or spastic tetraparesis. It is still unclear whether the ventral roots or the anterior horn are selectively damaged. Magnetic resonance imaging and delayed computed tomographic myelography were performed on a patient who showed severe wasting of the left triceps muscle without any sensory disturbance or long tract sign. On sagittal magnetic resonance images, a linear area was noted within the spinal cord at C6 and C7 spinal segments, which showed low signal intensity on T1-weighted image and high signal intensity on T2-weighted image. On axial T1-weighted image intramedullary low signal intensity area was observed, which was located in the left anterior horn. On axial T2-weighted image the area showed high signal intensity. A delayed (6 hours) computed tomographic scan after intrathecal injection of metrizamide revealed intramedullary enhancement in the area corresponding to the left anterior horn, which would represent cavitation or cystic necrosis. This is the first case report of cervical spondylotic amyotrophy, in which intramedullary lesion was confirmed only at the affected side of the spinal cord.


Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy.
Transthyretin (TTR) amyloidosis is an underdiagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for transthyretin amyloidosis cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation. This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure. ATTR-CM, New York Heart Association functional class II to III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400 mg, AG10 800 mg, or placebo twice daily for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR, and 2 established ex vivo assays (fluorescent probe exclusion and Western blot). AG10 treatment was well-tolerated, achieved target plasma concentrations and demonstrated near-complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by fluorescent probe exclusion of 92 ± 10% (mean ± SD) at trough and 96 ± 9% at peak (both p < 10-12 vs. placebo). Average serum TTR increased by 36 ± 21% and 51 ± 38% at 400 and 800 mg, respectively (both p < 0.0001 vs. placebo). Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild-type subjects. AG10 treatment restored serum TTR to the normal range in all subjects. AG10 has the potential to be a safe and effective treatment for patients with ATTR-CM. A phase 3 trial is ongoing. (Study of AG10 in Amyloid Cardiomyopathy; NCT03458130).


Role for E2F1 in p210 BCR-ABL downstream regulation of c-myc transcription initiation. Studies in murine myeloid cells.
Experiments were performed to elucidate the mechanism through which p210 BCR-ABL, by its downstream signals, regulates c-myc messenger RNA expression in hematopoietic cells. We studied a model system in which stable expression of p210 BCR-ABL in interleukin-3 (IL-3) dependent murine myeloid cell lines led to growth factor independent transformation. Active c-myc transcription was observed in p210 BCR-ABL transformed cells by nuclear run-on assay, and in heterologous reporter assays performed with the 5' regulatory region of murine c-myc linked to firefly luciferase. Transcription initiation occurred primarily from the P2 promoter in p210 BCR-ABL transformed cells. Cis and trans elements responsible for transcription initiation from the c-myc P2 promoter were studied. Expression of E2F1 protein in p210 BCR-ABL transformed cells accounted, in part, for binding to the E2F site of the P2 c-myc promoter. The functional importance of E2F1 expression in p210 BCR-ABL transformed cells toward c-myc transcription was established in reporter assays performed with the P2 c-myc promoter containing either wild-type or mutant E2F sites. Mutation of the E2F motif of P2 5' c-myc reduced activity of the promoter by 50%. By gel mobility shift, E2F1 was found in P2 c-myc band shift complexes along with the cyclin-dependent kinase 2. Therefore, coupling of E2F to components of the retinoblastoma-cyclin pathway defines a route from p210 BCR-ABL to c-myc transcription, which is required for p210 BCR-ABL transformation.


