[Effects of the polysaccharides isolated from ganoderma applanatum (PGA) on the level of PGE2 and gastric mucosal blood flow (GMBF) and gastric mucus secretion of rats with gastric mucosa injury].
To investigate the protective effects of the polysaccharides isolated from ganoderma applanatum (PGA) on gastric mucosal injury in rats and the underlying mechanism. Gastric ulcer was induced by either acetic acid or pylorus ligation in the rats. The level of PGE2 and GMBF, and gastric mucus secretion were examined respectively. After oral administration of PGA (250-1000 mg x kg(-1)) repeatedly, the level of PGE2 and GMBF were obviously increased in gastric mucosa of rats as compared with the model group. The secretions of both free mucus in stomach and mucus of gastric wall were enhanced apparently by PGA in a dose-dependent manner. PGA could strengthen gastric mucosa barrier by improving the level of PGE2, GMBF and the secretion of gastric mucus, which may be one of the mechanisms underlying the protective effect of PGA on the gastric mucosa during the gastric ulcer.


Renal receptors and effects of atrial natriuretic factor in compensatory renal hypertrophy.
In the present study we investigated the in vivo and in vitro renal responsiveness to ANF, and the adaptation of ANF receptors in compensatory renal hypertrophy in the rat. One week after left nephrectomy (UNx), plasma levels of immunoreactive ANF, blood pressure (MAP), hematocrit (Hct), and urine flow rate (V) were unaltered compared to control (C) rats. Baseline GFR and potassium excretion (UKV) were significantly higher, and sodium excretion (UNaV) tended to be elevated in UNx rats. Administered ANF led to similar dose-related decreases in MAP and increases in Hct in UNx and C rats. However, at each dose of infused ANF, absolute values and the increase in GFR and UNaV were higher in UNx than in C rats. Hypertrophied (H) kidneys were removed from UNx and perfused in vitro to determine distribution and density of ANF receptors, responsiveness to ANF, and receptor-mediated organ clearance of 125I-ANF1-28. The density of ANF receptors in cortex, outer medulla, and papilla of H kidneys was not significantly different from that in C kidneys. In H isolated kidneys, ANF led to dose-related increases in GFR, V, UNaV, and UKV that were indistinguishable (P greater than 0.05) from those in C kidneys. Receptor-mediated organ clearance of 125I-ANF1-28 in isolated H kidneys was 2.8 +/- .02 ml/min, a value not significantly different (P greater than 0.05) from that in C kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)


N300 indexes deficient integration of orthographic and phonological representations in children with dyslexia.
In transparent orthographies, like German, children with developmental dyslexia (DD) are mainly characterized by a reading fluency deficit. The reading fluency deficit might be traced back to a scarce integration of orthographic and phonological representations. In order to address this question, the present study used EEG to investigate the N300, an ERP component which has been associated with the integration of orthographic and phonological representations. Twenty children without DD and 18 children with DD performed a phonological (P)-orthographic (O) matching task (P-O condition), which tapped the integration of orthographic and phonological representations. A control task was applied which did not require the integration of orthographic and phonological representations and consisted only of orthographic information (O-O condition). The O-O condition revealed a similar N300 distribution between groups with a bilateral activity over fronto-temporal electrodes. However, in the P-O condition N300 differentiated the 2 groups of children. The control group revealed greater activity over left fronto-temporal electrodes, whereas the N300 was distributed bilaterally in the group of children with DD suggesting deficient integration of orthographic and phonological representations. These findings might be related to the reading fluency deficit as it was also observed that better reading fluency was correlated with higher (r=-.36) and earlier peaking (r=-.33) N300 amplitudes in the left hemisphere and attenuated N300 amplitudes (r=.45) in the right hemisphere. Standardized low-resolution electromagnetic tomography analysis (sLORETA) revealed that children with DD rely more on right temporo-parietal brain areas compared to children without DD. Furthermore, in order to rule out that earlier deficient processes might influence the group differences found in the N300, we analyzed the N170 for group differences. We did not find significant differences between children without DD and children with DD. In conclusion the results suggest deficient integration of orthographic and phonological representations in dyslexia, as indexed by the N300, and further highlight how this activity is relevant for fluent reading.


Clinical and radiological outcomes of a modified anatomic posterolateral corner reconstruction technique using a single semitendinosus autograft.
We aimed to assess the clinical and radiological outcomes of a modified anatomical posterolateral corner (PLC) reconstruction technique using a single autograft. This prospective case series included 19 patients with a posterolateral corner injury. The posterolateral corner was reconstructed using a modified anatomical technique that utilized adjustable suspensory fixation on the tibial side. Patients were evaluated subjectively using the international knee documentation form (IKDC), Lysholm, and Tegner activity scales and objectively by measuring the tibial external rotation angle, knee hyperextension, and lateral joint line opening on stress varus radiographs before and after surgery. The patients were followed-up for a minimum of 2 years. Both IKDC and Lysholm knee scores significantly improved from 49 and 53 preoperatively to 77 and 81 postoperatively, respectively. The tibial external rotation angle and knee hyperextension showed significant reduction to normal values at the final follow-up. However, the lateral joint line opening measured on the varus stress radiograph remained larger than the contralateral normal knee. Posterolateral corner reconstruction with a hamstring autograft using a modified anatomical reconstruction technique significantly improved both the subjective patient scores and objective knee stability. However, the varus stability was not completely restored compared with the uninjured knee. Prospective case series (Level of evidence IV).


The C57BL mice: an animal model for inflammatory demyelinating polyneuropathy.
Recently it has been reported that the C57BL mice can be used as a model of benign monoclonal gammopathy (MG). Since experimental models have until now failed to reproduce specific lesions of human dysglobulinemic polyneuropathies, we decided to investigate the peripheral nerve of these mice. The sciatic nerve and the serum from 14 C57BL mice were examined: 9 of these animals were found to have an IgG, kappa light chain MG, while in the other 5 no abnormalities were detected in the serum. In the 14 mice, features of demyelination were found in certain fibers, as well as onion-bulb formations around other myelinated fibers. Features of active demyelination were found in 10 animals and it must be underlined that three of these had no serum abnormalities. The decrease of the conduction velocities and the temperature coefficients Q10 of the C57BL mice suggest a good correlation between morphological and functional parameters. This strongly suggests that this strain of mice provides a suitable model for inflammatory demyelinating polyneuropathy (IDPN).


Resting oxygen consumption and ventilation in cystic fibrosis.
Resting oxygen consumption (VO2) and minute ventilation (VE) were measured on nine control subjects and 13 patients with cystic fibrosis (CF). In patients with CF, VO2 was 20% higher (P less than 0.01) when expressed per m2 and 47% higher (P less than 0.001) when expressed per kg body weight, and VE was 58% higher when expressed per m2 and 94% higher when expressed per kg body weight (P less than 0.001) than in control subjects. Repeated measures of VO2 and VE were highly reproducible over 2 hours (within-subject coefficients of variation: in controls, VO2 = 5.5%, VE = 7.4%; in CF, VO2 = 3.1%, VE = 5.1%). Since the increases in VE were greater than those in VO2, the ventilatory equivalent (VE/VO2) was 32% higher in CF than in controls. We conclude that size-corrected total energy expenditures and VE at rest are higher in patients with CF than in control subjects. Ventilation appears mechanically inefficient but necessary to keep arterial PCO2 from rising and oxygen saturation from falling at rest. Our results are consistent with observations that these patients have an abnormally large physiological dead space (Featherby et al.: Ann Rev Respir Dis 1969; 102:737).


Specific complications of monochorionic twin pregnancies: twin-twin transfusion syndrome and twin reversed arterial perfusion sequence.
Monochorionic twins are subjected to specific complications which originate in either imbalance or abnormality of the single placenta serving two twins. This unequal placental sharing can cause complications including twin-twin transfusion syndrome (TTTS), twin anemia-polycythemia sequence (TAPS), selective intrauterine growth restriction or twin reversed arterial perfusion sequence (TRAP). Monochorionicity also makes the management of these specific complications as well as that of a severe malformation in one twin hazardous since the spontaneous death of one twin exposes the co-twin to a risk of exsanguination into the dead twin and its placenta. The latter is responsible for the death of the co-twin in up to 20% of the cases and in ischemic sequelae in about the same proportions in the survivors. Although the symptoms of all these complications are very different, the keystone of their management comes down to either surgical destruction of the inter-twin anastomoses on the chorionic plate when aiming at dual survival or selective and permanent occlusion of the cord of a severely affected twin aiming at protecting the normal co-twin. This can be best achieved by fetoscopic selective laser coagulation and bipolar forceps cord coagulation respectively.


[The pathogenesis of the secondary adhesive processes. A clinical and experimental study (author's transl)].
According to the clinical experience the rate of relapses in operated adhesive processes is very high. We found tympanic pressure to be normal in one third of the cases, therefore the impaired tubal function cannot be the only reason for relapses. With a special method we could demonstrate that there is a great difference in the development of tympanic pressure in cases of operated adhesive processes compared with cases with normal elasticity of the tympanic membrane. So changes of the elasticity may be an important factor influencing the rate of relapses. We could support this conception using models for tympanometric experiments.


Calu-3 epithelial cells exhibit different immune and epithelial barrier responses from freshly isolated primary nasal epithelial cells in vitro.
Epithelial cell lines are often used to evaluate the effect of exogenous/endogenous stimuli on epithelial barrier function and innate immune responses in allergic airway diseases, without clear view on differences between epithelial cell lines and primary nasal epithelial cell responses. In this observational study, we compared the response of Calu-3 and primary nasal epithelial cells to two relevant exogenous stimuli: i.e. Staphylococcus aureus enterotoxin B (SEB) and house dust mite (HDM). Stimulation of Calu-3 cells with SEB decreased epithelial integrity in a dose dependent manner, which was associated with a significant increase in IL-6 and IL-8 production. In contrast, no alteration in barrier integrity or IL-6 and IL-8 production was seen when primary nasal epithelial cells were stimulated with SEB. HDM extract altered the integrity of primary nasal epithelial cells, but not of Calu-3 epithelial cells. Increased IL-8 production was seen after stimulation with HDM in primary nasal epithelial cells and not in Calu-3 epithelial cells. In conclusion, immune and barrier function differ between different epithelial cell types studied. As a consequence, care must be taken when interpreting data using different epithelial cell types.


