Technical Success and Complication Rates of Retrograde Arterial Access for Endovascular Therapy for Critical Limb Ischaemia: A Systematic Review and Meta-Analysis.
Antegrade crossing techniques via transfemoral access are often challenging and may be associated with technical and clinical failure when treating patients with critical limb ischaemia (CLI). The objective of this study was to summarise all available literature regarding retrograde endovascular treatment of patients with CLI and to investigate the technical success and complication rate of retrograde access. A systematic literature search was performed in PubMed, Scopus, and Cochrane Central until May 2020. A meta-analysis of 31 observational studies (29 retrospective and two prospective; 26 and five studies with low and moderate risk of bias, respectively) was conducted with random effects modelling. The incidence of adverse events peri-procedurally and during follow up were calculated. The 31 studies enrolled 1 910 patients who were treated endovascularly for femoropopliteal and/or infrapopliteal lesions causing CLI. Most of the patients had diabetes while more than half of the overall population had coronary artery disease and dyslipidaemia. All lesions were located in the infra-inguinal segment and most were chronic total occlusions (96%; 95% CI 85%-100%). Seven studies reported moderate or severe calcification in approximately half of the cases (45%; 95% CI 30%-60%). The overall technical success of the retrograde approach was 96% (18 studies; 95% CI 92%-100%). Perforation, flow limiting dissection, distal embolisation, and local haematoma at the retrograde access site were infrequent and observed in 2.1%, 0.6%, 0.1%, and 1.3% of the patients, respectively. The six month primary patency rate was 78% (five studies; 95% CI 46%-99%), the six month limb salvage rate was 77% (four studies; 95% CI 70%-84%). The results indicated that the retrograde or bidirectional antegrade/retrograde approach is safe and effective and facilitates angioplasty when antegrade treatment fails. However, prospective studies with standardised wound care and surveillance protocols are needed to investigate retrograde techniques in patients with CLI who failed antegrade revascularisation, to improve long term limb salvage and survival.


Validation of the Acoustic Voice Quality Index and the Acoustic Breathiness Index in the Persian Language.
This study aimed to validate the acoustic voice quality index version 03.01 (AVQIv3) and the acoustic breathiness index (ABI) in the Persian language. Six judges assessed the severity degree of the abnormal overall voice quality (hoarseness) and breathiness from continuous speech (cs) and sustained vowel (sv) in 136 voices samples of dysphonic and 45 vocally healthy participants. Firstly, the time length of cs and sv was balanced out for a higher level of ecological validity. Secondly, the concurrent validity and diagnostic accuracy were statistically analyzed with the Spearman rank-order correlation, and the receiver operating characteristics, likelihood ratio, and Youden index. There was substantial inter-rater reliability between judges regarding hoarseness and breathiness. Twenty syllables were identified as the standardized number of syllables for the cs part. Sufficient correlations were found between AVQI and hoarseness (rs = 0.74), and between ABI and breathiness (rs = 0.74), respectively. The thresholds of 1.63 (sensitivity of 73.2% and specificity of 91%) and 2.97 (sensitivity of 70% and specificity of 87%) yielded the highest level of diagnostic findings for AVQI and ABI, respectively. The AVQIv3 and ABI are reliable indices to quantify the abnormal overall voice quality and breathiness in the Persian language.


Targeting cPLA2 derived lipid hydroperoxides as a potential intervention for sarcopenia.
Defects in neuromuscular innervation contribute significantly to the age-related decline in muscle mass and function (sarcopenia). Our previous studies demonstrated that denervation induces muscle mitochondrial hydroperoxide production (H2O2 and lipid hydroperoxides (LOOHs)). Here we define the relative contribution of mitochondrial electron transport chain (ETC) derived H2O2 versus cytosolic phospholipase A2 (cPLA2) derived LOOHs in neurogenic muscle atrophy. We show that denervation increases muscle cPLA2 protein content, activity, and metabolites downstream of cPLA2 including LOOHs. Increased scavenging of mitochondrial H2O2 does not protect against denervation atrophy, suggesting ETC generated H2O2 is not a critical player. In contrast, inhibition of cPLA2 in vivo mitigates LOOH production and muscle atrophy and maintains individual muscle fiber size while decreasing oxidative damage. Overall, we show that loss of innervation in several muscle atrophy models including aging induces generation of LOOHs produced by arachidonic acid metabolism in the cPLA2 pathway contributing to loss of muscle mass.


Comparison of the performance of screening test for gestational diabetes in singleton versus twin pregnancies.
We compared the performance of the 50-g glucose challenge test (GCT) in singleton versus twin pregnancies and investigated the need for adjusting GCT cutoff values for gestational diabetes mellitus (GDM) in twin pregnancies among Korean women. A retrospective chart review was performed in women who underwent GCT at 24 to 28 weeks' gestation and delivered in our department between January 2000 and April 2008. GCT performance was compared between singleton and twin pregnancies for an ideal cutoff value of the GCT for GDM screening. GCT results were available in 3,578 pregnancies (3,435 singleton and 143 twin pregnancies). The mean GCT value was higher in the twin group than in the singleton group. Women in the twin group had a higher mean GCT value (P=0.043) and a higher incidence of GCT ≥130, ≥135, and ≥140 mg/dL (P=0.014, 0.005, and 0.015, respectively). The false positive rate for GCT ≥140 mg/dL was significantly higher in the twin than in the singleton group (P=0.042). The optimal GCT screening cutoff value appears to be ≥145 mg/dL in twin pregnancies. Our study demonstrates that the GCT is associated with a higher false positive rate in twin rather than singleton pregnancies. This study suggests we should consider adjusting the GCT cutoff value for GDM in Korean twin pregnancies.


Effect of Class II camouflage treatment on anterior arch length ratio and canine relationship.
To evaluate the influence of compensatory tipping of maxillary and mandibular incisors on the anterior arch length ratio and canine relationship in skeletal Class II malocclusion. The study was based on posttreatment lateral head films and dental casts of 88 patients. The sample was divided into a Class II malocclusion group (32 patients; ANB ≥5° and mean [± standard deviation] age, 20.82 ± 7.67 years) and a Class I malocclusion group (56 patients; 1° ≤ ANB ≤ 2.5° and mean [± standard deviation] age, 19.20 ± 5.04 years). Measurements obtained for anterior arch length and width, Bolton discrepancy, canine relationship, growth pattern, and incisor position were compared between the groups. The canine relationship was correlated with dental and skeletal variables (P <0.05). The mean ANB angles were 6.21° and 1.78° for the Class II and Class I malocclusion groups, respectively. The skeletal Class II group presented significantly larger mandibular anterior arch length, producing an unbalanced anterior arch length ratio. The canine relationship was more displaced toward Class II in this group. Anterior arch length ratio was the most influential variable in the canine relationship. The mandibular incisors had a higher compensation degree than the maxillary incisors. The groups were similar regarding overjet, overbite, and growth pattern. Class II malocclusion camouflage treatment with excessive proclination of the mandibular incisors was associated with an increase in mandibular arch length, negatively influencing the anterior arch length ratio and the final canine relationship. Mandibular anterior arch length reduction by interproximal stripping may be necessary in moderate to severe skeletal Class II malocclusion orthodontic treatment.


A new method for receptor autoradiography: [3H]opioid receptors in rat brain.
Opioid receptors can be labeled with [3H]ligands in lightly fixed tissue sections mounted on microscope slides. The preparation of these sections does not seem to alter any of the known characteristics of opioid receptors. The light microscopic autoradiographic distribution of these binding sites can be observed if one attaches emulsion-coated coverslips to these slides to obtain autoradiograms. The distribution of [3H]diprenorphine binding sites determined by this in vitro method is identical to the distribution found in earlier studies utilizing in vivo labeling of opioid receptors. In addition, [3H]opioid peptide binding sites and [3H]dihydromorphine binding sites may be similar, perhaps identical, to those for [3H]diprenorphine, an opiate antagonist. This method has several important advantages over earlier methods for determining the autoradiographic localization of receptors. It is possible, by washing, to reduce nonspecific binding to low levels. Since receptor labeling is performed with single tissue sections mounted on slides, one can examine different receptors in different but adjacent sections. One can use ligands that are not entirely suitable for in vivo labeling (For example, one can use [3H]peptides which do not normally cross the blood-brain barrier). One can perform autoradiographic studies after labeling tissues under a wide variety of conditions (For example, one can examine the effects of various ions and nucleotides on ligand binding distributions). This technique seems to be free of various artifacts, such as edge artifacts, which were common by techniques used in our laboratory earlier. Since one does not have to load an entire animal with radioactive ligand as one must with in vivo labeling, this approach is economically advantageous. One can use postmortem tissues, including that from humans to study receptor distribution with a high anatomical resolution.


A role for central A3-adenosine receptors. Mediation of behavioral depressant effects.
The behavioral effects of a selective A3 adenosine receptor agonist 3-IB-MECA (N6-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine) in mice and the localization of radioligand binding sites in mouse brain were examined. Low levels of A3 adenosine receptors were detected in various regions of the mouse brain (hippocampus, cortex, cerebellum, striatum), using a radioiodinated, high-affinity A3-agonist radioligand [125I]AB-MECA (N6-(3-iodo-4-aminobenzyl)-5'-N-methylcarboxamidoadenosine). Scatchard analysis in the cerebellum showed that the Kd value for binding to A3 receptors was 1.39 +/- 0.04 nM with a Bmax of 14.8 +/- 2.1 fmol/mg protein. 3-IB-MECA at 0.1 mg/kg i.p. was a locomotor depressant with > 50% reduction in activity. Although selective A1 or A2a antagonists reversed locomotor depression elicited by selective A1 or A2a agonists, respectively, the behavioral depressant effects of 3-IB-MECA were unaffected. 3-IB-MECA also caused scratching in mice, which was prevented by coadministration of the histamine antagonist cyproheptadine. The demonstration of a marked behavioral effect of A3 receptor activation suggests that the A3 receptor represents a potential new therapeutic target.


The unexpected mechanism of carbonyl hydrosilylation catalyzed by (Cp)(ArN[double bond, length as m-dash])Mo(H)(PMe(3)).
Complex (Cp)(ArN[double bond, length as m-dash])Mo(H)(PMe(3)) (2, Ar = 2,6-diisopropylphenyl) catalyzes the hydrosilylation of carbonyls by an unexpected associative mechanism. Complex 2 also reacts with PhSiH(3) by a σ-bond metathesis mechanism to give the silyl derivative (Cp)(ArN[double bond, length as m-dash])Mo(SiH(2)Ph)(PMe(3)).


