Four new diterpenes from the mangrove Ceriops tagal and structure revision of four dolabranes with a 4,18-epoxy group.
Four new diterpenes named tagalons A-D (1-4), comprising an isopimarane (1), two 16-nor-pimaranes (2-3), and a dolabrane (4), were isolated from the Chinese mangrove, Ceriops tagal, together with four known dolabranes containing a 4,18-epoxy group, viz. tagalene I (5), 4-epitagalene I (6), tagalsin A (7), and tagalsin B (8). The structures of these compounds were unambiguously established by HR-ESIMS and NMR spectroscopic data. Based on the new criteria of NOE interactions between H2-18/H3-19 and H2-18/H3-20, previously reported relative configurations of the above four known dolabranes were correctly revised as their C-4 epimers, respectively. The relative configuration of tagalon B (2) and the absolute configuration of tagalene I (5) were established by single-crystal X-ray diffraction analyses, conducted with Cu Kα radiation. Most notably, tagalons C (3) and D (4) exhibited selective cytotoxicities against the human breast cancer cell line MT-1 with IC50 values of 3.75 and 8.07μM, respectively; whereas tagalene I (5) displayed potent cytotoxic effects against four human breast cancer cell lines MDA-MB-453, MDA-MB-231, SK-BR-3, and MT-1 with IC50 values of 8.97, 8.97, 4.62, and 3.93μM, respectively.


How we did it: neopharyngeal stricture management with the nitinol stent in the laryngectomized patient: our disappointing results.
Serial dilatation, the mainstay of benign 'neopharyngeal' stricture management, can have inconsistent results. Nitinol stents, as a metallic self-expanding coil, may have a role in such patients. Such stents were inserted in four patients but two had to be removed because of intractable pain. It is concluded that nitinol stents are unlikely to have a significant role in the management of neopharyngeal stricture management.


Effect of bradykinin and prostaglandins on the release of calcitonin gene-related peptide-like immunoreactivity from the rat spinal cord in vitro.
1. The release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) from the dorsal horn of the rat spinal cord in vitro in response to dorsal root stimulation was measured by radioimmunoassay. 2. Stimulation of the dorsal roots (3 or 4 roots on each side) at 10 Hz for 5 min evoked a mean release (R1) of 134.3 +/- 17.5 (n = 10) fmol CGRP-LI; the release (R2) evoked by a second stimulation period 30 min later under control conditions was 77 +/- 10% (n = 10) of R1. Test compounds were applied to the preparation following release R1, and their effect calculated from the value of R2/R1. 3. Bradykinin (0.01-10 microM) had no significant effect on the basal release of CGRP-LI, but at 0.1-10 microM it increased 2-3 fold the release evoked by dorsal root stimulation. 4. This effect of bradykinin was prevented by indomethacin (10 microM), or by the B2-receptor antagonist, Hoe140 (1-10 microM). In the presence of Hoe140, bradykinin significantly reduced R2/R1; the explanation for this is not clear. 5. The B1-receptor agonist, Des-Arg9-bradykinin (10 microM), did not affect CGRP-LI release nor was the effect of bradykinin blocked by the B1-receptor antagonist, Des-Arg9-Leu8-bradykinin (10 microM). 6. Various prostaglandins were found to mimic the effect of bradykinin on CGRP-LI release. Their approximate order of potency was prostaglandin D2 (PGD2) = PGE1 > PGF2 alpha = PGE2; PGI2 was ineffective at 10 microM.7. Forskolin (30 muM) and 3-isobutyl l-methylxanthine (IBMX; 10 fM) also increased the evoked release of CGRP-LI.8. It is concluded that bradykinin acts on B2-receptors in the spinal cord, causing the formation ofprostanoids, which in turn cause an enhancement of neuropeptide release from primary afferent nerve terminals in the dorsal horn. This effect may be secondary to activation of adenylate cyclase. Because B2-receptors are mainly associated with primary afferent nerve terminals, it is likely that prostanoid production is also a function of these structures. Whether this action of bradykinin has any physiological function in nociceptive transmission remains unclear..


Implementation of the community network of reference laboratories for human influenza in Europe.
The increased need for accurate influenza laboratory surveillance data in the European Union required formalisation of the existing network of collaborating national influenza reference laboratories participating in the European Influenza Surveillance Scheme (EISS). To establish a Community Network of Reference Laboratories for Human Influenza in Europe (CNRL). Virologists in EISS defined the objective and tasks of the CNRL. Performance of the laboratories in the tasks was monitored by questionnaire-based inventories and quality control assessments (QCA). Subsequently, actions were defined to improve the performance of the CNRL. The CNRL started in April 2003 and included as of May 2004 32 laboratories in 24 European countries. The objective is to provide high quality reference services for human influenza surveillance, early warning and pandemic preparedness in Europe. The defined basic tasks are direct detection, culture, typing, subtyping and strain characterisation of influenza virus, diagnostic influenza serology and storage of clinical specimens and virus isolates. The questionnaire-based inventories and QCAs revealed that the majority of CNRL laboratories perform well in most of the basic tasks, although improvements are needed in certain areas of virus testing. Therefore, task groups have been established to further improve the methods used in the network. The CNRL has proven its usefulness during the 2003-2004 season by the reporting of accurate data concerning the flu epidemic caused by A/Fujian/411/2002 (H3N2)-like viruses and by the rapid sharing of information, protocols and reagents during the A(H5N1) and A(H7N3) epizootics in Asia and Canada. EISS has established a functioning Community Network of Reference Laboratories for Human Influenza in Europe and laid the foundation for further enhancement and collaborations. Important next steps include improving the laboratories to carry out all basic tasks and collaboration with the European Centre for Disease Prevention and Control.


In vivo evaluation of ankle kinematics and tibiotalar joint contact strains using digital volume correlation and 3 T clinical MRI.
In vivo evaluation of ankle joint biomechanics is key to investigating the effect of injuries on the mechanics of the joint and evaluating the effectiveness of treatments. The objectives of this study were to 1) investigate the kinematics and contact strains of the ankle joint and 2) to investigate the correlation between the tibiotalar joint contact strains and the prevalence of osteochondral lesions of the talus distribution. Eight healthy human ankle joints were subjected to compressive load and 3 T MRIs were obtained before and after applying load. The MR images in combination with digital volume correlation enabled non-invasive measurement of ankle joint kinematics and tibiotalar joint contact strains in three dimensions. The total translation of the calcaneus was smaller (0.48 ± 0.15 mm, p < 0.05) than the distal tibia (0.93 ± 0.16 mm) and the talus (1.03 ± 0.26 mm). These movements can produce compressive and shear joint contact strains (approaching 9%), which can cause development of lesions on joints. 87.5% of peak tensile, compressive, and shear strains in the tibiotalar joint took place in the medial and lateral zones. The findings suggested that ankle bones translate independently from each other, and in some cases in opposite directions. These findings help explain the distribution of osteochondral lesions of the talus which have previously been observed to be in medial and lateral regions of the talar dome in 90% of cases. They also provide a reason for the central region of talar dome being less susceptible to developing osteochondral lesions.


Induction of filopodia formation by α-Actinin-2 via RelA with a feedforward activation loop promoting overt bone marrow metastasis of gastric cancer.
Bone marrow metastasis (BMM) is underestimated in gastric cancer (GC). GC with BMM frequently complicate critical hematological abnormalities like diffused intravascular coagulation and microangiopathic hemolytic anemia, which constitute a highly aggressive GC (HAGC) subtype. HAGC present a very poor prognosis with peculiar clinical and pathological features when compared with not otherwise specified advanced GC (NAGC). But the molecular mechanisms underlying BMM from GC remain rudimentary. The transcriptomic difference between HAGC and NAGC were analyzed. Genes that were specifically upregulated in HAGC were identified, and their effect on cell migration and invasion was studied. The function of ACTN2 gene were confirmed by GC cell lines, bone-metastatic animal model and patients' tissues. Furthermore, the molecular mechanism of ACTN2 derived-BMM was explored by multiple immunofluorescence staining, western blot, chromatin immunoprecipitation, and luciferase reporter assays. We elucidated the key mechanisms of BMM depending on the transcriptomic difference between HAGC and NAGC. Five genes specifically upregulated in HAGC were assessed their effect on cell migration and invasion. The ACTN2 gene encoding protein α-Actinin-2 was detected enhanced the metastatic capability and induced BMM of GC cells in mouse models. Mechanically, α-Actinin-2 was involved in filopodia formation where it promoted the Actin filament cross-linking by replacing α-Actinin-1 to form α-Actinin-2:α-Actinin-4 complexes in GC cells. Moreover, NF-κB subunit RelA and α-Actinin-2 formed heterotrimers in the nuclei of GC cells. As a direct target of RelA:α-Actinin-2 heterotrimers, the ACTN2 gene was a positive auto-regulatory loop for α-Actinin-2 expression. We demonstrated a link between filopodia, BMM and ACTN2 activation, where a feedforward activation loop between ACTN2 and RelA is established via actin in response to distant metastasis. Given the novel filopodia formation function and the new mechanism of BMM in GC, we propose ACTN2 as a druggable molecular vulnerability that may provide potential therapeutic benefit against BMM of GC.


Histopathologic alterations after endovascular radiation and antiproliferative stents: similarities and differences.
Endovascular radiation and drug-eluting antiproliferative stents in experimental animals (normal pigs and rabbit arteries) show a decrease in the neointimal growth at 1 month vs. controls. However, this is accompanied by delayed healing characterized by persistence of neointimal fibrin (with or without inflammation), a decrease in smooth muscle cells, and incomplete endothelialization. Conversely, stainless steel control stents show complete healing with the neointima consisting of smooth muscle cells in a proteoglycan-collagen matrix and near complete luminal surface endothelialization. Long-term (3 and 6 months) animal studies fail to show any benefit with radiation or drug-eluting stents. These experimental results are discrepant from those seen clinically in man where both therapies have shown benefit at 6 months, suggesting that animal data may not be predictive of clinical results. The main differences can be explained on the basis of preclinical studies performed in juvenile animals without underlying atherosclerosis, which leads to accelerated healing in animals vs. man such that 1 month animal data likely correspond to 6 months in man. Therefore long-term (24-30 months) angiographic and/or IVUS follow-up studies in man will be required to determine if drug-eluting stents will behave similarly to animal studies at 3 and 6 months.