Impact of Haemophilus influenzae type b conjugate vaccination on hospitalization for invasive disease in children fifteen years after its introduction in Italy.
In Italy, Hib conjugate vaccine was introduced for infants in 1999 and included in the DTaP-HBV-IPV-Hib combination in 2001, with an uptake of 83.4% in 2002, >90% by 2005, and >95% by 2011. We estimated the impact of Hib vaccination on hospitalizations for H. influenzae invasive disease in children <5years. Age-specific hospitalization rates and hospitalization risk ratios (HRRs) with 95%CI during 2001-2013 were calculated performing time-series analysis. The number of cases reported to the national surveillance of invasive bacterial diseases was compared to the number of hospitalizations between 2007-2013. Hospitalization rates declined from 2.3 in 2001 to 0.9×100,000 in 2002 (HRR=0.4, 95%CI=0.3-0.6, p<0.05) among children 1-4years and from 5.4 in 2001 to 2.4×100,000 in 2005 (HRR=0.4, 95%CI=0.2-0.9, p<0.05) among infants. During 2007-2013: 401 cases were reported, 242 were typed, 12.4% were by serotype b; 861 hospital admissions were recorded. Applying the percentage of typed b strains retrieved from the surveillance to the number of hospitalizations for invasive H. influenzae disease, an estimated 107 episodes could be attributable to serotype b. These findings provided reassuring data on the impact of Hib vaccination on the burden of hospitalization for invasive disease in Italian children.


Frequent gamblers' perceptions of the role of gambling marketing in their behaviour: An interpretative phenomenological analysis.
This study explored how frequent gamblers perceive gambling marketing and the role they feel it has in their gambling behaviour. Ten frequent gamblers participated in semi-structured interviews oriented around their experiences of gambling marketing. An interpretative phenomenological analysis of the data led to three overarching themes: exploiting gambling marketing for personal gain; gambling marketing as a test of self-control; and safer gambling messages marketing perceived as ineffective. These themes encapsulated participants' views of gambling marketing as something they could take advantage of to increase their own gambling success. Marketing was also perceived as a test of self-control among self-identified experienced gamblers, although identified as a risk to those who are considered more vulnerable. Finally, safer gambling messages included within marketing was considered ineffective due to perceived insincerity and being seen as an 'afterthought' by marketers. In support of previous research, the current investigation highlights concerning narratives around self-control and perceived risk, as encapsulated within gambling marketing, and these are evident in the perceptions of frequent gamblers. Given gamblers' perceived lack of effectiveness of current safer gambling messages within marketing, future research should explore new avenues for safer gambling promotion.


Research into cancer metabolomics: Towards a clinical metamorphosis.
The acknowledgement that metabolic reprogramming is a central feature of cancer has generated high expectations for major advances in both diagnosis and treatment of malignancies through addressing metabolism. These have so far only been partially fulfilled, with only a few clinical applications. However, numerous diagnostic and therapeutic compounds are currently being evaluated in either clinical trials or pre-clinical models and new discoveries of alterations in metabolic genes indicate future prognostic or other applicable relevance. Altogether, these metabolic approaches now stand alongside other available measures providing hopes for the prospects of metabolomics in the clinic. Here we present a comprehensive overview of both ongoing and emerging clinical, pre-clinical and technical strategies for exploiting unique tumour metabolic traits, highlighting the current promises and anticipations of research in the field.


[Nasosinusal adenocarcinoma: molecular and genetic analysis by MLPA].
Intestinal-type sinonasal adenocarcinomas (ITACs) are rare epithelial tumours, primarily originating in the nasal cavities and paranasal sinuses and characterized by glandular structures. The aims of this study are: to determine the genetic alterations in ITACs by MLPA (Multiplex ligation-dependent probe amplification) and to correlate the findings to the clinical behavior and follow-up information of the patients. We performed a longitudinal prospective study on 20 patients with ITAC, seen in our department between 1998 and 2004. DNA was extracted from primary tumor samples and analyzed by MLPA. The T stage of our series was T2: 4 (20 %), T3: 6 (30 %), T4a: 3 (15 %) and T4b: 7 (35 %). All cases initially were N0 and M0. Seventeen patients (85 %) had professional exposure to wood dust. All patients underwent surgical intervention and 70 % received complementary radiotherapy. Overall 5 and 10 year survival was 42 % and 22 %, respectively. Gains were found most frequently for PTP4A3 and PDCD8 (65 %), TNRFSF7 (50 %), RECQL4 and LMO2 (45 %), and losses for BCL2 (70 %), IL13 (55 %), ABCB1 and RB1 (50 %), PIK3CA and CDH1 (45 %). Losses of F3, MIF, and BRCA1 significantly correlated with the posterior development of metastases and with worse survival. Also gains of PIK3CA, UTY, and RELA correlated with poor clinical outcome. Losses of BRCA1 and F3 were significant in multivariate analysis.


QSAR study on adenosine kinase inhibition of pyrrolo[2,3-d]pyrimidine nucleoside analogues using the hansch approach.
QSAR studies on series of pyrrolo[2,3-d]pyrimidine nucleoside analogues were performed for their adenosine kinase (AK) inhibitory activity using the Hansch approach. Significant correlations were obtained with hydrophobic parameter at position 'X'. Electronic and steric parameters on pyrimidine and pyrrole rings found to play an important role in the ligand-receptor interactions with the active sites of the enzyme. Presence of bulkier groups at 'X' and 'Y' positions seems to protect the title compounds from biodegradation, as is evident from their positive sterimol steric parameter B1 at these positions.


Organosolv and ionosolv processes for autohydrolyzed poplar fractionation: Lignin recovery and characterization.
Biomass fractionation plays a major role in the search for competitive biorefineries, where the isolation and recovery of the three woody fractions is key. In this sense, we have used autohydrolyzed hemicellulose-free poplar as feedstock to compare two fractionation processes, organosolv and ionosolv, oriented to lignin recovery. The recovered lignins were then characterize by different techniques (NMR, GPC, TGA). Both treatments were tested at different temperatures to analyze temperature influence on lignin recovery and properties. The highest lignin recovery was obtained with the ionosolv process at 135 °C, reaching a solid yield of ~70%. Lignin characterization showed differences between both treatments. Lignins enriched in C-O linkages and G units were recovered with the organosolv process, where increasing temperature led to highly depolymerized lignins. However, lignins with higher C-C linkages and S units contents were obtained with the ionosolv process, producing more thermically stable lignins. In addition, increasing temperature caused lignin repolymerization when employing ionic liquids as solvents. Therefore, this work outlines the most important differences between ionosolv and organosolv processes for biomass fractionation, focusing on lignin recovery and its properties, which is the first step in order to valorize all biomass fractions.


[Inspection of undesignated food color in imported chewing gum].
An unknown color in chewing gum imported from Canada was determined. The color was identified by TLC and HPLC as the trisodium salt of 3-hydroxy-4[(4-sulfopheny)azo]-2,7-naphthalenedisulfonic acid (RS-SA), one of the subsidiary colors of sunset yellow FCF. The concentration of RS-SA in sunset yellow FCF used in the chewing gum was 4.3%


Di-μ-chlorido-bis-[(2,2':6',2''-terpyridine-κ3 N,N',N'')copper(II)] bis-(tri-fluoro-methane-sulfonate).
In the centrosymmetric title complex, [Cu2Cl2(C15H11N3)2](CF3O3S)2, the CuII metal center is fivefold coordinated by two chloride ions and three nitro-gen atoms of the terpyridine ligand in a distorted square-pyramidal geometry; two tri-fluoro-methane-sulfonate ions complete the outer coordination sphere. π-π stacking inter-actions between the pyridyl rings in adjacent mol-ecules contribute to the alignment of the complexes in columns along the a-axis. This structure represents the first example of a binuclear dication of formula [Cu(terpy)2Cl2]2+ with tri-fluoro-methane-sulfonate as counter-ions.


Feelings of warmth correlate with neural activity in right anterior insular cortex.
The neural coding of perception can differ from that for the physical attributes of a stimulus. Recent studies suggest that activity in right anterior insular cortex may underlie thermal perception, particularly that of cold. We now examine whether this region is also important for the perception of warmth. We applied cutaneous warm stimuli on the left leg (warmth) in normal subjects (n = 7) during functional magnetic resonance imaging (fMRI). After each stimulus, subjects rated their subjective intensity of the stimulus using a visual analogue scale (VAS), and correlations were determined between the fMRI signal and the VAS ratings. We found that intensity ratings of warmth correlated with the fMRI signal in the right (contralateral to stimulation) anterior insular cortex. These results, in conjunction with previous reports, suggest that the right anterior insular cortex is important for different types of thermal perception.


[Initial polychemotherapy in the treatment of cancers of the head and neck. The efficacy and tolerance of 2 nonrandomized combinations in 48 patients].
Before loco regional treatment for head and neck cancer forty eight patients received one or the other of the following combined chemotherapy regimens: Regimen A (28 patients): high dosage methotrexate, bleomycin, cis-platin; regimen B (20 patients): common dosage methotrexate, bleomycin, hydroxyurea, vincristin. The effectiveness of regimen A seemed better than that of regimen B (46% responses versus 20%). This assessment must be accepted with caution, since, although the organization of treatment was strictly similar in the two groups, the study was not randomized, and there were noticeable differences between the two groups. Regimen B was associated with no toxicity. Regimen A was responsible for two fatalities. These two cases were linked to high dosage methotrexate. However, a combined chemotherapy regimen of type A with the high dosage methotrexate replaced by intermediate dosage methotrexate, seems feasible to us. Loco regional treatment was not impaired by initial chemotherapy with either regimen.


Inflammatory disease of the central nervous system.
Inflammatory diseases involving the central nervous system can be difficult to diagnose and frustrating to treat. The clinician can maximize successful treatment of these patients by recognizing the clinical signs in the early stages of disease, following a logical diagnostic plan to identify the specific etiologic agent involved, and formulating an appropriate and aggressive therapeutic plan. Treatment will not always be successful owing to lack of effective treatments and irreversible neurologic damage.


Characterization of the synergistic inhibitory effect of cyanidin-3-O-glucoside and catechin on pancreatic lipase.
This study aimed to identify novel pancreatic lipase (PL) inhibitors using affinity ultrafiltration combined with spectroscopy and molecular docking. Cyanidin-3-O-glucoside (C3G; IC50: 0.268 mg/mL) and catechin (IC50: 0.280 mg/mL) were shown to be potent PL inhibitors extracted from black rice and adzuki bean coat extracts. Isobologram analysis revealed that the combined use of C3G and catechin at a ratio of 2:3 had a remarkable synergistic effect (IC50 of the mixture: 0.201 mg/mL). The inhibitory mechanism of C3G-catechin mixture was of mixed type. The C3G-catechin mixture had a great impact on PL secondary structures. Molecular docking analysis further demonstrated that these polyphenols formed hydrophobic interactions and hydrogen bonds with amino acid residues in the binding pocket of PL. Collectively, C3G and catechin were shown to inhibit PL in a synergistic manner and can be potentially used for the development of food supplements for obesity prevention.