Diffusion-weighted MR imaging abnormalities in pediatric patients with surgically-treated intracranial mass lesions.
Diffusion-weighted imaging (DWI) is a magnetic resonance imaging (MRI) technique that measures the degree of water diffusion in vivo. DWI abnormalities are frequently observed on immediate postoperative imaging following surgical resection of gliomas in adults. These abnormalities subsequently demonstrate contrast enhancement, which may be confused with lesion recurrence. The purpose of this study was to investigate the occurrence of these postoperative abnormalities in pediatric patients with intracranial mass lesions. Thirty-three consecutive patients <or=18 years old with a newly diagnosed intracranial mass lesion underwent MRI, including DWI, before and immediately after surgical treatment. The median patient age was 9.9 years (range 0.2-18 years). Supratentorial and infratentorial lesions were identified in 22 and 11 patients, respectively. Infiltrative and noninfiltrative, as well as benign and malignant lesions, were included. Postoperative imaging demonstrated areas of reduced diffusion adjacent to the resection cavity in 20 (61%) cases. The median volume of these areas was 1.7 cm3 (range 0.3 cm3-12.0 cm3). Subsequent imaging studies in 9 of the 18 cases showed contrast enhancement in the area corresponding to the DWI abnormality. There were no clinical deficits attributable to any of the diffusion abnormalities. There was no association between the occurrence of these abnormalities and whether the lesion was infiltrative, non-infiltrative, benign, or malignant. DWI abnormality on immediate postoperative MRI is common following surgery for newly diagnosed intracranial mass lesions in pediatric patients. Focal contrast enhancement in the postoperative period may be confused with recurrence for some lesions. Our study suggests that immediate postoperative DWI is useful in interpreting new areas of focal contrast enhancement on subsequent imaging in children who have had surgery for brain tumors.


Evidence for thyrotropin receptor immunoreactivity in pretibial connective tissue from patients with thyroid-associated dermopathy.
Pretibial myxedema (PTM), mainly characterized by the accumulation of glycosaminoglycans in the dermis and subcutaneous tissue, is an extrathyroidal manifestation of autoimmune Graves' disease (GD), almost always associated with Graves' ophthalmopathy (GO). The thyrotropin receptor (TSH-R) has been proposed as the common target antigen in GD, GO and PTM, with evidence for receptor transcripts and/or protein in these locations. The aim of this study has been to investigate whether receptor protein is present in the pretibial tissues. Skin biopsies were obtained from two patients with PTM and two normal subjects without thyroid disease. A portion of each sample was fixed to produce semi-thin sections for Toluidine Blue or Periodic Acid Schiff (PAS) staining. The remainder was snap frozen to generate cryostat sections for immunohistochemical analysis using three monoclonal antibodies against TSH-R. In the skin from the two patients suffering from PTM, the dermis was infiltrated by inflammatory cells (lymphocytes, B cells, macrophages, mast cells) and adipocytes. The collagen fibers were dissociated by edema and by the accumulation of a PAS-positive material. Immunodetection of TSH-R produced positive staining on cells localized in the dermis, beneath the epidermis or close to the hypodermis. These cells were elongated and resembled fibroblasts. No immunoreactivity was observed in the dermis from control patients without thyroid disease. In conclusion, we have evidence for TSH-R immunoreactivity in the pretibium of patients with GD, GO and PTM. Further studies are needed to unambiguously identify the positive cells and determine whether the reactivity is due to the receptor itself or to a cross-reacting protein.


Sacral facet fractures in elite athletes.
Case series of elite athletes with sacral facet fractures. To report a case series of elite athletes with sacral facet fractures that may be an underrecognized career-ending injury. Injury of the posterior elements including spondylolysis and spondylolisthesis are well-known causes of back pain in the young athlete, but there has been only 1 previous case report of a sacral facet fracture. This study is a retrospective chart review of 3 elite athletes with severe back pain and sacral facet fractures. An 18-year-old gymnast with a 2-year history of back pain, a 14-year-old gymnast with a 6-month history of back pain, and a 14-year-old tennis player with a 18-year history of back pain. This series consists of 3 nationally competitive athletes with back pain severe enough to stop participation in sports. All patients had intra-articular sacral facet fractures proven by computed tomography, none of which were recognized on magnetic resonance imaging. Clinically, all had localized pain with back extension. Multiple tests and invasive procedures were performed without significant improvement prior to the correct diagnosis being made. Treatment with minimally invasive removal of the intra-articular fragments led to immediate pain relief and return to sport in 2 patients and transient though not long-lasting pain relief in the patient whose injury was undiagnosed for 2 years. Intra-articular sacral facet fractures may be an underrecognized and misdiagnosed career-ending injury in elite athletes. In patients who have localized pain with back extension, a computed tomographic scan, and not a magnetic resonance image, diagnosed this injury. Although this series is small, it seems that early recognition and treatment of sacral facet fractures maximize chances of pain resolution and return to sport.