Liver organoids: a promising three-dimensional model for insights and innovations in tumor progression and precision medicine of liver cancer.
Primary liver cancer (PLC) is one type of cancer with high incidence rate and high mortality rate in the worldwide. Systemic therapy is the major treatment for PLC, including surgical resection, immunotherapy and targeted therapy. However, mainly due to the heterogeneity of tumors, responses to the above drug therapy differ from person to person, indicating the urgent needs for personalized treatment for PLC. Organoids are 3D models derived from adult liver tissues or pluripotent stem cells. Based on the ability to recapitulate the genetic and functional features of in vivo tissues, organoids have assisted biomedical research to make tremendous progress in understanding disease origin, progression and treatment strategies since their invention and application. In liver cancer research, liver organoids contribute greatly to reflecting the heterogeneity of liver cancer and restoring tumor microenvironment (TME) by co-organizing tumor vasculature and stromal components in vitro. Therefore, they provide a promising platform for further investigation into the biology of liver cancer, drug screening and precision medicine for PLC. In this review, we discuss the recent advances of liver organoids in liver cancer, in terms of generation methods, application in precision medicine and TME modeling.


Solid waste facilities location using of analytical network process and data envelopment analysis approaches.
Selection of the appropriate site for solid waste facilities is a complex problem and requires an extensive evaluation process, because it is very difficult to develop a selection criterion that can precisely describe the preference of one location over another. Therefore selection of these sites can be viewed as a multiple criteria decision-making or multiple attributes decision-making problem. For this purpose, we propose a technique that can effectively take managerial preferences and subjective data into consideration, along with quantitative factors. The tool proposed here relies on the use of the analytical network process (ANP) and to help integrate managerial evaluations into a more quantitatively based decision tool, data envelopment analysis (DEA) is applied. In this paper, a location selection procedure is presented to construct an undesirable facility applying ANP and DEA approaches in two stages. In the first stage ANP approach is used, results of this stage are inputs for the second stage. In this stage, DEA is applied to select the best location. Finally, to illustrate the proposed framework, at "Results and discussion" section, a total of four undesirable facility locations are evaluated.


Effects of selective dopamine receptor agonists in rats trained to discriminate apomorphine from saline.
Rats (N = 12) were trained to discriminate apomorphine (0.25 mg/kg, IP) from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. When the discrimination was acquired, various doses of apomorphine as well as several other dopamine receptor agonists were injected before test sessions. Apomorphine (0.03-0.25 mg/kg, IP) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. The selective DA2 receptor agonist piribedil (0.25-8.0 mg/kg, IP) produced a dose-related increase in drug lever responding that was similar to that seen with apomorphine. On the other hand, administration of the selective DA1 receptor agonist SKF 38393 (1.0-32 mg/kg, IP) resulted in principally saline lever responding, even at doses that substantially reduced the rate of responding. Administration of dopamine (1.0-8.0 mg/kg, IP), which does not readily cross the blood-brain barrier, also resulted in principally saline lever responding. These results suggest that the discriminative stimulus properties of apomorphine are based on its action at a receptor that is similar to the DA2 receptor that has been characterized in the periphery and that this receptor is centrally located.


Molecular characterization and application of a novel cytoplasmic male sterility-associated mitochondrial sequence in rice.
Cytoplasmic male sterility (CMS) is a maternally inherited inability to produce functional pollen found in numerous flowering plant species. CMS is associated with mitochondrial DNA mutation, novel chimeric open reading frames (ORFs), and rearrangement of coding and noncoding regions of the mitochondrial genome. BLAST (Basic Local Alignment Search Tool) analysis indicated that L-sp1, a new sequence-characterized amplified region, is non-homologous to atp6-orfH79 (or atp6-orf79) and WA352 cloned CMS-associated genes. L-sp1 was found in 11 of 102 wild rice accessions belonging to four AA genome species: Oryza rufipogon, Oryza nivara, Oryza glumaepatula, and Oryza meridionalis. Using L-sp1, two new CMS lines were developed, from either low natural fertility plants or sterile plants, by backcrossing BC1F1 with Yuetai B. Northern blot and RT-PCR revealed that L-sp1 was only expressed in the anthers of w1/YTB, w2/YTB, w1/YTB//YTB, and w2/YTB//YTB when in the same cytoplasm background. L-sp1 is a single-copy chimeric CMS-associated gene found in the mitochondrial genome. It can be expressed in anthers with the same specific cytoplasm background, and will be a useful molecular marker for the development and marker-assisted selection of new CMS lines.


Vestibuloplasty and its impact on the long-term survival and success of dental implants in irradiated and non-irradiated patients after head and neck tumor therapy: a retrospective study.
This study aimed to evaluate the influence of vestibuloplasty on the clinical success and survival of dental implants in head and neck tumor patients. A retrospective single-center study was conducted. All patients received surgical therapy of a tumor in the head or neck and underwent surgical therapy and, if necessary, radiotherapy/radiochemotherapy. Patients with compromised soft tissue conditions received vestibuloplasty using a split thickness skin graft and an implant-retained splint. Implant survival and success and the influence of vestibuloplasty, gender, radiotherapy, and localizations were evaluated. A total of 247 dental implants in 49 patients (18 women and 31 men; mean age of 63.6 years) were evaluated. During the observation period, 6 implants were lost. The cumulative survival rate was 99.1% after 1 year and 3 years and 93.1% after 5 years for patients without vestibuloplasty, compared to a survival and success rate of 100% after 5 years in patients with vestibuloplasty. Additionally, patients with vestibuloplasty showed significantly lower peri-implant bone resorption rates after 5 years (mesial: p = 0.003; distal: p = 0.001). This study demonstrates a high cumulative survival and success rate of dental implants after 5 years in head and neck tumor patients, irrespective of irradiation. Patients with vestibuloplasty showed a significantly higher rate of implant survival and significantly lower peri-implant bone resorption after 5 years. Vestibuloplasty should always be considered and applied if required by the anatomical situations to achieve high implant survival/success rates in head and neck tumor patients.


Understanding the cognitive work of nursing in the acute care environment.
To combine human factors engineering techniques with qualitative observation of nurses in practice to analyze the nature of nurses' cognitive work and how environmental factors create disruptions that pose risks for medical errors. Few researchers have examined the nature of nurses' cognitive work while in practice with patients. Researchers have described the broad range of thinking processes required in the acute care work setting, but have failed to examine how such processes are conducted and influenced by the complex care environment. A combined research methodology enables researchers to better understand how the nursing process becomes disrupted and the potential influence of this disruption on the safe and effective care of patients. An ethnographic study, using mixed-methodological approaches, involved 7 staff registered nurses. The quantitative and qualitative data collection included field observation and summarative interviews. A high number of cognitive shifts and interruptions, and a nurse's cumulative cognitive load, create the potential for disrupting a nurse's attention focus during care of patients. A majority of interruptions occurred as nurses performed interventions, particularly medication preparation. New attention must be given to how care systems and work processes complement or interfere with nurses' cognitive work.


Phytomedicinal therapeutics for male infertility: critical insights and scientific updates.
Infertility is a significant cause of anxiety, depression, and social stigma among couples and families. In such cases, male reproductive factors contribute widely to the extent of 20-70%. Male infertility is a multifactorial disease with several complications contributing to its diagnosis. Although its management encompasses both modern and traditional medicine arenas, the first line of treatment, adopted by most males, focuses on the reasonably successful medicinal plant-based conventional therapies. Phyto-therapeutics, which relies on active ingredients from traditionally known herbs, influences sexual behavior and male fertility factors. The potency of these phyto-actives depends on their preparation methods and forms of consumption, including decoctions, extracts, semi-purified compounds, etc., as inferred from in vitro and in vivo (laboratory animal models and human) studies. The mechanisms of action therein involve the testosterone pathway for stimulation of spermatogenesis, reduction of oxidative stress, inhibition of inflammation, activation of signaling pathways in the testes [extracellular-regulated kinase (ERK)/protein kinase B(PKB)/transformation of growth factor-beta 1(TGF-β1)/nuclear factor kappa-light-chain-enhancer of activated B cells NF-kB signaling pathways] and mediation of sexual behavior. This review critically focuses on the medicinal plants and their potent actives, along with the biochemical and molecular mechanisms that modulate vital pathways associated with the successful management of male infertility. Such intrinsic knowledge will significantly further studies on medicinal plants that improve male reproductive health.


Case series: Heinz body formation in 13 multimorbid dogs following metamizole administration.
Heinz Body (HB) anemia is a result of oxidative damage and is an uncommon condition in dogs relative to cats. In this retrospective case series, clinical features, laboratory values, concurrent diseases, and outcomes of 13 multimorbid dogs that developed HBs after receiving metamizole are reported. Of the 13 dogs in this case series that developed HBs, 10 were older and multimorbid, but the only feature that all the dogs had in common was receiving metamizole. HBs were detected in 7 out of 13 dogs within a few days (3-10 days) after starting metamizole treatment. The metamizole dose was 38-159 mg/kg/day. The highest percentage of HBs detected was 28-95% (mean, 46%). There was no correlation between the percentage of HBs and the daily dose of metamizole. All but 1 dog had mild-to-severe anemia at the time of the highest HB appearance. The number of HBs did not correlate with the hematocrit at that time. In 8/12 dogs, no stress leukogram was present. Approximately half of the dogs with HBs also had evidence of gastrointestinal hemorrhage, which could have masked additional oxidative damage. In multimorbid dogs that develop regenerative anemia after receiving metamizole, hemolysis due to HB development caused by oxidative damage should be considered as an important differential diagnosis.


Social anxiety, hypomania and the bipolar spectrum: data, theory and clinical issues.
Reports in the literature indicate a subtle but consistent relationship between panic and bipolar II disorder. The possible connection between social phobia and bipolarity is less investigated. When we studied the treatment outcome of 32 social phobic patients administered either the reversible monoamine oxidase inhibitor (RIMA) meclobomide or the irreversible inhibitor MAOI phenelzine, we found that eighteen had remission > 50% of their socially anxious symptoms. Moreover, 14/18 of those improved became hypomanic, according to the Raskin Mania Scale (RMS) and the Young Mania Scale (YMS) coupled with expert clinical diagnosis. These findings possibly allude to a relationship of social phobia to bipolarity. Treatment with RIMA or MAOI exposed these subjects as having an atypical bipolar syndrome which is part of the bipolar spectrum. We then compared this special subset of subjects to the 18 socially phobic patients who failed to respond to RIMA's or MAOI's and to 26 patients with generalized anxiety disorder (GAD). Eleven of the 14 hypomanic responders gave histories of serious developmental deprivation (anaclisis); only 5/18 social phobics and 3/26 GADs without hypomanic responses had anaclitic histories. The author raises the possibility that anaclisis may have interacted with the impediment of volition of uncomplicated bipolar depression to produce social inhibition and anxiety. Finally, the author upholds the central role of depressive inhibition in bipolar disorder, which during antidepressant therapy often overshoots in a hypomanic direction; even in the absence of prior spontaneous hypomania, such disinhibition should classify this special subset of social phobic patients within the bipolar spectrum.


