First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): a phase II study conducted by the Hellenic Cooperative Oncology Group.
To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first-line chemotherapy in patients with advanced breast cancer (ABC). Paclitaxel is an active agent in ABC. Furthermore, our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC. From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m2) by three-hour infusion followed by carboplatin at an AUC of 6 mg x min/ml every three weeks. The median age of the patients was 56 years (range 28-75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen. A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m2/week (range 30.5-69.3) and the relative DI was 0.95 (range 0.5-1.2). Eight patients (12%, 95% confidence interval (CI): 5%-22%) achieved complete and 28 (42%, 95% CI: 30%-55%) partial responses. Grade 3-4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1.5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07-24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07-23+) months and median survival 20.4 (range 0.07-24.5+) months. The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.


Definition and causes of infertility.
Infertility is a common problem affecting one couple in six. It can be defined as the incapacity to fulfill pregnancy after reasonable time of sexual intercourse with no contraceptive measures taken. The evidence for changes in the prevalence of infertility is difficult to establish. This increase could be due to at least four factors: delayed childbearing, alterations in semen quality due to habits such as cigarette smoking and alcohol, changes in sexual behaviour and eliminations of most taboos. The study of infertile couple has always been focussed on different factors: ovulatory factor (present in about 20% of couples), utero-tubal peritoneal factor (present in ~30% of couples), semen migration factor (10% of cases) and male factor (30% of couples). Around 40% of all infertile couples exhibit a combination of factors and about 15% of couples may not display any objective alteration leading to a definite diagnosis. During the past two decades there have been three important changes in infertility practice. First, the introduction of assisted reproduction technologies has provided an opportunity to study basic reproductive processes. Second, societal changes have occurred such as the increase in the proportion of women over 35 years old seeking pregnancy. This fact is due to a later age for marriage and postponement of pregnancy. Third, the development of molecular biology and genetics has become very important for the study, diagnosis and assessment of couples, many of them considered until now as "unexplained infertile couples".


[Gastrointestinal haemorrhage due to aorto-intestinal fistula. 3 cases (author's transl)].
Three types of aorto-intestinal fistula may be associated with gastrointestinal bleeding: primary fistulae from an aneurysm, secondary fistulae related to an aorto-prosthetic anastomosis and paraprosthetic fistulae by intraduodenal protrusion of a graft. The prevalence of secondary and paraprosthetic fistulae increases with more widespread vascular surgery. Only if the diagnosis is always borne in mind in a patient with an aneurysm or an aortic prosthesis makes it possible to recognise an aorto-intestinal fistula in time. Upper GI series and endoscopy are more useful in reaching a diagnosis than arteriography but signs must be sought in the third and fourth parts of the duodenum. The lesion may even be missed on surgical exploration, being concealed before separation of the aorta and duodenum. Infection and the underlying general medical condition are factors in the gravity of the operative prognosis. One of our three patients treated surgically was saved by the insertion of an extra-anatomic bypass. The prognosis in paraprosthetic fistulae, the possible precursor stage of a secondary aorto-digestive fistula, is more favourable.


[Tricuspid valve replacement by right thoracotomy with minimal dissection in reoperations].
We report two cases of tricuspid valve replacement for tricuspid valve insufficiency as reoperations following mitral valve replacement through midline sternotomy. A right thoracotomy was used to approach the tricuspid valve. To avoid the risk of cardiac laceration, cardiopulmonary bypass was instituted after cannulation of the femoral artery and of superior vena cava through right atrium with balloon caval occlusion and inferior vena cava through the femoral vein with balloon caval occlusion. Without aortic cross clamping under mild hypothermia, right atriotomy was performed through adherent parietal pleura, pericardium, and right atrial wall without dissection. Tricuspid valve was replaced utilizing the bioprosthetic valve with good clinical results. These new measures were expeditiously carried out without dissection of the heart, which has been deemed to be the risk of reoperations.


Isolation, characterisation and antibacterial activity of new compounds from methanolic extract of seeds of Caesalpinia crista L. (Caesalpinaceae).
Phytochemical study on the methanolic extract of Caesalpinia crista afforded two novel compounds, 2-hydroxytrideca-3,6-dienyl-pentanoate and octacosa-12,15-diene along with known compounds 3-O-methylellagic acid 3'O-α-rhamnopyranoside, β-sitosterol and sucrose. Compound 3-O-methylellagic acid 3'O-α-rhamnopyranoside is reported for the first time from the plant. Molecular structures, of isolated compounds, were elucidated by using the NMR spectroscopy in combination with IR and mass spectral data. All isolated compounds, extract and fractions were evaluated for in vitro antibacterial activity against various Gram-positive and Gram-negative bacterial strains and found to be significantly active against Staphylococcus aureus and methicillin-resistant S. aureus (minimum inhibitory concentration: 64-512 μg mL(- 1)).


Up-Regulation of Antimicrobial Peptides Gallerimycin and Galiomicin in Galleria mellonella Infected with Candida Yeasts Displaying Different Virulence Traits.
Galleria mellonella has been described as a cheap and an easy-to-reproduce model for the study of fungal infections. We hypothesized that yeasts with higher virulence potential decrease survival and significantly trigger an immune response in G. mellonella through the regulation of innate immunity-related genes encoding antimicrobial peptides (AMPs) such as gallerimycin and galiomicin. Candida albicans SC5314 and Candida dubliniensis CBS 7987, selected because of their different virulence potential, were used for a killing assay followed by the determination of gene expression using qPCR. In vivo results confirmed a significantly (p = 0.0321) lower pathogenicity for C. dubliniensis than for C. albicans. Accordingly, the induction of C. dubliniensis AMPs was lower at all the selected time points post-infection (1 h, 24 h, 48 h). Moreover, we observed an extremely high regulation of the galiomicin gene compared to the gallerimycin one, suggesting a different role of the tested AMPs in protecting G. mellonella from candidiasis.


Biometry measurements using a new large-coherence-length swept-source optical coherence tomographer.
To evaluate the repeatability and reproducibility of the measurements obtained with the Argos, a new biometer with swept-source optical coherence tomography (SS-OCT), and to compare them with the results obtained with the IOLMaster 500 (partial-coherence interferometry [PCI]) and the Lenstar LS 900 (optical low-coherence reflectometry [OLCR]) biometers. Private practice, Lynwood, California, USA. Prospective observational study. All measurements were performed with the SS-OCT tomographer, the PCI biometer, and the OLCR biometer. Eyes (n = 107) were measured to evaluate the axial length (AL), central corneal thickness (CCT), aqueous depth, anterior chamber depth (ACD), lens thickness, pupil size, corneal diameter, and anterior corneal radius of curvature (RAV). Repeatability and reproducibility of the SS-OCT measurements showed comparable values and a low variation rate, with an interset mean difference of 0.01 mm for AL, 0.01 mm for CCT, 0.01 mm for aqueous depth and ACD, 0.03 mm for lens thickness, 0.10 mm for pupil size, 0.14 mm for corneal diameter, and 0.02 mm for RAV. The SS-OCT device correctly measured the AL in 96% of the cases compared with 79% for the OLCR device and 77% for the PCI device. Comparisons between the PCI device and SS-OCT device were -0.01 ± 0.05 mm for AL, -0.17 ± 0.20 mm for ACD, and -0.01 ± 0.05 mm for RAV. Comparison between the OLCR device and the SS-OCT device was 0.01 ± 0.06 mm for AL, 0.08 ± 0.15 mm for ACD, 0.00 ± 0.05 mm for RAV, 0.00 ± 0.01 mm for CCT, 0.07 ± 0.14 mm for aqueous depth, -0.23 ± 0.22 mm for lens thickness, -0.29 ± 0.53 mm for pupil size, and -0.34 ± 0.76 mm for corneal diameter. Axial length measurements with the new SS-OCT biometer were comparable to the PCI and OLCR measurements with a higher AL acquisition rate. Dr. Shammas is a consultant to Movu, Inc. Drs. Ortiz, Kim, and Chong have proprietary interest in the new technology.


Patterns of neuroleptic usage in continuously hospitalized chronic schizophrenic patients: evidence for development of drug tolerance.
A retrospective review of neuroleptic dosages over a five-year period in 19 chronic schizophrenic patients revealed that the majority (85 percent) had either consistent yearly increases or decreases in dosage, although clinical status remained unchanged. The authors present differences in adverse effects between the two groups and discuss the implications of their findings for the concepts of neuroleptic drug tolerance and supersensitivity psychosis.


Attention deficit hyperactivity disorder (ADHD): a practical scale for pediatricians.
Attention deficit hyperactivity disorder (ADHD) is a common disturbance causing school failure and social problems. Early diagnosis and intervention allow ADHD children to adjust and succeed at school and in daily life. To identify these patients, we designed a practical questionnaire for parents. When tested on children with ADHD (n = 100), children with psychiatric problems (n = 35), and on age- and sex-mached control children (n = 100), this scale was found to be highly useful in distinguishing these three groups from each other, especially after the identification and elimination of items with lower specificity. The use of the Hacettepe ADHD scale is recommended for pediatricians, general practitioners and teachers to allow earlier diagnosis of this condition.


Pattern formation in directional solidification under shear flow. II. Morphologies and their characterization.
In the preceding paper, we have established an interface equation for directional solidification under the influence of a shear flow parallel to the interface. This equation is asymptotically valid near the absolute stability limit. The flow, described by a nonlocal term, induces a lateral drift of the whole pattern due to its symmetry-breaking properties. We find that at not-too-large flow strengths, the transcritical nature of the transition to hexagonal patterns shows up via a hexagonal modulation of the stripe pattern even when the linear instability threshold of the flowless case has not yet been attained. When the flow term is large, the linear description of the drift velocity breaks down and transitions to flow-dominated morphologies take place. The competition between flow-induced and diffusion-induced patterns (controlled by the temperature gradient) leads to new phenomena such as the transition to a different lattice structure in an array of hexagonal cells. Several methods to characterize the morphologies and their transitions are investigated and compared. In particular, we consider two different ways of defining topological defects useful in the description of patterns and we discuss how they are related to each other.