Anthropogenic host plant expansion leads a nettle-feeding butterfly out of the forest: consequences for larval survival and developmental plasticity in adult morphology.
Recent anthropogenic eutrophication has meant that host plants of nettle-feeding insects became quasi-omnipresent in fertile regions of Western Europe. However, host plant resource quality - in terms of microclimate and nutritional value - may vary considerably between the 'original' forest habitat and 'recent' agricultural habitat. Here, we compared development in both environmental settings using a split-brood design, so as to explore to what extent larval survival and adult morphology in the nettle-feeding butterfly Aglais urticae are influenced by the anthropogenic environment. Nettles along field margins had higher C/N ratios and provided warmer microclimates to larvae. Larvae developed 20% faster and tended to improve their survival rates, on the agricultural land compared to woodland. Our split-brood approach indicated plastic responses within families, but also family effects in the phenotypic responses. Adult males and females had darker wing pigmentation in the drier and warmer agricultural environment, which contrasts with the thermal melanism hypothesis. Developmental plasticity in response to this microclimatically different and more variable habitat was associated with a broader phenotypic parameter space for the species. Both habitat expansion and developmental plasticity are likely contributors to the ecological and evolutionary success of these nettle-feeding insects in anthropogenic environments under high nitrogen load.


Tree decline in southeastern Australia: Nitrate reductase activity and indications of unbalanced nutrition in Eucalyptus ovata (Labill.) and E. camphora (R.T. Baker) communities at Yellingbo, Victoria.
The decline of riparian Eucalyptus camphora/E. ovata stands is examined in relation to an increase in nitrogen availability and to rising salinity in low-lying areas. There are several indications that declining stands are abnormally rich in N: (i) Nitrogen availability in declining stands was greater than that recorded in other Australian forests, was dominated by nitrification and was extremely variable. (ii) Nitrate concentrations in free soil water from declining forest on a dry site were many times those in the corresponding healthy forest. (iii) N/Mg ratios in foliage of declining trees on drier sites were at the extreme end of the recorded range and similar to those found in eucalypt plantations on agricultural soils. In addition, sites where the overstorey eucalypts are declining have been invaded by a variety of herbaceous weeds, most of which display characteristics of nitrophilous plants, e.g. nitrate reductase activity was greater in herbaceous weeds than in native overstorey or understory species in declining stands of E. camphora/E. ovata and was directly related to the concentration of nitrogen in foliage. These observations are consistent with recent suggestions that forest ecosystems may become N-saturated.


Antithrombin III-dependent anti-prothrombinase activity of heparin and heparin fragments.
Heparin and heparin fragments in the molecular mass range 1,700-20,000 Da were examined for their ability to accelerate the antithrombin III (AT III)-dependent inhibition of human factor Xa and the prothrombin converting complex (prothrombinase) during human prothrombin activation. The prothrombinase reaction was modeled by a 3-parameter 2-exponential equation to determine the initial rate of prothrombin activation and the pseudo-first order rate constants of inhibition of prothrombinase and in situ generated thrombin activity. The catalytic specific activities of the heparins increased with increasing molecular size for both the inhibition of prothrombinase and factor Xa. A 10-fold increase over the entire Mr range was found. In contrast to results obtained by others (Ellis, V., Scully, M. F., and Kakkar, V. V. (1986) Biochem. J. 233, 161-165; Barrowcliffe, T. W., Havercroft, S. J., Kemball-Cook, G., and Lindahl, U. (1987) Biochem. J. 243, 31-37), all the heparins showed a 5-fold higher rate of inhibition of factor Xa when compared with the inhibition of prothrombinase, indicating that the factor Va-mediated protection of factor Xa from inhibition by AT III/heparin is independent of the molecular size of the heparin. Our original approach has also revealed a hitherto unrecognized phenomenon, namely, in addition to the accelerating effect of the heparins on the rate of formation of the inactive AT III-factor Xa complex, heparins with Mr greater than 4,500 reduce the initial rate of thrombin generation in the presence of AT III in a concentration-dependent way. We hypothesize that the formation of the dissociable ternary AT III-heparin-factor Xa complex results in a (partial) loss of factor Xa activity towards its natural substrate prothrombin.


Inhibition of fast axonal transport in vitro by tetracaine: an increase in potency at alkaline pH, and no change in potency in calcium-depleted nerves.
Some of the present in vitro experiments compare the degree of inhibition of fast axonal transport produced by tetracaine at neutral and at alkaline pH. In desheathed spinal nerves from bullfrog, 0.5 mM tetracaine reduced the quantity of [3H]leucine-labeled proteins which were transported to a ligature by 43% at pH 7.2 and by 96% at pH 8.2; separate experiments established that transport was not affected by the pH change in the absence of tetracaine. The relationship between pH and transport-blocking potency of tetracaine (pKa 8.2) is such that the local anesthetic is more potent when more uncharged form of the molecule is present; this may reflect the easier penetration across the axonal plasma membrane by the uncharged form of the tetracaine molecule. The axonal smooth endoplasmic reticulum has been attributed the function of a calcium reservoir, and it appeared possible that local anesthetics could block axonal transport by releasing calcium from this structure. However, the inhibition of transport produced by 1 mM tetracaine (pH 7.1) in sheathed nerves was approximately 80% both in nerves with a lower than normal calcium content (47% of normal) and in nerves with a normal calcium content; this result does not support the hypothesis that inhibition of axonal transport by local anesthetics is mediated by an increase in intracellular free Ca2+, but does not rule out the hypothesis either.


Comparison the effect of Swedish massage and interferential electrical stimulation on labor pain and childbirth experience in primiparous women: a randomized controlled clinical trial.
Since mothers are more inclined toward non-pharmacological labor pain management methods, this study aimed to compare the effect of interferential electrical stimulation (IES) and Swedish massage (SM) on labor pain and childbirth experience (primary outcomes) and childbirth satisfaction, duration of active phase and side effects (secondary outcomes) in primiparous women. This randomized controlled trial was performed on 90 primiparous women. Participants were randomly assigned into three groups through the block randomization method. The SM group received two massage techniques of effleurage and petrissage, on T10-L1 and S2-S4 at cervical dilatation of 4 and 8-10 cm. The IES group received electrical stimulation in a similar way to SM group, with a base frequency of 4000 Hz and a pulse frequency of 80-120 Hz by a physiotherapist. Control group received only routine care. The mean pain was significantly lower in the SM group (adjusted mean difference (AMD) - 0.86; 95% confidence interval (95% CI) - 1.60 to - 0.11) and the IES group (AMD - 0.95; 95% CI - 1.70 to - 0.21) compared to the control group. The mean score of childbirth experience was significantly higher in the SM (MD 5.63; 95% CI 2.15-9.11) and IES (MD 3.66; 95% CI 0.18-7.14) group compared to the control group. The mean childbirth satisfaction in the SM (p = 0.003) and IES (p = 0.046) groups was significantly higher than the control group; and duration of the active phase of labor was significantly lower (p < 0.001) than the control group. No serious side effects were occurred in none of the groups. SM and IES are safe methods that can significantly reduce pain and duration of active phase and improve the experience and satisfaction of childbirth.


Evaluation of a new slide latex agglutination test for diagnosis of vaginal candidosis.
A new commercial slide latex particle agglutination test for rapid (2 min) diagnosis of vaginal candidosis was evaluated and compared with conventional methods. Of the 263 women studied, 63 (23.9%) had yeasts in the vagina. Clinical signs of vulvitis or vaginitis were seen in 23 women (8.8%) and 40 (15.2%) were harbouring yeasts without clinical signs. Yeast counts were generally higher in women with clinical signs of vaginal candidosis than in those without. The test was positive in 15 of the 23 women (65.2%) with clinical signs, the incidence of a positive test increasing in direct proportion to the amount of yeasts isolated. The test's sensitivity, specificity and predictive values were comparable to those of microscopy and culture. Being both rapid and simple to perform, this new test offers a useful alternative to conventional methods for the diagnosis of vaginal candidosis.


Soft tissue coverage of the ankle: An algorithm for appropriate flap selection and the experiences of a newly established Major Trauma Network.
Replication of the thin and pliable native skin around the ankle remains a challenge for plastic surgeons treating soft tissue defects in this region. Flap reconstruction constitutes the mainstay of management of such injuries. Subsequent management often entails revisional debulking surgery to permit normal footwear and an acceptable aesthetic outcome. In light of limited elective operating capacity throughout the covid-19 pandemic, we adopted an algorithm to inform reconstruction in such injuries and limit the need for revisional surgeries. This study presents this algorithm, which considers patient age, functional status, co-morbidities, body habitus and defect location. Retrospective analysis of a prospectively maintained database of all patients undergoing lower limb soft tissue reconstruction over 21 months was performed. All flap-based reconstructions of ankle defects were included; direct closures and skin grafts were excluded. All trauma patients were managed via a combined orthoplastic approach as per BOA-BAPRAS standards. All patients had Computed Tomography Angiography prior to their definitive reconstruction. Lower Extremity Functional Scale (LEFS) scores were analysed for patients with over 12 months of postoperative follow up, where available. 71 flaps were performed in 69 patients. Open ankle fracture was the most common cause (86%); other indications included osteomyelitis and surgical wound dehiscence. Mean age was 50 (13-87 years) with a higher proportion of males to females (ratio 1.25:1). There were 26 pedicled flaps (18 Medial Plantar Artery and 8 Peroneus Brevis) and 45 free flaps (22 Anterolateral thigh, 11 Superficial Circumflex Iliac Artery Perforator, 11 Gracilis and 1 Medial Sural Artery Perforator). Mean follow-up is 13.6 months. There were three flap failures, and four patients subsequently underwent delayed below knee amputation despite successful soft tissue healing. For the patients with a minimum of 12 months follow up, LEFS scores with an average of 51% were achieved (range 15-88%). Four patients have been listed for revisional/debulking surgery. Although soft tissue defects around the ankle can be difficult to manage, with careful planning and addressing each patient individually, supported by an algorithmic approach, good functional and aesthetic outcomes can be achieved with low rates of secondary revision surgery.