Cryopreservation effects on recombinant myoblasts encapsulated in adhesive alginate hydrogels.
Cell encapsulation in hydrogels is widely used in tissue engineering applications, including encapsulation of islets or other insulin-secreting cells in pancreatic substitutes. Use of adhesive, biofunctionalized hydrogels is receiving increasing attention as cell-matrix interactions in three-dimensional (3-D) environments can be important for various cell processes. With pancreatic substitutes, studies have indicated benefits of 3-D adhesion on the viability and/or function of insulin-secreting cells. As long-term storage of microencapsulated cells is critical for their clinical translation, cryopreservation of cells in hydrogels is being actively investigated. Previous studies have examined the cryopreservation response of cells encapsulated in non-adhesive hydrogels using conventional freezing and/or vitrification (ice-free cryopreservation); however, none have systematically compared the two cryopreservation methods with cells encapsulated within an adhesive 3-D environment. The latter would be significant, as evidence suggests adhesion influences the cellular response to cryopreservation. Thus, the objective of this study was to determine the response to conventional freezing and vitrification of insulin-secreting cells encapsulated in an adhesive biomimetic hydrogel. Recombinant insulin-secreting C2C12 myoblasts were encapsulated in oxidized RGD-alginate and cultured for 1 or 4days post-encapsulation, cryopreserved, and assessed up to 3days post-warming for metabolic activity and insulin secretion, and 1day post-warming for cell morphology. Besides certain transient differences in the vitrified group relative to the fresh control, both conventional freezing and vitrification maintained the metabolism, secretory activity, and morphology of the recombinant C2C12 cells. Thus, due to a simpler procedure and slightly superior results, conventional freezing is recommended over vitrification for the cryopreservation of C2C12 cells encapsulated in oxidized, RGD-modified alginate.


Effect of different artificial tears against desiccation in cultured human epithelial cells.
A large number of artificial tears is widely used to treat dry eye symptoms. To test the efficacy of these drugs independent of individual parameters in vitro models are required. As described previously, we employed a reproducible in vitro cell culture system to evaluate the desiccation protection capability of some artificial tears. In THE PRESENT PAPER DATA IS PRESENTED OF ANOTHER SET OF PHARMACEUTICAL AGENTS. Conjunctival epithelial cell line Chang 1-5c-4 (series 1) and the corneal cell line 2.040 pRSV-T (series 2) were cultured under standard conditions. Confluent cells were wetted for 20 min with artificial tears (Arufil Uno, Arufil, Lacrimal, Lacophthal sine, Siccaprotect, Tears Again, Vidisept EDO, Vistil, Wet Comod) or PBS as a control. After exposure to a constant air flow for 0, 15, 30 and 45 minutes respectively, cells were incubated with the vital dye alamarBlue. Subsequently, absorption of the oxidised form of the dye was assessed using an ELISA-Reader. Cell best survival rates in series 1 after 15 min were found for Lacrimal (0.89), Wet Comod (0.84) compared to PBS (0.66) and in series 2 for Vidisept EDO (0.57) and Lacrimal (0.56) compared to PBS (0.01). After 45 min highest survival was seen in series 1 for Lacrimal (0.46) and Lacophthal sine (0.36) compared to PBS (0.33) and in series 2 for Lacrimal (-0.06) and Arufil (-0.16) compared to PBS (-0.23). Both cell lines tested showed different susceptibility towards desiccation and the artificial tears showed differences in preventing cells from desiccation.


Modelling of signalling via G-protein coupled receptors: pathway-dependent agonist potency and efficacy.
A mathematical model is constructed to study promiscuous coupling of receptors to G-proteins and to simulate events leading to the activation of multiple effector pathways within a cell. The model is directed at a better understanding of the factors that determine the efficacy and potency of a drug. Assuming that the receptors can exist in multiple conformational states, and allowing for agonist specific conformation, a system of ordinary differential equations is constructed and subsequently pathway-dependent agonist efficacy and potency order is predicted. A simple case of the compartmentalization of receptors and G-proteins is also given, using the current model to illustrate the effects of spatial heterogeneity on the predicted response.


Risk perception, optimistic bias, and readiness to change sun related behaviour.
The incidence of skin cancer has had a rapid increase in Sweden during the last 20 years. Sun exposure is an important preventable risk factor for skin cancer. It is essential to develop interventions to change people's exposure to the sun. The perception of own susceptibility to harm is essential in theories about self-protective behaviour. The aim of the present paper was to examine the associations between different risk perceptions, sun-related behaviour, readiness to change, and optimism bias. A total of 722 visitors of a mobile skin cancer screening unit answered a questionnaire in the summer of 2001. The campaign was conducted at five different locations in Sweden. The participants in this study seemed to have realistic believes about the contribution of solar radiation to the risk of developing skin cancer, however, they seriously underestimated skin cancer incidence in the population and the impact of skin cancer on general health. People concerned about skin cancer seem to be aware of the fact that sun exposure is an important risk factor for skin cancer, but they fail to use this information in a consistent way to formulate a judgment of their own vulnerability to harm. People need to be informed about the high incidence of skin cancer, the personal risk factors of skin cancer, and the fact that unintentional as well as intentional sun exposure increases the risk of developing skin cancer.


Salivary cortisol in women with and without perimenstrual mood changes.
An increase in the activity of the hypothalamic-pituitary-adrenal axis (HPA axis) is frequently associated with major depression. During the premenstrual phase of their reproductive cycle some women experience depressive mood changes that are proposed to be of similar intensity to that experienced during periods of major depression. This study examined the secretion of cortisol, the end-product in the HPA axis, at different stages of the menstrual cycle in women with and without premenstrual depression. Women who experienced only mild physical and emotional changes in the premenstrual phase of their cycle had a significantly higher cortisol secretion on a premenstrual day (measured hourly) compared to a postmenstrual day. Those who were significantly more depressed premenstrually showed the opposite pattern of cortisol secretion with significantly lower levels on the premenstrual day compared with the postmenstrual day. Across the menstrual cycle, women who were significantly more depressed premenstrually also had lower evening cortisol levels in their premenstrual phase. The results of this study indicate that, unlike major depression where the underlying neurological changes are manifest as overactivity of the HPA axis, premenstrual depressive changes are associated with reduced HPA axis activity. Premenstrual depression may, therefore, be similar neurologically to seasonal affective disorder, which is associated with underactivity of the HPA axis.


Plasma lipids in Iranians with sickle cell disease: hypocholesterolemia in sickle cell anemia and increase of HDL-cholesterol in sickle cell trait.
The metabolism of lipids may be altered in sickle cell anemia and beta-thalassemia patients. Plasma lipids in 24 patients with sickle cell anemia (SS), 15 patients with sickle/beta-thalassemia (ST), 19 individuals with sickle cell trait (AS) and 62 healthy individuals (AA) were measured. Total cholesterol concentrations in both sexes with sickle cell anemia (SS males: 104.7, SS females: 142.7 mg/dl) and sickle/beta-thalassemia (ST males: 116.7, ST females: 137.5 mg/dl) were lower (P<0.05) than AS (AS males: 171.5, AS females: 185.4 mg/dl) and normal individuals (AA males: 173.7, AA females: 183.0 mg/dl). The mean HDL-cholesterol in males with SS (35.6 mg/dl) and ST (40.7 mg/dl) were (P=0.001) lower than AS males (58.9 mg/dl). However, the mean HDL-cholesterol in females with SS (43.2 mg/dl) was lower (P<0.001) than AS females (62.7 mg/dl). The mean LDL-cholesterol of males with SS (53.8 mg/dl) was lower (P<0.01) than AS (89.4 mg/dl) and control males (115.9 mg/dl). Males with ST had a lower (P<0.001) LDL-cholesterol (58.0 mg/dl) compared to control males. In females with SS the LDL-cholesterol (78.3 mg/dl) was lower (P<0.001) than control females (124.3 mg/dl). However, females with ST had lower (P<0.05) LDL-cholesterol (61.6 mg/dl) than AS (101.7 mg/dl) and control females. There was no significant difference in total concentrations of cholesterol and triglycerides between males and females with AS and those with normal hemoglobin. However, the HDL-cholesterol in both genders with AS was higher (P<0.001) than normal subjects. Also, the concentration of LDL-cholesterol in both males and females with AS was lower than control males (P<0.05) and females. Hemolytic stress could be associated with a significant reduction in plasma lipids and lipoproteins. It appears that patients with sickle cell anemia and individuals with sickle cell trait are at a lower risk for coronary artery disease.


Cortical asymmetry--a preliminary study: neurons-glia, female-male.
Previous studies on human cortical area 39 suggested that neuron:glial ratios differed between the sexes. These findings were the inspiration for the present investigation which dealt with neuronal and glial counts in area 39 in the male and female rat cerebral cortex. Transverse, celloidin or frozen sections, were cut from male and female brains (respectively) from 90-day-old Long-Evans rats. Neurons and glia were counted on enlarged photographs of stained sections, including area 39, with 35-mm Kodak Panatomic-X film using a Zeiss photomicroscope (X400). Five-by-three-inch prints were taped together in sequence to yield a 640X enlarged "montage" of area 39. Five cell types were differentiated with reference to a standard: neurons, astrocytes, oligodendrocytes, "dark astrocytes," and unidentified glia. The data were analyzed with a two-way analysis of variance (ANOVA: five cell types by two hemispheres). Student's t test and a paired t test were used when appropriate. The neuron:glial ratios in the male rats were consistently higher than those in the females in both hemispheres. The male right side had 12% (P less than 0.05) more neurons than the left; the female had 13% (P less than 0.05) more neurons on the left than the right. Similar, but not identical, asymmetrical patterns were seen with the glial cells.