The processing of interleukin-1 beta studied with antibodies raised against synthetic peptides from the precursor N-terminal region.
The exact sequence of events during processing of human interleukin-1 beta (IL-1 beta) and the fate of the N-terminal region are unknown. We have used anti-peptide sera specific for the precursor and mature regions of IL-1 beta to study biosynthesis. These were raised against peptides corresponding to amino acids 1-15, 17-32, and 43-54 of the precursor and a peptide corresponding to the C-terminal 33 amino acids of mature human IL-1 beta. Antiserum to the mature region peptide immunoprecipitated the 35-kD precursor from cell lysates and 17-kD mature IL-1 beta and a 31-kD protein from the culture supernatants from radiolabeled human peripheral blood monocytes stimulated with lipopolysaccharide (LPS). Antisera to peptides from the precursor region also immunoprecipitated the 35-kD IL-1 beta precursor but not the 31-kD or 17-kD forms. Of the precursor-specific sera, only antiserum to amino acids 1-15 specifically recognized any other proteins; a peptide of 18 kD and a low molecular weight peptide, both of which accumulated in the medium. The 18-kD protein was not recognized by any of the other antisera and is unlikely to be the N-terminal region of the precursor removed during processing. Pulse-chase experiments indicated that the 31-kD protein could be a processing intermediate and also that it was itself an end product along with full-length precursor. Only 17-kD mature IL-1 beta had biological activity.


Phosphorus Incorporation into Co9 S8 Nanocages for Highly Efficient Oxygen Evolution Catalysis.
The improvement of activity of electrocatalysts lies in the increment of the density of active sites or the enhancement of intrinsic activity of each active site. A common strategy to realize dual active sites is the use of bimetal compound catalysts, where each metal atom contributes one active site. In this work, a new concept is presented to realize dual active sites with tunable electron densities in monometal compound catalysts. Dual Co2+ tetrahedral (Co2+ (Td )) and Co3+ octahedral (Co3+ (Oh )) coordination active sites are developed and adjustable electron densities on the Co2+ (Td ) and Co3+ (Oh ) are further achieved by phosphorus incorporation (P-Co9 S8 ). The experimental results and density functional theory calculations show that the nonmetal P doping can systematically modulate charge density of Co2+ (Td ) and Co3+ (Oh ) in P-Co9 S8 and simultaneously improve the electrical conductivity of Co9 S8 , which substantially enhances oxygen evolution reaction performance of P-Co9 S8 .


Prostaglandin E2 down-regulates the expression of HLA-DR antigen in human colon adenocarcinoma cell lines.
Prostaglandins (PG) have been implicated in the pathogenesis of cancer and play an important role in immune regulation. Colon cancer is associated with elevated levels of PGE2, while aspirin, the prototypical inhibitor of PG synthesis, appears to reduce the incidence of colon cancer by 50%. We have observed that in human colon cancer the expression of HLA class I and II antigens is reduced or lost; loss of HLA antigens is suspected to be a mechanism by which the malignant cell escapes the immune surveillance. We investigated the effect of these eicosanoids on the expression of HLA antigens in human colon adenocarcinoma cell lines. PGE2 down-regulated the expression of the class II antigen HLA-DR in SW1116 cells (65% reduction at 2.8 x 10(-8) M). This effect was dose- and time-dependent, reversible, and specific (PGF2 alpha and LTB4 had no effect; the expression of carcinoembryonic antigen and class I genes were not affected). Aspirin induced the expression of HLA-DR in HT29 cells, a cell line not expressing constitutively HLA-DR. The reduction of HLA-DR by PGE2 was accompanied by reduced messenger RNA (mRNA) levels of HLA-DR alpha and reduced transcription of the corresponding gene. In contrast to HLA-DR, none of these three eicosanoids affected the expression of HLA class I genes, as assessed via determination of protein expression by fluorescence flow cytometric analysis and evaluation of the corresponding class I mRNA levels. We conclude that PGE2 specifically down-regulates the expression of HLA-DR, while it does not affect the expression of class I antigens.(ABSTRACT TRUNCATED AT 250 WORDS)


Variability of Ole e 9 allergen in olive pollen extracts: relevance of minor allergens in immunotherapy treatments.
Clustered severe adverse reactions to immunotherapy with olive pollen extracts have been occasionally reported in areas where olive trees are extensively grown. Allergic patients from these areas, in addition to the major olive pollen allergen Ole e 1, frequently recognize a recently described allergen, Ole e 9. We aimed to develop an immunoassay to measure Ole e 9 concentration and to study the variability of this allergen in olive pollen extracts. Monoclonal antibodies (mAb) to Ole e 9 were produced from mice immunized with the pure allergen. One of these mAbs was used to develop a sandwich ELISA with an anti-olive pollen extract rabbit serum as the tracer. Olive pollen batches from several suppliers were analyzed using this method. These batches were also analyzed for Ole e 1 content and biological activity. A 10-fold variation between the extreme values was found for the biological activity of the batches analyzed. Ole e 1 concentration showed a 25-fold variation. Variability of Ole e 9 concentration was extremely high, up to 161 times. The ratio Ole e 1/Ole e 9 varied in a range from 0.6 to 390.4. The availability of a mAb-based ELISA for Ole e 9 made it possible for us to detect an important source of variability in olive pollen batches. This variability may be the cause of outbreaks of adverse reactions in the course of immunotherapy treatments, which have sometimes been observed among olive-allergic patients living in areas with very high levels of airborne olive pollen.


Low-friction arthroplasty with Boneloc bone-cement: outcome at 2 to 4 years.
We report the clinical and radiologic outcome of 109 Chamley low-friction arthroplasties implanted with Boneloc bone-cement (Biomet, Bridgend, South Wales, UK) into 104 patients. The mean follow-up was 30 months (range, 2-48 months). There were 72 women (mean age, 71 years) and 32 men (mean age, 72). Cartridge-packed cement was used in 37 cases and vacuum-packed cement in 72 cases. Survivorship analysis based on revision for aseptic loosening showed 79% survival at 4 years. Seventeen (15.5%) hips have been revised for aseptic loosening to date, in which all stems and 4 cups were loose. Extensive femoral osteolysis was always present and resulted in 4 cases of femoral cortical perforation at revision. Survivorship analysis based on revision and radiologic failure showed only 55% survival over the same period. When radiologic loosenings were included as failures, the vacuum-packed cement performed significantly worse than the cartridge-packed cement it replaced. These poor results were consistent with the withdrawal of Boneloc from clinical use in 1995, and we recommend indefinite follow-up for surviving prostheses.


Borrelia yangtzensis sp. nov., a rodent-associated species in Asia, is related to Borrelia valaisiana.
Twenty-nine isolates of Lyme borreliosis (LB) group spirochaetes collected from ticks and rodents in China and Japan were included in a multilocus sequence analysis (MLSA). Using a different typing system, three of these strains had previously been identified as being divergent from other LB spirochaete species and the name 'Borrelia yangtze' sp. nov. was proposed. The data presented here confirm that the genetic distance, calculated using sequences of MLSA housekeeping genes, to other known LB group spirochaete species was < 95 % and to Borrelia valaisiana was 96.67 % (which represents the most closely related species within the group of LB spirochaetes). This and the fact that these strains are ecologically distinct from B. valaisiana (rodent-transmitted vs bird-transmitted) provide strong support for the validation of the proposed species status. We suggest the name Borrelia yangtzensis sp. nov. The type strain is Okinawa-CW62T ( = DSM 24625T = JCM 17189T).


Phenylobacterium muchangponense sp. nov., isolated from beach soil, and emended description of the genus Phenylobacterium.
A Gram-staining-negative, non-motile, aerobic bacterium, designated strain A8T, was isolated from the beach soil of Muchangpo, Korea. Cells were rod-shaped (0.5-0.6×0.7-1.3 µm) and colonies were colourless, circular with entire edges and had a glistening surface. The isolate grew optimally at 25-35 °C and did not require NaCl for growth. Strain A8T could not assimilate acetate, DL-lactate, succinate, antipyrine or chloridazon, but weakly assimilated L-phenylalanine. Major fatty acids were summed feature 7 (comprising C18:1ω7c/ω9t/ω12t), C16:0 and summed feature 4 (comprising C16:1ω7c/ iso-C15:0 2-OH). The major isoprenoid quinone was ubiquinone-10 and the DNA G+C content was 72.3 mol%. Comparative 16S rRNA gene sequence studies showed that strain A8T belonged to the family Caulobacteraceae, class Alphaproteobacteria and was most closely related to type strains of members of the genus Phenylobacterium (95.7-97.1 % similarity). Signature nucleotides and phylogenetic analysis of the 16S rRNA gene sequence also suggested that strain A8T was affiliated with the genus Phenylobacterium. Low DNA-DNA relatedness values (3.0±1.8-11.5±3.2 %) indicated that strain A8T represented a distinct species that was separated from other type strains in the genus Phenylobacterium. On the basis of evidence from a polyphasic study, it is proposed that strain A8T (=KACC 15042T=LMG 25973T) represents the type strain of a novel species, Phenylobacterium muchangponense sp. nov. An emended description of the genus Phenylobacterium is also presented.


Teat onchocercosis in cows with reference to prevalence, species involved and pathology.
The present study reports teat onchocercosis in cows in the province of Kars in north eastern Turkey with reference to the prevalence, species involved and pathological findings. In the study, 600 cows of various breeds and ages slaughtered in the local abattoir were examined and 145 (24%) were found to have various lesions on their teats, of which 45 (31%) were infected with three Onchocerca species (Onchocerca gutturosa, O. lienalis and an unidentified Onchocerca spp.), identified according to their morphological characteristics. Gross pathological examination of the teats with lesions revealed scabies and chaps of varying sizes, healed sores and small nodules. Histopathologically, large numbers of microfilariae were commonly observed within the collagenous fibre bundles of the dermis, with only a few microfilariae in the dermis in some cases. The microfilariae were also often found to have accumulated around the perivascular spaces and were frequently associated with infiltration by inflammatory cells, predominantly eosinophil leukocytes and mononuclear cells. In two cases, microfilariae were discovered exclusively in the lumen of the capillaries of the dermal papillaries. In one case, in which microfilarae were not encountered, sections of adult worms surrounded by neutrophil leukocytes were detected free in the teat canal. The presence of extensive teat lesions along with microfilariae of the Onchocerca species as found in this study warrants further assessment of the impact of onchocercosis on dairy farming.


Transport of neurotransmitter precursors in a syncytial epithelium.
1. Tegumental transport of choline at concentrations ranging from 0.005-5.0 mM provided no evidence for saturable, carrier-mediated entry of this amine in the tegument of the rat tapeworm (Hymenolepis diminuta). 2. In contrast, the large neutral amino acid tryptophan appears to be taken up via a high-affinity transporter. In the 1st quartile of 17-day-old tapeworms (Km = 0.033 mM, Vmax = 0.7 nmol.min-1.g-1), in the 2nd quartile (Km = 0.015 mM, Vmax = 0.3 nmol.min-1.g-1), in the 3rd quartile (Km = 0.022 mM, Vmax = 0.5 nmol.min-1.g-1) and in the 4th quartile (Km = 0.025 mM, Vmax = 0.5 nmol.min-1.g-1) saturable tryptophan transport was kinetically characterized. 3. The non-saturable diffusion component (Kd) for tryptophan transport ranged from 3.8-10.2 microliters.min-1.g-1. 4. These studies suggest choline does not appear to be transported across the tapeworm tegument. Saturable transport of tryptophan via a high-affinity carrier is reported, and no regional variations in indole amino acid uptake were detected.