Water-lactose behavior as a function of concentration and presence of lactic acid in lactose model systems.
The presence of high amounts of lactic acid in acid whey restricts its ability to be further processed because lactose appears to remain in its amorphous form. A systematic study is lacking in this regard especially during the concentration step. Hence, the main aim of the study was to establish the structure and behavior of water molecules surrounding lactose in the presence of 1% (wt/wt) lactic acid at a concentration up to 50% (wt/wt). Furthermore, the crystallization nature of freeze-dried lactose with or without lactic acid was established using differential scanning calorimetry and Fourier transform infrared spectroscopy. Two mechanisms were proposed to describe the behavior of water molecules around lactose molecules during the concentration of pure lactose and lactose solutions with lactic acid. Pure lactose solution exhibited a water evaporation enthalpy of ~679 J·g(-1), whereas lactose+ lactic acid solution resulted in ~965 J·g(-1) at a 50% (wt/wt) concentration. This indicates a greater energy requirement for water removal around lactose in the presence of lactic acid. Higher crystallization temperatures were observed with the presence of lactic acid, indicating a delay in crystallization. Furthermore, less crystalline lactose (~12%) was obtained in the presence of lactic acid, indicating high amorphous nature compared with pure lactose where ~50% crystallinity was obtained. The Fourier transform infrared spectra revealed that the strong hydration layer consisting lactic acid and H3O(+) ions surrounded lactose molecules via strong H bonds, which restricted water mobility, induced a change in structure of lactose, or both, creating unfavorable conditions for lactose crystallization. Thus, partial or complete removal of lactic acid from acid whey may be the first step toward improving the ability of acid whey to be processed.


An update on the pharmacotherapy for endometrial cancer.
Endometrial cancer (EC) is the seventh most common malignancy in women. Most cases have a favorable prognosis because they present an early stage disease at diagnosis. Treatment currently comprises surgery with or without adjuvant approaches. A combination of radiation therapy, chemotherapy or hormonal therapy (HT) is usually administered. This article gives an update concerning the role of synthetic drugs in EC, reviewing the most recent data from Phase III randomized-controlled trials onwards. Over the years, chemotherapy has become the treatment mainstay in both high-risk or locally advanced EC and in metastatic or recurrent disease. Carboplatin plus paclitaxel is currently considered the standard chemotherapy regimen with a well-tolerated toxicity profile. HT is an alternative option in women with advanced EC and important co-morbidities, and in young women with very early stage disease. Basic results of EC treatment during the last decade were collected. There is a need of more advances in treatment. The use of biomarkers, necessary for the success of a therapeutic strategy, and the identification of an ad-hoc population, are two important goals. In the authors' opinion, the development of comprehensive tumor bio-banks and international networks represent the right approach to foster translational studies and obtain improvement in patient outcomes.


An immuno-histochemical study of ferritin in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys.
Iron is increased in the substantia nigra of patients with Parkinson's disease, but the mechanism of its accumulation is unknown. We report the distribution of ferritin in the basal ganglia of hemiparkinsonian monkeys made by MPTP. We stereotactically injected MPTP unilaterally into the caudate nucleus of four monkeys, and the substantia nigra and the basal ganglia regions were stained for L-ferritin by an immunohistochemical method. The ferritin immuno-staining was most intense in the pallidum and the pars reticulata of the substantia nigra on both injected and non-injected sides. No significant difference was noted in the immunostaining for ferritin in the pars compacta of the substantia nigra between the injected and the non-injected side. Iron was increased in the pars compacta of the substantia nigra of this hemiparkinsonian monkeys in our previous study. Normal ferritin immunostaining on the injected side would indicate that iron accumulation is not related to altered metabolism of L-ferritin in this model.