Sirtuins, Cell Senescence, and Vascular Aging.
The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition; and (2) stress-induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, and contribute to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that SIRT1, SIRT3, and SIRT6 show protective functions against vascular aging, and definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and nicotinamide adenine dinucleotide stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation.


Full-depth profiles of PAHs in the Western South China Sea: Influence of Upwelling and Mesoscale Eddy.
Oceanic processes such as coastal upwelling and mesoscale eddy, could influence the spatial distribution and environmental behaviors of semi-volatile organic pollutants in the marine environment. Seawater samples were collected from the full-depth water columns from the South China Sea (SCS), and PAH concentrations (∑14PAH) in the continental shelf and the open basin areas were 16-110 and 10-93 ng/L respectively. Results of isomeric ratios and principal component analysis illustrated PAHs' mixed sources (petrogenic and pyrogenic). PAH inventory of the SCS seawater was estimated as 100 ± 58 thousand tons, and the majority of them was stored in the intermediate and deep water masses. Generally, full-depth profiles of dissolved PAHs showed an "enrichment in surface and exhaustion in the deep" pattern, and this might be influenced by the oceanic processes such as coastal upwelling or eddy diffusion. In the cross-shelf area, upwelling could enhance the scavenging efficiency of PAHs on the upper layer, and increase the pollutant concentration in the medium and deep water. While in the open-basin area, PAHs were more likely influenced by the halocline stratification and eddy diffusion, and their vertical fluxes due to eddy diffusion was estimated to be 1.2 × 10-6 g s-1. This study highlighted the influences of oceanic processes in transport PAHs in the marginal sea, further study is needed to investigate their seasonal variations related to the monsoon characteristics.


Frequency of toll-like receptor 4 variants and association with treatment response in children with primary immune thrombocytopenia.
To investigate the frequency of toll-like receptor 4 (TLR4) variants c.896A>G (p.Asp299Gly) and c.1196C>T (p.Thr399Ile) among Egyptian children with primary immune thrombocytopenia (pITP), and their association with disease course and response to treatment. A case-control study that included 80 children with pITP and 50 age- and sex-matched healthy controls. TLR4 c.896A>G and c.1196C>T variants were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Patients were classified according to their response to treatment after 3 months as responders and nonresponders. Compared with controls, children with pITP had significantly higher minor allele frequencies of TLR4 p.Asp299Gly (16.25% vs. 6%, odds ratio [OR] 3.04, 95% confidence interval [CI]: 1.16-9.36, p = .014) and p.Thr399Ile (20% vs. 4%, OR 6, 95% CI: 2.02-24.01, p < .001). The presence of p.Asp299Gly variant was significantly associated with chronic ITP (OR 7.78, 95% CI: 2.04-35.69, p < .001) and non-response to therapy with steroid (OR 11.67, 95% CI: 1.32-104.08, p = .012), but not thrombopoietin-receptor agonist (OR 1.67, 95% CI: 0.35-8.19, p = .464). Likewise, having p.Thr399Ile variant was significantly associated with chronic ITP (OR 5.14, 95% CI: 1.6-17.4, p = .002) and non-response to therapy with steroid (OR 6.1, 95% CI: 1.01-49.06, p = .046) but not thrombopoietin-receptor agonist (OR 1.57, 95% CI: 0.33-7.58, p = .515). The presence of TLR4 p.Asp299Gly or p.Thr399Ile variant may be associated with ITP predisposition, chronicity, and non-response to upfront steroid therapy. These findings enhance our understanding of the complex pathophysiology of pITP with potentially important clinical implications.


Low intraspecific variation in the rRNA internal transcribed spacer 2 (ITS2) of the Australian paralysis tick, Ixodes holocyclus.
Ixodes holocyclus has a narrow, discontinuous distribution along the east coast of Australia. We studied ticks from 17 localities throughout the geographic range of this tick. The ITS2 of I. holocyclus is 793 bp long. We found nucleotide variation at eight of the 588 nucleotide positions (1.4%) that were compared for all ticks. There were eight different nucleotide sequences. Most sequences were not restricted to a particular geographic region. However, sequences F, G and H, which had an adenine at position 197, were found only in the far north of Queensland--all other ticks had a guanine at this position. The low level of intraspecific variation in this tick (0.7%) contrasts with the sequence divergence between I. holocyclus and its close relative, I. cornuatus (13.1%). These data indicate that I. holocyclus does not contain cryptic species despite possible geographic isolation of some populations. We conclude that variation in the ITS2 is likely to be informative about the phylogeny of the group.


Organisation and function of the Phaeospirillum molischianum photosynthetic apparatus.
We have investigated the organisation of the photosynthetic apparatus in Phaeospirillum molischianum, using biochemical fractionation and functional kinetic measurements. We show that only a fraction of the ATP-synthase is present in the membrane regions which contain most of the photosynthetic apparatus and that, despite its complicated stacked structure, the intracytoplasmic membrane delimits a single connected space. We find that the diffusion time required for a quinol released by the reaction centre to reach a cytochrome bc1 complex is about 260 ms. On the other hand, the reduction of the cytochrome c chain by the cytochrome bc1 complex in the presence of a reduced quinone pool occurs with a time constant of about 5 ms. The overall turnover time of the cyclic electron transfer is about 25 ms in vivo under steady-state illumination. The sluggishness of the quinone shuttle appears to be compensated, at least in part, by the size of the quinone pool. Together, our results show that P. molischianum contains a photosynthetic system, with a very different organisation from that found in Rhodobacter sphaeroides, in which quinone/quinol diffusion between the RC and the cytochrome bc1 is likely to be the rate-limiting factor for cyclic electron transfer.


Differences in breeding and motility betweenPardosa Pullata (Clerck) andPardosa Prativaga (L. Koch), (Lycosidae, Araneae) in relation to habitat.
Populations ofPardosa pullata (Clerck) andP. prativaga (L. Koch) were studied under experimental and field conditions. In the field attention has been paid to pure as well as to mixed populations of the species. Differences in breeding and motility were found, which are discussed in relation to the habitat of the two species.


Postmenopausal virilization due to ovarian stromal hyperthecosis.
A 53-year-old woman presented with hirsutism of long duration and virilization of recent onset. She was gravida 12 para 9. The 17-ketosteroids were normal, gonadotropins were in the post-menopausal range, and the serum testosterone was in the male range. After bilateral oophorectomy, the testosterone became normal. Ovarian pathology revealed stromal hyperthecosis.


Understanding the needs of children following large-scale disasters and the role of government.
No one who experiences a disaster is untouched by it. Children and their families are often among the most affected. This article explains how mental health and medical professionals can assist families and communities in dealing with common disaster-related stress reactions in children. An overview of disaster research and examples of special concerns about children are given. In addition, an overview of the role of local, state, and federal governments, as well as other organizations, is provided.


Evaluation of human milk fortification from the time of the first feeding: effects on infants of less than 31 weeks gestational age.
To determine whether human milk fortification from the time of the first feeding significantly improves weight gain and bone mineral status in infants of <31 weeks estimated gestational age as compared with delayed or standard human milk fortification. This was a retrospective pre-post design. In all, 95 infants born at <31 weeks estimated gestational age were compared. There were 53 infants in the early fortification group (EFG) and 42 infants in the delayed fortification group (DFG). They were compared with regard to weight gain at 34 weeks postmenstrual age (PMA), and their serum levels of calcium, phosphorus and alkaline phosphatase levels were compared as an indicator of bone mineral status. The practice change of fortifying all human milk given to preterm infants at <34 weeks PMA commenced in June 2009. The usual practice of fortification took place once an infant had reached a feeding volume of 50 to 100 ml kg(-1) per day. The new practice fortified all human milk with a powdered human milk fortifier to 24 calories per ounce, starting with the first feeding, no matter how small the volume. There were no differences in weight gain between the EFG and the DFG. The group that received fortification from the time of the first feeding were significantly less likely to have alkaline phosphatase levels >500 U l(-1) from 33 weeks PMA onward. There was no incidence of feeding intolerance with early fortification. Fortification of human milk from the time of the first feeding does not affect weight gain at 34 weeks PMA, but is related to a lower incidence of elevated alkaline phosphate levels and does not cause feeding intolerance.


Effectiveness of nutrition interventions in the pre-ESRD and the ESRD population.
Malnutrition is present in approximately 40% of patients treated with maintenance dialysis, and several serum proteins that are associated with malnutrition are also associated with decreased survival in this patient population. This article will review interventions to treat malnutrition in patients with chronic renal failure, as well as those treated with maintenance hemodialysis and peritoneal dialysis. Effectiveness of the interventions, as well as the design of trials to evaluate these interventions, are discussed.


Matching visual stimuli on the basis of global and local features by chimpanzees (Pan troglodytes) and rhesus monkeys (Macaca mulatta).
This study was designed to examine whether chimpanzees and monkeys exhibit a global-to-local precedence in the processing of hierarchically organized compound stimuli, as has been reported for humans. Subjects were tested using a sequential matching-to-sample paradigm using stimuli that differed on the basis of their global configuration or local elements, or on both perceptual attributes. Although both species were able to discriminate stimuli on the basis of their global configuration or local elements, the chimpanzees exhibited a global-to-local processing strategy, whereas the rhesus monkeys exhibited a local-to-global processing strategy. The results suggest that perceptual and attentional mechanisms underlying information-processing strategies may account for differences in learning by primates.


Statistical Approaches to Address Multi-Pollutant Mixtures and Multiple Exposures: the State of the Science.
The purpose of this review is to describe the most recent statistical approaches to estimate the effect of multi-pollutant mixtures or multiple correlated exposures on human health. The health effects of environmental chemicals or air pollutants have been widely described. Often, there exists a complex mixture of different substances, potentially highly correlated with each other and with other (environmental) stressors. Single-exposure approaches do not allow disentangling effects of individual factors and fail to detect potential interactions between exposures. In the last years, sophisticated methods have been developed to investigate the joint or independent health effects of multi-pollutant mixtures or multiple environmental exposures. A classification of the most recent methods is proposed. A non-technical description of each method is provided, together with epidemiological applications and operational details for implementation with standard software.