Cyclic AMP post-transcriptionally regulates the biosynthesis of a major bacterial autoinducer to modulate the cell density required to activate quorum sensing.
In Vibrio cholerae, expression of the quorum sensing regulator HapR is induced by the accumulation of a major autoinducer synthesized by the activity of CqsA. Here we show that the cAMP-cAMP receptor protein complex regulates cqsA expression at the post-transcriptional level. This conclusion is supported by the analysis of cqsA-lacZ fusions, the ectopic expression of cqsA in Deltacrp mutants and by Northern blot analysis showing that cqsA mRNA is unstable in Deltacrp and Deltacya (adenylate cyclase) mutants. Addition of cAMP to the culture of a Deltacya mutant restored cqsA mRNA stability and cholera autoinducer 1 production. Lowering intracellular cAMP levels by addition of d-glucose increased the cell density required to activate HapR. These results indicate that cAMP acts as a quorum modulator.


Levodopa-induced dyskinesias and continuous subcutaneous infusions of apomorphine: results of a two-year, prospective follow-up.
Twelve patients with levodopa-induced dyskinesias were treated with continuous subcutaneous apomorphine. A markedly significant reduction in peak dose dyskinesias occurred over a two-year follow-up.


A case of subarachnoid and intracerebral hemorrhages complicated by trichosporonosis.
Trichosporonosis has an extremely poor prognosis. In this report, we describe a case of subarachnoid hemorrhage and intracerebral hemorrhage due to a fungal aneurysm caused by Trichosporon. A 71-year-old woman who experienced subcortical hemorrhage developed a subarachnoid hemorrhage. Endovascular parent artery occlusion was performed for a fungal aneurysm in the left posterior cerebral artery caused by Trichosporon. After surgery, voriconazole and liposomal amphotericin B were administered. The patient died of massive left putamen hemorrhage. Effective treatment for intracranial hemorrhage due to trichosporonosis has not yet been established and an accumulation of cases is required.


Clinical Features, Risk Factors, and Management of Candida Keratitis.
To determine the clinical features, predisposing factors, and management of infectious keratitis caused by Candida spp. Retrospective chart review. The medical records of 52 patients (54 eyes) with Candida keratitis were available for statistical analysis. Thinning of the corneal stroma was identified in 34 eyes (63.0%), and corneal perforation occurred in 16 eyes (29.6%). Corneal thinning and perforation were more common in Candida albicans compared with non-albicans (P-val < .001, P = .09, respectively). The most common predisposing factors for Candida keratitis were topical steroid use (21 patients, 40.4%), previous corneal transplantation (17 patients, 32.7%), and preexisting ocular surface disease (15 patients, 28.8%). Fourteen eyes (25.9%) required cyanoacrylate glue application and 10 eyes (18.5%) underwent therapeutic penetrating keratoplasty (TPK). Local immunosuppression and ocular surface disease play an important role in Candida keratitis. C. albicans appears to be more invasive compared with non-albicans spp.


Composition-Dependent Hot Carrier Relaxation Dynamics in Cesium Lead Halide (CsPbX3 , X=Br and I) Perovskite Nanocrystals.
Cesium-based perovskite nanocrystals (NCs) have outstanding photophysical properties improving the performances of lighting devices. Fundamental studies on excitonic properties and hot-carrier dynamics in perovskite NCs further suggest that these materials show higher efficiencies compared to the bulk form of perovskites. However, the relaxation rates and pathways of hot-carriers are still being elucidated. By using ultrafast transient spectroscopy and calculating electronic band structures, we investigated the dependence of halide in Cs-based perovskite (CsPbX3 with X=Br, I, or their mixtures) NCs on the hot-carrier relaxation processes. All samples exhibit ultrafast (<0.6 ps) hot-carrier relaxation dynamics with following order: CsPbBr3 (310 fs)>CsPbBr1.5 I1.5 (380 fs)>CsPbI3 NC (580 fs). These result accounts for a reduced light emission efficiency of CsPbI3 NC compared to CsPbBr3 NC.


Gastrin and cholecystokinin in the Eastern Grey kangaroo, Macropus giganteus giganteus.
Gastrin and CCK are believed to have a common ancestor. The gastrin structure has probably evolved from CCK-like peptides at a stage later than the amphibians. To trace the evolution of gastrin and CCK we have determined their structures in an Australian marsupial, the Eastern Grey kangaroo. The brain CCK was identical to CCK-8 of most mammals. The larger form of kangaroo gastrin was a 33mer with the sequence pELHPQDLPHLMTDLSKKKGPWQEEDAAY(SO3)GWMDF-NH2. The 11 italic residues indicate differences from human gastrin. Gastrin-15 and gastrin-16 comprised about 70% of the total immunoreactivity and resulted from cleavage after the second and third residue, respectively, of the unusual tribasic cleavage site. The smaller forms of kangaroo gastrin differ from most other mammalian gastrins in that the N-termini are not blocked with a pyroGlu moiety. Unlike other gastrins, kangaroo gastrin is more than 95% sulfated. The present study indicates that the gastrin structure, as defined by having a Tyr at position 6 from the C-terminus, evolved before the marsupials diverged from the other mammals 130 million years ago.


Women's lifelong exposure to neighborhood poverty and low birth weight: a population-based study.
To determine whether women's lifelong residential environment is associated with infant low birth weight. We performed race-specific stratified and multivariate binomial regression analyses on an Illinois vital record dataset of non-Latino White and African-American infants (1989-1991) and their mothers (1956-1975) with appended United States census income information. Non-Latino White women (N = 267) with a lifelong residence in low-income neighborhoods had a low birth weight (<2,500 g) incidence of 10.1% vs. 5.1% for White women (N = 10,647) with a lifelong residence in high-income neighborhoods; RR = 2.0 (1.4-2.9). African-American women (N = 18,297) with a lifelong residence in low-income neighborhoods had a low birth weight incidence of 17% vs. 11.7% for African-American women (N = 546) with a lifelong residence in high-income areas; RR = 1.5 (1.2-1.8). The adjusted population attributable risk (PAR) percent of LBW for lifelong residence in low-income neighborhoods was 1.6% for non-Latino White and 23.6% for African-American women. Non-Latino White and African-American women's lifelong residence in low-income neighborhoods is a risk factor for LBW; however, African-Americans experience a greater public health burden from this phenomenon.


Applicability of SSCP analysis for MHC genotyping: fingerprinting of Ovar-DRB1 exon 2 alleles from Finnish and Russian breeds.
The applicability of single strand conformation polymorphism (SSCP) analysis for major histocompatibility complex (MHC) genotyping in sheep was studied. A panel of Ovar-DRB1 exon 2 'allele fingerprints' was defined. The panel could accelerate DRB1 genotyping of new breeds when already existing sequences are used as references in SSCP analysis. In this study, seven new exon 2 sequences and 19 different alleles in total were detected from 31 animals of Finnish and Russian sheep breeds. Ovar-DRB1*0201 was detected in all the six grey Finnsheep animals included in this study, suggesting reduced MHC diversity within these animals.


Protein Misfolding Cyclic Amplification Cross-Species Products of Mouse-Adapted Scrapie Strain 139A and Hamster-Adapted Scrapie Strain 263K with Brain and Muscle Tissues of Opposite Animals Generate Infectious Prions.
Transmission of prions between mammalian species is limited by a "species barrier," a biological effect involving an increase in incubation period to decrease the percentage of animals succumbing to disease. In this study, we used protein misfolding cyclic amplification (PMCA) technique, which accelerates the conversion of prion proteins in vitro. Direct interspecies PMCA involving 144 cycles confirmed that both mouse-adapted scrapie strain 139A and hamster-adapted 263K could use brain homogenates of opposite species to form proteinase K (PK)-resistant PrP proteins (PrPres). Newly formed interspecies prions could stably propagate themselves in subsequent serial PMCA passages. The two types of PMCA-generated cross-species PrPres changed their glycosylation profiles, which was similar to that observed during interspecies infection by the mouse agent 139A in vivo. These profiles were distinct from individual seeded PrPSc and possessed properties of new hosts. Comparative analysis with respect to PK resistance showed no significant diversity between PMCA-PrPres and native PrPSc or between brain and muscle PrPres. However, PrPres from the relatively early cycles of serial PMCA showed lower PK resistance than those from later cycles. Inoculation of these PMCA products amplified with homogeneous or heterogeneous brain tissues (cross-species products) induced experimental transmissible spongiform encephalopathies. These results suggested that PMCA can help prion strains to overcome species barrier and to propagate efficiently both in vitro and in vivo.


Fate of mutagenicity produced during anaerobic biodegradation of the herbicide chlornitrofen (CNP).
The mutagenicity of chlornitrofen (CNP)-containing solutions has been reported to increase during anaerobic biodegradation. In the present study, the fate of this increased mutagenicity under subsequent aerobic and anaerobic incubation conditions was investigated using two Salmonella tester strains, YG 1024 (a frameshift-detecting strain) and YG 1029 (a base-pair-substitution-detecting strain). Mutagenicity for both YG 1024 and YG 1029 strains increased during nine-day anaerobic biodegradation. During subsequent anaerobic incubation, the increased mutagenicity decreased gradually for YG 1029 but did not change significantly for YG 1024. By contrast, the increased mutagenicity decreased rapidly after the conversion to aerobic incubation for both YG 1024 and YG 1029 strains. The rapid decrease in mutagenicity during aerobic incubation was due to decreases, not only in an identified mutagenic metabolite (CNP-amino) but also in unidentified mutagenic metabolites.


Is therapy with calcium and vitamin D and parathyroid autotransplantation useful in total thyroidectomy for preventing hypocalcemia?
Routine calcium and vitamin D administration and routine autotransplantation of parathyroid glands can prevent hypocalcemia after total thyroidectomy. Routine autotransplantation of 1 or more parathyroid glands and oral calcium and vitamin D supplementation was used in 252 patients. One, 2, or 3 parathyroid glands were autotransplanted in 223, 27, and 2 patients, respectively. Routine oral calcium and vitamin D was administered in postoperative period in all patients. Postoperative hypocalcemia occurred in 17%, of whom 1.6% had minor symptoms related to hypocalcemia. No patient developed permanent hypocalcemia during the follow-up period. The postoperative stay was 1 day in 93.6% of the cases. The incidence of postoperative hypocalcemia and hospital stay was higher in patients who underwent autotransplantation of more than 1 parathyroid gland. Routine oral calcium and vitamin D supplementation and autotransplantation of at least 1 parathyroid gland effectively reduced symptomatic hypocalcemia and permanent hypoparathyroidism in total thyroidectomy.