A case-control study on risk factors for leukemia in a district of Japan.
A case control study was performed with 142 leukemia patients and 284 controls matched for age and sex. Occupation, birth order, past medical history, and drinking and smoking habits were compared in these two groups. Persons born first or fourth were found to have a higher incidence of leukemia. History of a fracture was one of the risk factors for acute leukemia, and a history of gastroduodenal ulcer was a risk factor for chronic leukemia. This may suggest that extensive exposure to X-rays in diagnosis and treatment is a risk factor for leukemia. There was a significant dose-response relationship between the amount of smoking and the incidence of acute nonlymphocytic leukemia, but not between the amount of alcohol consumption and the incidence of leukemia. Thus, smoking was one of the risk factors for acute leukemia.


[Cycloheximide-dependent mutants of the yeast Saccharomyces cerevisiae].
Selection of sup1 and sup2 mutants in the yeast Saccharomyces cerevisiae on cycloheximide containing media revealed classes of mutants that either are completely unable to grow on YAPD without cycloheximide or need this drug under high temperature incubation (30 or 36 degrees C). Some of these mutants also exhibit the growth dependence on another antibiotic--trichodermin, and, at the same time, the osmotic dependence. A hypothesis claiming that sup1 and sup2 mutations cause conformational lability fo yeast cytoplasmic ribosomes has been put forward. It is also proposed that binding of cycloheximide and trichodermin to the mutant ribosomes cause their conformational shift, which compensates the functional defects.


Famous talker effects in spoken word recognition.
Previous work has demonstrated that talker-specific representations affect spoken word recognition relatively late during processing. However, participants in these studies were listening to unfamiliar talkers. In the present research, we used a long-term repetition-priming paradigm and a speeded-shadowing task and presented listeners with famous talkers. In Experiment 1, half the words were spoken by Barack Obama, and half by Hillary Clinton. Reaction times (RTs) to repeated words were shorter than those to unprimed words only when repeated by the same talker. However, in Experiment 2, using nonfamous talkers, RTs to repeated words were shorter than those to unprimed words both when repeated by the same talker and when repeated by a different talker. Taken together, the results demonstrate that talker-specific details can affect the perception of spoken words relatively early during processing when words are spoken by famous talkers.


Heterogeneity of cytochrome P-450 in rat testis microsomes.
Cytochrome P-450 appears to be a component of the steroid-coverting enzymes, 17alpha-hydroxylase and 17,20-lyase, which catalyze sequential steps in sex hormone synthesis. Further evidence indicates that the steroid substrates of these enzymes bind to cytochrome P-450 during catalysis. The present report deals with the problem of whether a single form of cytochrome P-450 mediates both enzyme reactions or whether two enzymes are involved. Both activities are competitively inhibited by a number of the same inhibitors. Because K1 values of competitive inhibitors are dissociated constants, and thus a property of the cytochrome, different magnitudes of K1, determined for the same inhibitor with each enzyme, are consistent with the participation of more than one form of cytochrome P-450. Differences in the K1 values were found to be statistically significant and varied from 3- to 10-fold. Two competitive inhibitors retarded velocities with one reaction but not the other. In addition, the enzyme activities were markedly different in their sensitivity to carbon monoxide inhibition. The conclusion based on these two lines of evidence is that separate enzymes and different forms of cytochrome P-450 are involved in each reaction.


Assessing the utility of seed coat-specific promoters to engineer cell wall polysaccharide composition of mucilage.
Polysaccharide composition of seed mucilage was successfully modified using three seed coat-specific promoters driving expression of genes encoding cell wall-modifying enzymes. Arabidopsis thaliana seed coat epidermal cells synthesize and secrete large quantities of mucilage, a specialized secondary cell wall composed of cellulose, hemicellulose, and pectin. The composition and structure of mucilage confers its unique properties of expansion, extrusion, and adherence. We are developing seed mucilage as a model to study the biochemical and biological consequences of manipulating cell wall polysaccharides in vivo using cell wall-modifying enzymes. To specifically engineer mucilage composition and avoid altering other cell types, seed coat-specific promoters are required. In this study, we investigated the ability of seed coat-specific promoters from three genes, TESTA-ABUNDANT2 (TBA2), PEROXIDASE36 (PER36), and MUCILAGE-MODIFIED4 (MUM4), to express the cell wall modifying β-galactosidase (BGAL)-encoding gene MUCILAGE-MODIFIED2 (MUM2) and complement the mum2 mutant. The strength of the three promoters relative to one another was found to vary by two to 250 fold, and correlated with their ability to rescue the mum2 mutant phenotype. The strongest of the three promoters, TBA2p, was then used to examine the ability of three MUM2 homologs to complement the mum2 extrusion and cell wall composition phenotypes. The degree of complementation was variable and correlated with the amino acid sequence similarity between the homologous gene products and MUM2. These data demonstrate that all three seed coat-specific promoters can drive expression of genes encoding carbohydrate-active enzymes in a spatial and temporal pattern sufficiently to modify polysaccharide composition in seed mucilage without obvious negative consequences to the rest of the plant.