Locally elevated cortisol in lymphoid organs of the developing zebra finch but not Japanese quail or chicken.
Glucocorticoids are important for production of functional lymphocytes and immunity. In altricial neonates, adrenal glands are unresponsive and local glucocorticoid synthesis in lymphoid organs may be necessary to support lymphocyte development. Precocial neonates, in contrast, have fully responsive adrenal glucocorticoid production, and lymphoid glucocorticoid synthesis may not be necessary. Here, we found that in altricial zebra finch hatchlings, lymphoid organs had dramatically elevated endogenous glucocorticoid (and precursor) levels compared to levels in circulating blood. Furthermore, while avian adrenals produce corticosterone, finch lymphoid organs had much higher levels of cortisol, an unexpected glucocorticoid in birds. In contrast, precocial Japanese quail and chicken offspring did not have locally elevated lymphoid glucocorticoid levels, nor did their lymphoid organs contain high proportions of cortisol. These results show that lymphoid glucocorticoids differ in identity, concentration, and possibly source, in hatchlings of three different bird species. Locally-regulated glucocorticoids might have species-specific roles in immune development.


Murine mercury-induced autoimmunity: the role of T-helper cells.
Genetically mercury-susceptible (H-2s) mice in which the nude (athymic) mutation had been introduced, and euthymic (H-2s) mice treated with anti-CD4 monoclonal antibodies were used to determine the importance of T-helper (CD4+) cells for induction of autoimmunity by mercury, and to study the possibility of using anti-CD4 MAb for treatment of manifest autoimmunity. SJL/N and (A.SW x SJL-nu) F1 x SJL-nu BC (H-2s) mice homozygous for the nude mutation (nu/nu) were treated with 10 mg HgCl2/litre drinking water for 6 weeks. These mice developed neither the antinucleolar antibodies (ANoA) nor the systemic immune-complex (IC) deposits seen in mercury-treated littermates heterozygous for the nude mutation (nu/+). The nu/nu mice showed a significant and substantial reduction of splenocytes with pan-T-(CD3+), T-helper-(CD4+) and T-cytotoxic/suppressor (CD8+) markers, which was accompanied by a severe reduction of the proliferative response to Concanavalin A. Euthymic SJL/N mice given an initial intravenous (i.v.) injection of 100 micrograms anti-CD4 MAb (clone GK 1.5, rat IgG2b), followed by 6 weeks treatment with 100 micrograms anti-CD4 MAb intraperitoneally (i.p.) every third day in combination with 10 mg HgCl2/litre drinking water, did not develop ANoA or systemic IC-deposits. These features were seen in controls i.p. injected with rat IgG2b and given HgCl2 in the drinking water. The anti-CD4 MAb-treated mice showed very few CD4+ splenocytes, but a significant increase of CD8+ cells and severely impaired T-cell function. The possibility of treating longstanding autoimmune conditions with anti-CD4 MAb was examined by giving euthymic SJL mice HgCl2 for 3 months, followed by a mercury-free interval of 3 months and finally 7 weekly injections of 1 mg anti-CD4 MAb. This therapy caused a severe reduction of CD4+ cells, but there was no decline in the ANoA titre. In conclusion, induction of systemic autoimmunity by mercury was strictly dependent on T cells, specifically T-helper (CD4+) cells, and mercury-induced ANoA persisted for a long time after stopping mercury treatment. At this late stage, the autoimmune condition was no longer amenable for anti-CD4 MAb therapy.


Globoside promotes activation of ERK by interaction with the epidermal growth factor receptor.
Globoside (Gb4), a globo-series glycosphingolipid (GSL), has been characterized as a stage-specific embryonic antigen (SSEA), and is highly expressed during embryogenesis as well as in cancer tissues. However, the functional role and molecular mechanism of Gb4 are so far unknown. GSLs were preferentially inhibited by treatment with D-threo-1-ethylenedioxyphenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4), a nanomolar inhibitor of GSL synthesis, in two carcinoma cell lines, HCT116 and MCF7. The effect of EtDO-P4 was examined by MTT assay, FACS, wound assay, western blotting, and RTK array analysis. The functional role of Gb4 was determined by the exogenous addition of various GSLs, and an assay utilizing GSL-coated latex beads. Both cell lines contained higher levels of neutral GSLs than of sialic acid-containing GSLs. Gb4 was one of the major neutral GSLs. The depletion of total GSLs caused significant reduction of cell proliferation, but had less effect on cell apoptosis or motility. EtDO-P4 treatment also suppressed activation of the epidermal growth factor receptor (EGFR)-induced ERK pathway and various receptor tyrosine kinases (RTKs). The reduced activation of ERK was restored by the exogenous addition of Gb4, but not by the addition of gangliosides (GM1, GM2, GM3, and GD1a). The GSL-coated bead assay indicated that Gb4 forms a complex with EGFR, but not with other RTKs. Taken together, Gb4 promotes activation of EGFR-induced ERK signaling through direct interaction with EGFR. A globo-series GSL, Gb4, promotes EGFR-induced MAPK signaling, resulting in cancer cell proliferation. These findings suggest a possible application of Gb4 in cancer diagnostics and drug targeting.


Characterisation of intracranial aneurysms with MR angiography.
The purpose of this study was to compare the accuracy of 3D time-of-flight (TOF) acquisitions in the characterisation of intracranial aneurysms. Fourteen patients with aneurysms proven on intra-arterial angiography were first studied with a 3D TOF acquisition. When the aneurysms were incompletely demonstrated, additional MR angiography (MRA) acquisitions were performed, including black-blood MRA, 2D TOF, phase-contrast and contrast-enhanced TOF.3D TOF MRA was sufficient for detection of the aneurysm in 13 of 14 cases and characterisation of the aneurysm was possible in 6. All the initial shortcomings of the TOF technique could be analysed and explained by means of additional MRA techniques. This study suggests that the combination of different MRA techniques offers new possibilities for noninvasive investigation of intracranial aneurysms.


A rare case report of pleomorphic adenoma of the upper lip: An unusual clinical presentation.
Pleomorphic adenoma is the most common salivary gland tumor which accounts for about 60% of all salivary neoplasms. It is also known as "mixed tumor because of its wide cytomorphologic diversity". Pleomorphic adenoma salivary glands mostly occurs on the palate, but the involvement of the upper lip is rare. The present report describes a case of a 62-year-old male with asymptomatic firm nodular swelling attached with upper lip which was later diagnosed as pleomorphic adenoma in the excisional biopsy.


Ontogenetic instars of Melanozetes paramollicomus sp. nov., with remarks on morphological ontogeny of Sphaerozetinae (Acari: Oribatida: Ceratozetidae).
Although the juvenile instars of oribatid mite subfamily Sphaerozetinae is well known compared to the other subfamilies of Ceratozetidae (Ceratozetinae and Trichoribatinae), information on morphological ontogeny of some species is still incomplete. Herein, Melanozetes paramollicomus sp. nov. is proposed from Ethiopia, based on adult and juvenile instars. Additionally, comparative analysis of ontogenetic instars of species belonging various genera of Sphaerozetinae with known juveniles, is given, and the major characteristics of juvenile instars of 20 species are presented.


Discrimination among eight modified michaelis-menten kinetics models of cellulose hydrolysis with a large range of substrate/enzyme ratios: inhibition by cellobiose.
The kinetics of exoglucanase (Cel7A) from Trichoderma reesei was investigated in the presence of cellobiose and 24 different enzyme/Avicel ratios for 47 h, in order to establish which of the eight available kinetic models best explained the factors involved. The heterogeneous catalysis was studied and the kinetic parameters were estimated employing integrated forms of Michaelis-Menten equations through the use of nonlinear least squares. It was found that cellulose hydrolysis follows a model that takes into account competitive inhibition by cellobiose (final product) with the following parameters: Km = 3.8 mM, Kic = 0.041 mM, kcat = 2 h-1 (5.6 x 10-4 s-1). Other models, such as mixed type inhibition and those incorporating improvements concerning inhibition by substrate and parabolic inhibition, increased the modulation performance very slightly. The results support the hypothesis that nonproductive enzyme substrate complexes, parabolic inhibition, and enzyme inactivation (Selwyn test) are not the principal constraints in enzymatic cellulose hydrolysis. Under our conditions, the increment in hydrolysis was not significant for substrate/enzyme ratios <6.5.


Bronchial asthma and hypovitaminosis D in Saudi children.
Asthma, a common lung disease in children, is caused by excessive immune responses to environmental antigens. Given the immuno-modulatory properties of vitamin D, the aim of the current study was to investigate the relationship between vitamin D levels and markers of asthma severity. This was investigated in a 70 Saudi children with and without asthma and were recruited from the King Abdul Aziz University Hospital, Jeddah, Saudi Arabia, over the period of 11 months (May 2011-April 2012). Childhood asthma control test instrument was employed to assess the level of asthma control among asthmatic patients. Anthropometric measurements were taken and interviewer-administrated questionnaire was completed for all study participants. Pulmonary function test was performed by recording changes in the peak expiratory flow. Venous blood samples were withdrawn for measurements of vitamin D, bone profile, cytokines profile (interleukin-10, tumor necrosis factor-alpha, platelets derived growth factor), and atopy markers (IgE and eosinophil count). Hypovitaminosis D is highly prevalent among asthmatic children with highly significant increase in several markers of allergy and asthma severity as compared with healthy control children. Significant correlations between several inflammatory and immunological markers and vitamin D levels were also found. Finally, lower 25-hydroxyvitamin D levels were associated with a higher asthma prevalence in multivariable analysis. Our study showed that hypovitaminosis D is highly prevalent in the whole population in addition to a highly significant increase in several markers of allergy and asthma severity among asthmatic children as compared with healthy control children.


Running training and co-ordination between breathing and running rhythms during aerobic and anaerobic conditions in humans.
The study was carried out on ten triathletes, six sprinters and ten subjects not trained in running (controls) to assess the effects of training history on the co-ordination between breathing and running rhythms during running on a treadmill. Three exercise intensities were used: 50%, 80% and 110% of the subject's anaerobic threshold (AT). All three intensities were performed twice: once with spontaneous breathing and once with breathing intentionally co-ordinated to the running rhythm. Heart rate, respiratory parameters and leg movements were continuously recorded. Blood lactate concentrations were measured discontinuously. The degree of co-ordination between running and breathing was quantified as the percentage of inspirations and/or expirations starting during the same phase of step. The results showed that the degree of both spontaneous and intended co-ordination at aerobic exercise intensities was in all three groups the same and increased in all groups with increasing intensity from 50% to 80% of AT; further increase of intensity to 110% of AT was associated with a significant decrease of co-ordination in controls and sprinters, whereas triathletes were able to maintain the same high degree of co-ordination as at 80% of AT. It was concluded that running training of either type at aerobic work loads had no effect on the co-ordination between running and breathing rhythms. At anaerobic intensities, however, the degree of co-ordination between running and breathing rhythms was higher in the endurance trained athletes than in the sprinters or in the untrained subjects. The degree of co-ordination increased with increasing regularity of breathing.(ABSTRACT TRUNCATED AT 250 WORDS)


Pervasive refusal syndrome or anorexia nervosa: a case report with a successful behavioural treatment.
Pervasive refusal syndrome (PRS) is a rare psychiatric disease that affects children. It was first described by Lask in 1991 (Arch Dis Child 66:866-869, 1991). Recently, Otasowie and Collaborators reported a systematic review about PRS. Despite this, PRS has not yet been classified in DSM-5 and ICD-11 and the lack of evidence-based treatment makes this syndrome a real challenge for clinicians. The aim of this paper is to present our experience through the description of a case report and its treatment. The case reported is a girl aged 11 years that fits the clinical picture described in the literature of PRS. In previous reports, behavioural treatment was not used or appreciated; our case adds new knowledge regarding the PRS diagnosis and the successful behavioural treatment during hospitalization, which we describe in all its phases. PRS is a rare, life-threatening syndrome; it would be extremely important to have an official and evidence-based treatment guide. Level V, case report.