Calcium transients and neural induction in vertebrates.
Evidence indicates that a variety of different types of Ca2+ transients (i.e., standing gradients, pulses and propagating waves) may be occurring both simultaneously and sequentially during neural induction in vertebrate embryos. Transients have been observed in the dorsal marginal zone and in the presumptive neural ectoderm, suggesting that they may be generated within two distinct germ layers at separate embryological locations. It has been proposed that the Ca2+ transients might have multiple roles during the period of neural induction, ranging from: activating the expression of early neural genes; contributing to the inhibition of BMP-4 signalling; generating secretion gradients of morphogens; regulating and co-ordinating convergent extension; and establishing and reinforcing dorsoventral axis specification. Both intra- and extracellular stores (either acting separately or in combination) have been shown to generate the neuralizing Ca2+ transients via well-established release mechanisms, and transients have been shown to propagate between connected cells, suggesting an intercellular signalling dimension. Thus, good evidence is accumulating to suggest that Ca2+ might be a key central regulator in the process of neural induction.


Polydimethylsiloxane films doped with NdFeB powder: magnetic characterization and potential applications in biomedical engineering and microrobotics.
This work reports the fabrication, magnetic characterization and controlled navigation of film-shaped microrobots consisting of a polydimethylsiloxane-NdFeB powder composite material. The fabrication process relies on spin-coating deposition, powder orientation and permanent magnetization. Films with different powder concentrations (10 %, 30 %, 50 % and 70 % w/w) were fabricated and characterized in terms of magnetic properties and magnetic navigation performances (by exploiting an electromagnet-based platform). Standardized data are provided, thus enabling the exploitation of these composite materials in a wide range of applications, from MEMS/microrobot development to biomedical systems. Finally, the possibility to microfabricate free-standing polymeric structures and the biocompatibility of the proposed composite materials is demonstrated.


An analysis of the craniofacial complex in different occlusal categories.
Fourteen linear and fourteen angular cephalometric dimensions were measured from cephalographs of ninety male British Caucasians in Angle Class I, II, and III malocclusion categories. Univariate statistical analysis showed varying contrasts between these categories, depending upon which dimension was compared. Multivariate analysis of all the angular and linear dimensions combined revealed significant contrasts between the three occlusal categories. This study, therefore, showed that only with a multivariate approach will the intricacies of the craniofacial skeleton be interpreted.


Prevention of heterotopic ossification after spinal cord injury with indomethacin.
A randomized, prospective, double-blind, placebo-controlled clinical trial. To determine the effect of indomethacin on the prevention of heterotopic ossification (HO) following spinal cord injury (SCI). County Hospital, Miami, Florida, USA. Sixteen patients were treated with slow-release indomethacin 75 mg daily and 17 patients received placebo for a period of 3 weeks. Prevention was started 21+/-14 days after SCI. In both groups of patients there was similar age of the patients as well as the level of SCI and ASIA impairment scale. Two methods were used to diagnose HO, bone scintigraphy and radiographic examination. Bone scintigraphy with technetium labeled methylene-diphosphonate was used for diagnosis of early stage, while radiography was used for diagnosis of late stage of HO development. A significantly lower incidence of early HO was found in the indomethacin group (25%) than in the placebo group (65%; P<0.001). Similarly there was a significant reduction of late HO in the indomethacin group (12.5%) as compared to the placebo group (41%; P<0.001). Our data suggest that indomethacin used during the first 2 months after SCI is effective in prevention of HO in a significant number of patients.


Radioimmunoassay of cholecystokinin: comparison of different tracers.
We have compared the binding of cholecystokinin (CCK) antibodies with different sequence-specificities to Bolton-Hunter labeled CCK-33 (125I-BH-CCK-33), CCK-8 (125I-BH-CCK-8) and chloramine-T iodinated gastrin-17 (125I-gastrin-17). The antibody binding was expressed as the final antiserum dilution ('titer') and the effective equilibrium constant of the binding (Ko eff). Antibodies specific for the C- or the N-terminal sequence of CCK-8 all bound well to 125I-BH-CCK-8. In contrast, some of the antibodies directed against the common C-terminus of CCK and gastrin displayed remarkably low binding of 125I-gastrin-17 or 125I-BH-CCK-33, whereas all antisera specific for the N-terminal or midsequence of CCK-33 bound 125I-BH-CCK-33 well. The lower binding of 125I-BH-CCK-33 to some C-terminal antibodies raised against gastrin may be due to a C-terminal conformation of CCK-33 different from that of gastrin. In accord with the high specific radioactivity of 125I-BH-CCK-8, the best sensitivity of CCK radioimmunoassays was obtained with the CCK-8 tracer.


[Oral single-dose toxicity study of a new antineoplastic agent S-1, and its components, CDHP, and Oxo].
S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that produced by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, the single-dose toxicity of S-1 as well as that of its components, CDHP and Oxo, was investigated in mice, rats, and dogs. The following results were obtained. 1. In mice and rats, excretion of diarrheal stools, salivation, and alopecia were observed after S-1 administration. In severe cases, the animals subsequently showed emaciation due to weight loss or suppressed weight gain, decreased spontaneous motor activity, an anemic appearance, bradypnea, prone position, and death. In the CDHP and Oxo treatment groups of rats, the only toxic signs were soft or diarrheal stools on the dosing day. 2. In dogs, vomiting and excretion of diarrheal, mucous, or soft stools was observed after S-1 administration. In the CDHP and Oxo treatment groups, excretion of soft and diarrheal stools and vomiting were observed relatively frequently from the dosing day until day 1. 3. In the pathological examination of the animals given S-1, mice and rats showed pulmonary congestion/edema, dark red discoloration of the mesenteric lymph nodes, atrophy of lymphatic tissues such as the thymus and lymph nodes, decreases of lymphocytes in the splenic white pulp and mesenteric lymph nodes, a decrease in bone marrow cells, congestion of the glandular stomach, and aggregates of bacteria in the lung, liver, or spleen. In dogs, abnormal changes were observed mainly in the lymphatic organs such as the thymus and lymph nodes. 4. The LD50 values of S-1 in terms of the amount FT they contained were estimated to be 549 mg/kg for mice(male), 441-551 mg/kg for rats (both sexes) and about 53 mg/kg for dogs (male). The LD50 values of CDHP and Oxo were 2000 mg/kg or higher for both rats (both sexes) and dogs (male). 5. Hematopoietic and lymphatic impairments, immunosuppression associated with respiratory were considered to be the cause of death from S-1. The toxicity of S-1 reflects the toxicity of 5-FU and was not found the different toxicity by the addition of CDHP and Oxo.


Botulinum toxin changes intrafusal feedback in dystonia: a study with the tonic vibration reflex.
To investigate the possible role of botulinum toxin (BT-A) injection in reducing muscle afferent feedback, we evaluated electrophysiologically 10 right-handed patients with writer's cramp before and 3 weeks after treatment. The ratio between pre- and postinjection values of maximal M-wave (M-max), maximal voluntary contraction (MVC), and tonic vibration reflex (TVR) were measured in the injected muscles (wrist flexors or extensors). In all the subjects, BT-A injection reduced the TVR more than the M-max and MVC (mean ratio +/- SD: TVR, 0.24 +/- 0.22; MVC, 0.59 +/- 0.32; M-max, 0.68 +/- 0.24; P = 0.003). Long-term evaluation of 2 patients disclosed that, after 7 months, when some clinical benefits persisted, M-max and MVC had fully recovered, whereas the TVR was still depressed. This special sensitivity of the TVR to suppression by BT-A injection could be mediated by the chemodenervation of intrafusal muscle fibers, leading to a reduction in spindle inflow to the central nervous system during vibration. The action on intrafusal fibers could alter sensorimotor integration, thus contributing to the clinical benefits of BT-A injection.


A human case of otoacariasis involving a histiostomatid mite (Acari: Histiostomatidae).
A 31-year-old Saudi man was seen at an ear, nose, and throat clinic at Riyadh, Saudi Arabia, with bilateral itching in the external auditory canal. On otoscopic examination, the skin lining the ear canal was thickened with whitish sheets of sloughed cells and thick discharge. Large numbers of mites of an undescribed species closely related to members of the genus Loxanoetus (Histiostomatidae) were present. The patient underwent successive washings of the ear canal with saline and 70% ethanol at intervals of 2-3 months and was treated with antibiotics. Treatment with Eurax (crotamiton) ear drops for one week cleared the mite infestation. This represents the first reported case of human otoacariasis involving a histiostomatid mite. Based on the known biology of histiostomatid mites and the associated hosts of Loxanoetus and related genera, there is reason to speculate that the patient acquired the infestation while swimming in a lake or pond where this mite was present.


The morphological analysis of autophagy in primary skeletal muscle cells infected with Toxoplasma gondii.
Toxoplasma gondii is an obligate intracellular protozoan parasite, the causative agent of toxoplasmosis, one of the most widespread zoonoses in the world. During the host immune response, tissue cysts are formed, allowing the maintenance of the parasite within the host cell. Autophagy, a degradation process of cellular components, is critical for cellular homeostasis. Recently, it has been proposed that autophagy participates in host-pathogen interactions. Autophagic inducers (rapamycin or glucose plus serum deprivation) inhibited infection and parasite proliferation in a clinically relevant model of primary skeletal muscle cells (SkMC). The ultrastructural analysis showed in SkMC submitted to autophagic stimuli the presence of structures suggestive of autophagosomes close to the parasitophorous vacuole containing degraded parasites. Fluorescence microscopy results pointed out the increase in LC3 puncta in these cells after incubation with autophagic inducers. In the present study, SkMC autophagy controlled the proliferation of tachyzoites inside the cell, data reinforced by ultrastructural evidences and increased LC3 expression.


An in vitro model for chemical extraction of carbon dioxide via modified peritoneal dialysis.
An in vitro model of a new method for paracorporeal removal of CO2, consisting of modified peritoneal dialysis combined with chemical extraction of predominantly bicarbonate CO2, is presented. The peritoneal cavity was simulated by a bubble oxygenator into which 10% CO2 was diffused. Bicarbonate was initially added, but subsequently regenerated by the system. An insoluble chemical (barium hydroxide lime) was used to precipitate the bicarbonate and produce OH- ions, which prevent the acidosis anticipated with the loss of bicarbonate. CO2 removal was computed from the gas flow rate and CO2 concentration as measured with an infrared analyzer. The rate of CO2 removal was found to be a directly linear function of dialysate flow rate, gas flow rate, and concentration of bicarbonate. The model removed 60 ml/min of CO2, but it is capable of removing more, since the variables affecting CO2 removal are controllable by the observer. This new method can extract bicarbonate CO2 without causing depletion of bicarbonate or requiring an infusion of alkali. It is potentially useful in management of hypercapnic respiratory failure and as an adjunct to "apneic oxygenation" in respiratory distress syndrome.