The impact of comorbid gastroesophageal reflux disease on endoscopic sinus surgery quality-of-life outcomes.
Chronic rhinosinusitis (CRS) and gastroesophageal reflux disease (GERD) are common entities that overlap in patient demographics. The pathophysiologic role of GERD has yet to be elucidated, but it is postulated that extraesophageal reflux may contribute to worsening symptoms of CRS. This study seeks to investigate whether patients with CRS with and without a history of GERD experience comparable quality-of-life (QOL) improvement after endoscopic sinus surgery (ESS). An adult cohort (n = 229) with medically refractory CRS was prospectively assessed following ESS using 3 disease-specific QOL constructs. A patient subset with a history of comorbid GERD was retrospectively identified (n = 72) and preoperative and postoperative QOL were compared to patients without GERD (n = 157). Patients with comorbid GERD and CRS were comparable across all baseline patient characteristics (p > 0.050) with the exception of patients with a history of GERD; those patients were less likely to have undergone allergy testing (p < 0.002) and were older (53.8 years vs 47.6; p < 0.002). Similarly, baseline objective and subjective measures of disease were comparable between patients with CRS with and without GERD (p > 0.050). Both groups experienced significant QOL improvement across all QOL constructs (p ≤ 0.021), and no difference was detected in the magnitude of that improvement between patients with and without a history of GERD (p > 0.050). Similarly, patients on active medical therapy for GERD (n = 49) had QOL gains comparable to patients not reporting GERD medical therapy (p > 0.050). Patients electing ESS for CRS with and without comorbid GERD have comparable baseline characteristics and QOL outcomes following surgery.


Benefits of concurrent delivery of hyaluronan and IGF-1 cues to regeneration of crosslinked elastin matrices by adult rat vascular cells.
Elastin, a major component of vascular matrices, critically determines vascular mechanics and maintains the quiescence of smooth muscle cells (SMCs). Attempts to regenerate elastin in elastin-compromised blood vessels using tissue-engineering approaches is limited by the unavailability of elastogenic cues to upregulate poor elastin output and matrix assembly by adult vascular cells. We previously showed that hyaluronan (HA) elastogenically stimulates aortic SMCs, although these effects are highly specific to HA fragment size. The elastogenic response of SMCs can also be modulated with growth factors such as insulin-like growth factor (IGF-1). Here, we evaluate the benefits of concurrent delivery of HA fragments (0.76-2000 kDa) and IGF-1 (500 ng/ml) to elastin synthesis, organization and crosslinking. The study outcomes show that, relative to supplement-free cultures, IGF-1 and long-chain HA/large HA fragments, but not HA oligomers, together induce multifold increases in the synthesis of elastin precursors, structural elastin matrix yields and crosslink densities within cell layers, and encourage elastic fibre formation. These outcomes are not all obtained when either of the cues is provided separately. IGF-1 and large HA fragments (>20 kDa) also together inhibit cell proliferation, a concern in elastin-compromised vessels, where SMC hyperproliferation is common. The results will benefit efforts to provide exogenous or scaffold-based elastogenic cues (IGF-1 + HMW HA/large HA fragments) to enable robust and faithful regeneration of elastin matrix structures in vivo or in vitro. The present outcomes may be used to restore elastin matrix homeostasis in de-elasticized vessels and tissue-engineered constructs that may be grafted as a substitute.


Transcriptome Revealed Exposure to the Environmental Ammonia Induced Oxidative Stress and Inflammatory Injury in Spleen of Fattening Pigs.
Ammonia is one of the major environmental pollutants that seriously threaten human health. Although many studies have shown that ammonia causes oxidative stress and inflammation in spleen tissue, the mechanism of action is still unclear. In this study, the ammonia poisoning model of fattening pigs was successfully established. We examined the morphological changes and antioxidant functions of fattening pig spleen after 30-day exposure to ammonia. Effects of ammonia in the fattening pig spleen were analyzed from the perspective of oxidative stress, inflammation, and histone methylation via transcriptome sequencing technology (RNA-seq) and real-time quantitative PCR validation (qRT-PCR). We obtained 340 differential expression genes (DEGs) by RNA-seq. Compared with the control group, 244 genes were significantly upregulated, and 96 genes were significantly downregulated in the ammonia gas group. Some genes in Gene Ontology (GO) terms were verified and showed significant differences by qRT-PCR. The KEGG pathway revealed significant changes in the MAPK signaling pathway, which is strongly associated with inflammatory injury. To sum up, the results indicated that ammonia induces oxidative stress in pig spleen, activates the MAPK signaling pathway, and causes spleen necrosis and injury. In addition, some differential genes encoding epigenetic factors were found, which may be involved in the response mechanism of spleen tissue oxidative damage. The present study provides a transcriptome database of ammonia-induced spleen poisoning, providing a reference for risk assessment and comparative medicine of ammonia.


Recent advances in postoperative pulmonary rehabilitation of patients with non‑small cell lung cancer (Review).
Non‑small cell lung cancer (NSCLC) accounts for ~85% of lung cancer cases and has high morbidity and mortality rates. Over the past decade, treatment strategies for NSCLC have progressed rapidly, particularly with the increasing use of screening programs, leading to improvements in the initial diagnosis and treatment of early‑stage and preinvasive tumors. Surgical intervention remains the primary treatment for early‑stage NSCLC. Thoracoscopic lobectomy has become the main treatment for early‑stage NSCLC, as it results in less postoperative bleeding and pain and fewer complications. However, the complication rate for thoracoscopic lobectomy due to sputum retention and weakened respiratory muscle strength remains as high as 19‑59%. Treating NSCLC remains challenging in terms of postoperative pulmonary rehabilitation. In the present review, recent advances in postoperative pulmonary rehabilitation for patients with NSCLC were presented in order to assist researchers in developing improved treatments to enhance postoperative pulmonary rehabilitation for such patients.


Background parenchymal enhancement and uptake as breast cancer imaging biomarkers: A state-of-the-art review.
Within the past decade, background parenchymal enhancement (BPE) and background parenchymal uptake (BPU) have emerged as novel imaging-derived biomarkers in the diagnosis and treatment monitoring of breast cancer. Growing evidence supports the role of breast parenchyma vascularity and metabolic activity as probable risk factors for breast cancer development. Furthermore, in the presence of a newly-diagnosed breast cancer, added clinically-relevant data was surprisingly found in the respective imaging properties of the non-affected contralateral breast. Evaluation of the contralateral BPE and BPU have been found to be especially instrumental in predicting the prognosis of a patient with breast cancer and even anticipating their response to neoadjuvant chemotherapy. Simultaneously, further research has found a link between these two biomarkers, even though they represent different physical properties. The aim of this review is to provide an up to date summary of the current clinical applications of BPE and BPU as breast cancer imaging biomarkers with the hope that it propels their further usage in clinical practice.


Rifaximin: a review of its use in the management of traveller's diarrhoea.
Oral rifaximin, a semisynthetic rifamycin derivative, is an effective and well tolerated antibacterial for the management of adults with non-invasive traveller's diarrhoea. Rifaximin was significantly more effective than placebo and no less effective than ciprofloxacin in reducing the duration of diarrhoea after treatment initiation for illness contracted during travel to diverse geographic locations. While rifaximin is effective in patients with Escherichia coli-predominant traveller's diarrhoea, it appears ineffective in patients infected with inflammatory or invasive enteropathogens. Rifaximin has a broad spectrum of antibacterial activity in vitro and undergoes negligible systemic absorption (<0.4%). In contrast to systemically absorbed antibacterials, such as the fluoroquinolones and macrolides, the acquisition of resistance to rifaximin would have limited consequences for global public health, as rifaximin has no role in the management of systemic infections. Rifaximin shows promise as chemoprophylaxis against traveller's diarrhoea and is a valuable new option for the management of traveller's diarrhoea caused by non-invasive bacterial strains.


Novel presenilin 1 variant (P117A) causing Alzheimer's disease in the fourth decade of life.
Over 160 rare genetic variants in presenilin 1 (PSEN1) are known to cause Alzheimer's disease (AD). In this study we screened a family with early-onset AD for mutations in PSEN1 using direct DNA sequencing. We identified a novel PSEN1 genetic variant which results in the substitution of a Proline with an Alanine at codon 117 (P117A). The P117A variant was present in all demented individuals and fifty percent of at risk individuals. This variant occurs at a site where three other disease-causing variants have been previously observed. In vitro functional studies demonstrate that the P117A variant results in an altered Abeta42/total Abeta ratio consistent with an AD causing mutation. The P117A variant is a novel mutation in PSEN1, which causes early-onset AD in an autosomal dominant manner.


Titanium Powder Coating Using Metal 3D Printing: A Novel Coating Technology for Cobalt-Chromium Alloy Implants.
Three-dimensional (3D) printing with a direct metal fabrication (DMF) technology has been innovatively introduced in the field of surface treatment of prostheses. The purpose of this study was to determine whether such modifications on the surface of cobalt-chromium (CoCr) alloy by titanium powder coating using DMF improves the osseointegration ability of CoCr alloy. We compared the in vitro and in vivo ability of cells to adhere to DMF-coated CoCr alloy with machining. Biological and morphological responses to human osteoblast cell lines were examined by measuring cell proliferation rate and observing expression of actin filament. For in vivo study, we inserted different specimens in each medulla of the distal femurs of rabbit. After 3 months, the distal femurs were harvested, and a push-out test and histomorphometric analyses were performed. The cell proliferation rate and cell adhesion in the DMF group were higher compared with those in the machined group. Human osteoblast cells on the DMF-coated surface were more strongly adhered and well-proliferated compared with those on the other surface. In the in vivo test, there was a significant difference in the ultimate shear strength between the DMF and machined groups (2.49 MPa vs. 0.87 MPa, respectively, p = 0.001). In the histomorphometric analysis, there was a significant difference in the mean bone-to-implant contact percentages between the DMF and machined groups (72.3 ± 6.2% vs. 47.6 ± 6.9%, respectively, p < 0.001). Titanium coating of CoCr alloy with 3D metal printing provides optimal surface characteristics and a good biological surface both in vitro and in vivo.


The Trapping Index: How to integrate the Eulerian and the Lagrangian approach for the computation of the transport time scales of semi-enclosed basins.
In this work, we investigated if the Eulerian and the Lagrangian approaches for the computation of the Transport Time Scales (TTS) of semi-enclosed water bodies can be used univocally to define the spatial variability of basin flushing features. The Eulerian and Lagrangian TTS were computed for both simplified test cases and a realistic domain: the Venice Lagoon. The results confirmed the two approaches cannot be adopted univocally and that the spatial variability of the water renewal capacity can be investigated only through the computation of both the TTS. A specific analysis, based on the computation of a so-called Trapping Index, was then suggested to integrate the information provided by the two different approaches. The obtained results proved the Trapping Index to be useful to avoid any misleading interpretation due to the evaluation of the basin renewal features just from an Eulerian only or from a Lagrangian only perspective.