CMIID: A comprehensive medical information identifier for clinical search harmonization in Data Safe Havens.
Over the last decades clinical research has been driven by informatics changes nourished by distinct research endeavors. Inherent to this evolution, several issues have been the focus of a variety of studies: multi-location patient data access, interoperability between terminological and classification systems and clinical practice and records harmonization. Having these problems in mind, the Data Safe Haven paradigm emerged to promote a newborn architecture, better reasoning and safe and easy access to distinct Clinical Data Repositories. This study aim is to present a novel solution for clinical search harmonization within a safe environment, making use of a hybrid coding taxonomy that enables researchers to collect information from multiple repositories based on a clinical domain query definition. Results show that is possible to query multiple repositories using a single query definition based on clinical domains and the capabilities of the Unified Medical Language System, although it leads to deterioration of the framework response times. Participants of a Focus Group and a System Usability Scale questionnaire rated the framework with a median value of 72.5, indicating the hybrid coding taxonomy could be enriched with additional metadata to further improve the refinement of the results and enable the possibility of using this system as data quality tagging mechanism.


Filarial hyperinfection in two neotropical primates from eastern Amazon peri-urban areas.
We report two cases of disseminated hyperinfection by filariae in free-living primates Saimiri sciureus and Saguinus niger from eastern Amazon. Histopathological examination showed the presence of Dipetalonema gracile microfilariae in blood, liver, lungs, spleen, small intestine, kidney, brain, liver, and adults in peritoneal thoracic cavity.


Guinea pig respiratory response to isocyanates.
Exposure to some isocyanates (e.g., toluene diisocyanate) has been associated with development of respiratory sensitization. In this study, guinea pig respiratory response to protein conjugates of isocyanatoethyl methacrylate (IEM) and isocyanatoethyl propionate (IEP) was evaluated. Guinea pigs were exposed to daily induction exposures with an aerosol of bovine serum albumin (BSA) or BSA conjugated with IEM or IEP. After approximately 2 weeks significant increases in respiratory rate occurred in the guinea pigs exposed to the isocyanate conjugates. The number of animals responding was related to the degree of conjugation of isocyanate to protein. No response to unconjugated BSA was observed. The isocyanates conjugated to another carrier, guinea pig serum albumin (GSA), elicited responses. In guinea pigs responding to BSA-IEM, 0.01 ppm IEM monomer did not elicit responses; 0.1 to 0.4 ppm IEM vapor elicited responses similar to conjugates but which were delayed; 0.5 and 0.6 ppm induced irritation responses. An IEM polymer aerosol that contained less than 0.004% monomer did not elicit a response. These data suggest a response threshold. Guinea pig developing responses to either of the isocyanate conjugates displayed cross-reactions to challenge with the other. A conjugate of BSA with hexyl isocyanate (HI) did not induce cross-responses in guinea pigs reactive to BSA-IEM. Application of BSA-IEP or IEP monomer to the scratched skin of guinea pigs that responded by inhalation to BSA-IEP resulted in immediate wheal and flare responses not seen in unexposed animals. All of these findings suggest induction of Type I hypersensitivity (asthmatic) directed toward the isocyanate portion of the conjugate and not the protein.


Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.
X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.


Relationship between filtering bleb vascularization and surgical outcomes after trabeculectomy: an optical coherence tomography angiography study.
To explore the relationship between the bleb vasculature and surgical outcome after trabeculectomy (TRAB) using optical coherence tomography angiography (OCT-A). A prospective study was conducted, which included 26 eyes of 26 primary glaucoma patients in the final analysis. Thereinto, six patients underwent TRAB combined 5-FU and 12 patients received subconjunctival 5-FU injection postoperation. The bleb vessel was evaluated using OCT-A 1 week, 2 weeks, 1 month, 3 months, and 6 months after TRAB. Intraocular pressure (IOP), filtering bleb height, and bleb wall thickness were recorded at the same time. Pearson's correlation analysis and linear regression analysis were performed to determine the correlation of the vessel area data with other parameters. Compared with vessel area 1 week after surgery, there was significant increase of the vessel area (△vessel area) 2 weeks (11.13 ± 11.91%, p < 0.05) and 1 month (16.91 ± 14.85%, p < 0.0001) after surgery in all patients. The △vessel area was significantly greater in acute angle closure (AAC) and primary angle closure glaucoma (PACG) 1-month post-TRAB as compared with that 1 week (p < 0.05). The results indicated that the △vessel area 1-month post-TRAB was positive correlated with IOP 6-month post-TRAB (β = 3.88, p = 0.042). Filtering bleb vascularization evaluation using OCT-A could potentially predict IOP 6-month post-TRAB. Surgery effect predicted by filtering bleb vascularization detection is conducive to the select specific postoperative intervention to improve the success rate of TRAB.


Concise synthesis of flavocommelin, 7-O-methylapigenin 6-C-, 4'-O-bis-β-D-glucoside, a component of the blue supramolecular pigment from Commelina communis.
Flavocommelin, 7-O-methylapigenin 6-C-, 4'-O-bis-β-D-glucoside, was synthesized in 9 steps from the C-glycosylation of 6-O-benzy-4-O-methylphloroacetophenone via the introduction of a cinnamoyl residue by aldol condensation and the formation of a C-ring by regioselective and oxidative ring-closure to regio- and stereoselective O-glycosylation for an overall yield of 31%.


Topiramate in children and adolescents with epilepsy and mental retardation: a prospective study on behavior and cognitive effects.
The aim of the present study was to assess the behavioral and cognitive effects following treatment with topiramate in children and adolescents with epilepsy with mild to profound mental retardation. The study group comprised 29 children, 16 males and 13 females, aged 3 to 19 years, affected by partial (4) and generalized (25) crypto/symptomatic epilepsy and mental retardation (7 mild, 5 moderate, 15 severe, 2 profound), who were administered topiramate (TPM) as add-on therapy to their baseline antiepileptic treatment. At baseline, 3 months, 6 months, and 12 months, parents or caregivers of each patient were administered a questionnaire based on the Holmfrid Quality of Life Inventory. After a 3-month follow-up, the add-on topiramate caused overall mild to moderate cognitive/behavioral worsening in about 70% of children and adolescents with mental retardation and epilepsy. After 6 and 12 months of follow-up, global worsening persisted in 31 and 20.1% of cases, respectively. In conclusion, this trial confirms that TPM can have significant adverse cognitive and behavioral side effects, even in mentally disabled children and adolescents.


An acetylated derivative of vitexin halts MDA-MB-231 cellular progression and improves its immunogenic profile through tuning miR- 20a-MICA/B axis.
The activating immune ligands, MICA/B, act as a "kill me" signal through the NKG2D receptor expressed on natural killer (NK) cells. Recently, the oncogenic miR-20a was found to mediate immune escape through repressing MICA/B levels in breast cancer (BC) cells. However, targeting miR-20a-MICA/B using natural compounds has rarely been investigated. Our group has successfully isolated 3'-O-acetylvitexin that showed cytotoxic effects against colon cancer cells but has never been evaluated in BC. Our aim is to investigate the effects of 3'-O-acetylvitexin on BC cell lines and to further elucidate its molecular mechanism of action.The results showed that 3'-O-acetylvitex depicted a more pronounced dose-dependent repression of TNBC cellular viability, colonogenicity and migration capacity than Vitexin. 3'-O-acetylvitexin treatment resulted in a marked dose-dependent repression of miR-20a with a concomitant dose-dependent increase in MICA/B expression. In conclusion, 3'-O-acetylvitexin might act as a promising therapeutic agent for TNBC patients.


Evidence that the enoyl-CoA hydratase bifunctional protein of mouse liver peroxisomes is identical with the 70,000 dalton peroxisomal membrane protein.
Peroxisomal enoyl-CoA hydratase was purified from livers of mice treated with di-(2-ethylhexyl)phthalate and its properties compared with those of the 70 kDa protein present in the membranes prepared by carbonate extraction of peroxisomes. The two proteins had identical subunit molecular masses, of about 70,000 daltons. Limited proteolysis of these proteins using the V8 proteinase of S. aureus yielded identical peptide maps, with these peptides crossreacting with antiserum raised against the 70 kDa membrane protein. These data are consistent with the proposal that the peroxisomal 70 kDa membrane protein and the peroxisomal enoyl-CoA hydratase are the same protein.


Apical ballooning syndrome in a postoperative patient with normal microvascular perfusion by myocardial contrast echocardiography.
Apical ballooning syndrome is classically described as transient left ventricular (LV) dysfunction, marked LV akinesia, and normal or near-normal coronary arteries. The etiology is unclear and there is limited information based on case reports and small case series. We describe a 35-year-old woman who underwent surgical hepatectomy and developed apical ballooning syndrome in the postoperative period. The novel use of myocardial contrast echocardiography (MCE) in this setting demonstrated intact microvascular perfusion and lack of coronary flow-limiting abnormalities despite apical akinesis. In select patients with similar clinical presentations, performing MCE is safe and may be pursued as an alternative to invasive coronary angiography.


The regulation of RNA synthesis in yeast. V. tRNA charging studies.
The stringent control of RNA synthesis in the yeast Saccharomyces cerevisiae may be evoked either by starving for a required amino acid or by inhibiting protein synthesis. The response is non-coordinate in that the synthesis of ribosomal and messenger RNA is depressed whereas that of transfer RNA continues. If protein synthesis is blocked in starved cells then tRNA synthesis is stimulated. In this paper, the relationship between the level of tRNA charging and the transcriptional and translational state of the yeast cell has been examined. When cells are starved for an amino acid the corresponding tRNA species only becomes uncharged. This effect can be counteracted by the addition of protein synthesis inhibitors to the starved cells. In contrast, the same inhibitors provoked the discharge of tRNA in growing (non-starved) yeast. Similar results were obtained when protein synthesis was blocked using a temperature-sensitive mutant. These contrasting effects of translation inhibition on tRNA charging in starved and non-starved cells correlate with the changes that inhibition evoked in the transcriptional state of those cells. The data indicate that tRNA synthesis is under autoregulatory control and that tRNA charging may also play an important role in the regulation of rRNA synthesis.


Alliance not compliance: coaching strategies to improve type 2 diabetes outcomes.
To explore strategies for improving patient outcomes in type 2 diabetes. The literature related to type 2 diabetes management, behavior change, communication, diabetes self-management, and coaching. The strategies currently suggested for improving patient outcomes, e.g., increasing provider adherence to evidence-based management guidelines, streamlining practice systems, and promoting patient lifestyle changes through intensive education, have produced mixed outcomes. Of the many complexities involved in managing type 2 diabetes, motivating patients to change behavior may be the most challenging. A suggestion for improving patient self-management of type 2 diabetes is to use coaching communication within a framework of behavior change in the context of the primary care encounter between nurse practitioners (NPs) and their patients. Given the varied outcomes of current strategies, coaching by NPs may provide a feasible alternative for improving patient outcomes in type 2 diabetes. Coaching communication can be implemented during office visits as an intervention without cost. To effectively implement this approach, however, practicing NPs and NP students need more formal education in this expected but underdeveloped NP role competency. NPs are called upon to contribute to the body of knowledge needed to validate the merits of coaching for their patients.