On the cost and prevention of iatrogenic multiple pregnancies.
Multiple pregnancies are an undesirable complication of IVF and of ovulation induction and/or ovulation enhancement without IVF. Studies based on published population data and data from the Centers for Disease Control and Prevention indicate that savings from the mitigation of iatrogenic multiples would save money in the billions (10(9)) of US dollars on a national basis. The aim of this study was to determine whether, using real data from a major regional insurance carrier for the interval 2005-2009 covering obstetric costs requiring hospitalization and neonatal costs through the first year, it was possible to show that the cost saved by eliminating iatrogenic multiple births would be adequate to fund a protocol to minimize iatrogenic multiple births. The net savings on an annual basis for the study group of 13,478 was about US$4.4 million. Applying the regional findings to national data suggests savings of approximately US$6.3 billion if national iatrogenic multiples were eliminated. These findings indicate that the health insurance industry should be able to offer infertility coverage at a lower rate by requiring a treatment algorithm designed to essentially eliminate iatrogenic multiple pregnancies. It is concluded that efforts should be made to assure a singleton birth when treating infertility.


Biological and clinical significance of cytogenetic abnormalities in low-risk and high-risk gastrointestinal stromal tumors.
We report cytogenetic findings in 19 c-Kit-positive gastrointestinal stromal tumors (GISTs) that represent a heterogenous group of mesenchymal neoplasms with respect to site, histology, and biologic behavior. All of the GISTs (5 low-risk, 11 high-risk, 3 recurrences) displayed clonal chromosomal aberrations; 15 were hypo- to near-diploid, and 4 were near-triploid and hypotetraploid. The most common abnormalities were loss of chromosomes 14 and/or 22, demonstrated in 14 GISTs irrespective of site or predominant phenotype. Ten cases (2 low-risk, 5 high-risk, 3 recurrences) were characterized by loss of both chromosomes 14 and 22, 2 cases (1 low-risk, 1 high- risk), by loss of chromosome 14; and 2 high-risk cases, by loss of chromosome 22. Additional chromosomal aberrations occurred preferentially in high-risk and recurrent GISTs, including loss of 9p and 1p in 8 cases each, loss of 15 in 6 cases, loss of 3p in 5 cases, loss of 13q and 10q in 4 cases each, loss of 19 in 3 cases, and complete or partial gains of chromosomes 5 and 4 in 2 cases each. More significantly, 5 of 6 patients with clinically aggressive GISTs, including 2 recurrences and 3 metastasing GISTs, were additionally characterized by loss of 9p; four of these had additional loss of chromosomes 1p and 15. The presented results herein indicate that loss of chromosome 14 and/or 22 is an early change in GIST tumorigenesis irrespective of site or differentiation, whereas malignant transformation and progression of GISTs appear to be associated with an increasing incidence of additional secondary aberrations.


Square wave adsorptive stripping voltammetric determination of famotidine in urine.
Electrochemical studies of famotidine were carried out using voltammetric techniques: cyclic voltammetry, linear sweep and square wave adsorptive stripping voltammetry. The dependence of the current on pH, buffer concentration, nature of the buffer, and scan rate was investigated. The best results for the determination of famotidine were obtained in MOPS buffer solution at pH 6.7. This electroanalytical procedure enabled to determine famotidine in the concentration range 1x10(-9)-4x10(-8)molL(-1) by linear sweep adsorptive stripping voltammetry (LS AdSV) and 5x10(-10)-6x10(-8)molL(-1) by square wave adsorptive stripping voltammetry (SW AdSV). Repeatability, precision and accuracy of the developed methods were checked. The detection and quantification limits were found to be 1.8x10(-10) and 6.2x10(-10)molL(-1) for LS AdSV and 4.9x10(-11) and 1.6x10(-10)molL(-1) for SW AdSV, respectively. The method was applied for the determination of famotidine in urine.


Comparison of carcinogenesis by two isomers of nitroso-2,6-dimethylmorpholine.
The cis and trans isomers of nitroso-2,6-dimethylmorpholine (Me2NMOR) have been separated and administered to Fischer 344 rats at doses corresponding to their proportion in the mixture prepared from the commercial amine (approximately 2 cis to 1 trans). The mixture of isomers was given at 2 doses, 50 mg per liter of drinking water and 20 mg per liter. A standard volume of each solution was given (20 ml per day per rat) on 5 days of each week and the animals were treated for the same time at either higher or lower dose levels. Almost all of the animals died with basal cell carcinomas and/or papillomas of the upper gastrointestinal tract. The time at which the rats died with the tumors was used as a measure of carcinogenic potency. Survival of the treated animals was consistently longer at the lower dose of each isomer. It was concluded that the trans isomer of Me2NMOR is a more potent carcinogen in rats than the cis isomer.


A pilot study of a new method of cognitive stimulation using abacus arithmetic in healthy and cognitively impaired elderly subjects.
This study explores the applicability of a cognitive stimulation method based on abacus arithmetic in elderly people with and without cognitive impairment. This observational and prospective pilot study was performed in 2 hospitals. The study assessed the applicability of a programme of arithmetic training developed for use in the elderly population. The primary endpoint was an evaluation of the stimulation programme, in terms of usability, satisfaction, and participation, in healthy elderly controls and elderly patients with mild cognitive impairment or Alzheimer disease. Secondary endpoints were family satisfaction, caregiver burden, and the behaviour and cognition of patients. Usability, satisfaction, and degree of participation were high. The Mini-Mental State Examination showed significant changes (23.1±4.8 before the intervention vs 24.9±4.2 afterwards, P=.002); there were no changes on the Trail Making Test parts A and B, Yesavage Geriatric Depression scale, and Zarit caregiver burden scale. The study suggests that cognitive stimulation with abacus arithmetic may be used in elderly people with and without cognitive impairment. Further studies will be needed to evaluate the efficacy of this kind of programmes.


Structure and reactivity of the chromophore of a GFP-like chromoprotein from Condylactis gigantea.
Here we present the study of the chromophore structure of the purple chromoprotein from Condylactis gigantea. Tandem mass spectrometry and 1H and 13C NMR of the chromopeptide reveal that the protein contains a chromophore with a chemical structure identical to that of the red fluorescent protein from Discosoma sp. A single A63G substitution demonstrates that the nature of the first amino acid of the XYG chromophore-forming sequence is dispensable for the chromoprotein red shift development. It has been recently proposed that post-translational reactions at the acylimine, a chemical group that accounts for the red fluorescence, might be an additional source of spectral diversity of proteins homologous to the Aequorea victoria green fluorescent protein (GFP). We have examined the reactivity of the chromophore acylimine group within the C. gigantea purple chromoprotein. Like other proteins with the acylimine-modified chromophore, the purple chromoprotein suffers a hypsochromic spectral shift to the GFP-like absorbance (386 nm) upon mild denaturation. NMR analysis of the chromopeptide suggests this hypsochromic spectral shift is due to H2O addition across the C=N bond of the acylimine. However, unlike the red fluorescent protein from Discosoma sp., denatured under harsh conditions, the wild-type chromoprotein exhibits only slight fragmentation, which is induced by complete hydrolysis of the acylimine. A model suggesting the influence of the amino acid X side chain on protein fragmentation is presented.


New classification of ELPAT for living organ donation.
In the literature, varying terminology for living organ donation can be found. However, there seems to be a need for a new classification to avoid confusion. Therefore, we assessed existing terminology in the light of current living organ donation practices and suggest a more straightforward classification. We propose to concentrate on the degree of specificity with which donors identify intended recipients and to subsequently verify whether the donation to these recipients occurs directly or indirectly. According to this approach, one could distinguish between "specified" and "unspecified" donation. Within specified donation, a distinction can be made between "direct" and "indirect" donation.


Pediatric participation in non-therapeutic research.
United Stated federal regulations allow participation of children in greater than minimal risk research with no potential for direct benefit under narrowly defined circumstances. This type of research is controversial, as it runs contrary to the best interest standard, on which we base most decisions made on behalf of children. I argue that such research is ethically defensible if a fully informed, scrupulous, and virtuous parent would choose to enroll his or her child in the study. Further, I defend the current regulations, which allow local Institutional Review Boards to approve more than minimal risk, nontherapeutic research when the research involves children with the medical condition being studied, but requires federal review for similarly risky studies that involve healthy children. Because families of children with medical diseases tend to be more familiar with the health care system and with medical procedures, they are more able to make informed decisions about the burdens of research participation. Further, parents of children with medical conditions have a morally significant interest in advancing medical knowledge about their child's condition. It is appropriate to take this interest into account when evaluating the ethical status of a research study.


A prospective study of congenital malformations among live born neonates at a University Hospital in Western Saudi Arabia.
To estimate the incidence of major and minor congenital malformations among liveborn infants at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Estimation of risk factors were also evaluated. Between March 2004 and May 2005, a total of 5356 babies born at King Abdulaziz University Hospital, were enrolled in this study for malformations. Details of cases were recorded after parents' interviews, clinical, radiological, and laboratory evaluations. One hundred and forty-seven (27.06/1000 livebirth) and 13 (2.39/1000 birth) stillbirth had congenital anomalies. In all livebirth, incidences of major anomalies were 93.9% and minor were 6.1%. Mothers of 95.9% with congenital malformation were healthy, 3.4% were diabetic and 0.7% had cardiac malfomation. In 38.8% of cases parents were consanguineous. Among the liveborn births, the most common system involved was cardiovascular (7.1/1000), followed by musculoskeletal/limb (4.1/1000), external genitalia (2.8/1000), urinary (2.6/1000), multiple chromosomal (2.2/1000), orofacial (1.9/1000), central nervous system (1.9/1000), skin (1.7/1000), multiple single gene (1.3/1000), multiple sequence (0.75/1000), eyes (0.56/1000), unclassified (0.19/1000), musculoskeletal/abdominal (0.19/1000), endocrine (0.19/1000). High incidence of major malformation in Jeddah. Importance of Genetic Counseling is revealed in our study since more than three quarters of mothers were under 36 years, and may well plan future pregnancies.