Primary site and second site revertants of missense mutants of the evolutionarily invariant tryptophan 64 in iso-1-cytochrome c from yeast.
The three missense mutants cyc1-132, cyc1-166 and cyc1-189 in the yeast Saccharomyces cerevisiae contain nonfunctional and thermolabile iso-1-cytochromes c and have different replacements of the tryptophan at position 64 which corresponds to the invariant tryptophan residue found in cytochromes c from all eukaryotic species. The cyc1-166 and cyc1-189 mutants contain single replacements of, respectively, serine 64 and cysteine 64, while the cyc1-132 mutant contains a double replacement of glycine 64 and alanine 65 instead of the normal tryptophan 64 and aspartic acid 65. Twenty-three intragenic revertants having at least partially functional iso-1-cytochromes c arose from these three missense mutants by single amino acid replacements of either tryptophan, phenylalanine, tyrosine or leucine at position 64, or by second-site replacements in which the mutant residues at position 64 are retained and the normal serine 45 is replaced by phenylalanine 45. Specific activities of the iso-1-cytochromes c were estimated by growth of strains on lactate medium and are as follows, in terms of the normal, for iso-1-cytochromes c altered specifically in the ways shown: 100% for phenylalanine 64; 25% for tyrosine 64; between 0 and 25% for leucine 64; 100% for phenylalanine 45, cysteine 64; 25% for phenylalanine 45, serine 64; between 0 and 25% for phenylalanine 45, glycine 64, alanine 65; and 0% for serine 64, for cysteine 64, and for glycine 64, alanine 65 iso-1-cytochromes c. The results demonstrate that small residues of glycine, serine, and cysteine at position 64 are incompatible with function; they imply that many of the 10 amino acids accessible by single base-pair substitution but not observed in primary site revertants also are incompatible with function; and they show that large hydrophobic residues of phenylalanine, leucine, and tyrosine at position 64 are capable of restoring at least partial function. The second site revertants indicate that deleterious effects of the three missense mutants can be compensated by the introduction of phenylalanine 45, which may occupy space normally filled by tryptophan 64. Altered shapes of Calpha-band spectra and at least partial instability were characteristics of all iso-1-cytochromes c found lacking tryptophan 64. Apparently, the principal role of the invariant tryptophan is stabilization of the active protein structure, by providing a large hydrophobic group at the proper location.


Long-term outcome and cost-effectiveness of parenteral nutrition for acute gastrointestinal failure.
Although there are several published audits of long-term home parenteral nutrition for chronic gastrointestinal failure, there is little data concerning the long-term outcome following prolonged in-patient parenteral nutrition for an episode of acute gastrointestinal failure. Between 1983 and 1 July 1993, 162 patients received total parenteral nutrition (TPN) in our unit for acute gastrointestinal failure for a total of 4997 patient days and using 192 central venous catheters. Over the 10 years there were 11 mechanical complications resulting in one death. Although the overall catheter infection rate was 5.7%, in the last 4 years it was 0%, associated with a reduction in the frequency of site dressing and change of giving set from three times to once weekly. All patients had lost more than 10% of their body weight before TPN. In the non-malignant group, fed for more than 21 days (mean 50 days), the 10-year survival was 74% at a cost of 4723 pounds sterling per year of life saved. In the malignant group, the 5-year survival was 27% at a cost of 8351 pounds sterling per year of life saved. These costs compare favourably with other technologies, such as dialysis for acute renal failure. Better patient selection, fewer complications and lower costs are obtained when this treatment is carried out by an expert team.


Immunohistochemical and molecular assessment of human herpesvirus type 8 in gastrointestinal tumours.
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract, histologically identified as highly cellular spindle or epithelioid cell tumours, and often positive for CD34 (60-70%). Kaposi's sarcomas (KSs) are similar to GISTs: they are most often found in the gastrointestinal tract (although cutaneous lesions do occur), they are also composed of spindle or epithelioid cells (although erythrocytes are also seen), and the tumour cells are nearly all positive for CD34. Human herpesvirus type 8 (HHV-8) DNA has been found consistently in all types of KS, in particular in CD34 positive KS tumour cells. However, the association between HHV-8 and GIST has not been investigated. To assess the presence of HHV-8 in GISTs. Paraffin wax embedded tissues of 86 primary GISTs and their recurrent or metastatic tumours were analysed immunohistochemically for the CD34 antigen and HHV-8 latent nuclear antigen 1 (LNA-1) and by means of the nested polymerase chain reaction (PCR) and real time PCR for HHV-8 DNA. None of the 86 GISTs contained HHV-8 DNA sequences or LNA-1 positive cells. These results demonstrate the lack of HHV-8 infection in GIST tumour cells. HHV-8 does not appear to play a role in the pathogenesis of GIST, irrespective of the status of the tumour.


A new method for obtaining biomicroscopic photographs of the vitreous.
We describe a new method for obtaining photographs of the vitreous in vivo using an automatic-exposure photo-slitlamp microscope in combination with a high-speed color-reversal film and a Goldmann-type contact lens. Using our method, we investigated the microscopic characteristics of various vitreoretinal disorders. The patients studied comprised four cases with rhegmatogenous retinal detachments and one case with the sudden onset of vitreous floaters with posterior vitreous detachment (PVD). Our technique enabled us to obtain detailed images of vitreoretinal relationships, and to obtain a clearer understanding of vitreoretinal disorders than has been provided by previous methods. We conclude that our method is useful for clinical investigations of various vitreoretinal disorders.


JAHK: a low frequency antigen associated with the rG complex of the Rh blood group system.
We have investigated a 'new' low frequency antigen JAHK, which is a marker for the rare Rh gene complex rG. The rG haplotype does not produce any D, c or E antigens, but does produce a strong G antigen. The rG haplotype [d(C)(e)G] is associated with weak C and weak e antigens. Three unrelated rG/dce individuals and one rG/rG propositus were JAHK+. In addition, three propositi whose red cells had a typical expression of C and/or e antigen, which could not be shown to be rG because of a normal D antigen produced by the haplotype in trans, were also JAHK+. Families of three of the propositi demonstrate the inheritance of JAHK as a Mendelian dominant character. It is likely that the JAHK antigen results from conformational changes in an RhCcEe protein that has the amino acid characteristic of c antigen at position 16 and the amino acid residues characteristic of C antigen at positions 60, 68, and 103. JAHK has been assigned the number RH53.


An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2.
Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, where exome sequencing may become an important diagnostic tool to solve clinically or genetically complex cases. We describe an Italian family in which three sisters were affected by ataxia with postural/intentional myoclonus and involuntary movements at onset, which persisted during the disease. Oculomotor apraxia was absent. Clinical and genetic data did not allow us to exclude autosomal dominant or recessive inheritance and suggest a disease gene. Exome sequencing identified a homozygous c.6292C > T (p.Arg2098*) mutation in SETX and a heterozygous c.346G > A (p.Gly116Arg) mutation in AFG3L2 shared by all three affected individuals. A fourth sister (II.7) had subclinical myoclonic jerks at proximal upper limbs and perioral district, confirmed by electrophysiology, and carried the p.Gly116Arg change. Three siblings were healthy. Pathogenicity prediction and a yeast-functional assay suggested p.Gly116Arg impaired m-AAA (ATPases associated with various cellular activities) complex function. Exome sequencing is a powerful tool in identifying disease genes. We identified an atypical form of Ataxia with Oculoapraxia type 2 (AOA2) with myoclonus at onset associated with the c.6292C > T (p.Arg2098*) homozygous mutation. Because the same genotype was described in six cases from a Tunisian family with a typical AOA2 without myoclonus, we speculate this latter feature is associated with a second mutated gene, namely AFG3L2 (p.Gly116Arg variant). We suggest that variant phenotypes may be due to the combined effect of different mutated genes associated to ataxia or related disorders, that will become more apparent as the costs of exome sequencing progressively will reduce, amplifying its diagnostics use, and meanwhile proposing significant challenges in the interpretation of the data.


Blood and muscle metabolic responses to draught work of varying intensity and duration in horses.
Three standardbred trotters performed treadmill exercise at a velocity of 2 m s-1 with a draught load of both 34 kiloponds (kp) (test 1) and 80 kp (test 2), and also at 7 m s-1 with 34 kp (test 3). The heart rate increased to average values of 111 (+/- 5), 157 (+/- 10) and 197 (+/- 7) beats min-1 in tests 1, 2, and 3, respectively. Plasma free fatty acids increased only during tests 1 and 2. Blood lactate and muscle glucose-6-phosphate and lactate concentrations were low after tests 1 and 2, but high after test 3, where also muscle glycogen utilisation was greatest. Muscle creatine phosphate and adenosine triphosphate concentrations decreased after test 3 only. The study indicates that oxidative metabolism is most important for energy supply in muscles when exercise is performed with draught loads of both 34 and 80 kp at a low velocity. Glycogenolysis with lactate accumulation and phosphagen breakdown becomes much more important when, with a draught load of 34 kp, the velocity of exercise increases.


6-Mercaptopurine transport in human lymphocytes: correlation with drug-induced cytotoxicity.
6-mercaptopurine (6-MP) is efficacious in the treatment of inflammatory bowel disease (IBD). However, about one-third of patients respond poorly to therapy. This study aimed to characterize the inherent differences in 6-MP transport that may cotribute to the differences in treatment responses. Intracellular 6-MP accumulation was assayed in Epstein-Barr virus (EBV)-transformed lymphocytes from IBD patients, using (14) C-radiolabeled 6-MP. Cell proliferation was determined by methyl thiazolyl tetrazolium (MTT) assay. Apoptosis was assayed based on the activation of caspase 3. The expressions of 15 potential 6-MP transporters were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Intracellular 6-MP accumulation, varying significantly among patients, was carrier-dependent and partially sodium-dependent. 6-MP cytotoxicity was, at least in part, due to apoptosis and correlated with intracellular drug accumulation. The efflux transporters did not appear to contribute to the variability of intracellular drug accumulation between patients, since none correlated with drug accumulation or cytotoxicity. Rather, differential expression of five influx/uptake transporters might be a key contributor to the difference in the accumulation of and susceptibility to the drug. The heterogeneity of the drug transporters may be the reason for the therapeutic sensitivity of 6-MP in IBD patients. As the 6-MP uptake is a carrier-mediated and partially sodium-dependent process, future studies are necessary to evaluate the role of the putative transporters and their correlation with drug sensitivity in patients.