A macrophage cell model for pH and volume regulation.
A whole-cell model of a macrophage (mphi) is developed to simulate pH and volume regulation during a NH4Cl prepulse challenge. The cell is assumed spherical, with a plasma membrane that separates the cytosolic and extracellular bathing media. The membrane contains background currents for Na+, K+ and Cl-, a Na(+)-K+ pump, a V-type H(+)-extruder (V-ATPase), and a leak pathway for NH4+. Cell volume is controlled by instantaneous osmotic balance between cytosolic and extracellular osmolytes. Simulations reveal that the mphi model can mimic alterations in measured pH(i) and cell volume (Vol(i)) data during and after delivery of an ammonia prepulse, which induces an acid load within the cell. Our analysis indicates that there are substantial problems in quantifying transporter-mediated H+ efflux solely from experimental observations of pH(i) recovery, as is commonly done in practice. Problems stemming from the separation of effects arise, since there is residual NH4+ dissociation to H+ inside the mphi during pH(i) recovery, as well as, proton extrusion via the V-ATPase. The core assumption of conventional measurement techniques used to estimate the H+ extrusion current (I(H)) is that the recovery phase is solely dependent on transporter-mediated H+ extrusion. However, our model predictions suggest that there are major problems in using this approach, due to the complex interactions between I(H), NH3/NH4+ buffering and NH3/NH4+ efflux during the active acid extrusion phase. That is, the conventional buffer capacity-based I(H) estimation must also take into account the perturbation that a prepulse challenge brings to the cytoplasmic acid buffer itself. The importance of this whole-cell model of mphipH(i) and volume regulation lies in its potential for extension to the characterization of several other types of non-excitable cells, such as the microglia (brain macrophage) and the T-lymphocyte.


[Surgical treatment of acromioclavicular dislocation using the Balser hookplate].
The surgical technique applied to 17 patients for acromioclavicular separation is described in this paper. Ligament repair and Balser's hookplate were used. Advantages over surgical joint fixation were recorded from twelve patients in clinical and radiological follow-up checks. No major complications were recordable from implants. Postoperative immobilisation of the patients was not necessary. Timing of plate removal is variable. In follow-up examinations, ten of the twelve patients were satisfied with the therapeutic result.


Correction to: Genetic diversity of the Thao people of Taiwan using Y-chromosome, mitochondrial DNA and HLA gene systems.
Following publication of the original article [1], we have been notified that Additional file 3 was published with track changes.


Outcomes of subsequent abdominal operations after an initial ventral hernia repair.
Nearly 20% of ventral hernia repair (VHR) patients require a subsequent abdominal operation (SAO), and mesh position may impact the complexity and outcome of the SAO. Retrospective review of VHR with mesh from 2006 to 2020 from an internal database and the ACHQC. Primary outcomes measured incidence, complexity, and complications of SAO relative to mesh position. SAO was required in 433 of 2539 (17.1%) patients, totaling 671 operations; 197/893 (22.1%) with intraperitoneal mesh (IPM) and 236/1646 (14.3%) with extraperitoneal mesh (EPM; p < 0.001). SAO was directly related to VHR in 180 (232 total SAOs) and unrelated in 253 (439 total SAOs). There were no significant differences in complications after SAO between IPM and EPM, nor any difference in adhesion complexity. Incidence of SAO is higher with IPM, but surgical outcomes are similar. Due to the risk of secondary mesh infection with IPM, significantly more of these were removed at the time of SAO.


Copro-PCR based detection of Schistosoma eggs using mitochondrial DNA markers.
We report on a sensitive, specific and easy to interpret PCR based diagnostic tool for the detection of Schistosoma japonicum eggs in the faeces of infected mammalian hosts. Primer pairs were designed to amplify regions of the mitochondrial DNA of the parasite. The specificity of the PCR primers was tested using either faecal samples from non-infected hosts or hosts infected with the related schistosome species S. mansoni. Sensitivity was investigated in a study, which differentiated the presence or absence of eggs in faecal samples. PCR results were correlated with analysis of the samples by microscopy. PCR analysis provided a level of sensitivity of 87.7%, while specificity was 100%. The PCR-based assay could detect mitochondrial DNA from as little as 0.3 of a single egg. The overall detection threshold of the PCR test was >or=60 eggs per gram of faeces. Advantages of this technique include the ability to scale-up screening and the reproducibility and simplicity of interpretation of results compared with standard microscopic methods.


Determinants of unresectability and outcome of patients with occult colorectal hepatic metastases.
Patients chosen for liver resection of colorectal liver metastases are a select group with minimal disease, favorable tumor biology and earlier presentation when compared to unresectable patients. Despite intense preoperative assessments, operative detection of occult unresectable disease is inevitable for a small group of patients. The aim of this study was to evaluate determinants of occult unresectability, and to establish if patients with occult unresectable disease demonstrate survival benefits similar to resected patients, or more similar to patients diagnosed with metastatic disease who were never explored. A retrospective medical record review was performed on 171 patients with colorectal hepatic metastases who underwent exploration with the intent of performing a curative liver resection. Patient and tumor characteristics, operative findings and survival were evaluated. Univariate and multivariate analysis were performed to evaluate determinants of unresectability, and survival was determined by Kaplan-Meier analysis. One hundred forty-six patients were completely resected and 25 patients were found to have occult unresectable disease during exploration. Of these 25 patients, 10 had more extensive hepatic disease than expected which precluded resection, while 15 patients had unexpected extrahepatic disease. Of the 15 patients with extrahepatic disease, 7 had otherwise resectable liver metastases. Only bilobar disease was a statistically significant finding associated with occult unresectability on multivariate analysis (P = 0.05). Resected patients had a median survival of 37 months, while unresected patients had a median survival of 17 months (P < 0.005). At 3 and 5 years, the overall survival for resected patients was 52% and 29%. The survival at 3 years for patients with occult unresectable disease was only 5%, with no 5 year survivors. The majority of patients with occult unresectable colorectal hepatic metastases had bilobar disease or extrahepatic spread. Despite the process of patient selection that leads to an attempt for curative resection, patients with occult unresectable disease identified at exploration suffer from poor survival that approximates the outcome of patients never considered for resection.


You sound familiar: carrion crows can differentiate between the calls of known and unknown heterospecifics.
In group-living animals, it is adaptive to recognize conspecifics on the basis of familiarity or group membership as it allows association with preferred social partners and avoidance of competitors. However, animals do not only associate with conspecifics but also with heterospecifics, for example in mixed-species flocks. Consequently, between-species recognition, based either on familiarity or even individual recognition, is likely to be beneficial. The extent to which animals can distinguish between familiar and unfamiliar heterospecifics is currently unclear. In the present study, we investigated the ability of eight carrion crows to differentiate between the voices and calls of familiar and unfamiliar humans and jackdaws. The crows responded significantly more often to unfamiliar than familiar human playbacks and, conversely, responded more to familiar than unfamiliar jackdaw calls. Our results provide the first evidence that birds can discriminate between familiar and unfamiliar heterospecific individuals using auditory stimuli.


The effects of incorporated tritium and bromodeoxyuridine on the frequency of sister chromatid exchanges.
Cells in third mitosis treated during the first cell cycle with 3H-TdR and during the next two cycles with BrdU (without 3H-TdR) show a typical pattern of chromosome differentiation which allows identification of sister chromatid exchanges occurring during the first (SCE1), second (SCE2) and third cycles (SCE3). Chromosomes labeled only with 3H-TdR had the most SCEs; those labeled only with BrdU, the second highest number; and those labeled with 3H-TdR plus BrdU, the fewest. Since BrdU and 3H-TdR are well known inducers of SCEs, the relatively low frequency of exchanges produced by the combined action of these two compounds is paradoxical. It is assumed that SCEs are generated by the abnormal recombination of double-strand DNA breaks occurring at the junctions between completely and partially duplicated replicon clusters. Thus, agents that induce absolute blocks to DNA fork displacement will favor the appearance of SCEs because double-strand breaks have more time to occur at junctions. Conversely, agents that inhibit the initiation of replication will decrease the probability of SCEs. Ionizing radiation delays the onset of cluster replication. Therefore, in 3H-TdR plus BrdU-substituted chromosomes the radiation from tritium may inhibit the appearance of BrdU-induced SCEs. Since the inhibition does not exist in chromosomes substituted only with BrdU, the frequency of SCEs in these elements is higher than in double-substituted chromosomes. During the first cell cycle the onset of cluster replication is normal. However, the incorporation of 3H-TdR in the replication fork may enhance the appearance of double-strand breaks, thus inducing a high frequency of SCEs.