Behavioral interactions rather than milk availability determine decline in milk intake of weanling rats.
We examined the relation between milk availability and milk intake during the period in which rat pups gradually abandon milk as a food source. The amount of milk produced by rat dams does not change from postpartum Day 15 to Day 20, but decreases thereafter and completely disappears around Day 30. In contrast, the amount of milk actually obtained by pups does begin to decline between Days 15 and 20. This decline in milk intake can be attenuated by integrating 20-day-old pups into 15-day-old litters. We concluded that pups do not begin to ingest less milk because of diminishing milk supplies. Rather, the decreased tendency of mothers to nurse older pups and the diminished tendency of older pups to extract available milk, together appear to underlie the decline in pups' milk consumption. Milk supplies decline after changes in behavioral interactions and may play an instrumental role in the eventual abandonment of suckling.


Proteome Analyses Using iTRAQ Labeling Reveal Critical Mechanisms in Alternate Bearing Malus prunifolia.
Alternate bearing (AB) trees, including Malus prunifolia, are characterized by alternating cycles of heavy (ON tree) and low (OFF tree) fruit loads. The mechanisms regulating the AB phenomenon have not been fully characterized. We completed an iTRAQ-based investigation of M. prunifolia to identify the proteome and metabolic differences between the leaves of ON and OFF trees. We identified 667 differentially expressed proteins, and they influenced multiple biochemical pathways, including photosynthesis, carbohydrate metabolism, glycolysis, protein processing, redox activities, and secondary metabolism. Bioinformatics analyses indicated photosynthesis was the most significant biological process affecting the AB. We observed that 47 photosynthetic proteins affecting photosystem I and II reaction centers, cytochrome b6/f complex, electron transport, and light-harvesting chlorophyll were less abundant in ON tree leaves than in OFF tree leaves. Additionally, physiological analyses validated the potential metabolic activities. Nitrogen and phosphorus contents were significantly higher in ON tree leaves, while potassium levels were lower. Starch content, ZR, GA4+7 levels, and flower control gene expression levels (i.e., MdFT1, MdLFY, MdAP1, and MdSPL9) were lower in ON tree leaves than in OFF tree leaves, suggesting they affected the AB phenotype. Our findings help further investigate on the photosynthesis as well as other processes in AB. Those identified DEPs and important biological processes can be useful theoretical basis and provide new insights into the molecular mechanisms regulating AB in perennial woody plants.


Prenatal diagnosis of nonrhizomelic chondrodysplasia punctata (Conradi-Hünermann syndrome).
Chondrodysplasia punctata has been classified into two major types including the rare autosomal recessive "rhizomelic type" and a more common but genetically heterogenous nonrhizomelic type (referred to by some authors as "Conradi-Hünermann (CH) type"). The former is typically lethal, manifesting serious anomalies, and allowing several instances of confident prenatal diagnosis. The latter being milder has more subtle anomalies and prenatal diagnosis has been uncommonly reported (confined to cases diagnosed incidentally by flat-plate X-ray examination of the mother in late third trimester, and a case found by directed ultrasound performed in a Mendelian affected mother). Cases included 1) a young primigravida thought to be affected with Conradi-Hünermann syndrome presented at 16 weeks gestation for prenatal diagnosis and counseling. Ultrasound examination of the fetus detected assymetric limb shortness allowing the presumptive diagnosis of an affected fetus which was confirmed after delivery near term. 2) A normal 38-year-old multipara with unremarkable family history underwent routine fetal ultrasound evaluation at 18 weeks gestation. Disorganization of the spine, premature echogenicity of femoral epipheses, and frontal bossing with depressed nasal bridge were described. Neonatal examination confirmed suspicion of CH. Case 1 demonstrates the importance of solid clinical diagnosis in Mendelian malformation-affected parents for directing prenatal diagnostic efforts. Case 2 represents the first index case of CH diagnosed antenatally by ultrasound. Diagnostic clues which must be considered in establishing these diagnoses are discussed, as are some of the difficulties and limitations in antenatal counseling such cases.