A new theory for thermal influences on endolymphatic flow.
We applied thermal stimuli to the partly isolated posterior canal of the bullfrog half-head preparation. Warming or cooling stimuli to the canal side changed the activity of the semicircular nerve. Our results suggest that changes in the endolymphatic density might be responsible for convection flow in the semicircular canal as well as calorically induced nystagmus.


[Problems and pitfalls in controlled clinical studies (author's transl)].
The problems encountered in prospective clinical trials are discussed: knowledge of the literature, precise formulation of the question answering the problem, number and qualifications of patients, duration of the trial, parameters to be measured. A surgical trial can hamper the education of the residents, or it can be devaluated by incompetent surgeons. Patients do not come for follow-up for several reasons (change of domicile, absence of disturbances, disagreeable tests).


LIF (AM424), a promising growth factor for the treatment of ALS.
Growth factors are theoretically promising agents for ALS therapy, but have been disappointing in subcutaneous delivery due to either toxicity or lack of major efficacy. Leukaemia inhibitory factor (LIF), was named after its effect on haemopoietic cells, and belongs to a group of cytokines which includes CNTF, IL-6, CT-1, OM and IL-11. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in the survival of both motor and sensory neurones, while reducing denervation induced muscle atrophy. Its effects in muscle also include stimulating myoblast proliferation in vitro, and up-regulation after muscle injury. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. In published studies of both axotomy induced neuronal death and in the Wobbler mouse models LIF is active at doses of 10 microg/kg delivered systemically, well below the expected maximum tolerated dose suggested by primate safety studies. LIF is expressed in low levels by spinal cord neurones with significant up-regulation when the neurones are damaged by BOAA toxin, an excitatory amino acid associated with a form of ALS. This augments other evidence suggesting LIF is a trauma factor playing a role in the injury response of adult neuronal tissue, and may be more effective than related growth factors. Taken together, the data suggests LIF is a physiologically relevant trophic factor with implications in clinical medicine as a therapy for ALS, and a human recombinant form (AM424), entered human clinical trials during 1998.


"PRIMORDIAL CHANT". SÁNDOR FERENCZI AS AN ORPHIC POET.
Ferenczi's deviations from Freudian thinking have caused enormous controversy. This paper re-examines Ferenczi's theoretical and technical innovations through the lens of Orpha-one of his most characteristic and valuable contributions, the culmination point of his thought, and the leitmotif of his work. So far research on Ferenczi's Orpha concept has been relatively sparse and there is still much obscurity about this term that he adopted from or co-created with his "evil genius" Elizabeth Severn. The following paper will attempt to shed more light on the origin, evolution, functions, and the philosophical foundations of the Orpha concept. Along with the theoretical, therapeutic and philosophical aspects, this point of view will enable a better understanding of the poetic value and the lyricism of Ferenczi's work. Orphic harmony-the fusion of Dionysian ecstasy and Apollonian clarity into the "principal instinct of tranquility" proclaimed by Ferenczi in 1930 and into the "primordial chant of cosmic unity" (Herder), emerges as the essence of the Ferenczian work and worldview.


The role of Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 regulator of transcription activation (RTA) in control of gene expression.
The mechanisms that control the replication state, latency versus lytic, of human herpesviruses have been under intense investigations. Here we summarize some of the recent findings that help define such mechanisms for Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV-8). For HHV-8, the viral regulator of transcription activation (RTA) is a key mediator of the switch from latency to lytic gene expression in infected cells. RTA is necessary and sufficient to drive HHV-8 lytic replication and the production of viral progeny. The RTA is an immediate-early gene product, it is the initial activator of expression of a multitude of viral and cellular genes that have been implicated in the replication of HHV-8 and pathogenesis of KS. Interactions of RTA with a number of viral promoters, and with a number of transcription factors or transcriptional co-activators are highlighted. Modulation of transactivation, through alternate RTA-protein, or RTA-promoter interactions, is hypothesized to participate in the selective tissue tropism and differential pathogenesis observed in KS.


Differentiation of mesenchymal stem cells into nucleus pulposus cells in vitro.
To find a new source of seed cells for constructing tissue-engineered intervertebral disc, nucleus pulposus (NP) cells and mesenchymal stem cells (MSCs) were isolated from New Zealand white rabbits. The nucleus pulposus cells population was fluorescence-laelled and co-cultured with MSCs with or without direct contact. Morphological changes were observed every 12 h. Semi-quantitative reverse transcriptase-polymerase chain reaction was performed to assess the expression levels of Sox-9, aggreacan and type II collagen every 24 h after the co-culture. MSCs treated with direct contact rounded up and presented a ring-like appearance. The expression of marker genes was significantly increased when cells were co-cultured with direct contact for 24 h. No significant change was found after coculture without direct contact. Co-culture of NP cells and MSCs with direct contact is a reliable method for generating large amount of NP cells used for cell-based tissue engineering therapy.


Activity of docetaxel (Taxotere) in small cell lung cancer. The Early Clinical Trials Group of the EORTC.
Docetaxel (Taxotere) is a new cytotoxic compound with a broad spectrum of activity in preclinical studies. This paper reports a phase II trial in patients with previously-treated small cell carcinoma of the lung. 34 patients received 100 mg/m2 of docetaxel in an intravenous infusion given over 1 h every 21 days. Seven partial responses were reported (25% of 28 evaluable patients). Duration of response was 3.5-12.6 months. Toxicities were predominantly neutropenia, alopecia and asthenia. Docetaxel is a new compound with activity in previously-treated patients with small cell lung cancer, and is suitable for evaluation in combination with other cytotoxic drugs active in this disease.


Expression of hypoxia-inducible factor (HIF-1alpha), VEGF-C and VEGF-D in non-invasive and invasive breast ductal carcinomas.
Hypoxia-inducible factor 1 alpha (HIF-1alpha) is a transcription factor that may play an important role in tumour growth and metastasis by its regulation of angiogenesis and lymphangiogenesis to survive cellular hypoxia. Lymphangiogenesis is promoted by vascular endothelial growth factors (VEGF)-C and VEGF-D, but the correlation between the expression of HIF-1alpha and VEGF-C or VEGF-D in human breast carcinoma is not well elucidated. This study examined the pathobiological role of these molecules in human breast ductal carcinoma. The expressions of HIF-1alpha, VEGF-C and VEGF-D were analyzed in 10 normal mammary epithelia, 12 fibroadenomas, 20 ductal carcinomas in situ (DCISs and 36 invasive ductal carcinomas (IDCs) by immunohistochemistry, comparing clinicopathological parameters. HIF-1alpha expression in nuclei was found in DCIS and IDC, but not in normal or fibroadenoma cells. The HIF-1alpha labelling index was significantly correlated with the degree of VEGF-C expression in IDC (p < 0.001), but not in DCIS. HIF-1alpha expression was significantly correlated with tumour necrosis and with the Van Nuys prognostic index (VNPI) (p < 0.05, p < 0.05, respectively) in the 20 DCISs. On the other hand, VEGF-D levels, but not those of HIF-1alpha and VEGF-C, were significantly higher in cases with lymph node metastasis and estrogen receptor expression in carcinoma cells (p < 0.01, p < 0.05, respectively) in the 36 IDCs. These findings suggest that HIF-1alpha is expressed in the early stage of mammary carcinogenesis, in which the expression correlates with necrosis in the DCISs and with VEGF-C expression in the IDCs, the latter resulting in a higher frequency of metastasis to regional lymph nodes.


Influence of S9 mix composition on the SOS response in Escherichia coli PQ37 by polycyclic aromatic hydrocarbons.
To investigate the variability in test results obtained with the SOS chromotest (Escherichia coli PQ37 genotoxicity assay) when varying the composition of the exogenous metabolizing system (S9 mix), we examined the influence of different S9 and NADP concentrations, of buffer pH value, of SDS concentrations, the effects of E. coli PQ37 density and centrifugation steps on the expression of beta-galactosidase (beta g) and alkaline phosphatase (ap) activity, the calculated induction factors (IFs) and SOS-inducing potencies (SOSIPs). Additionally we examined the metabolic potency (stability) of S9 mix when stored at 37 degrees C before use. Initially, we used 0-5000 ng (= 0-20 nmole) benzo[a]pyrene (B[a]P) as a reference compound for the test procedure in the presence of standard S9 mix. Subsequently, to evaluate the results of S9 mix variations we examined several polycyclic aromatic hydrocarbons (PAHs) using both the standard and a modified S9 mix composition and test protocol. We observed the highest beta g and ap activities and/or IFs using only 11-27 microliters 9000 x g liver supernatant (S9) from Aroclor 1254-induced rats per assay (20-50% of standard amount) and calibrating the S9 mix Tris buffer to pH 7.8-8.0. 60-300 micrograms NADP/assay (10-50% of standard) was sufficient for optimum activation of PAHs. In contrast to previous investigations about the variability of the SOS chromotest in the absence of a metabolizing system, higher induction factors were obtained when using higher bacterial densities (12-18 x 10(6) cfu/assay). Centrifugation steps as recommended by other investigators were not necessary when using optimum S9 amounts. The metabolic activity of S9 mix remained nearly constant approximately 20 min after preparation, but decreased to 80% of its activity in about 1 h.


Factors modifying radiation induced stimulation in plants: pre-irradiation seed moisture content.
The effect of moisture content of seeds at the time of irradiation in relation to radiation-induced stimulation was investigated on rice (Oryza sativa c.v. D-6-2-2). The optimum moisture content was 8% for stimulation measured as seedling height. It is concluded that seed moisture at the time of irradiation plays an important role in the expression of stimulation and its reproducibility.