Genomic organization and expression of the rat TRPM-2 (clusterin) gene, a gene implicated in apoptosis.
We describe the genomic structure of the rat TRPM-2 gene. This gene is induced de novo during the regression of the prostate and other hormone-dependent tissues after hormone ablation and plays an important role in apoptosis, or active cell death. TRPM-2 is a single copy gene, organized into nine exons, ranging in size from 47 base pairs (exon I) to 412 base pairs (exon IV), spanning a region of 13,750 base pairs. Comparison with sequences registered in the data bases shows that it has extensive homology to SGP-2, a gene that is expressed constitutively in the testis, although the sequences diverge dramatically in the 5'-untranslated region of the mRNA (coded for by exon I in TRPM-2), raising the possibility of alternative exon I usage in SGP-2. Primer extension, S1 nuclease protection, and extensive polymerase chain reaction analysis suggest that the TRPM-2 transcript from the prostate and the SGP-2 transcript from the testis are in fact identical and only contain the exon I sequence identified in the TRPM-2 genomic clone. Analysis of the promoter region of the TRPM-2 gene demonstrates that the putative control region contains several potential regulatory elements that may regulate the complex tissue-specific control of a gene which must be constitutively expressed in some tissues but repressed in others until induced during active cell death.


Studies of myelin proteins in multiple sclerosis brain tissue.
Using radioimmunoassays (RIA) for the myelin specific proteins, myelin proteolipid protein (PLP) and myelin basic protein (MBP) and an enzyme assay for the activity of the myelin marker enzyme 2'3' cyclic-3' phosphohydrolase (CNPase), we have studied plaque, periplaque and normal appearing white matter (NAWM) tissue. We found that all three mylein proteins are decreased in all regions, including NAWM, of MS brain, with a decreasing gradient from NAWM to perregion. Surprisingly, when the ratios of the proteins were calculated, MBP activity, although decreased was found to be relatively preserved.


Climate change impacts on groundwater discharge-dependent streamflow in an alpine headwater catchment.
Climate change will have-and, in much of the world, is already having-a pronounced impact on alpine water resources. A deeper understanding of the future role of groundwater in alpine catchments, including quantification of climate change impacts on groundwater discharge, is vital for understanding the future of alpine water resources as a whole. Here, we develop and couple a geophysics-informed groundwater model with a net recharge model to investigate the impacts of climate change on a nival-regime alpine headwater catchment with significant unconfined Quaternary aquifer coverage. Flow in the groundwater-fed stream at the catchment outlet is analysed to determine changes in its annual dynamics. Comparing the periods 2020-2040 and 2080-2100 under ten RCP-8.5 climate models, we find a 35 % decrease in mean groundwater discharge and an increase in no-flow periods from ~0 % to 4.3 %. We also observe significant changes to the timing of monthly mean discharge maxima and minima, which shift ~1 month and ~5 months earlier, respectively. While groundwater has the potential to dampen the impacts of snow cover loss, currently perennial nival-regime alpine streams could be at risk of becoming intermittent by the end of the century. Our study underscores the increasingly critical role that groundwater will play in alpine catchments and emphasizes the need for quantitative understanding of the limits to its buffering capacity.


Sequence polymorphism of HLA DR beta 1 alleles relating to T-cell-recognized determinants.
HLA class II molecules are a highly polymorphic family of dimeric cell-surface proteins primarily involved in regulating T-cell responses to extrinsic antigens. To define regions of class II molecules involved in T-cell recognition, we have now compared sequences of three HLA DR beta cDNA clones obtained from cells that all express the same serologically defined determinants but differ in terms of T-cell-recognized specificities. The comparisons indicate that very few (one to four) nucleotides differ between what are almost certainly alleles of the DR beta 1 locus. All differences were in the first domain of the molecule and all localized to a region from amino acids 71-86. Because all differences were found only in this region of the molecule, and because DR alpha-chains seem to be relatively non-polymorphic, these positions in the DR beta-chain must have a major role in influencing T-cell recognition of the DR molecule.


Metabolomic analysis of endometrial cancer by high-resolution magic angle spinning NMR spectroscopy.
To analyze endometrial metabolite profiles between patients with endometrial cancer and controls. Seventeen (17) women with endometrium cancer and 18 controls were enrolled in this study. 1H HR-MAS (High Resolution-Magic Angle Spinning) NMR (Nuclear Magnetic Resonance) spectroscopy data obtained from endometrial tissue samples of patients with endometrial cancer and control group were analyzed with bioinformatics methods. Principal component analysis (PCA) and the partial least squares discriminant analysis (PLS-DA) score plots obtained with the multivariate statistical analysis of pre-processed spectral data shows a separation between the samples from patients with endometrial cancer and controls. Analysis results suggest that the levels of lactate, glucose, o-phosphoethanolamine, choline, glycerophosphocholine, phosphocholine, leucine, isoleucine, valine, glutamate, glutamine, n-acetyltyrosine, methionine, taurine, alanine, aspartate and phenylalanine are increased in patients with endometrial cancer compared to the controls. The metabolomics signature of patients with endometrial cancer is different from that of benign endometrial tissue.


No evidence that Spexin impacts LH release and seasonal breeding in the ewe.
Spexin (SPX) is a recently identified peptide hormone of 14 amino acids. Interestingly, Spx and Kiss1 genes share a common ancestor gene. Considering that KISS1 peptides are key controllers of breeding in mammals and circumstantial evidence that SPX regulates gonadotropins in some fish species, we hypothesized that SPX may play a KISS1-related role in sheep. Here, we cloned the ovine Spx cDNA, performed in vivo injection and infusion of SPX (i.c.v. route, with or without concomittant KISS1 presence) and assessed a potential regulation of Spx expression by season, thyroid hormone and estradiol in the medio-basal hypothalamus of the ewe. Our data do not provide support for a role of SPX in the control of the gonadotropic axis in the ewe.


[Beyond Content Alone: What Cancer Patients Consider as Important in Professional Psychosocial Support].
In this study we wanted to find out what cancer patients expect from professional psychosocial support. Within a multicenter prospective study, patients were asked about their expectations from professional psychosocial support two years after diagnosis. Using qualitative methods, categories were built from the answers. The answers were assigned to the categories. 447 patients were contacted and 285 answers were obtained. Getting information as well as interaction with enough time for listening was considered as important. Support should result in enhancement of psychological strength. Apart from contents, aspects of how support is given such as attention and competence are important. There should be enough time for the consideration of individual needs. Both getting information and competence as well as listening and personal conversation are important.


A phase II study of DaunoXome in advanced urothelial transitional cell carcinoma.
Liposomal encapsulation of anthracyclines is claimed to reduce toxicity and to improve pharmacokinetics. Therefore, 15 patients with locally advanced or metastatic transitional cell cancer (TCC) of the urinary tract were entered into a phase II study assessing the response rate (WHO criteria) and toxicity of DaunoXome 100 mg/m2 given as a 1 h infusion every third week. During treatment, 6 patients remained stable and 8 had progressive disease. 1 patient died of pulmonary embolism after the first cycle and was not evaluable for response. No patient developed grade 4 myelotoxicity. Grade 3 leucopenia was seen in 5 patients and grade 1 thrombocytopenia in 1 patient, with no treatment-related changes of biochemical liver and kidney function tests. 4 patients complained of angina pectoris-like chest pain during the initial phase of the first or second infusion. The event was associated with a decrease in systolic blood pressure by 20-30 mm in 1 patient leading to permanent treatment discontinuation. In the other 3 and all subsequent patients, intramuscular application of 100 mg hydrocortisone 1 h prior to DaunoXome infusion prevented similar hypotensive reactions. In this study, intravenous (i.v.) DaunoXome 100 mg/m2 every third week showed no anticancer activity in advanced TCC.


An optical method for measurement of dioxygen concentration based upon quenching of phosphorescence.
An optical method for measuring oxygen concentrations in aqueous solutions is described. This method is based upon the oxygen-dependent quenching of phosphorescence. Phosphorescence excitation and emission spectra and lifetimes of some of the probe molecules suitable for measurement of oxygen in aqueous solutions are given. The probes include fluorescein derivatives, 4'5'-diiodofluorescein, eosin Y, 5(and 6)-carboxyeosin, erythrosin, and 5(and 6)-carboxyerythrosin as well as the Zn(II), Y(III), Sn(IV), Lu(III), and Pd(II) derivatives of meso-tetra-(4-sulfonatophenyl)-porphine, meso-tetra-(N-methyl-4-pyridyl)-porphine and coproporphyrin. The phosphorescence lifetimes of the given probes were found to depend upon the oxygen concentration by a simple Stern-Volmer relationship with a quenching constant of approximately 10(9) M-1 S-1. Binding of the molecules to bovine serum albumin decreased the quenching constant for oxygen by approximately an order of magnitude and also inhibited probe self-quenching, indicating that at the protein binding site the probes are somewhat protected from collision with quenchers. The use of this optical method for measuring oxygen is demonstrated for reactions catalyzed by glucose oxidase and by cytochrome c oxidase. It is shown that, using this method oxygen concentrations can be measured from approximately 250 microM (air saturation) down to the nanomolar range.


Comparative serum protein binding of anthracycline derivatives.
The binding of doxorubicin, iododoxorubicin, daunorubicin, epirubicin, pirarubicin, zorubicin, aclarubicin, and mitoxantrone to 600 microM human serum albumin and 50 microM alpha 1-acid glycoprotein was studied by ultrafiltration at 37 degrees C and pH 7.4. Anthracycline concentrations (total and free) were determined by high-performance liquid chromatography (HPLC) with fluorometric detection. Binding to albumin (600 microM) varied from 61% (daunorubicin) to 94% (iododoxorubicin). The binding to alpha 1-acid glycoprotein (50 microM) was more variable, ranging from 31% (epirubicin) to 64% (zorubicin), and was essentially related to the hydrophobicity of the derivatives. Simulations showed that the total serum binding varied over a broad range from 71% (doxorubicin) to 96% (iododoxorubicin). We recently reported that the binding to lipoproteins of a series of eight anthracycline analogues could be ascribed to chemicophysical determinants of lipophilicity [2]. The present study was conducted to evaluate in vitro the contribution of albumin and alpha 1-acid glycoprotein to the total serum binding of these drugs.