Antitumor effects of PLGA nanoparticles encapsulating the human PNAS-4 gene combined with cisplatin in ovarian cancer.
Human PNAS-4 (hPNAS-4), as a pro-apoptotic gene, can inhibit tumor growth when overexpressed in some malignant cells. Poly (lactic-co-glycolic acid) (PLGA) was used as a gene transfer vector due to the advantage of sustained release, nontoxicity and biodegradability. In this study, we aimed to investigate the effect of PLGA nanoparticles encapsulating hPNAS-4 combined with cisplatin (DDP) on ovarian carcinoma. Expression of hPNAS-4 was determined by RT-PCR. Mice bearing intraperitoneal ovarian carcinomas were treated with PBS, pVAX-PLGA nanoparticles (P-P), pVAX-hPNAS-4-PLGA nanoparticles (PhP-P), DDP and PhP-P plus DDP, respectively. Intraperitoneal tumors were weighed to assess the antitumor efficacy. The percentage of proliferative cells and apoptotic cells was evaluated by Ki-67 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. The anti-angiogenic effects were detected by CD31 staining and the alginate-encapsulate assay. Overexpression of hPNAS-4 was detected by RT-PCR in the PhP-P and PhP-P plus DDP groups. PhP-P exerted significant antitumor activity through induction of apoptosis, inhibition of cell proliferation and suppression of angiogenesis, compared with treatment with P-P or PBS alone. The combination of PhP-P with DDP showed enhanced antitumor activity compared with therapy of PhP-P or DDP alone. PLGA encapsulating hPNAS-4 combined with DDP may have promising applications in the therapy of ovarian cancer.


Decreased interleukin-2 beta-chain receptor expression by interleukin-4 on LGL: influence on the IL-2 induced cytotoxicity and proliferation.
Addition of increasing amounts of interleukin-4 (IL-4) to large granular lymphocytes (LGL) had a selective downregulative effect on the interleukin-2 beta-chain (p70) receptor expression. A 40% inhibition of the p70 expression compared to untreated cells was already observed after a 24-h incubation with IL-4. This decrease in p70 receptor expression had a marked suppressive effect on their proliferative response to IL-2. In addition, LGL cultured in the presence of both IL-2 and IL-4 substantially decreased the cytotoxic activity against the erythroleukemia cell line K562. Our data therefore indicate an important regulative role for IL-4 on the LAK-generation.


Comparison of diabetes diagnostic categories in the U.S. population according to the 1997 American Diabetes Association and 1980-1985 World Health Organization diagnostic criteria.
To compare the 1997 American Diabetes Association (ADA) and the 1980-1985 World Health Organization (WHO) diagnostic criteria in categorization of the diabetes diagnostic status of adults in the U.S. Analyses are based on a probability sample of the U.S. population age 40-74 years in the 1988-1994 Third National Health and Nutrition Examination Survey (NHANES III). People with diabetes diagnosed before the survey were identified by questionnaire. For 2,844 people without diagnosed diabetes, fasting plasma glucose was obtained after an overnight 9 to < 24-h fast, HbA1c was measured, and a 2-h oral glucose tolerance test was administered. Prevalence of diagnosed diabetes in this age-group is 7.9%. Prevalence of undiagnosed diabetes is 4.4% by ADA criteria and 6.4% by WHO criteria. The net change of -2.0% occurs because 1.0% are classified as having undiagnosed diabetes by ADA criteria but have impaired or normal glucose tolerance by WHO criteria, and 3.0% are classified as having impaired fasting glucose or normal fasting glucose by ADA criteria but have undiagnosed diabetes by WHO criteria. Prevalence of impaired fasting glucose is 10.1% (ADA), compared with 15.6% for impaired glucose tolerance (WHO). For those with undiagnosed diabetes by ADA criteria, 62.1% are above the normal range for HbA1c compared with 47.1% by WHO criteria. Mean HbA1c is 7.07% for undiagnosed diabetes by ADA criteria and 6.58% by WHO criteria. The number of people with undiagnosed diabetes by ADA criteria is lower than that by WHO criteria. However, those individuals classified by ADA criteria are more hyperglycemic, with higher HbA1c values and a greater proportion of values above the normal range. This fact, together with the simplicity of obtaining a fasting plasma glucose value, may result in the detection of a greater proportion of people with undiagnosed diabetes in clinical practice using the new ADA diagnostic criteria.