Selenium protein identification and profiling by mass spectrometry: A tool to assess progression of cardiomyopathy in a whale model.
Non-ischemic cardiomyopathy is a leading cause of congestive heart failure and sudden cardiac death in humans and in some cases the etiology of cardiomyopathy can include the downstream effects of an essential element deficiency. Of all mammal species, pygmy sperm whales (Kogia breviceps) present the greatest known prevalence of cardiomyopathy with more than half of examined individuals indicating the presence of cardiomyopathy from gross and histo-pathology. Several factors such as genetics, infectious agents, contaminants, biotoxins, and inappropriate dietary intake (vitamins, selenium, mercury, and pro-oxidants), may contribute to the development of idiopathic cardiomyopathy in K. breviceps. Due to the important role Se can play in antioxidant biochemistry and protein formation, Se protein presence and relative abundance were explored in cardiomyopathy related cases. Selenium proteins were separated and detected by multi-dimension liquid chromatography inductively coupled plasma mass spectrometry (LC-ICP-MS), Se protein identification was performed by liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS), and Se protein profiles were examined in liver (n=30) and heart tissue (n=5) by SEC/UV/ICP-MS detection. Data collected on selenium proteins was evaluated in the context of individual animal trace element concentration, life history, and histological information. Selenium containing protein peak profiles varied in presence and intensity between animals with no pathological findings of cardiomyopathy and animals exhibiting evidence of cardiomyopathy. In particular, one class of proteins, metallothioneins, was found to be associated with Se and was in greater abundance in animals with cardiomyopathy than those with no pathological findings. Profiling Se species with SEC/ICP-MS proved to be a useful tool to identify Se protein pattern differences between heart disease stages in K. breviceps and an approach similar to this may be applied to other species to study Se protein associations with cardiomyopathy.


Bone induction by Ewing's sarcoma. Transplantation into athymic nude mice.
Fresh specimens from two cases of Ewing's sarcoma were implanted in thigh muscles of nude athymic mice. Ewing's sarcomas induced differentiation of mouse-derived new bone in the same fashion as osteogenic sarcomas and chondrosarcomas. Control transplants of eight primary nonosseous and metastatic tumors did not induce bone formation. The osteoinductive action of Ewing's sarcoma is submitted as evidence of its origin from an osteogenic cell rather than from a hematopoietic cell line.


Cutaneous leiomyosarcoma: case reports and review of the literature.
Two patients with leiomyosarcomas are described, both men with lesions located in the upper trunk. Both lesions were present for more than 10 years. The diagnosis was established after excisional biopsy. The diagnostic criteria are a tumor size greater than 2.5 cm in diameter; a mitotic rate of 1 or more per 5 high-power fields in cellular areas; and electron microscopic verification of smooth muscle cells. The literature is reviewed and the clinical presentation of the 2 patients is discussed. Wide excision is the treatment of choice after histological diagnosis.


Asymmetric Arylation of Diazoesters with Anisoles Enabled by Cooperative Gold and Phosphoric Acid Catalysis.
An enantioselective insertion of a carbene into the Csp2-H bond of anisole derivatives has been accomplished using an achiral gold complex and a chiral phosphoric acid as the catalytic system, providing a novel protocol for the synthesis of chiral α,α-diaryl acetates. Density functional theory calculations reveal the reactivity and the origin of the enantioselectivity of this reaction.


Do individuals respond to cost-sharing subsidies in their selections of marketplace health insurance plans?
The Affordable Care Act (ACA) provides assistance to low-income consumers through both premium subsidies and cost-sharing reductions (CSRs). Low-income consumers' lack of health insurance literacy or information regarding CSRs may lead them to not take-up CSR benefits for which they are eligible. We use administrative data from 2014 to 2016 on roughly 22 million health insurance plan choices of low-income individuals enrolled in ACA Marketplace coverage to assess whether they behave in a manner consistent with being aware of the availability of CSRs. We take advantage of discontinuous changes in the schedule of CSR benefits to show that consumers are highly sensitive to the value of CSRs when selecting insurance plans and that a very low percentage select dominated plans. These findings suggest that CSR subsidies are salient to consumers and that the program is well designed to account for any lack of health insurance literacy among the low-income population it serves.


[Surgical treatment of total anomalous pulmonary venous connection--clinical aspects of pulmonary venous obstruction].
During November 1986 and May 1997, 19 patients with total anomalous pulmonary venous connection (TAPVC) underwent repair surgery. 20 operations including two reoperations were performed. 8 of 19 patients were classified as Darling type Ia, 5 as type IIa, 4 as type III and 2 patients were type IV. Two patients were operated under emergency circumstances within 24 hours after admission, 7 patients were after a short term stabilization of 4.4 days, and the other 11 patients received surgical treatment after a mean of 8.8 days as scheduled cases. For the anostomosis, the common pulmonary venous chamber or the vertical vein was connected with the left atrium in type Ia and III cases; in type IIa and IV cases the cut-back method was performed. Persistent pulmonary hypertension and post-operative pulmonary venous obstruction (PVO) affected the post-operative clinical course. Persistent pulmonary hypertension caused the death of one patient with type IIa and III each, just after operation. One type IV patient died 50 days after operation. The autopsy revealed post-operative obstructions of the remote parts of the pulmonary veins on the anostomosis site. Two patients (type IIa, III) successfully underwent reoperation due to PVO. Post-operative cardiac catheterization was performed after 12 month in 12 cases. Persistent pulmonary hypertension was found in 4 patients, and a type III patient was reoperated because of stenosis of the anostomosis site. The other three patients had persistent pulmonary hypertension without any demonstrable PVO. Persistent pulmonary hypertension and PVO are combined as TAPVC complex. The difficulty to reoperated patients with persistent pulmonary hypertension caused by PVO is one major problem. So preoperative prevention of PVO by normalization the morphologic changes of the pulmonary veins by using drugs could be a different view point in TAPVC therapy after the initial operation.


A comparison of OKT3 monoclonal antibody and corticosteroids in the treatment of acute renal allograft rejection.
The monoclonal antibody OKT3 (Ortho Pharmaceutical, Raritan, NJ) was utilized in two separate protocols for treatment of acute renal allograft rejection in patients receiving cyclosporine, azathioprine, and prednisone for maintenance immunosuppression. In Group I, 54 patients received steroids for primary treatment of acute rejection with OKT3 used for resistant rejections and second rejection episodes. In Group II, 34 patients received OKT3 as primary treatment of acute rejection while steroids were used for rescue and second rejection episodes. OKT3 successfully reversed 82% of initial acute rejection episodes in Group II as compared with a 63% reversal with steroids in Group I. Rescue treatment was required in only 15% of Group II patients compared with 33% of Group I patients. Overall patient survival was 96% and 94%, respectively, for steroid primary and OKT3 primary treatments. Allograft survival at 3 months was identical, 74% in both groups. Based on allograft survival data, OKT3 is equally effective either as primary treatment for allograft rejection, or for rescue therapy if initial corticosteroid treatment fails.


Comparison of gatifloxacin and levofloxacin administered at various dosing regimens to hospitalised patients with community-acquired pneumonia: pharmacodynamic target attainment study using North American surveillance data for Streptococcus pneumoniae.
This work aimed at determining the target attainment potential of gatifloxacin and levofloxacin in specific age-related patient populations such as elderly (> or =65 years) versus younger (<65 years) hospitalised patients with community-acquired pneumonia (CAP). Previously described population pharmacokinetic models of gatifloxacin and levofloxacin administration in patients with serious CAP were utilised to simulate gatifloxacin and levofloxacin pharmacokinetics. Pharmacokinetic simulations and susceptibility data for Streptococcus pneumoniae from the ongoing national surveillance study, Canadian Respiratory Organism Susceptibility Study (CROSS), were then used to produce pharmacodynamic indices of free-drug area under the curve over 24h relative to the minimum inhibitory concentration (free-drug AUC(0-24)/MIC(all)). Monte Carlo simulations were then used to analyse target attainment both of gatifloxacin and levofloxacin to achieve free-drug AUC(0-24)/MIC(all)> or =30 against S. pneumoniae in patients with CAP. Dosing regimens for gatifloxacin were 400 mg once daily (qd) administered to younger patients (<65 years) and gatifloxacin 200 mg qd to elderly patients (> or =65 years). Dosing regimens for levofloxacin were simulated as 500 mg, 750 mg and 1000 mg qd administered to elderly patients as well as younger patients. Monte Carlo simulations using gatifloxacin 400mg against S. pneumoniae yielded probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 of 96.6% for all patients, 92.3% for younger patients and 97.7% for elderly patients. When administered to elderly patients, a reduced dose of gatifloxacin 200mg qd could achieve a target attainment potential of 91.4%. Monte Carlo simulation using levofloxacin 500 mg qd yielded probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 of 92.3% for all patients, 95.7% for elderly patients compared with 72.7% for younger patients. Using levofloxacin 750 mg and 1000 mg qd had probabilities of achieving free-drug AUC(0-24)/MIC(all) of 30 of 97.0% and 98.3%, 98.1% and 99.2%, and 90.1% and 95.2% for all patients, elderly patients and younger patients, respectively. The probability of achieving free-drug AUC(0-24)/MIC(all) of 100 was low both with gatifloxacin and levofloxacin, except in the case of elderly patients receiving levofloxacin in a dose of 1000 mg qd (78.5%). We conclude that gatifloxacin and levofloxacin pharmacokinetics in elderly patients with CAP are markedly different from those of younger patients. Higher gatifloxacin/levofloxacin AUC and longer half-life (t(1/2)) values in elderly patients with CAP compared with younger patients provide better pharmacodynamic parameters (free-drug AUC(0-24)/MIC) leading to a higher probability of pharmacodynamic target attainment and improved bacteriological outcome against S. pneumoniae. Gatifloxacin 400mg qd results in a high probability of target attainment and improved bacteriological outcome against S. pneumoniae both in young and elderly CAP patients. However, gatifloxacin administered at a lowered dose of 200 mg qd in elderly patients could still be successful in producing a favourable antibacterial effect. Levofloxacin administered at a dose of 750 mg qd results in a high probability of target attainment and improved bacteriological outcome against S. pneumoniae in all patients with CAP.


Neuroimaging at 3T vs 7T: Is It Really Worth It?
Food and Drug Administration approval of 7T MR imaging allows ultrahigh-field neuroimaging to extend from the research realm into the clinical realm. Increased signal is clinically advantageous for smaller voxels and thereby high spatial resolution imaging, with additional advantages of increased tissue contrast. Susceptibility, time-of-flight signal, and blood oxygen level-dependent signal also have favorable clinical benefit from 7T. This article provides a survey of clinical cases showcasing some advantages of 7T.


Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors.
Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2. Whereas inhibition of 11β-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11β-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. So far, no selective 11β-HSD2 inhibitor has been developed and neither animal studies nor clinical trials have been reported based on 11β-HSD2 inhibition. Starting from the lead compound glycyrrhetinic acid, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11β-HSD1 and 11β-HSD2 in cell lysates. Several hydroxamic acid derivatives showed high selectivity for 11β-HSD2. The most potent and selective compound is active against human 11β-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11β-HSD1.