[Long term results of partial laryngectomies in patients suffering from laryngeal cancer].
The aim of the study was to evaluate the results of partial laryngectomies in patients with laryngeal cancer treated in the 2(nd) Clinical Department of Laryngology SUM in Zabrze in the years 1990-2000. Retrospective clinical material includes 209 patients in whom surgery was a primary treatment method. No distant metastases (M1) or another malignant cancer were found. The group consisted of 20 (10%) women and 189 (90%) men. The mean age was - 51.2 years. The stage of the neoplasm progression was defined as T1 in 91 patients (44%), T2 in 109 patients (52%). In other 9 patients (4%) the progression stage was T3 and T4. Clinical examination in 191 patients (91%) did not show enlarged lymph nodes in the area of head and neck (N0). In the group of remaining 18 patients (9%) the node progression was found to be N1-N3. In all 209 patients the squamous cell carcinoma of various stage of malignancy (G1-G3) was found in preoperative histopathological tests, out of which five cases were of papillary squamous cell carcinoma. The most common operation in the analyzed group was a chordectomy - 83 surgeries (40%), followed by 38 (18%) vertical partial laryngectomies, 28 (13%) horizontal glottis surgeries, 19 (9%) frontal-lateral and frontal-anterior operations, and supracricoid operations with a reconstruction of CHEP and CHP type, a total of 20 operations (9%). Other types of partial operations were performed less commonly. In 79 patients (38%) partial laryngectomy was complemented with a nodal operation, while cervical lymph nodes were not removed in 130 patients (62%). In 19 cases (9%) the metastases of squamous cell carcinoma to regional lymph nodes were confirmed in postoperative material. 82 patients of the study group (39%) underwent radiotherapy. The median of the observation period was 9 years. Local recurrence, nodal recurrence and distant metastasis are rated as treatment failure. Treatment effectiveness was evaluated with relation to local control, overall survival, disease-free survival and cause specific survival. All the aforementioned parameters were analyzed with the method of updated percentages. The level of statistical significance was assumed to be p ≤ 0.05. The updated 5-year and 10-year percentage of overall survivals was respectively 75% and 63%. The updated 5-year and 10-year percentage of cancer specific survivals was 85% and 79%, respectively. The updated 5-year and 10-year percentage of disease-free survivals was 72% and 56%, respectively. The percentage of 5-year and 10 year local controls was 86% and 79%, respectively.


Effects of levosimendan on markers of left ventricular diastolic function and neurohormonal activation in patients with advanced heart failure.
In this randomized, placebo-controlled study, it was found that a 24-hour levosimendan infusion improves echocardiographic markers of abnormal left ventricular diastolic function (transmitral flow patterns and mitral annulus velocities, as assessed by transthoracic pulse-wave Doppler and tissue Doppler imaging, respectively) and reduces substances of excessive neurohormonal activation (plasma B-type natriuretic peptide and interleukin-6) in patients with advanced heart failure. Moreover, levosimendan-treated patients had fewer events and longer progression-free survival during a 5-month follow-up compared with those who received placebo. Thus, levosimendan seems to be effective in improving left ventricular diastolic function and reducing neurohormonal activation in patients with severe heart failure.


Subtype-selective Na(v)1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives.
A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain.


Nanovesicles of nitrendipine with lipid complex for transdermal delivery: pharmacokinetic and pharmacodynamic studies.
Vesicular transdermal delivery can enhance the bioavailability of a drug especially affected by first-pass metabolism, e.g. nitrendipine. However effective transdermal delivery employs permeation enhancer, e.g oleic acid (OA) with ceramide 2, stearic acid, behenic acid, and cholesteryl sulfate lipid complex. This study investigated the preparation, characterization of physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential in rats, of nitrendipine-loaded nanovesicles of ceramide 2, stearic acid, behenic acid and cholesteryl sulfate containing oleic acid gel (NOVG). The nanovesicles were made using film hydration method and characterized for physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential. Nitrendipine-loaded nanovesicles of ceramide-2 containing oleic acid (NOV-5) have shown fluxes in the range of 4.88-24.72 μg/cm(2)/h nitrendipine oral suspension (NOS) at equal dose. NOVG-5 has shown almost 33% reduction in blood pressure in the first hour and a further decrease of 25% in the second hour to restore the normal pressure. The permeation increases with increase in OA content. OA gets integrated in vesicle wall and enhances its permeability, whereas ceramide content makes sure that skin does not become damaged even after permeation. NOVG-5 has shown the most favorable physicochemical properties and good permeation through skin providing good management of hypertension during crucial initial hours.


Conformation of colicin A: apparent difference between cytoplasmic and extracellular polypeptide chain.
Cytoplasmic colicin A has the ability to bind to membranes and to form stable dimers. This form remains stable even in the presence of 1% SDS at 25 degrees C. Both of these properties were not observed for extracellular colicin A suggesting a possible difference in the conformation between cytoplasmic and extracellular colicin A.


Structure of the embryonic primate spinal cord at the closure of the first reflex arc.
Early development of the spinal cord was studied in macaque monkey embryos, using light- and electron microscopy, Golgi impregnation and [3H]thymidine radioautography. All neurons engaged in the first reflex arc are generated before E27 in the 165 day gestation period. The earliest-generated cells differentiate into motoneurons while the commissural and association neurons are generated later. Synaptogenesis starts at E27 in the basal plate, and 2 days later in the alar plate. The first synapses appear as symmetrical junctions situated on the neuronal perikarya and proximal dendrites. Closure of the first spinal reflex are is established within 2 days and follows an antidromic pattern as related to the physiological spread of nerve impulses: synapses on motoneuronal somata and primary dendrites in the basal plate appear first and are followed by synapses in the alar plate, between dorsal root axon collaterals and somata of borderline (commissural/association) neurons. Commissural axons grow towards the floor plate, cross the midline and proceed caudo-rostrally, while association fibers remain ipsilateral. The first wave of apoptosis (programmed cell death) thins out dense populations of nerve and glial cells by E30. Some of the early-generated borderine cells that form commissural and association interneurons, seem to play the role of transient target cells and die once the definitive axonal pathways are established. Since transient cells form numerous synapses, deprivation from the afferent impulses is not a likely cause of their elimination. The present results indicate that the initial developmental events, including formation of the first reflex arc in the primate spinal cord, occur considerably earlier in respect to birth than in other mammals, but that the schedule of cellular events and cellular mechanisms seem to be the same.


The relationship of lifetime history of depression on the ovarian tumor immune microenvironment.
Depression is associated with a higher ovarian cancer risk. Prior work suggests that depression can lead to systemic immune suppression, which could potentially alter the anti-tumor immune response. We evaluated the association of pre-diagnosis depression with features of the anti-tumor immune response, including T and B cells and immunoglobulins, among women with ovarian tumor tissue collected in three studies, the Nurses' Health Study (NHS; n = 237), NHSII (n = 137) and New England Case-Control Study (NECC; n = 215). Women reporting depressive symptoms above a clinically relevant cut-point, antidepressant use, or physician diagnosis of depression at any time prior to diagnosis of ovarian cancer were considered to have pre-diagnosis depression. Multiplex immunofluorescence was performed on tumor tissue microarrays to measure immune cell infiltration. In pooled analyses, we estimated odds ratios (OR) and 95% confidence intervals (CI) for the positivity of tumor immune cells using a beta-binomial model comparing those with and without depression. We used Bonferroni corrections to adjust for multiple comparisons. We observed no statistically significant association between depression status and any immune markers at the Bonferroni corrected p-value of 0.0045; however, several immune markers were significant at a nominal p-value of 0.05. Specifically, there were increased odds of having recently activated cytotoxic (CD3+CD8+CD69+) and exhausted-like T cells (CD3+Lag3+) in tumors of women with vs. without depression (OR = 1.36, 95 %CI = 1.09-1.69 and OR = 1.24, 95 %CI = 1.01-1.53, respectively). Associations were comparable when considering high grade serous tumors only (comparable ORs = 1.33, 95 %CI = 1.05-1.69 and OR = 1.25, 95 %CI = 0.99-1.58, respectively). There were decreased odds of having tumor infiltrating plasma cells (CD138+) in women with vs. without depression (OR = 0.54, 95 %CI = 0.33-0.90), which was similar among high grade serous carcinomas, although not statistically significant. Depression was also related to decreased odds of having naïve and memory B cells (CD20+: OR = 0.54, 95 %CI = 0.30-0.98) and increased odds of IgG (OR = 1.22, 95 %CI = 0.97-1.53) in high grade serous carcinomas. Our results provide suggestive evidence that depression may influence ovarian cancer outcomes through changes in the tumor immune microenvironment, including increasing T cell activation and exhaustion and reducing antibody-producing B cells. Further studies with clinical measures of depression and larger samples are needed to confirm these results.


Low-level laser therapy induces human umbilical vascular endothelial cell proliferation, migration and tube formation through activating the PI3K/Akt signaling pathway.
Low-level laser therapy (LLLT) has been recognized as a light therapy that may be used for tissue regeneration, inflammation reduction, and pain relief. We intended to evaluate the effects of LLLT on the proliferation, migration, and tube formation of HUVECs as well as their related mechanisms. HUVECs were exposed to laser irradiation under different laser parameters (irradiation dose, interval and power intensity) in order to choose the optimal parameters, which were determined by the increase in proliferation of HUVECs as follows: irradiation dose of 4.0 J/m2, interval time of 12 h and 6 times in total. The HUVEC proliferation, migration, and tube formation, and levels of angiogenesis-related genes (HIF-1α, eNOS and VEGFA) were examined following LLLT. As suggested by the obtained data, LLLT (1.0, 2.0 and 4.0 J/m2) increased the HUVEC proliferation, migration, and tube formation in dose-and time-dependent manner, accompanied with increases in the levels of HIF-1α, eNOS, and VEGFA. Furthermore, the regulatory mechanism regarding the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway was explored, phosphorylation levels of PI3K and Akt proteins were assessed by Western blot assay, which showed the enhancement of phosphorylation of PI3K, Akt, and mTOR by LLLT. The inhibitor for the PI3K/Akt axis was used to verify the involvement of PI3K/Akt signaling pathway. The obtained results suggested that the inhibition of the PI3K/Akt signaling pathway attenuated the effects of LLLT on proliferation, migration, and angiogenesis of HUVECs. In conclusion, LLLT promotes the proliferation, migration, and angiogenesis of HUVECs via activation of the PI3K/Akt signaling pathway.