Evaluation of immune responses of stabilised SAT2 antigens of foot-and-mouth disease in cattle.
Foot-and-mouth disease (FMD) vaccines with improved stability and less reliant on a cold-chain are needed to improve the longevity of immune responses elicited in animals. This is especially so for serotypes O and SAT2 which are unstable in mildly acidic pH conditions or at elevated temperatures leading to dissociation of the capsid (146S particle) and loss of immunogenicity. Previously, stabilised SAT2 viruses were generated by reverse genetic approaches and assessed in vitro and in vivo with a guinea pig trial. Here we investigated the efficacy and comparative immunological responses of two thermostable and wild-type SAT2 vaccines over 5months followed by challenge. We assessed humoral immune responses elicited in cattle in terms of total and neutralizing antibodies and IgG1/2 isotyping; and cell-mediated responses of IFN-γ as in vitro markers of protection. Whilst there were significant differences in total and neutralizing antibodies for the vSAT2-93H group compared to other vaccinated groups after the first vaccination, there were no significant differences after the second immunization. Following intra-dermolingual challenge all vaccinated groups were fully protected as determined by the absence of generalized lesions. These results provide proof that two vaccine doses, consisting of SAT2 antigen combined with ISA206B adjuvant, administered 4-6 weeks apart were able to protect animals up to 5months pv. Additionally, vSAT2-93Y had significantly higher levels of IFN-γ after challenge and had a lower clinical score indicative of better protection compared to other vaccinated groups and the importance of cell mediated responses and antigen stability in protection.


Bovine serum albumin conformation on methyl and amine functionalized surfaces compared by scanning force microscopy.
We investigated the adsorption of albumin on chemically modified gold surfaces by scanning force microscopy operating both in contact and noncontact mode. The surface modification was performed with thiol-based self-assembling molecules carrying amine or methyl groups. The albumin on the aminoethanethiol-coated gold formed a uniform layer and single molecules could be distinguished. On the dodecanethiol-coated surface the protein adsorbed in aggregates or single isolated molecules depending on the incubation time. The width of the albumin molecule on both surface was similar, but the height was much lower on the amine than on the methyl surface. This was interpreted as a difference in the conformation of albumin depending on the substrate, and could explain the promotion of cell adhesion on amine-treated polymers coated with albumin.


Review article: dexmedetomidine: does it have potential in palliative medicine?
Dexmedetomidine, is a α( 2) adrenergic agonist approved by the Food and Drug administration for sedation and analgesia. A highly potent α(2) adrenergic agonist, it has quick onset of action, with peak effects within 1 hour of administration. It is metabolized in the liver and eliminated in the urine as a glucuronide. Dexmedetomidine is a substrate and inhibitor of cytochrome oxidase 2D6, but clinical evidence of significant drug interactions is lacking. Clinical trials suggest efficacy for the treatment of delirium in the intensive care unit setting with efficacy comparable to haloperidol and benzodiazepines. Dexmedetomidine also has an opioid-sparing action and can act to enhance analgesia. The purpose of this article is to review the pharmacodynamics and pharmacology of dexmedetomidine, and examine its potential use in the palliative care population, especially with regard to the management of delirium.