A model of long-term survival following adjuvant therapy for stage 2 breast cancer.
Following adjuvant therapy for breast cancer, some patients will die of this tumour while the remainder will die of other causes. Deaths from breast cancer tend to follow a lognormal distribution, while deaths from other causes can be approximated by national demographic data. By combining these two survival models, we have generated an age-specific method for estimating the impact of treatment on overall long-term survival. Treatment was designed to operate by one of two mechanisms: an increase in cured fraction, or an increase in median tumour-related survival time among uncured patients. This analysis revealed that, for young and middle-aged patients, an increase in cured fraction has substantially greater long-term clinical impact than an increase in median survival time. Unfortunately, the non-parametric tests traditionally used in prospective clinical trials cannot distinguish between these two mechanisms of action.


Very-low-birth-weight infant outcomes in 11 South American NICUs.
To describe and analyze outcomes in very-low-birth-weight (VLBW) infants treated in 11 Neonatal Intensive Care Units (NICUs) from four South American countries. This study is the first of a multination collaboration and can serve as a baseline for future quality and resource utilization efforts. Biodemographic data and multiple outcome measures were prospectively collected from October 1997 until August 1998. A logistic regression model was used to define risk factors in primary outcome measures, death, and bronchopulmonary dysplasia (BPD). Center differences were compared using chi-squared analysis. In 385 VLBW infants enrolled, mortality rate was 27%, with a range from 11% to 51% among NICUs. A lower BW, lower gestational age (GA), lack of antenatal steroids (AS), and air leaks (AL) were associated with increased risk of death. A lower BW, lower GA, AL, need for surfactant, necrotizing enterocolitis, and need for intubation were associated with increased risk of BPD. This study provides actual information about VLBW infants' prognosis in a SA region. Mortality rate variability among NICUs may be explained by differences in population and resources, but also by lack of implementation of proven beneficial therapies such as AS administration.


Implantation of spheric phakic posterior chamber intraocular lenses in astigmatic eyes.
To evaluate the simultaneous correction of spherical and cylindrical ametropia through implantation of phakic posterior chamber (PC) intraocular lenses (IOLs) combined with a limbal incision. Eye Department, Schlosspark-Klinik, Charité University Berlin, Berlin, Germany. In 5 hyperopic and 7 myopic eyes with varying astigmatic measurements, a refractive correction was achieved by implanting phakic PC IOLs (Staar Surgical Co.) and performing limbal incisions of different lengths. The incisions were placed approximately 1.0 mm from the limbus with a mean depth of 600 microm and a length of 6.0 mm +/- 0.9 (SD). The phakic PC IOLs were implanted after the limbal incisions were placed. In the 5 hyperopic eyes, the astigmatism decreased from 2.7 diopters (D) preoperatively to 0.5 D at a mean of 7.5 +/- 1.7 months without alteration of the axis of highest bowing. In the 7 myopic eyes, it decreased from 2.2 D preoperatively to 0.7 D at 7.2 +/- 2.6 months. In 3 hyperopic eyes and 1 myopic eye, the limbal incisions were repeated. The observed mean postoperative spherical equivalent was close to emmetropia. Repeat incisions were necessary in eyes exhibiting astigmatism greater than 2.5 D. The advantage of limbal incisions in combination with phakic PC IOL implantation is demonstrated not only by the astigmatic reduction but also by the axis stability. It will be interesting to see whether toric phakic lenses can achieve the same postoperative results, especially in axis stability and reduction of higher degrees of astigmatism.


A sensorimotor theory of temporal tracking and beat induction.
In this paper, we develop a theory of the neurobiological basis of temporal tracking and beat induction as a form of sensory-guided action. We propose three principal components for the neurological architecture of temporal tracking: (1) the central auditory system, which represents the temporal information in the input signal in the form of a modulation power spectrum; (2) the musculoskeletal system, which carries out the action and (3) a controller, in the form of a parieto-cerebellar-frontal loop, which carries out the synchronisation between input and output by means of an internal model of the musculoskeletal dynamics. The theory is implemented in the form of a computational algorithm which takes sound samples as input and synchronises a simple linear mass-spring-damper system to simulate audio-motor synchronisation. The model may be applied to both the tracking of isochronous click sequences and beat induction in rhythmic music or speech, and also accounts for the approximate Weberian property of timing.


Studies on the pathophysiological role of thyroidal prostaglandin E (PGE) in Graves' disease.
A potential role for prostaglandin E (PGE) of thyroid origin in the pathogenesis of the hyperthyroidism of Graves' disease was investigated in vivo. The venous-arterio prostaglandin E (PGE) concentration gradient across the thyroid was measured in 5 patients undergoing subtotal thyroidectomy for Graves' disease. This gradient (161 +/- 14 pg/ml; mean /+- SE) was significantly greater than that found in 11 patients undergoing surgery for hyperparathyroidism and thyroid nodules (64 +/- 20 pg/ml; P < 0.01). This suggests that there is a net increase in PGE output by the thyroid gland in Graves' disease, but the thyroid cell-type responsible for this increased PGE output is unknown. In contrast to previous reports, thyrotropin (TSH) did not stimulate thyroid cell PGE generation in vitro, providing evidence against a role for TSH in this phenomenon. Administration of maximal doses of indomethacin to two thyrotoxic patients did not significantly alter peripheral thyroid hormone concentrations. These data suggest that thyroidal PGE has a function other than to stimulate thyroid hormone secretion in Graves' disease.


A comparison of the effects of morphine, enkephalin, kyotorphin and D-phenylalanine on rat central neurones.
1 Morphine, Met-enkephalin, kyotorphin and D-phenylalanine have been applied by microiontophoresis to neurones in the globus pallidus and cerebral cortex of rats anaesthetized with urethane. 2 In the pallidum, most cells were inhibited by all the agonists, with a high correspondence between cells inhibited by Met-enkephalin and D-phenylalanine and by Met-enkephalin and kyotorphin. Whereas responses to Met-enkephalin were readily antagonized by naloxone, responses to kyotorphin and D-phenylalanine were not. 3 In the cerebral cortex a high proportion of cells was excited by all four agonists and antagonism by naloxone was less consistent than in pallidum. 4 It is concluded that the naloxone-reversible analgesic effects of kyotorphin and D-phenylalanine may be mediated indirectly, rather through an activation of opiate receptors.


Venom peptides cathelicidin and lycotoxin cause strong inhibition of Escherichia coli ATP synthase.
Venom peptides are known to have strong antimicrobial activity and anticancer properties. King cobra cathelicidin or OH-CATH (KF-34), banded krait cathelicidin (BF-30), wolf spider lycotoxin I (IL-25), and wolf spider lycotoxin II (KE-27) venom peptides were found to strongly inhibit Escherichia coli membrane bound F1Fo ATP synthase. The potent inhibition of wild-type E. coli in comparison to the partial inhibition of null E. coli by KF-34, BF-30, Il-25, or KE-27 clearly links the bactericidal properties of these venom peptides to the binding and inhibition of ATP synthase along with the possibility of other inhibitory targets. The four venom peptides KF-34, BF-30, IL-25, and KE-27, caused ≥85% inhibition of wild-type membrane bound E.coli ATP synthase. Venom peptide induced inhibition of ATP synthase and the strong abrogation of wild-type E. coli cell growth in the presence of venom peptides demonstrates that ATP synthase is a potent membrane bound molecular target for venom peptides. Furthermore, the process of inhibition was found to be fully reversible.


Case note descriptions of the placenta: are they worthwhile?
In 429 placentae, measurements were made of weight, diameter, shape, eccentricity of the cord and weight and length of the cord, and the results were compared with Apgar score of the infant at birth and its standardized birth weight. There was no evidence that cord eccentricity, placental shape or "thickness", or the dimensions of the cord had any significant relation to the growth of the fetus or its condition at birth. The value of routine recording of crude measurements and qualitative assessments of the placenta in case notes is questioned.


Transcatheter Aortic Valve Replacement: A Solution for the Young, Inoperable and Regurgitant.
Transcatheter aortic valve replacement (TAVR) has become an established treatment for patients with severe aortic stenosis and high surgical risk. Ten years of technological advances in valve structure and delivery systems alongside growing operator and centre experience has opened TAVR implantation to an increasingly broad range of patients. The extension to off-label use however needs careful consideration and monitoring. Through discussion of our case involving an inoperable 24-year-old male with severe aortic regurgitation (AR), we highlight the need for an experienced and multidisciplinary team, together with early and extensive patient and family disclosure and engagement, prior to considering any off-label application of TAVR.


Minority trauma patients tend to cluster at trauma centers with worse-than-expected mortality: can this phenomenon help explain racial disparities in trauma outcomes?
To determine whether minority trauma patients are more commonly treated at trauma centers (TCs) with worse observed-to-expected (O/E) survival. Racial disparities in survival after traumatic injury have been described. However, the mechanisms that lead to these inequities are not well understood. Analysis of level I/II TCs included in the National Trauma Data Bank 2007-2010. White, Black, and Hispanic patients 16 years or older sustaining blunt/penetrating injuries with an Injury Severity Score of 9 or more were included. TCs with 50% or more Hispanic or Black patients were classified as predominantly minority TCs. Multivariate logistic regression adjusting for several patient/injury characteristics was used to predict the expected number of deaths for each TC. O/E mortality ratios were then generated and used to rank individual TCs as low (O/E <1), intermediate, or high mortality (O/E >1). A total of 556,720 patients from 181 TCs were analyzed; 86 TCs (48%) were classified as low mortality, 6 (3%) intermediate, and 89 (49%) as high mortality. More of the predominantly minority TCs [(82% (22/27) vs 44% (67/154)] were classified as high mortality (P < 0.001). Approximately 64% of Black patients (55,673/87,575) were treated at high-mortality TCs compared with 54% Hispanics (32,677/60,761) and 41% Whites (165,494/408,384) (P < 0.001). Minority trauma patients are clustered at hospitals with significantly higher-than-expected mortality. Black and Hispanic patients treated at low-mortality hospitals have a significantly lower odds of death than similar patients treated at high-mortality hospitals. Differences in TC outcomes and quality of care may partially explain trauma outcomes disparities.


Large-scale sequencing of the rabbit corneal endothelial cDNA library.
This study sought to identify novel or active genes in corneal endothelial cells with description of the gene-expression profile. We performed the single-pass sequencing of 1,000 clones from a rabbit corneal endothelial cDNA library. Inserts of the library were amplified by polymerase chain reaction (PCR), sequenced, and compared with several databases. We used four database similarity search programs: FASTA, BLASTN, TBLASTX, and BLASTX. Of the sequences generated, 618 (61.8%) showed sequence homology with known genes, whereas 192 (19.2%) matched previous reported expression sequence tags (ESTs) and 174 (17.4%) showed no sequence similarity. Among the homologous clones to known genes are collagen type VIII, secreted protein acidic and rich in cysteine (SPARC), lysyl oxidase, phosphatidylcholine-2-acylhydrolase, and thrombospondin. Several matched ESTs, and no matched clones that showed high frequency were also detected. Large-scale sequencing can be useful in obtaining a profile of the active genes. Several ESTs showed relatively frequent expression, suggesting that these genes may have important functions in the corneal endothelium.