Supine hypoxemia following nebulizated salbutamol in patients with chronic airway obstruction.
Inhaled beta-adrenergic agonists can decrease arterial oxygen tension (PaO2). A decrease in PaO2 can also be observed with supine posture. We assessed the effect on PaO2 of supine posture following salbutamol nebulization inpatients with chronic airflow obstruction. Twelve patients (10 males, 2 females mean age 60 yr) with FEV1/FVC = 0.65 (mean 0.54) and resting PaO2 = 60 mm Hg while breathing room air (mean 76.5 mm Hg) were included in a prospective randomized double-blind double crossover study conducted for 2 consecutive days. On each study day, each patient successively underwent baseline PaO2 measurement; nebulization of either salbutamol (0.5% solution, 1 cm3) or saline; two supervised 30-min periods in the supine or seated posture, with PaO2 measurement at the end of each period. PaO2 values were compared with analysis of variance for repetitive measurements (6 values for each patient). PaO2 values (mean +/- SD; mm Hg) were similar at baseline (day 1: 76.5 +/- 8.1; day 2: 76.6 +/- 8.6), after saline + seated (74.8 +/- 7.2), after saline + supine (74.9 +/- 7.5), and after salbutamol + seated (74.3 +/- 7.3). In contrast, PaO2 after salbutamol + supine (70.8 +/- 10.1) was significantly lower than all other values (p <0.05), six patients exhibited large PaO2 decreases (from 9 to 21 mm Hg). Hypoxemia induced by the combination of nebulized salbutamol and supine posture may represent a potential hazard of bronchodilator therapy.


Engineered tumor cell-derived vaccines against cancer: The art of combating poison with poison.
Tumor vaccination is a promising approach for tumor immunotherapy because it presents high specificity and few side effects. However, tumor vaccines that contain only a single tumor antigen can allow immune system evasion by tumor variants. Tumor antigens are complex and heterogeneous, and identifying a single antigen that is uniformly expressed by tumor cells is challenging. Whole tumor cells can produce comprehensive antigens that trigger extensive tumor-specific immune responses. Therefore, tumor cells are an ideal source of antigens for tumor vaccines. A better understanding of tumor cell-derived vaccines and their characteristics, along with the development of new technologies for antigen delivery, can help improve vaccine design. In this review, we summarize the recent advances in tumor cell-derived vaccines in cancer immunotherapy and highlight the different types of engineered approaches, mechanisms, administration methods, and future perspectives. We discuss tumor cell-derived vaccines, including whole tumor cell components, extracellular vesicles, and cell membrane-encapsulated nanoparticles. Tumor cell-derived vaccines contain multiple tumor antigens and can induce extensive and potent tumor immune responses. However, they should be engineered to overcome limitations such as insufficient immunogenicity and weak targeting. The genetic and chemical engineering of tumor cell-derived vaccines can greatly enhance their targeting, intelligence, and functionality, thereby realizing stronger tumor immunotherapy effects. Further advances in materials science, biomedicine, and oncology can facilitate the clinical translation of tumor cell-derived vaccines.


Allelic association analysis of the functional insertion/deletion polymorphism in the promoter region of the serotonin transporter gene in bipolar affective disorder.
The human serotonin transporter gene (5-HTT) is a candidate for the pathogenesis of mood disorders, including bipolar disorder (BPD). The 5-HTT gene has a 44-bp insertion/deletion polymorphism within the promoter region (5-HTTLPR) with 2 allelic forms, the long (l) and the short (s) variants, which affect transcriptional rates of the 5-HTT gene. Association between the low-activity s variant and BPD has been suggested but remains controversial, as replication has not been consistent. In the present study, we examined the frequency of this polymorphism in a group of 266 Brazilian BPD patients and 306 control subjects. Genotyping for the 5-HTTLPR was performed using PCR. The allele frequencies were found to differ between BPD patients and controls (p=0.03), with a higher frequency of the l allele in the patients compared with the controls (60.5% vs 54.4%). The distribution of genotypes also differed significantly between cases and controls (chi2=10.4, 2 df, p=0.005), with higher frequency of heterozygous l/s genotype in the BPD patient group (52.6% vs 44%). Because prior evidence from gene expression studies indicated that l/s and s/s genotypes are not distinguishable biochemically, we compared the distribution of the l/l genotype and the combined group l/s plus s/s between case and controls, but there was no significant difference (chi2=0.22). Likewise, a logistic regression model considering a dominant role for the s variant was not significant (OR=0.92, 95% CI 0.64-1.32). Our results suggest that the low-activity s variant does not influence susceptibility to BPD in our population.


Performance in the cross-maze and slip funnel tests of four pairs of rat lines selectively bred for divergent alcohol drinking behavior.
Alcohol naive rats from lines genetically selected for high and low alcohol drinking and founded on either Wistar (P/NP lines) and distinct heterogeneous stocks (AA/ANA and replicate HAD/LAD lines) were tested in the explorative cross-maze and the inescapable slip funnel. Rats of the low alcohol-consuming ANA, NP, LAD1 and LAD2 lines all exhibited a shorter latency before initiating exploration of the maze than did their high alcohol-consuming counterparts (66, 51, 33 and 51% of the values for AA, P, HAD1 and HAD2 lines, respectively). Significant line differences were also found with the slip funnel test (AA > ANA for time in a sprawling posture; P > NP but HAD1 < LAD1 and HAD2 < LAD2 for time escaping), but the directions of line differences were not consistently related to those in alcohol drinking.


A multicenter, prospective, randomized, comparative evaluation of dual- versus triple-lumen catheters for hemodialysis and apheresis in 485 patients.
The purpose of this study is to compare a new temporary triple-lumen catheter (TLC) for dialysis that has a third lumen devoted to fluid and medication administration or blood sampling with a marketed dual-lumen catheter (DLC). Four hundred eighty-five patients referred for acute hemodialysis or apheresis were randomly assigned to either a TLC or DLC in a multicenter, prospective, randomized trial. Analysis of blood flow rates was completed on 464 patients (228 patients, DLC; 236 patients, TLC) with a total of 1,681 hemodialysis (808 treatments, DLC; 873 treatments, TLC) and 82 apheresis treatments (37 treatments, DLC; 45 treatments, TLC). During hemodialysis, a median achieved flow rate (AFR) of 267 mL/min was realized for both groups (P = 0.58). During apheresis, a median AFR of 72.5 mL/min (range, 50 to 150 mL/min) was achieved in the DLC group, and 87 mL/min (range, 60 to 150 mL/min), in the TLC group (P = 0.14). Three hundred ninety-three patients (193 patients, DLC; 200 patients, TLC) had blood and catheter tip cultures performed on removal, and catheter-related bloodstream infection (CRBSI) status was determined. Thirty-one patients (7.9%) had a CRBSI: 16 patients (8.3%), DLC; and 15 patients (7.5%), TLC (P= 0.77). Incidence densities of CRBSI were 12.4/1,000 DLC-days and 10.2/1,000 TLC-days (P = 0.59). The CRBSI incidence of 18.2/1,000 catheter-days for femoral sites was significantly greater than the 7/1,000 catheter-days for jugular sites (P = 0.02) and 6.6/1,000 catheter-days for combined jugular and subclavian sites (P = 0.01). In multivariate analysis, antibiotic use was the only factor related to CRBSI (odds ratio, 0.30; 95% confidence interval, 0.12 to 0.76). There were no statistically significant differences in rates of other complications between the 2 catheters. Results show that the new TLC is similar to the marketed DLC.


Maternal influence on the decision to adopt Norplant.
To examine maternal influence and related variables on adolescents' decision to adopt Norplant. A prospective study of 121 adolescent females who received Norplant through a hospital-based outpatient adolescent gynecology service. Each patient completed self-report questionnaires about her decision process, sexual behaviors and standardized measures of depression and anxiety at their insertion appointment or first-follow-up appointment. Almost 40% of the sample reported that their mother significantly influenced their decision to use Norplant and 61% of all patients stated that they had informed their mother of their choice of this contraceptive method. Through logistic regression, six variables were found to be significantly associated with mother as the most important decision source. These included: obtaining information about Norplant from a parent, maintaining the same sexual partner, past pill use, and not knowing other adolescents who boast about using the Norplant system. These data suggest that when parental consent is not required, adolescent females disclose sensitive information regarding choice-making to their mothers when they decided to adopt Norplant.


Tracheoesophageal displacement index and predictors of airway obstruction for fetuses with neck masses.
There are no established selection guidelines to determine which fetuses with giant neck masses may benefit from delivery using an ex utero intrapartum treatment procedure. The purposes of this study were to describe the tracheoesophageal displacement index (TEDI), a novel measurement of fetal airway displacement, and to correlate this measurement and other prenatal findings to the extent of airway obstruction at birth. The medical records of all fetuses with giant neck masses evaluated between 2001 and 2011 were reviewed. At birth, each infant's airway was categorized as uncomplicated or complicated. Prenatal variables were correlated with airway difficulty. There were 24 fetuses with large neck masses (11 lymphatic malformations, 10 teratomas, 3 others). One fetus died in utero, and 3 underwent pregnancy termination. Variables associated with a complicated airway at birth included polyhydramnios, teratoma diagnosis, and tracheoesophageal displacement index. Tracheoesophageal displacement index greater than 12 correlated strongly with a complicated airway (area under the curve = 0.80). All fetuses classified with an uncomplicated airway (n = 7) had a diagnosis other than teratoma and normal amniotic fluid volume. In fetuses with giant neck masses, the presence of polyhydramnios, teratoma diagnosis, or tracheoesophageal displacement index greater than 12 are predictive of a complicated airway at birth. Our data suggest that fetuses without any of these findings may be delivered safely without an ex utero intrapartum treatment approach.


Vitamin D suppresses ferroptosis and protects against neonatal hypoxic-ischemic encephalopathy by activating the Nrf2/HO-1 pathway.
Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal death, and vitamin D (VD) is a neuroprotection nutrition whose deficiency is associated with its risk. However, the mechanism of VD involved in neonatal HIE is not well known. In this experiment a hypoxic-ischemic brain damage (HIBD) model was established by using the Rice-Vannucci method, rats were intraperitoneally injected with 0.1 µg/kg VD every day for two weeks. The brain damage and mitochondria injury were examined by hematoxylin-eosin (HE) staining and transmission electron microscope (TEM), respectively. The oxidation response and inflammatory factors were determined by enzyme-linked immunosorbent assay (ELISA), and the cell viability was determined by Cell Counting Kit-8 (CCK-8). mRNA and protein expression were detected by quantitative real real-time PCR (qRT-PCR), Western blot, and immunofluorescence. The results showed VD effectively ameliorated brain histologic damage and mitochondria injury induced by hypoxic ischemia (HI). VD elevated the expression of Nrf2 and HO-1, which resulted in increased levels of GPX4, superoxide dismutase (SOD), and glutathione (GSH) and reduced content of malondialdehyde (MDA) and reactive oxygen species (ROS), resulting in decreased ferroptosis in HI-treated rats. Moreover, VD reduced the secretion of inflammatory factors, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β. VD suppresses ferroptosis through activation of the Nrf2/HO-1 signaling pathway and exerts a protective role in neonatal HIE.