Suboptimal activation of CD8(+) T cells by melanoma-derived altered peptide ligands: role of Melan-A/MART-1 optimized analogues.
Suboptimal activation of T lymphocytes by tumor cells may contribute to the failure of the immune system to control tumor growth. We recently demonstrated that Melan-A/MART-1-reactive CTLs can be anergized by peptide analogues with partial agonist/antagonist functions, which selectively impair interleukin (IL)-2 release. Here we analyze the potential expression of partial agonist/antagonist peptides by tumor cells and their role in suboptimal T-cell activation. HLA-bound peptide fractions were eluted from HLA-A*0201/Melan-A/MART-1(+) melanoma cells and analyzed for reconstitution of the MART-1-specific T-cell epitope. Among the peptide fractions able to induce IFN-gamma release by MART-1-specific T cells, only fraction 43-44 activated IL-2 production by anti-MART-1 T cells, whereas the remaining two fractions acted as peptide antagonists by inhibiting IL-2 release in response to the native epitope. A comparable down-modulation of IL-2 release could also be induced by the MART-1-derived peptide 32-40, previously identified in one of the two anergizing fractions. A substantial deficit in IL-2 release was additionally detected in tumor-specific CD8(+) T cells infiltrating melanoma lesions. To overcome IL-2 impairment by peptide antagonists, anti-MART-1 T cells were generated by in vitro sensitization with the two optimized analogues Melan-A/MART-1(27-35) 1L (with superagonist features) and Melan-A/MART-1(26-35) 2L (with improved HLA-A*0201 binding). T cells raised with the superagonist Melan-A/MART-1(27-35) 1L showed resistance to the inhibition of IL-2 release mediated by melanoma-derived peptide fractions, whereas Melan-A/MART-1(26-35) 2L-specific T cells appeared to be as sensitive as T cells raised with the parental epitope. This resistance was associated with the enhanced ability of Melan-A/MART-1(27-35) 1L-specific T cells to release IL-2. Taken together, these data indicate that melanoma cells can process and present on their surface peptides inhibiting optimal T-cell activation against immunodominant epitopes and that the usage of optimized peptide analogues could represent a promising approach for overcoming tumor-induced immunosuppression and possibly designing more successful vaccines for cancer patients.


Folding of single-stranded circular DNA into rigid rectangular DNA accelerates its cellular uptake.
Despite the importance of the interaction between DNA and cells for its biological activity, little is known about exactly how DNA interacts with cells. To elucidate the relationship between the structural properties of DNA and its cellular uptake, a single-stranded circular DNA of 1801 bases was designed and folded into a series of rectangular DNA (RecDNA) nanostructures with different rigidities using DNA origami technology. Interactions between these structures and cells were evaluated using mouse macrophage-like RAW264.7 cells. RecDNA with 50 staple DNAs, including four that were Alexa Fluor 488-labeled, was designed. RecDNA with fewer staples, down to four staples (all Alexa Fluor 488-labeled), was also prepared. Electrophoresis and atomic force microscopy showed that all DNA nanostructures were successfully obtained with a sufficiently high yield. Flow cytometry analysis showed that folding of the single-stranded circular DNA into RecDNA significantly increased its cellular uptake. In addition, there was a positive correlation between uptake and the number of staples. These results indicate that highly folded DNA nanostructures interact more efficiently with RAW264.7 cells than loosely folded structures do. Based on these results, it was concluded that the interaction of DNA with cells can be controlled by folding using DNA origami technology.


Diagnosis of amyloid neuropathy.
Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis and the acquired light-chain amyloidosis, the result of a plasma cell dyscrasia, are multisystem disorders with cardiovascular, autonomic and peripheral nerve involvement. There are numerous investigational modalities available to diagnose systemic amyloidosis and to assess the extent of organ involvement, but it is frequently misdiagnosed due to its heterogeneous clinical presentations and misleading investigation findings. An accurate and timely diagnosis of amyloid neuropathy can greatly impact on the outcomes for patients, especially as there will soon be new gene-silencing treatments for hereditary transthyretin amyloidosis.


Soluble Mucosal Addressin Cell Adhesion Molecule 1 and Retinoic Acid are Potential Tools for Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease Treated with Vedolizumab: A Proof of Concept Study.
Vedolizumab [VDZ], a humanized monoclonal antibody targeting α4β7 integrin, is effective in induction and maintenance therapy in patients with inflammatory bowel disease [IBD] who have not adequately responded to standard therapies, and high vedolizumab trough levels [VTLs] have been associated with clinical remission. The α4β7 integrin binds to endothelial MAdCAM-1 and is upregulated by retinoic acid [RA]. The aim of this study was to determine the relationships between soluble MAdCAM-1 [sMAdCAM-1] and RA concentrations during clinical remission with VDZ maintenance therapy. In a retrospective study performed in IBD patients treated with VDZ, we measured VTL, sMAdCAM-1 and RA concentrations. Among the 62 included patients [38 Crohn's disease], 24 relapsed and 38 stayed in remission from Weeks 10 to 30 after VDZ initiation. During this maintenance therapy, the median values of VTLs and RA were 15.4 µg/mL and 0.97 ng/mL, respectively, whereas sMAdCAM-1 was undetectable [<0.41 ng/mL] in 67.3% of samples. The positive predictive value [PPV] of undetectable sMAdCAM-1 for clinical remission was 80.0%, with a corresponding sensitivity of 74.6%. On multivariate analysis, undetectable sMAdCAM-1 and high VTLs [>19 µg/mL] were independently associated with clinical remission [OR = 7.5, p = 0.006 and OR = 2.2, p = 0.045, respectively]. The combination of sMAdCAM-1 < 0.41 ng/mL and VTL > 19 µg/mL was the best pharmacokinetic profile, with a PPV of 95.2%. Median values of sMAdCAM-1 and RA were significantly higher [p = 0.0001] before VDZ therapy than during the follow-up [sMAdCAM-1: 40.5 vs < 0.41 ng/mL; RA: 1.7 vs 0.97 ng/mL]. Only RA > 1.86 ng/mL before VDZ therapy was predictive of clinical remission during the follow-up (Area Under a Receiver Operating Characteristic curve [AUROC] = 80.7%). Undetectable sMAdCAM-1 appears strongly associated with clinical remission during VDZ maintenance therapy. Combination of undetectable sMAdCAM-1 with high VTL is also potentially interesting for therapeutic drug monitoring. Baseline RA concentrations are predictive of clinical remission. These findings need to be confirmed in further prospective studies.


Tufted angioma of the maxilla: a rare case with unique clinical presentation.
Tufted angioma is an uncommon benign vascular tumor usually presenting in early childhood and affecting mainly the skin. It has been associated with Kasabach-Merritt syndrome, a severe coagulopathy of poor prognosis. There have been very few published cases of oral tufted angiomas, and maxillary bone involvement has not been hitherto reported. We present a case of a 10-year-old Caucasian boy with an erythematous left maxillary gingival mass accompanied by subjacent hard tissue swelling. Radiologic evaluation revealed an irregular mixed radiolucent and radiopaque area in the left maxilla, accompanied by alveolar ridge erosion, cortical plate expansion, and displacement and divergence of the premolars. The histopathologic examination showed scattered irregular tufted lobules of variably sized vascular spaces inside the subepithelial connective tissue and among the underlying bone trabeculae, exhibiting a "cannonball" appearance. Immunohistochemical evaluation found positivity for CD31, CD34, and smooth muscle actin, and a final diagnosis of tufted angioma with osseous involvement was rendered. A thorough review of the pertinent literature revealed only 9 previously published intraoral tufted angioma cases, the salient demographic and clinicopathologic features of which are summarized.


Brain scale-free properties in awake rest and NREM sleep: a simultaneous EEG/fMRI study.
Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) studies revealed that spontaneous activity in the brain has scale-invariant properties, as indicated by a frequency spectrum that follows a power-law distribution. However, current knowledge about the exact relationship between scaling properties in EEG and fMRI signals is very limited. To address this question, we collected simultaneous EEG-fMRI data in healthy individuals during resting wakefulness and non-rapid eye movement (NREM) sleep. For either of these conditions, we found that both EEG and fMRI power spectra followed a power-law distribution. Furthermore, the EEG and fMRI scaling exponents were highly variable across subjects, and sensitive to the choice of reference and nuisance variables in EEG and fMRI data, respectively. Interestingly, the EEG exponent of the whole brain selectively corresponded to the fMRI exponent of the thalamus during NREM sleep. Together, our findings suggest that scale-free brain activity is characterized by robust temporal structures and behavioral significance. This motivates future studies to unravel its physiological mechanisms, as well as its relevance to behavior.


Npr2 null mutants show initial overshooting followed by reduction of spiral ganglion axon projections combined with near-normal cochleotopic projection.
Npr2 (natriuretic peptide receptor 2) affects bifurcation of neural crest or placode-derived afferents upon entering the brain stem/spinal cord, leading to a lack of either rostral or caudal branches. Previous work has shown that early embryonic growth of cochlear and vestibular afferents is equally affected in this mutant but later work on postnatal Npr2 point mutations suggested some additional effects on the topology of afferent projections and mild functional defects. Using multicolor lipophilic dye tracing, we show that absence of Npr2 has little to no effect on the initial patterning of inner ear afferents with respect to their dorsoventral cochleotopic-specific projections. However, in contrast to control animals, we found a variable degree of embryonic extension of auditory afferents beyond the boundaries of the anterior cochlear nucleus into the cerebellum that emanates only from apical spiral ganglion neurons. Such expansion has previously only been reported for Hox gene mutants and implies an unclear interaction of Hox codes with Npr2-mediated afferent projection patterning to define boundaries. Some vestibular ganglion neurons expand their projections to reach the cochlear apex and the cochlear nuclei, comparable to previous findings in Neurod1 mutant mice. Before birth, such expansions are reduced or lost leading to truncated projections to the anteroventral cochlear nucleus and expansion of low-frequency fibers of the apex to the posteroventral cochlear nucleus.


[Neoplastic development of laryngeal amyloidosis. Apropos of a case].
The authors report the case of a 62 years old patient who presented a squamous laryngeal carcinoma 8 years after the discovery of amyloidosis localized to one vocal cord. In this patient, a relationship would seem to exist between the two pathologies, with degeneration of amyloidosis being responsible, though a random coexistence cannot, of course, be completely excluded. After a review of laryngeal amyloidosis and its management, this particular case is discussed in relation to other cases described in the literature.