Mid-term evaluation of the new Glaukos iStent with phacoemulsification in coexistent open-angle glaucoma or ocular hypertension and cataract.
To evaluate the mid-term efficacy and safety of the GTS-400-iStent combined with phacoemulsification in patients with cataract and open-angle glaucoma (OAG) or ocular hypertension (OHT). Prospective, non-comparative, uncontrolled, interventional case series study. Subjects underwent phacoemulsification and two GTS-400 implantation. Efficacy outcomes: intraocular pressure (IOP) and antiglaucoma medications. Safety outcomes: complications, best-corrected visual acuity and endothelial cell count (ECC). Follow-up was 1 year. 20 patients were enrolled (mean age: 75.1 ± 8.6 years). Mean medicated baseline IOP was 19.95 ± 3.71 mm Hg and 26 ± 3.11 mm Hg without medication. Mean final IOP was 16.75 ± 2.24, determining a final IOP decrease of 35.68% (9.42 ± 3 mm Hg; p<0.001), from baseline washout IOP. Mean number of medications fell from 1.3 ± 0.66 to 0.3 ± 0.57 (P<0.001). 75% of patients were off medications at one year. Mean ECC decreased from 2289.64 ± 393.5 cells/mm(2) to 1986.95 ± 520.58 cells/mm(2). Combined cataract surgery with implantation of GTS-400-iStent seems to be an effective and safe procedure.


The compound 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone induces apoptosis via reactive oxygen species-regulated mitogen-activated protein kinase, protein kinase B, and signal transducer and activator of transcription 3 signaling in human gastric cancer cells.
Hit, Lead & Candidate Discovery It is reported that 1,4-naphthoquinones and their derivatives have potent antitumor activity in various cancers, although their clinical application is limited by observed side effects. To improve the therapeutic efficacy of naphthoquinones in the treatment of cancer and to reduce side effects, we synthesized a novel naphthoquinone derivative, 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ). In this study, we explored the effects of NTDMNQ on apoptosis in gastric cancer cells with a focus on reactive oxygen species (ROS) production. Our results demonstrated that NTDMNQ exhibited the cytotoxic effects on gastric cancer cells in a dose-dependent manner. NTDMNQ significantly induced mitochondrial-related apoptosis in AGS cells and increased the accumulation of ROS. However, pre-treatment with N-acetyl-L-cysteine (NAC), an ROS scavenger, inhibited the NTDMNQ-induced apoptosis. In addition, NTDMNQ increased the phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK) and decreased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and Signal Transducer and Activator of Transcription 3 (STAT3); these effects were blocked by mitogen-activated protein kinase (MAPK) inhibitor and NAC. Taken together, the present findings indicate that NTDMNQ-induced gastric cancer cell apoptosis via ROS-mediated regulation of the MAPK, Akt, and STAT3 signaling pathways. Therefore, NTDMNQ may be a potential treatment for gastric cancer as well as other tumor types.


The effect of size at birth, maturation threshold and genetic differences on the life-history of Daphnia magna.
Life-history traits of 101 clones from two populations of Daphnia magna were measured under controlled environmental conditions in the laboratory. Some individuals had four juvenile instars, others had five. This depended on their length at birth and on the population they came from. Females in the group with five juvenile instars were smaller at birth but larger and older at maturity than those with four juvenile instars. Within groups of females with equal numbers of preadult instars (instar groups) age and size at maturity increased with size at birth. This relationship differed significantly among instar groups for both age and size at maturity. Significant differences in age and size at maturity between two populations became non-significant when size at birth was used as a covariable in AN-COVA. Within populations, size at birth depended on the clone and on the parity of the clutch. First-clutch offspring were considerably smaller than those from later clutches. The results suggest that variability in life-history traits is common within and between clones, but that most of this variation can be accounted for by size at birth and the number of pre-adult instars.


Compartmentalization of the nucleus.
The nucleus is a spatially organized compartment. The most obvious way in which this is achieved is at the level of chromosomes. The positioning of chromosomes with respect to nuclear landmarks and with respect to each other is both non-random and cell-type specific. This suggests that cells possess molecular mechanisms to influence the folding and disposition of chromosomes within the nucleus. The localization of many proteins is also heterogeneous within the nucleus. Therefore, chromosome folding and the localization of proteins leads to a model in which individual genes are positioned in distinct protein environments that can affect their transcriptional state. We focus here on the spatial organization of the nucleus and how it impacts upon gene expression.


Severe hypertriglyceridemia in a nondiabetic treated with low dose insulin infusion.
We report a case of a 54-year-old man with severe HTG which did not respond to conventional anti lipid therapies. He was treated with intravenous insulin and concurrent dextrose infusions which led to a dramatic reduction in serum triglyceride levels.


Surgery for Normocalcemic Hyperparathyroidism.
Primary hyperparathyroidism is the most common cause of hypercalcemia, accounting for about 90% of all cases. This disorder is characterized by overactive parathyroid glands, leading to increased parathyroid hormone and excess serum calcium.


New records of Pectinariidae (Polychaeta) from Lizard Island, Great Barrier Reef, Australia and the description of two new species.
Five species of Pectinariidae have previously been reported from Australia. This study documents the first records of this family from the Lizard Island region: Pectinaria antipoda is recorded, in addition to its already currently wide Australian distribution; two new species, Amphictene lizardensis n. sp. and Pectinaria carnosus n. sp. were also discovered and described. A key to all Australian species of Pectinariidae is provided.


Dual dopamine agonist treatment in Parkinson's disease.
We studied the effectiveness of cabergoline as an adjunct in patients with early Parkinson's disease receiving another dopamine agonist (pramipexole or ropinirole), at the maximal permitted dose. The study enrolled 47 patients: 35 had motor fluctuations and were receiving a dopamine agonist with levodopa; and 12, without motor fluctuations, were receiving a dopamine agonist without levodopa. These medications had in all cases failed to achieve adequate symptom control. In the 35 patients with motor fluctuations, when cabergoline was added to therapy, the time spent in the OFF period decreased by 65.6% (from 3.14+/-1.11 to 1.08+/-1.07 hours p<0.0001); and the Unified Parkinson's Disease Rating Scale (UPDRS) motor score decreased by 19.24% (from 41.68+/-12.6 to 33.66+/-10.22; (p<0.0001) during the OFF condition, and by 7.11% (from 17.01+/-6.63 to 15.8+/-7.22; p<0.001) during the ON condition. Nocturnal akinesia improved in all the patients except one. In the 12 patients without motor fluctuations, when cabergoline was added, the UPDRS score improved by 34.4% (from 23.5+/-5.3 to 15.5+/-4.7). This open study shows that dual dopamine agonist therapy can be useful in the symptomatic treatment of patients with early or more advanced Parkinson's disease receiving therapy with or without levodopa.


Dry eye in rheumatoid arthritis patients under TNF-inhibitors: conjunctival goblet cell as an early ocular biomarker.
Dry eye disease (DED) is common in Rheumatoid Arthritis (RA) patients. The application of conjunctival goblet cell count as a clinical biomarker to diagnose and respond to treatment can take place in rheumatoid arthritis patients under TNF-inhibitors (TNFi) therapy. This study aimed to investigate the ocular surface parameters and the long-term effects of TNFi therapy on ocular surface features and goblet cell count of rheumatoid arthritis patients. At baseline, rheumatoid arthritis patients eligible to TNFi were compared to healthy controls (similar age/gender), regarding Ocular Surface Disease Index (OSDI) questionnaire, Schirmer I test, tear break-up time test, vital dye staining of the ocular surface, and conjunctival impression cytology. DED severity grade, impression cytology score, and goblet cell count were analyzed. Rheumatoid arthritis patients were followed after three (3 M) and 12 months (12 M), during TNFi treatment. Sixteen rheumatoid arthritis patients and 24 controls were compared: a higher frequency of abnormal OSDI (68.8% vs. 16.7%, p = 0.002), Schirmer's test < 10 mm (37.5% vs. 8.3%, p = 0.042), meibomian gland dysfunction (50% vs. 8.3%, p = 0.007), abnormal impression cytology (75% vs. 8.3%, p < 0.001), and mild to moderate DED (81.3% vs. 4.2%, p < 0.001) were observed in rheumatoid arthritis patients, who also had lower goblet cell count [325 (274-707) cells/mm2 vs. 742 (562-863) cells/mm2, p = 0.004]. The presence of Meibomian gland dysfunction was associated with higher disease activity scores (p < 0.05). The prospective early observation of these patients at 3 M showed an increase improvement in tear production by Schirmer's test [13 (7.5-17.5) vs. 23.5 (16-35); p = 0.001], and an improvement in impression cytology score [1 (0.5-2) vs. 1 (0-1), p = 0.031] and in goblet cell count [325 (274-707) vs. 931 (656-1,244), p < 0.001]. Eight RA responders to TNFi were also re-evaluated at 12 M with further improvement in goblet cell count [393 (275-827) vs. 872 (502-1,185) vs. 1,079 (867-1,244), p = 0.047]. Multifactorial DED is frequent in RA patients, comprising aqueous, lipid, and mucin components. TNFi prompt improves tear production and recovers the goblet cells, which can be a biomarker of the pathological process and response to therapy in this population.


Drp1-mediated mitochondrial fission induced autophagy attenuates cell apoptosis caused by 3-chlorpropane-1,2-diol in HEK293 cells.
3-chlorpropane-1,2-diol (3-MCPD) is a heat-induced food process contaminant that threatens human health. As the primary target organ, the morphological and functional impairment of kidney and the related mechanism such as apoptosis and mitochondrial dysfunction were observed. However, the precise molecular mechanism remains largely unclear. This study aimed to explore the important role of mitochondrial fission and autophagy in the 3-MCPD-caused apoptosis of human embryonic kidney 293 (HEK293) cells. The results showed that blockage of dynamin-related protein-1 (Drp1) by mitochondrial division inhibitor 1 (Mdivi-1, 15 μM) apparently restored 3-MCPD-induced mitochondrial dysfunction, accompanied by prevented the collapse of mitochondrial membrane potential and ATP depletion, and suppressed the occurrence of autophagy. Induction of autophagy occurred following 2.5-10 mM 3-MCPD treatment for 24 h via AMPK mediated mTOR signaling pathway. Meanwhile, enhancement of autophagy by pretreatment with rapamycin (1 nM) alleviated the loss of cell viability and apoptosis induced by 3-MCPD whereas suppression of autophagy by 3-methyladenine (1 mM) further accelerated apoptosis, which was modulated through the mitochondria-dependent apoptotic pathway. Taking together, this study provides novel insights into the 3-MCPD-induced apoptosis in HEK293 cells and reveals that autophagy has potential as an effective intervention strategy for the treatment of 3-MCPD-induced nephrotoxicity.