[Socioeconomic differences in physical activity in the middle-aged working population: The role of education, occupation, and income].
Regular physical activity has positive effects on health at all ages. This study aims to investigate how far physical activity and regular sports engagement, as a more specific type of physical activity, are associated with socioeconomic factors in the middle-aged working population. Data were obtained from 21,699 working men and women aged between 30 and 64 years who participated in the 2009 and 2010 population-based national German Health Update (GEDA) surveys conducted by the Robert Koch Institute. Besides a multi-dimensional index of socioeconomic status (SES), three single dimensions of SES (education, occupation, and income) were used to analyse socioeconomic differences in total physical activity and regular sports engagement. While the prevalence of total physical activity increased with lower SES, the proportion of people with regular sports engagement decreased with lower SES. These associations remained after adjusting for age in men and women. After mutual adjustment of the three single socioeconomic dimensions, physical activity was independently associated with lower education and lower occupational status. Regular sports engagement was observed to be independently associated with higher education, higher occupational status, as well as higher income after mutual adjustment. This study demonstrates significant socioeconomic differences in physical and sports activity in the middle-aged working population. Education, occupation, and income show varying independent associations with physical activity behaviour. Such differences need to be considered when identifying target groups for health-enhancing physical activity interventions.


Boerhaave's syndrome. Computed tomographic findings and diagnostic considerations.
Boerhaave's syndrome, or spontaneous rupture of the esophagus, may present with atypical chest pain mimicking an acute thoracic aortic dissection. We describe such a case and discuss the utility of a thoracic computed tomographic scan in arriving at a prompt diagnosis. The importance of early diagnosis is reviewed with particular attention to these roentgenographic findings.


The cutaneous stress response system in three-spined stickleback and European flounder exposed to oxidative stress: Different mode of action.
In fish, the skin is directly exposed to multiple environmental stressors and provides the first line of defense against harmful external factors. It turned out that cortisol and melatonin (Mel) are involved in fish cutaneous stress response system (CSRS) similar to mammalian. This study investigates the mode of action of CSRS in two teleost species of different biology and skin characteristics, the three-spined stickleback and the European flounder, after exposure to oxidative stress induced by a potassium dichromate solution. The cutaneous stress response system presents different ways of action in two studied species: Mel concentration increases in the skin of both species, but cortisol concentration increases in the skin only in sticklebacks. Data suggest that stickleback skin cells can produce cortisol. However, cortisol is not involved in the response to oxidative stress in flounders. In stickleback skin, two genes encoding AANAT and ASMT/HIOMT (enzymes involved in Mel synthesis), aanat1a and asmt2, are expressed, but in flounder skin, only one, asmtl. Because gene expression does not change in stickleback skin after exposure to stress, the source of increased Mel is probably outside the skin. A lack of expression of the gene encoding AANAT in flounder skin strongly suggests that Mel is transported to the skin by the bloodstream from other sites of synthesis. Pigment dispersion in the skin after exposure to oxidative stress is found only in sticklebacks.


The effect of patella taping on vastus medialis oblique and vastus laterialis EMG activity and knee kinematic variables during stair descent.
The purpose of this study was to evaluate the effect of patella taping in normal subjects. Previous work has established positive effects of patella taping on patellofemoral pain syndrome patients, but the mode of action remains unclear. It has been hypothesized that taping brings about subtle changes in the internal physiological environment of the joint. It could be expected that in normal joints taping would bring about a measurable change in function, as the joint is no longer operating in an optimal physiological environment. 10 normal female subject's (21.4+/-1.2 years) vastus medialis oblique (VMO) and vastus laterialis (VL) EMG activity and knee kinematics (peak stance flexion angle and angular velocity) were assessed during a step descent, with and without a taped patella. The effect of taping was to significantly decrease VMO and VL EMG activity. Taping also significantly reduced peak stance phase knee flexion and peak stance phase knee flexion angular velocity. In normal asymptomatic subjects patella taping created a situation in which their performance was changed to one similar to that of the pathological patellofemoral pain syndrome population. It would appear that taping caused the joint to function sub-optimally supporting the hypothesis that taping could change the functioning of the patellofemoral joint.


On the different roles of the cerebral hemispheres in mental imagery: the "o'Clock Test" in two clinical cases.
This paper develops the hypothesis of different roles of the two hemispheres in imaginal processes. A test designated the "o'Clock Test" is proposed, which contains closely confrontable perceptual and imaginal tasks. It enables examination of the abilities both to generate mental images and to explore them in their right and left halves (R + L Condition). This test was used to examine two patients, one severely affected by hemi-inattention resulting from a right posterior lesion, and the other with a selective deficit of imagery due to a left occipital lesion. The former demonstrated left neglect in both perceptive and imaginal capacities, while the latter was able to perform correctly only the perceptive tasks. These results suggest that the right hemisphere has functions of organization and spatial exploration at both perceptive and imaginal levels, and that the left hemisphere's role is to generate mental images.


Virtual reality balance training to improve balance and mobility in Parkinson's disease: a systematic review and meta-analysis.
In the last few years, virtual reality (VR) has been increasingly used to strengthen the effect of balance training (BT) in Parkinson's disease (PD). We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the effects of VR-BT relative to BT alone for improving balance and mobility PD subjects with balance/mobility difficulties. Four electronic databases were searched: two reviewers independently selected RCTs, extracted data, and applied the Cochrane risk-of-bias tool for randomized trials (version 2) and the GRADE framework for assessing the certainty of evidence. Primary outcomes were balanced (Berg Balance Scale-BBS), mobility (Timed Up and Go-TUG) and walking speed. Secondary outcomes were falls, walking distance and stability, spatial gait parameters, balance confidence, sensory integration ability, motor signs and quality of life. We included 22 studies (901 patients). Meta-analysis on fourteen trials (430 patients) showed a mean difference (MD) of 2.09 points (95% confidence interval [CI] 0.86-3.33) on BBS favoring VR-BT compared to BT (low certainty evidence). Subgroup analyses showed higher balance improvement in most affected subjects (moderate certainty evidence) and using VR rehabilitation-specific systems vs. VR non-specific systems. Eight trials (236 patients) assessing mobility showed a MD of 1.55 s (95% CI 0.04-3.06) on TUG favoring VR-BT (very low certainty evidence). No differences were observed in walking speed. Estimated effects were not maintained for any outcome at follow-up. This review suggests that VR-BT is more effective than BT to improve balance in PD subjects immediately after training, particularly in individuals with higher postural instability at baseline.


A case of hyperhemolysis syndrome in sickle cell disease and concomitant COVID-19.
Hyperhemolysis syndrome (HHS) is an uncommon transfusion reaction described in several hematologic disorders, including sickle cell disease (SCD). HHS is characterized by a decline in hemoglobin (Hb) values below pre-transfusion levels following transfusion of red blood cells (RBCs), coupled with laboratory markers consistent with hemolysis. The proposed pathophysiologic mechanisms underlying HHS include increased phosphatidylserine expression, macrophage activation, and complement dysregulation. Many pathophysiologic mechanisms thought to contribute to HHS have been similarly described in cases of severe COVID-19. A 28-year-old male with a history of HbSS presented with shortness of breath, right-sided chest pain, and a two-day history of fever. Polymerase chain reaction (PCR) detected SARS-CoV-2 infection with the omicron variant. The patient required an RBC transfusion (pre-transfusion hemoglobin [Hb]5.8 g/dL) with an immediate post-transfusion Hb of 6.3 g/dL. However, Hb rapidly declined to 1.7 g/dL, and lactate dehydrogenase (LDH) rose to 8701 u/L. The absolute reticulocyte count of 538 × 109/L correspondingly fell to 29 × 109/L. Despite additional RBC transfusions and initiation of immunosuppressive therapy, he expired on Day 9(D9). Given the similarities in their proposed pathophysiology, patients with SCD and concomitant SARS-CoV-2 infection may be predisposed to developing HHS.


Epidemiology course for medical students focuses on proposal writing.
Teaching epidemiology to medical students is often seen as a difficult, if not impossible, task. After experimenting with several other approaches, faculty at the West Virginia University School of Medicine have developed a course centered around the production of a research proposal using National Institutes of Health criteria and format. The course content, while comprehensive, emphasizes the clinical uses of epidemiology. Lectures are combined with self-study and individualized teaching to assist the students as they explore their chosen topic. This problem-solving approach to teaching and learning epidemiology in medical school has proved both effective and more acceptable to students, as evidenced by the quality of their research proposals, National Medical Examination Board Scores, student evaluations, and improved faculty-student interaction.


Extra-amniotic balloon with PGE2 versus extra-ovular Foley catheter with PGF2alpha in mid-trimester pregnancy termination.
The objective of this study was to compare the efficacy and side effects of two methods of mid-trimester labor induction, extra-amniotic balloon with intracervical prostaglandin (PG) E2 (0.5 mg x 2) vs. extra-ovular Foley catheter with intrauterine PGF2alpha (1 mg/h x6). A cohort of 32 and 36 cases indicated for mid-trimester termination was enrolled and managed with extra-amniotic balloon and extra-ovular Foley catheter methods, respectively. Outcomes of induction-to-delivery interval, induction failure, and occurrence of side effects were assessed. There were no statistical differences in maternal age, parity, gestational age or fetal birth weight between the two groups. Compared with the extra-ovular Foley catheter with PGF2alpha group, the induction-to-delivery interval was significantly shorter in the extra-amniotic balloon plus PGE2 group. There was no significant difference in side effects and major complications developed in either groups. The extra-amniotic balloon with intracervical PGE2 is more efficient in reducing the induction-to-delivery interval for termination of mid-trimester pregnancies than the extra-ovular Foley catheter with intrauterine PGF2alpha.


[Brain protection during ischemia: state-of-the-art].
The paper reviews the studies dealing with cerebral ischemia and neuroprotection. On this basis, the authors make conclusions on the perspectives of development of this direction and indicate the difficulties investigators and practitioners face in solving the problems in the protection of the brain from local and global ischemic lesion. Current views of the effectiveness of drugs and procedures used in daily practice and the authors' own experience in solving this topical anesthesiological and resuscitative problem are given.