In-vitro profile of a new beta-lactam, ceftobiprole, with activity against methicillin-resistant Staphylococcus aureus.
Ceftobiprole is a novel, broad-spectrum cephalosporin with in-vitro activity against common Gram-positive and Gram-negative organisms. It forms a stable inhibitory complex with Staphylococcus aureus penicillin-binding protein (PBP) 2' (2a), resulting in enhanced activity against methicillin-resistant S. aureus (MRSA). In recent studies of methicillin-susceptible S. aureus, the ceftobiprole MIC(90) value was most frequently < or =1.0 mg/L (MIC range < or =0.25-1.0 mg/L). For MRSA, MIC(90) values were generally 2.0 mg/L (MIC range < or =0.06-4.0 mg/L). MICs for all streptococcal species, except penicillin-resistant Streptococcus viridans but including penicillin-resistant Streptococcus pneumoniae, ranged from < or =0.008 to 2.0 mg/L. Ceftobiprole is active against Enterococcus faecalis (MIC(90) = 4 mg/L), but not generally active against Enterococcus faecium (MIC(90) > 16 mg/L). Ceftobiprole displayed bactericidal activity against Gram-negative pathogens comparable to that of cefepime, ceftazidime or piperacillin-tazobactam in early studies. However, recent data show activity against Pseudomonas aeruginosa similar to that of cefepime but less than that of ceftazidime. Ceftobiprole, like cefepime, is stable in the presence of most class A non-extended spectrum beta-lactamases and inducible class C beta-lactamases. Ceftobiprole is a poor inducer of AmpC beta-lactamase and a poor substrate for hydrolysis by AmpC beta-lactamase. Studies of ceftobiprole in several animal models have demonstrated potent in-vivo efficacy against infections caused by MRSA, including strains intermediately resistant to vancomycin. It was also efficacious in murine infections caused by Gram-negative bacteria with MIC values < or =2 mg/L. The broad spectrum of activity demonstrated by ceftobiprole in vitro and in vivo suggests that it may have potential for empirical treatment of suspected Gram-negative and Gram-positive infections, including those caused by MRSA.


Traceability of biotech-derived animals: application of DNA technology.
Traceability is increasingly becoming standard across the agri-food industry, largely driven by recent food crises and the consequent demands for transparency within the food chain. This is leading to the development of a range of traceability concepts and technologies adapted to different industry needs. Experience with genetically modified plants has shown that traceability can play a role in increasing public confidence in biotechnology, and might similarly help allay concerns relating to the development of animal biotechnology. Traceability also forms an essential component of any risk management strategy and is a key requirement for post-marketing surveillance. Given the diversity of traceability concepts and technologies available, consideration needs to be given to the scope and precision of traceability systems for animal biotechnology. Experience to date has shown that conventional tagging and labelling systems can incorporate levels of error and may not have sufficient precision for biotech-derived animals. Deoxyribonucleic acid (DNA) technology can overcome these difficulties by tracing animals and animal by-products through their DNA code rather than an associated label. This offers the possibility of tracing some by-products of animal biotechnology through the supply chain back to source animals, offering unprecedented levels of traceability. Developments in both DNA sampling and analysis technology are making large-scale applications of DNA traceability increasingly cost effective and feasible, and are likely to lead to a broader uptake of DNA traceability concepts.


Physical fitness prospects in the elderly.
Approximately 44% of the population over age 65 has some degree of physical disability; the prevalence increases with age, particularly for women. Methods for measuring functional activity in the elderly have been reported for approximately 25 years, but there is disagreement and ambiguity about the purposes and circumstances of measurement. A summary of a panel report of the 1981 National Conference of Fitness and Aging includes major pathophysiologic changes associated with aging and beneficial physiologic effects of exercise in the elderly. Studies substantiate the beneficial effects of physical exercise and rhythmic and movement therapy. Physical fitness programs impact on the restoration and preservation of health, particularly in the geriatric population. Physicians should take the initiative in establishing guidelines for these programs to ensure their timeliness and appropriateness.


In situ delivery of bone marrow cells and mesenchymal stem cells improves cardiovascular function in hypertensive rats submitted to myocardial infarction.
This work aimed to evaluate cardiac morphology/function and histological changes induced by bone marrow cells (BMCs) and cultured mesenchymal stem cells (MSCs) injected at the myocardium of spontaneously hypertensive rats (SHR) submitted to surgical coronary occlusion. Female syngeneic adult SHR, submitted (MI) or not (C) to coronary occlusion, were treated 24 h later with in situ injections of normal medium (NM), or with MSCs (MSC) or BMCs (BM) from male rats. The animals were evaluated after 1 and 30 days by echocardiography, histology of heart sections and PCR for the Y chromosome. Improved ejection fraction and reduced left ventricle infarcted area were observed in MSC rats as compared to the other experimental groups. Treated groups had significantly reduced lesion tissue score, increased capillary density and normal (not-atrophied) myocytes, as compared to NM and C groups. The survival rate was higher in C, NM and MSC groups as compared to MI and BM groups. In situ injection of both MSCs and BMCs resulted in improved cardiac morphology, in a more physiological model of myocardial infarction represented by surgical coronary occlusion of spontaneously hypertensive rats. Only treatment with MSCs, however, ameliorated left ventricle dysfunction, suggesting a positive role of these cells in heart remodeling in infarcted hypertensive subjects.


pVHL interacts with Ceramide kinase like (CERKL) protein and ubiquitinates it for oxygen dependent proteasomal degradation.
Mutations of Ceramide kinase-like (CERKL) gene are associated with retinitis pigmentosa (RP), an inherited degenerative eye disease. CERKL encodes an antioxidant protein which is critical to photoreceptor survival, its deficiency causes retinal degeneration as a result of oxidative damage. However, the regulation of CERKL in response to oxidative stress, and its contribution to photoreceptor survival remain unclear. pVHL, the substrate receptor of RING finger-type SCF like ECV ubiquitin ligase, binds and ubiquitinates a number of hydroxylated proteins for proteasomal degradation. Due to hydroxylated proteins which are modified by PHD1-3, pVHL dependent ubiquitin-proteasomal degradation pathway is blocked by PHD1-3 inhibitors (e.g. hypoxia or oxidative stress). In this study, we identified pVHL as an important regulator of CERKL. Western blot and in vivo ubiquitination assays showed hypoxia up-regulates CERKL at protein level by down-regulating its poly-ubiquitination. By Co-IP and domain mapping studies, we found CERKL complexes with ECV ligase via pVHL. Through overexpression and small RNA interference analysis, we demonstrated pVHL ubiquitinates CERKL for proteasomal degradation. Additionally, our work showed that the oxygen sensors PHD1 and PHD3 are involved in CERKL degradation. Collectively, our results indicated that pVHL interacts with CERKL and ubiquitinates it for oxygen dependent proteasomal degradation.


Cadmium-induced proximal tubular dysfunction in a cadmium-polluted area.
Health examinations were performed in 147 people living in a cadmium-polluted area, Kosaka Town, Japan. 33 of 147 residents had some indications of proximal tubular dysfunction, such as renal glucosuria, tubular proteinuria, and aminoaciduria, and 10 of them were diagnosed as having multiple proximal tubular dysfunctions. Detailed examinations revealed that none of the cases had any causal diseases other than chronic cadmium poisoning. Residents' mean cadmium intake and mean urinary cadmium concentration were over 3 times as high as those in control areas. From these findings, renal lesions identified in these residents were concluded as chronic cadmium poisoning induced by environmental cadmium pollution.


[Effects of elevated atmospheric CO2 concentration on endogenous hormones in gingko leaves].
With top-opened chamber system, this paper studied the responses of endogenous hormones abscisic acid (ABA), indoleacetic acid (IAA), zeatin riboside (ZR) and gibberellins (GA3) in gingko leaves to elevated atmospheric CO2 concentration (ambient + 350 micromol x mol(-1), EC). The results showed that EC could decrease the ABA content. After treated with EC for 120 days, the ABA content could be decreased by 63.0%, in comparing with the control. EC could also decrease the contents of IAA and ZR, and the decrement could reach significant with the extension of the treatment. The IAA content was 2 times higher after 100 days treatment, and ZR content was 2.5 times higher after 80 days treatment than those of CK. Under EC, the peak of GA3 appeared earlier. The (IAA + GA3 + ZR)/ABA ratio decreased gradually with the growth of gingko, and was obviously higher than the control at later stage (after 40-60 days treatment), indicating that elevated atmospheric CO2 concentration could promote the growth and development of gingko.


[Clinical analysis of 62 cases of chronic thromboembolic pulmonary hypertension treated with pulmonary thromboendarterectomy without early and late deaths].
To retrospectively evaluate the effects of pulmonary thromboendarterectomy (PTE) on chronic thromboembolic pulmonary hypertension (CTEPH). Sixty-two cases of CTEPH operated with PTE from October 2002 to September 2008 at Anzhen Hospital were retrospectively reviewed and were assigned into either proximal CTEPH group (n = 46) or distal CTEPH group (n = 16). No early death was reported. 15 had residual pulmonary hypertension and 23 had pulmonary reperfusion injury postoperatively. And reperfusion injury was recovered with the support of ventilation or ECMO. Between pre and post-procedure, the pulmonary artery systolic pressure changed from 91 +/- 38 mm Hg to 53 +/- 21 mm Hg, the pulmonary vascular resistance from 916 +/- 548 dynxsxcm(-5) to 368 +/- 302 dynxsxcm(-5) (t = 6.896, P = 0.0001), and the arterial partial pressure of oxygen (PaO(2)) from 51 +/- 7 mm Hg to 90 +/- 7 mm Hg and the arterial oxygen saturation (SaO(2)) from 87.0% +/- 3.9% to 96.1% +/- 3.3%, P < 0.05. With the follow-up of (24.8 +/- 14.6) months (cumulative follow-up was 121.6 patient-years), there was no late death and 38 were in NYHA functional class I, 20 class II, 2 class III and 2 class IV. According to Kaplan-Meier actuarial curve, the freedom from reembolism at 3 years was 96.7% +/- 2.8%. The linear bleeding rate related to anticoagulation was 2.47% patient-years, and the linear thromboembolic rate related to anticoagulation is 1.64% patient-years. The early and mid-long term survival rate of PTE procedure on CTEPH is acceptable and the complication rate related to anticoagulation with warfarin is relatively low.


Multiple levels of sensory integration in the intrinsic sensory neurons of the enteric nervous system.
1. The enteric nervous system (ENS) is present in the wall of the gastrointestinal tract and contains all the functional classes of neuron required for complete reflex arcs. One of the most important and intriguing classes of neuron is that responsive to sensory stimuli: sensory neurons with cell bodies intrinsic to the ENS. 2. These neurons have three outstanding and interrelated features: (i) reciprocal connections with each other; (ii) a slow excitatory post-synaptic potential (EPSP) resulting from high-speed firing in other sensory neurons; and (iii) a large after-hyperpolarizing potential (AHP) at the soma. Slow EPSP depolarize the cell body, generate action potentials (APs) and reduce the AHP. Conversely, the AHP limits the firing rate and, hence, reduces transmission of slow EPSP. 3. Processing of sensory information starts at the input terminals as different patterns of APs depending on the sensory modality and recent sensory history. At the soma, the ability to fire APs and, hence, drive outputs is also strongly determined by the recent firing history of the neuron (through the AHP) and network activity (through the slow EPSP). Positive feedback within the population of intrinsic sensory neurons means that the network is able to drive outputs well beyond the duration of the stimuli that triggered them. 4. Thus, sensory input and subsequent reflex generation are integrated over several hierarchical levels within the network on intrinsic sensory neurons.