Coating of betanin and carvone Co-loaded nanoliposomes with synthesized cationic inulin: A strategy for enhancing the stability and bioavailability.
Betanin (BET) and carvone (CAR) as antioxidant and antibacterial compounds were co-loaded in the coated nanoliposomes (NLPs) with cationic inulin to improve their stability and bioavailability. A cationic inulin was successfully synthesized and used for surface coating of the NLPs. The zeta potential, particle size, and PDI values of the coated NLPs were 21.70 ± 7.00 mV, 143.5 ± 15.2 nm, and 0.35 ± 0.03 respectively. The encapsulation efficiency values of the coated NLPs for BE and CAR were 86.1 ± 3.9 and 77.2 ± 5.2 %, respectively. Electron microscopy results showed that the coated NLPs had spherical and core-shell structures. The slowest sustained release profile in the simulated gastrointestinal condition was obtained for the coated NLPs. The physical and oxidative stability of NLPs, as well as the physical stability of loaded compounds were improved by surface coating. In conclusion, the developed nanocarrier is a suitable platform to use all benefits of BET and CAR in the food industry.


Studies on chemical carcinogens and mutagens. XXIX. Mutagenic N-trimethylsilylmethyl-N-nitrosourea as a biological alkylating agent equivalent to N-methyl-N-nitrosourea (MNU).
N-Trimethylsilylmethyl-N-nitrosourea (TMS-MNU), a silicon analogue of N-neopentyl-N-nitrosourea (neoPNU), was assayed for mutagenicity and/or cytotoxicity on a series of E. coli B tester strains, S. typhimurium TA100, Chinese hamster V79, and cultured murine leukemia L1210 cells. All the biological activities demonstrated in this study reveal that this nitrosourea is a biological methylating agent equivalent to N-methyl-N-nitrosourea (MNU) but definitely distinguished from all the other alkylnitrosoureas examined so far, including neoPNU (the carbon analogue of TMS-MNU). The proposed molecular mechanism is that trimethylsilylmethanediazohydroxide is produced by hydrolytic activation of TMS-MNU and undergoes a nucleophilic cleavage of the Si--CH2 chemical bond at a high rate to form methanediazohydroxide (the reactive intermediate of MNU) which, in turn, methylates the informational biopolymer leading to mutagenesis.


Hapten inhibition of adsorption: specificity of the Sophora japonica lectin.
Since hapten inhibition of precipitation is relatively time consuming, we have developed a hapten inhibition of adsorption assay to explore the sugar binding specificity of the Sophora japonica lectin. Adsorbents were prepared with Sephadex and p-aminophenyl beta-D-galactopyranoside using the CNBr procedure. The ability of simple saccharides to inhibit the binding of lectin to the adsorbent was performed employing a fixed amount of adsorption with respect to the logarithm of micromoles of inhibitor yielded sigmoid shaped curves. The quantities of various saccharides required to cause 50% inhibition of the lectin--adsorbent interaction relative to D-galactose were within+/-5% of the relative inhibiting potencies of the sugars in


MicroRNA-155 facilitates skeletal muscle regeneration by balancing pro- and anti-inflammatory macrophages.
Skeletal muscle has remarkable regeneration capacity and regenerates in response to injury. Muscle regeneration largely relies on muscle stem cells called satellite cells. Satellite cells normally remain quiescent, but in response to injury or exercise they become activated and proliferate, migrate, differentiate, and fuse to form multinucleate myofibers. Interestingly, the inflammatory process following injury and the activation of the myogenic program are highly coordinated, with myeloid cells having a central role in modulating satellite cell activation and regeneration. Here, we show that genetic deletion of microRNA-155 (miR-155) in mice substantially delays muscle regeneration. Surprisingly, miR-155 does not appear to directly regulate the proliferation or differentiation of satellite cells. Instead, miR-155 is highly expressed in myeloid cells, is essential for appropriate activation of myeloid cells, and regulates the balance between pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages during skeletal muscle regeneration. Mechanistically, we found that miR-155 suppresses SOCS1, a negative regulator of the JAK-STAT signaling pathway, during the initial inflammatory response upon muscle injury. Our findings thus reveal a novel role of miR-155 in regulating initial immune responses during muscle regeneration and provide a novel miRNA target for improving muscle regeneration in degenerative muscle diseases.


Inhibition of catechol-O-methyltransferase increases estrogen-DNA adduct formation.
The association found between breast cancer development and prolonged exposure to estrogens suggests that this hormone is of etiologic importance in the causation of the disease. Studies on estrogen metabolism, formation of DNA adducts, carcinogenicity, cell transformation, and mutagenicity have led to the hypothesis that reaction of certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, with DNA forms depurinating adducts [4-OHE1(E2)-1-N3Ade and 4-OHE(1)(E2)-1-N7Gua]. These adducts cause mutations leading to the initiation of breast cancer. Catechol-O-methyltransferase (COMT) is considered an important enzyme that protects cells from the genotoxicity and cytotoxicity of catechol estrogens, by preventing their conversion to quinones. The goal of the present study was to investigate the effect of COMT inhibition on the formation of depurinating estrogen-DNA adducts. Immortalized human breast epithelial MCF-10F cells were treated with 4-OHE2 (0.2 or 0.5 microM) for 24 h at 120, 168, 216, and 264 h postplating or one time at 1-30 microM 4-OHE2 with or without the presence of COMT inhibitor (Ro41-0960). The culture media were collected at each point, extracted by solid-phase extraction, and analyzed by HPLC connected with a multichannel electrochemical detector. The results demonstrate that MCF-10F cells oxidize 4-OHE2 to E1(E2)-3,4-Q, which react with DNA to form the depurinating N3Ade and N7Gua adducts. The COMT inhibitor Ro41-0960 blocked the methoxylation of catechol estrogens, with concomitant 3- to 4-fold increases in the levels of the depurinating adducts. Thus, low activity of COMT leads to higher levels of depurinating estrogen-DNA adducts that can induce mutations and initiate cancer.


Epidemiological survey of human brucellosis in Inner Mongolia, China, 2010-2014: A high risk groups-based survey.
Brucellosis, a zoonosis which can seriously harm public health. Inner Mongolia is known as an endemic region of human brucellosis in China. The aim of this study is to present the epidemic of human brucellosis in Inner Mongolia from 2010 to 2014, and to provide the evidence of preventing from brucellosis in endemic areas. The study included 838,956 participants by cluster random sampling from 2010 to 2014. The contents of this study included questionnaire survey and serological testing. The seropositive rate was calculated based on the serological testing results, tested to determine whether the participants were infected by brucellosis. The new brucellosis cases were diagnosed using the questionnaire data and serological testing results then and the incidence rate was obtained. We also plotted spatial distribution maps based on the seropositive and incidence rate of human brucellosis. The total seropositive and incidence rate of human brucellosis among the high risk groups in Inner Mongolia from 2010 to 2014 was 35.91‰ and 18.25‰, respectively. The epidemic of the mid-eastern Inner Mongolia was decreased, however, the epidemic has worsened in western Inner Mongolia. Despite the epidemic of human brucellosis among the high risk groups of Inner Mongolia decreased significantly from 2010 to 2014, increased prevention and control measures are urgently needed.


Spleen cells from adult mice given total lymphoid irradiation (TLI) or from newborn mice have similar regulatory effects in the mixed leukocyte reaction (MLR). II. Generation of antigen-specific suppressor cells in the MLR after the addition of spleen cells from newborn mice.
Spleen cells from newborn BALB/c mice were added to the mixed leukocyte reaction (MLR) between a variety of responder and stimulator cells. The newborn cells nonspecifically suppressed the uptake of (3H)-thymidine and the generation of cytolytic cells regardless of the responder-stimulator combination used. Suppressor cell activity fell rapidly during the first 4 days after birth, and could not be detected by day 20. Newborn spleen cells inhibited the generation of nonspecific suppressor cells during the MLR but did not inhibit the generation of antigen-specific suppressor cells. Thus, newborn spleen cells exhibit a pattern of regulation of the MLR similar to that reported previously for spleen cells from adult mice given total lymphoid irradiation (TLI). These regulatory interactions provide a model that explains the ease of induction of transplantation tolerance in vivo in newborn mice and in TLI-treated adult mice.


Echocardiographic assessment of residuals after transvenous intracardiac lead extraction.
Detection of residual fibrotic tissue, called ghosts, after lead extraction is a new phenomenon in cardiology. This paper aims at describing the phenomenon of ghosts and determining their characteristic features. The study group consisted of 580 consecutive patients who underwent transvenous lead extraction (TLE) due to local infection, endocarditis and a superfluous lead. Each patient was clinically examined with the application of transthoracic echocardiography and transesophageal echocardiography directly before and after TLE. In the study population ghosts were detected in 110 patients (19%), and in 470 cases (81%) fibrotic tissue residuals were not found. Ghosts were most often located along the originally implanted lead's route. Longer ghosts were found after the removal of cardiac resynchronization therapy (CRT) and dual chamber pacing (DDD) devices. The local infection and infective endocarditis are associated with a larger number of ghosts revealed after the removal procedure (p = 0.006). The type of the implanted device: CRT/ICD/double chamber pacemaker/single chamber pacemaker, similar to the number of leads, did not impact on the number of the detected ghosts. The relationship between abrasions of the leads and the presence of ghosts proved significant, however (p = 0.043). TLE is associated with the presence of fibrotic tissue residuals in approx. 19% of patients. Indications for lead extraction due to local infection and endocarditis yielded significantly more cases of ghosts than in the entire patient population. The presence of abrasions is a good predictor for the presence of ghosts on the leads.


Immuno-cross-reactivity between alpha-macroglobulins from pig, dog, rat and man including human pregnancy-associated alpha 2-glycoprotein.
The antigenic relationships between the alpha-macroglobulins in human blood plasma and in serum from pig, dog and rat were investigated using ordinary immunoelectrophoresis and line immunoelectrophoresis. The results imply that these alpha-macroglobulins are more or less antigenically related. This is true also for human pregnancy-associated alpha 2-glycoprotein which is the only alpha-macroglobulin without reported proteinase-inhibiting properties. Among the alpha-macroglobulins a reciprocal cross-reactivity was observed for eight pairs, indicating a close structural relationship.