Racial and Ethnic Disparities in Services and the Patient Protection and Affordable Care Act.
We examined prereform patterns in insurance coverage, access to care, and preventive services use by race/ethnicity in adults targeted by the coverage expansions of the Patient Protection and Affordable Care Act (ACA). We used pre-ACA household data from the Medical Expenditure Panel Survey to identify groups targeted by the coverage provisions of the Act (Medicaid expansions and subsidized Marketplace coverage). We examined racial/ethnic differences in coverage, access to care, and preventive service use, across and within ACA relevant subgroups from 2005 to 2010. The study took place at the Agency for Healthcare Research and Quality in Rockville, Maryland. Minorities were disproportionately represented among those targeted by the coverage provisions of the ACA. Targeted groups had lower rates of coverage, access to care, and preventive services use, and racial/ethnic disparities were, in some cases, widest within these targeted groups. Our findings highlighted the opportunity of the ACA to not only to improve coverage, access, and use for all racial/ethnic groups, but also to narrow racial/ethnic disparities in these outcomes. Our results might have particular importance for states that are deciding whether to implement the ACA Medicaid expansions.


Attainment of the Patient-acceptable Symptom State in 548 patients with rheumatoid arthritis: Influence of demographic factors.
To explore the clinical and socio-demographic factors associated with Patient Acceptable Symptom Status (PASS) in Rheumatoid Arthritis (RA). In a post-hoc analyses of a cross-sectional study, RA patients from 11 countries were included. PASS was assessed as acceptable/not acceptable status by the patient. Variables collected included socio-economic (gender, age and country gross domestic product (GDP) per capita) and clinical variables: DAS28-3vESR (28 joint counts and Erythrocyte Sedimentation Rate), the patient-reported Rheumatoid Arthritis Impact of Disease (RAID) score and its seven domains (scored 0 to 10). Patients in PASS or not were compared through univariable tests and factors associated with PASS assessed by multivariable forward conditional logistic regression. A similar analysis was performed in the subgroup patients in DAS28 remission (n=168). A total of 548 patients were included: 80.5% female, mean (±SD) age 55.8±12.8years, disease duration 13.6±10.6 years, DAS28 3.6±1.5. Overall, 360 (65.7%) considered themselves to be in PASS. Independent factors positively associated with being in PASS were age>50 years [odds ratio, OR 1.67; (95% confidence Interval: 1.04-2.67)], a lower DAS28 [OR: 1.28 (1.08-1.52)], lower pain [OR:1.45 (1.27-1.64)] and better emotional well-being [OR:1.28 (1.13-1.45)]. Among patients in remission, being in PASS was positively associated with less severe pain [OR: 2.50 (1.79-3.84)], age>50 years [OR 3.30 (1.03 to10.87)] and living in a country of the low GDP category [OR: 5.08; (1.34-19.23)]. Being in PASS is related to many factors besides disease activity, including age, perceived impact of the disease and national GDP.


Efficient removal of 3,6-dichlorocarbazole with Fe0-activated peroxymonosulfate: performance, intermediates and mechanism.
Nowadays, polyhalogenated carbazoles (PHCZs) are a major pollutant that has recently sparked widespread concern. In this work, peroxymonosulfate (PMS) was activated by zero valent iron (Fe0) to remove 3,6-dichlorocarbazole (3,6-CCZ). First, the key parameters influencing 3,6-CCZ degradation (PMS dosage, Fe0 dosage, initial pH, temperature and co-existing ions) were determined. Under the determined optimum conditions, the removal rate of 3,6-CCZ reached 100% within 1.5 h. Sulfate radicals (SO4·-), hydroxyl radicals (OH·), and singlet oxygen (1O2) generated in the reaction were directly identified with 0.1 M 5,5-dimethyl-1-pyrrolidine N-oxide (DMPO) by in-situ electron paramagnetic resonance (EPR) and indirectly identified by radical quenching experiments. The main reactive oxygen species (ROS) were different from most reported hydroxyl radicals (OH·) and sulfate radicals (SO4·-). In this study, it was found that OH· and 1O2 play a major role. Then, fresh and reacted Fe0 were characterized by XRD, SEM, and XPS. Iron corrosion products such as Fe2O3, Fe3O4, and FeOOH were generated. Finally, 3,6-CCZ degradation intermediates were identified by GC-MS and its degradation pathway was speculated. The intermediate pathway confirmed the combined action of (OH·) and (1O2) in 3,6-CCZ removal. This study provides new insight into the activation mechanism of Fe0-activated PMS and the removal mechanism of 3,6-CCZ.Highlights Fe0 is a long-lasting and efficient catalyst of PMS for the degradation of 3,6-CCZ.The key parameters influencing 3,6-CCZ degradation were determined.The degradation pathways of 3,6-CCZ were inferred.OH· and 1O2 were the main ROS in Fe0-activated PMS system.


Ferroelectric molecular films for nanoscopic ultrahigh-density memories.
The formation and visualization of nanometer-scale polarized domains in ultrathin ferroelectric molecular films by scanning-probe microscopy are described. These operations to the ferroelectric domains correspond to the "writing" and the "reading" process, respectively, for the data-storage application. In addition, nanometer-scale structures and the local electrical properties of the local domains, including the interface effect, are discussed. The achieved minimum diameter of the written ferroelectric domains was 30 nm. The size of the "recording" dot corresponds to the recording density of about 230 Gbit/in.(2). The "erasing" process by switching domains was also demonstrated. Furthermore, nanometer-scale ferroelectric domains using VDF oligomer molecular films were successfully formed, which has opened the way to the control of single molecular dipoles.


Phase transition and potential biomedical applications of thermoresponsive compositions based on polysaccharides, proteins and DNA: A review.
Smart thermoresponsive polymers have long attracted attention as materials of a great potential for biomedical applications, mainly for drug delivery, tissue engineering and wound dressing, with a special interest to injectable hydrogels. Poly-N-isopropylacrylamide (PNIPAM) is the most important synthetic thermoresponsive polymer due to its physiologically relevant transition temperature. However, the use of unmodified PNIPAM encounters such problems as low biodegradability, low drug loading capacity, slow response to thermal stimuli, and insufficient mechanical robustness. The use of natural polysaccharides and proteins in combinations with PNIPAM, in the form of grafted copolymers, IPNs, microgels and physical mixtures, is aimed at overcoming these drawbacks and creating dual-functional materials with both synthetic and natural polymers' properties. When developing such compositions, special attention should be paid to preserving their key property, thermoresponsiveness. Addition of hydrophobic and hydrophilic fragments to PNIPAM is known to affect its transition temperature. This review covers various classes of natural polymers - polysaccharides, fibrous and non-fibrous proteins, DNA - used in combination with PNIPAM for the prospective biomedical purposes, with a focus on their phase transition temperatures and its relation to the natural polymer's structure.


Botulinum neurotoxin type A in the treatment of classical Trigeminal Neuralgia (BoTN): study protocol for a randomized controlled trial.
Trigeminal neuralgia is characterized by paroxysmal facial pain attacks. Adequate prophylactic drug therapy is often limited by the lack of efficacy and intolerance due to central nervous system side effects. Subcutaneous injections of botulinum toxin type A are a promising treatment option for patients with unsatisfactory response to drug therapy or neurosurgical intervention. Its effects are expected to last for at least 3 months, so it could be a potential long-term treatment. This is the study protocol of a prospective, placebo-controlled, double blind clinical trial investigating the add-on therapy of subcutaneous administration of botulinum toxin type A injections to standard treatment in therapy-refractory classical trigeminal neuralgia. BoTN is a prospective, double blind, placebo-controlled trial with a randomized withdrawal design in which a single blind phase is followed by a double blind phase (see also Methods and design). Eligible patients with classical trigeminal neuralgia who are otherwise refractory to medical and neurosurgical treatment will receive subcutaneous injections of botulinum toxin type A into injection sites of the affected trigeminal branch. In the first phase all patients will receive botulinum toxin type A in a single blinded intervention. Twelve weeks later therapy responders will be allocated to the verum or placebo (saline) arm in a double blind, randomized manner. These injections will be performed at the same sites as the first injections. This trial will be conducted in a tertiary outpatient clinic specialized in the treatment of headache and facial pain. There will be three investigators performing the injections who are experienced in the treatment of headache and facial pain and trained in botulinum toxin type A injections. BoTN is designed to assess the efficacy and safety of subcutaneous botulinum toxin type A injections in addition to standard prophylactic treatment in therapy-refractory trigeminal neuralgia. EU Clinical Trials Register: EudraCT-No: 2014-001959-24 https://www.clinicaltrialsregister.eu/ctr-search/rest/download/trial/2014-001959-24/DE Date of trial registration 26 August 2014.


Effects of chronic vardenafil treatment persist after end of treatment in rats with acute arteriogenic erectile dysfunction.
In our previous study, chronic vardenafil treatment improved erectile function soon after the end of the treatment in rats with acute arteriogenic erectile dysfunction (ED). The aim of this study is to evaluate whether the effects of chronic vardenafil treatment persist after the end of treatment using rats with acute arteriogenic ED. Rats were randomly divided into three groups: (i) control; (ii) ligation; and (iii) vardenafil + no treatment. Rats in the ligation and vardenafil + no treatment groups underwent ligature of the bilateral internal iliac arteries to induce acute arteriogenic ED and were subsequently treated with vehicle or vardenafil (4.0 mg/kg/day), respectively, for 3 weeks. Subsequently, all rats were kept for a further 2 weeks with no treatment. Rats in the control group underwent sham surgery. Erectile function was assessed by changes in intracavernous pressure (ICP). Smooth muscle (SM)/collagen ratios in corpus cavernosum were analyzed by Masson trichrome staining. Transforming growth factor-β1 (TGF-β1 ) mRNA and protein levels in corpus cavernosum (CC) were, respectively, evaluated by real-time polymerase chain reaction (PCR) analysis and Western blotting analysis. ICP/mean arterial pressure (MAP) in the ligation group remained significantly lower than that in control group (P < 0.01). Despite no treatment for 2 weeks, ICP/MAP in the var + no treatment group remained significantly higher than that in ligation group (P < 0.05). SM/collagen ratio in the ligation group remained significantly lower when compared with the control group (P < 0.01). The ratio in the var + no treatment group remained significantly higher when compared with the ligation group at 2 weeks after the end of treatment (P < 0.05). TGF-β(1) mRNA and protein levels did not differ among the groups. The effects of chronic vardenafil treatment on erectile function and penile structure persist, even after the end of treatment, in acute arteriogenic ED rats.


Erratum: Intranasal Delivery of Immunotherapeutic Nanoformulations for Treatment of Glioma Through in situ Activation of Immune Response [Corrigendum].
[This corrects the article DOI: 10.2147/IJN.S240551.].