Antithrombotic therapy in peripheral arterial disease.
The management of elderly patients with peripheral arterial disease requires a multidisciplinary and individualized approach, especially for patients requiring intervention and for those on antithrombotic therapy. Communication between the patient's primary physician, consulting medical specialists, and vascular surgeon is essential because all may contribute synergistically to deliver optimal care to the patient. This article reviews the pathophysiology of peripheral arterial disease, and data regarding the use of antiplatelet and anticoagulant agents.


Breast cancer screening: controversies and future directions.
Recent criticisms of the mature breast cancer screening trials claimed that there is no evidence that screening saves lives. This has developed into a major public controversy, causing physicians, women, and policy analysts to rethink and debate mammography-screening guidelines. We have studied this subject from a different perspective -- using computer simulation to fit a simple growth model to clinical data. We can thus provide another viewpoint of the screening controversy that may help elucidate the underlying biology and aid policy makers in devising sound screening guidelines. We agree with some reviewers that there is partial validity to the criticism. Based on our studies, we have arrived at a new explanation of why screening has not lived up to expectations. Our fundamental hypothesis is that breast cancers often undergo periods during which they are temporarily dormant. In addition, surgical intervention to remove primary tumors can interrupt this dormancy. Therefore screening finds smaller tumors with fewer positive lymph nodes, which is beneficial. But then the resulting extirpation accelerates the growth of dormant distant micrometastases, and results in earlier relapses than in women who have not been screened. This partly offsets the early detection advantage. One hypothetical mechanism proposed to explain this biology is that surgical wounding, particularly for premenopausal node-positive patients, can trigger the angiogenesis of dormant avascular micrometastases.


Trends in Pediatric Emergency Department Visits for Mental Health Conditions and Disposition by Presence of a Psychiatric Unit.
To examine trends in mental health (MH) visits to pediatric emergency departments (EDs) and identify whether ED disposition varies by presence of a hospital inpatient psychiatric unit (IPU). Cross-sectional study of 8,479,311 ED visits to 35 children's hospitals from 2012 to 2016 for patients aged 3 to 21 years with a primary MH or non-MH diagnosis. Multivariable generalized estimating equations and bivariate Rao-Scott chi-square tests were used to examine trends in ED visits and ED disposition by IPU status, adjusted for clustering by hospital. From 2012 to 2016, hospitals experienced a greater increase in ED visits with a primary MH versus non-MH diagnosis (50.7% vs 12.7% cumulative increase, P < .001). MH visits were associated with patients who were older, female, white non-Hispanic, and privately insured compared with patients of non-MH visits (all P < .001). Forty-four percent of MH visits in 2016 had a primary diagnosis of depressive disorders or suicide or self-injury, and the increase in visits was highest for these diagnosis groups (depression: 109.8%; suicide or self-injury: 110.2%). Among MH visits, presence of a hospital IPU was associated with increased hospitalizations (34.6% vs 22.5%, P < .001) and less transfers (9.2% vs 16.2%, P < .001). The increase in ED MH visits from 2012 to 2016 was 4 times greater than non-MH visits at US children's hospitals and was primarily driven by patients diagnosed with depressive disorders and suicide or self-injury. Our findings have implications for strategic planning in tertiary children's hospitals dealing with a rising demand for acute MH care.


Oxalate consumption by lactobacilli: evaluation of oxalyl-CoA decarboxylase and formyl-CoA transferase activity in Lactobacillus acidophilus.
This study was undertaken to evaluate the oxalate-degrading activity in several Lactobacillus species widely used in probiotic dairy and pharmaceutical preparations. Functional characterization of oxalyl-CoA decarboxylase and formyl-CoA transferase in Lactobacillus acidophilus was performed in order to assess the possible contribution of Lactobacillus in regulating the intestinal oxalate homeostasis. In order to determine the oxalate-degrading ability in 60 Lactobacillus strains belonging to 12 species, a screening was carried out by using an enzymatic assay. A high variability in the oxalate-degrading capacity was found in the different species. Strains of Lact. acidophilus and Lactobacillus gasseri showed the highest oxalate-degrading activity. Oxalyl-CoA decarboxylase and formyl-CoA transferase genes from Lact. acidophilus LA14 were cloned and sequenced. The activity of the recombinant enzymes was assessed by capillary electrophoresis. Strains of Lactobacillus with a high oxalate-degrading activity were identified. The function and significance of Lact. acidophilus LA14 oxalyl-CoA decarboxylase and formyl-CoA transferase in oxalate catabolism were demonstrated. These results suggest the potential use of Lactobacillus strains for the degradation of oxalate in the human gut. Identification of probiotic strains with oxalate-degrading activity can offer the opportunity to provide this capacity to individuals suffering from an increased body burden of oxalate and oxalate-associated disorders.


Calcium metabolism, serum thyroid-stimulating hormone, prolactin, and growth hormone in spontaneously hypercholesterolemic rats.
We have shown previously that spontaneously hypercholesterolemic (SHC) rats exhibit abnormal bone metabolism with advanced bone resorption, which develops with age. In this study, we measured serum levels of growth hormone, thyroid-stimulating hormone, and prolactin in addition to several parameters of calcium metabolism and renal function in young (6-week) and old (24-week) SHC rats and compared these with age-matched Sprague-Dawley rats. In young SHC rats, urinary excretion of hydroxyproline and serum levels of calcium were significantly elevated and excretion of protein into urine and urea nitrogen in the serum were normal, suggesting that calcium metabolism was abnormal without kidney dysfunction at this age. Serum growth hormone and thyroid-stimulating hormone levels were markedly higher (20- to 30-fold and 4- to 5-fold, respectively) in young and old SHC rats, whereas serum prolactin levels were similar. A high level of serum thyroid-stimulating hormone was associated with elevated levels of thyroxine and triiodothyronine in young SHC rats, but not old ones. These results demonstrate that the rat exhibits abnormalities in endocrine function as well as calcium metabolism preceding the occurrence of renal dysfunction.


Clifton Briggs Leech: first director of the pediatric cardiac clinic at the Johns Hopkins Harriet Lane Home for Invalid Children.
The history of Helen Taussig is well known. Contrary to popular belief, however, she was not the first director of the pediatric cardiology clinic at the Harriet Lane Home for Invalid Children. She was second director, succeeding Clifton B. Leech. Edwards A. Park, Chief of Pediatrics at Johns Hopkins, appointed Leech the first director of the pediatric cardiac clinic in the fall of 1928. In this vignette, I summarize the contributions of Clifton Leech to the development of paediatric cardiology.


An anaerobic dynamic membrane bioreactor (AnDMBR) for landfill leachate treatment: performance and microbial community identification.
In this study, a pilot-scale anaerobic dynamic membrane bioreactor was operated for 142days for treating landfill leachate. Under stable operation, average COD removal efficiency of 62.2% was achieved when the reactor was fed with the raw leachate containing total ammonium concentration above 3000mg/L and COD above 13,000mg/L. The methane content in the biogas was in the range of 70-90%, and the average methane yield was 0.34L/g CODremoved at the organic loading rate of 4.87kg COD/(m(3)d). Pyrosequencing analyses indicated that during the operation the archaeal community was relatively stable while obvious changes took place in the bacterial community. Alkaliphilus, Petrimonas, Fastidiosipila and vadinBC27 were the abundant fermentation bacteria in bacterial communities. Moreover, phylum TM6 gradually became the most dominant bacterial community and reached the highest relative abundance of 32.9% as the operation elapsed. In archaeal communities, genus Methanosarcina was identified as the dominant methanogen.


[In vitro antimicrobial, antiadherent and antifungal activity of Brazilian medicinal plants on oral biofilm microorganisms and strains of the genus Candida].
The antimicrobial, antifungal and antiadherent activity of aroeira-do-sertão, mallow and guava tree on oral biofilm microorganisms and oral candidiasis was evaluated in vitro. The extracts were shown to be effective in inhibiting the growth of bacteria of the oral biofilm and fungi of oral candidiasis, thus suggesting that these extracts can be used as alternative means of dental therapy.


The secondary antibody response induced in tissue cultures.
The conditions for induction of memory cells (B-MC) and evocation of the secondary antibody (Ab) response in tissue cultures (TC) were estimated. (1) In vivo primed B-MC cells were isolated 6-150 d after priming and stimulated in TC with different doses of sheep red blood cell (SRBC) antigen. The Ab response has a strict time and dose dependence: only small doses (10(5)) evoke a secondary response, high doses (10(8), 10(9)) a state of immediate tolerance. (2) Antigen added to TC directly with B-MC rescued their Ab production for a long period. Addition of the antigen 1 or 2 d after setting the TC, follows the Ab-response decay, comparable with virgin cells (B-ICC). (3) Primed B-MC stimulated in TC responded preferentially with an IgM secondary response; the same cell suspension adoptively transferred into isologous recipients switched into IgG cells. (4) Virgin, immunocompetent, B-ICC were primarily stimulated in TC with a small dose of antigen (10(5) SRBC); after 7 d of cultivation the cells were transferred into isologous recipients, SCID mice and into TC. In all cases, the secondary response of IgM was determined, 10 times higher than in the primary controls.


Modelling climate change: the role of unresolved processes.
Our understanding of the climate system has been revolutionized recently, by the development of sophisticated computer models. The predictions of such models are used to formulate international protocols, intended to mitigate the severity of global warming and its impacts. Yet, these models are not perfect representations of reality, because they remove from explicit consideration many physical processes which are known to be key aspects of the climate system, but which are too small or fast to be modelled. The purpose of this paper is to give a personal perspective of the current state of knowledge regarding the problem of unresolved scales in climate models. A recent novel solution to the problem is discussed, in which it is proposed, somewhat counter-intuitively, that the performance of models may be improved by adding random noise to represent the unresolved processes.


The area postrema: a brain monitor and integrator of systemic autonomic state.
The area postrema is a medullary structure lying at the base of the fourth ventricle. The area postrema's privileged location outside of the blood-brain barrier make this sensory circumventricular organ a vital player in the control of autonomic functions by the central nervous system. By virtue of its lack of tight junctions between endothelial cells in this densely vascularized structure and the presence of fenestrated capillaries, peptide and other physiological signals borne in the blood have direct access to neurons that project to brain areas with important roles in the autonomic control of many physiological systems, including the cardiovascular system and systems controlling feeding and metabolism. However, the area postrema is not simply a conduit through which signals flow into the brain, but it is now being recognized as the initial site of integration for these signals as they enter the circuitry of the central nervous system.


Exogenous rh-urokinase modifies inflammation and Pseudomonas aeruginosa infection in a rat chronic pulmonary infection model.
The effect of recombinant human urokinase (rh-UK) in a rat model of chronic Pseudomonas aeruginosa pulmonary infection was studied. Efficacy was assessed by lung histology and quantitative bacteriology. Male Sprague-Dawley rats received 1 x 10(4) or 1 x 10(5) P. aeruginosa encapsulated in agar beads via the intratracheal route on day 1. Intratracheal administration of up to 12,500 units of rh-UK on day 21 led to a dose-dependent disappearance of viable organisms from the lungs by day 24 in rats receiving 10(4) organisms. In slightly longer term infections (30 days), rh-UK was still effective in facilitating the disappearance of the organisms from the lungs of most of the treated animals. rh-UK was effective in eliminating organisms when animals were infected with 10(4), but not 10(5) bacteria. In vitro analysis revealed that rh-UK was not directly toxic for the organisms. Histologically, lungs from short-term infected control animals exhibited acute inflammation, inflammatory cell infiltrates, and fibrin deposition. Histology of lungs from UK-treated, short-term infected rats revealed decreased airway inflammation and cellular infiltration compared with infected controls. Lungs from infected animals treated with 12,500 units of rh-UK were histologically indistinguishable from the lungs of uninfected control animals, except for the foreign body reaction. These results indicate that exogenous rh-UK may be efficacious in the treatment of pulmonary inflammation accompanying exposure to Gram-negative bacteria such as P. aeruginosa.


Two-dimensional circularly polarized IR photon echo spectroscopy of polypeptides: four-wave-mixing optical activity measurement.
A coherent two-dimensional (2D) optical spectroscopy utilizing circularly polarized (CP) beams, which was shown to be useful in studying molecular chirality in condensed phases, was theoretically proposed recently [Cho et al. J. Chem. Phys. 2003, 119, 7003]. A photon echo (PE) version of 2D optical activity spectroscopy is discussed in this paper. Considering various dipeptide and polypeptide systems, where the amide I local modes constitute the set of basis modes used to describe exciton and biexciton states as linear combinations of those basis modes, we present numerically simulated 2D circularly polarized IR PE spectra. It is shown that this novel spectroscopic method can provide additional information on the angles between the transition magnetic dipole and the transition electric dipole of two different vibrationally excited states, which are highly sensitive to the 3D structure and chirality of a given polypeptide. Also, a hierarchical relation of IR absorption, vibrational circular dichroism, 2D IR PE, and 2D CP-IR PE is discussed to show advantages of 2D optical activity spectroscopy in general.


Gender-dependent effects of high-fat lard diet on cardiac function in C57Bl/6J mice.
Increased availability of fatty acids released from insulin-resistant adipose tissue may lead to excess fatty acid uptake in nonadipose organs, including the heart. Accumulation of toxic fatty acid intermediates may affect cardiac function. Our aim was to identify to which extent high-fat diet feeding leads to alterations in cardiac function and whether this depends on gender and (or) duration of high-fat diet feeding. Male and female C57Bl/6J mice (n = 8 per group) of 12 to 16 weeks old were fed a low-fat (10% energy) or high-fat (45% energy) lard diet for 6 or 12 weeks. Plasma lipid levels, echocardiography, and left ventricular pressure-volume relationships were obtained at 2, 1, and 0 weeks before termination, respectively. In both male and female mice, the high-fat diet increased body weight and plasma lipid content. At 10 weeks, significant increases were observed for plasma total cholesterol (males: +44%; females: +86%), phospholipids (+16% and +34%), and triglycerides (+27% and +53%) (all p < 0.001). In male mice, but not in female mice, the high-fat diet significantly affected cardiac function at 12 weeks with increased end-systolic volume (25.4 ± 6.2 vs. 17.0 ± 6.7 µL, p < 0.05), increased end-systolic pressure (72.1 ± 6.9 vs. 63.6 ± 6.9 mm Hg, p < 0.01), and decreased ejection fraction (61.2% ± 4.5% vs. 68.1% ± 3.7%, p < 0.01), indicating reduced systolic function. Multiple linear regression analysis indicated a significant diet-gender interaction for end-systolic volume and ejection fraction. In conclusion, high-fat diet feeding increased body weight and plasma lipid levels in male and in female mice, but resulted in impairment of cardiac function only in males.


[Gas gangrene panophthalmitis (author's transl)].
Gas gangrene panophthalmitis is a rare condition of penetrating injury to the globe. The infecting organism is usually Clostridium perfringens. Characteristic symptoms are a brawny swelling of the lids, marked chemosis, coffee-coloured discharge, hypopyon, ring abscess of the cornea, formation of gas bubbles in the anterior chamber, rise of intraocular tension and early amaurosis. Treatment consists in the evisceration or enucleation of the globe, rarely in the exenteration of the orbit. Antibiotics along (Penicillin, Tetracyclines) are insufficient. Administration of antiserum is almost completely abandoned, it is probably more dangerous than helpful. The use of hyperbaric oxygen is not indicated in cases of gas gangrene panophthalmitis. Extraocular extension of the infection and its danger for the individual is prevented by well-times surgical procedure.


An argyrophil III method for the demonstration of micro- and oligodendroglia.
Micro- and oligodendroglia, plasma and nucleoli of nerve cells, capillary wall and nuclei of astrocytes become visible when sections of formol fixed human brain are immersed, without any previous treatment, into a physical developer of pH 10.5. The staining is inhibited by the catalytic activity of the tissue elements involved. By means of pretreatments with 1% performic acid and 30% sodium rhodanide dissolved in 0.4% sodium hydroxide, the catalytic activity in the unwanted tissue elements is suppressed, and this results in an elective demonstration of micro- and oligodendroglia. Reducing groups of the tissue or any kind of performed nuclei play no role in this silver staining.


Influence of administration methods on the accumulation of ALA-induced Pp-IX in mouse tongue tumors.
5-Aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) has been used as a photosensitizer in photodynamic therapy (PDT) for oral cancer. This study investigates the optimal method of administrating ALA by analyzing PpIX fluorescence in tongue tumor tissue. Protoporphyrin IX intensities in the mouse (C3H)-transplanted tongue cancer (NR-S1) were compared with those in normal tongue after intraperitoneal (i.p.), oral (p.o.) or topical administration of ALA. Tongues were sampled at various times after ALA administration. PpIX intensities were obtained from frozen sections of each sample by using a spectrophotometer. Protoporphyrin IX intensity in the tumor group peaked at 3 h after the i.p. and 5 h after the p.o. administration of ALA, and these levels were about twice as high as those in the normal group. Maximum PpIX accumulation in the tongue tumor tissue was seen at 5 h after p.o. administration of ALA. In contrast, the topical administration of 20% ALA cream was associated with the lowest PpIX accumulation in the tumor throughout the experiments. These results suggested that p.o. administration of ALA was the most effective method in ALA-PDT for oral cancer.


Interictal behavior abnormality in temporal lobe epilepsy. A specific syndrome or nonspecific psychopathology?
Two studies examine the degree to which the traits measured by the Bear and Fedio personality inventory are specific to temporal lobe epilepsy. In the first study, none of the 18 traits discriminated among a group of temporal lobe epileptics with behavioral-psychiatric disorders, a group of patients with concomitant neurological and behavioral-psychiatric disorders, and a group of patients with psychiatric but not neurological illness. The second study demonstrated that a very large percentage of variance in the traits can be accounted for by presence or absence of psychiatric illness. The results of these two studies suggest that previously reported differences between temporal lobe epileptics and normals on these trait variables reflect underlying differences in degree of nonspecific psychopathology and do not necessarily indicate the presence of a specific behavioral syndrome in temporal lobe epilepsy.


An evaluation of the efficacy of injectable microencapsulated vitamin B12 in increasing and maintaining the serum and liver vitamin B12 concentrations of lambs.
To develop a long-acting Vitamin B12 injection to prevent Co deficiency in sheep. Formulations of microencapsulated Vitamin B12 in lactide-glycolide polymers were injected intramuscularly or subcutaneously into the anterior neck region of groups of 10 lambs and their efficacy determined from changes in serum and liver Vitamin B12 concentrations. The 95:5 lactide glycolide and the 100 lactide formulations containing more than 12.5% Vitamin B12 w/w significantly increased and maintained serum Vitamin B12 concentrations for at least 210 days as well as liver Vitamin B12 concentrations in treated lambs when compared with untreated controls. Injections of microencapsulated Vitamin B12 in lactide/glycolide copolymers are able to increase and maintain the Vitamin B12 status of lambs for at least 210 days. Another option for the prevention of Co deficiency in sheep is now available using a long acting injectable Vitamin B12.


Study of quantitative elastography with supersonic shear imaging in the diagnosis of breast tumours.
This study was undertaken to evaluate the value of quantitative elastography in the diagnosis of breast tumours. Conventional ultrasound (US) and quantitative elastography were performed in 108 women with 114 breast lesions by two experienced radiologists, and pathological results were available in all cases. For each lesion, the maximum, mean, and minimum (min) elasticity and elasticity ratio between lesions and surrounding tissue were measured. The Breast Imaging Reporting and Data System (BI-RADS) categories were assessed with conventional US in all lesions. Malignant lesions exhibited significantly higher maximum and mean elasticity (111.57 ± 69.29 kPa and 54.49 ± 33.70 kPa) than did benign lesions (59.00 ± 45.3 kPa and 36.64 ± 26.18 kPa) (p<0.01). For maximum elasticity versus BI-RADS, performance results were sensitivity 60.9 % vs. 78.3%, specificity 85.3% vs. 98.5%, positive predictive value (PPV) 73.7% vs. 97.3 %, negative predictive value (NPV) 76.3% vs. 87.0 % and accuracy 75.4% vs. 90.3%. BI-RADS had significantly better accuracy than maximum elasticity (p<0.01). Maximum and mean elasticity of invasive ductal carcinoma (IDC) were significantly higher than those of fibroadenoma (p<0.01), whereas the difference was not statistically significant with fibroadenosis, papilloma and inflammation (p>0.01). Maximum and mean elasticity and elasticity ratio of BI-RADS 5 were all significantly higher than those of BI-RADS 3 (p<0.01). Reliability for maximum and mean elasticity were almost perfect [intraclass correlation coefficients (ICC)=0.87 and 0.79]. Shear-wave elastography gives quantitative elasticity information that could potentially help in breast-lesion characterisation, although it cannot replace conventional BI-RADS in the differentiation of breast lesions.