Foliar Phenolic Compounds in Norway Spruce with Varying Susceptibility to Chrysomyxa rhododendri: Analyses of Seasonal and Infection-Induced Accumulation Patterns.
Secondary phenolic metabolites are involved in plant responses to various biotic stress factors, and are apparently important for the defense against fungal pathogens. In this study, we investigated their role in defense against the rust Chrysomyxa rhododendri in Norway spruce. The fungal pathogen undergoes a seasonal lifecycle with host shift; after overwintering in rhododendron shrubs, it attacks the sprouting current-year spruce needles and causes needle fall in autumn. Repeated infections lead to reduced timber yield and severe problems with rejuvenation in subalpine Norway spruce forests. Trees with varying susceptibility to infection by C. rhododendri were selected and foliar phenolic composition was assessed using UHPLC-MS. We report on seasonal accumulation patterns and infection-related changes in the concentrations of 16 metabolites, including flavonoids, stilbenes, simple phenylpropanoids and the precursor shikimic acid, and their correlation with the infection degree of the tree. We found significant variation in the phenolic profiles during needle development: flavonoids were predominant in the first weeks after sprouting, whereas stilbenes, picein and shikimic acid increased during the first year. Following infection, several flavonoids and resveratrol increased up to 1.8 fold in concentration, whereas picein and shikimic acid were reduced by about 70 and 60%, respectively. The constitutive and early stage infection-induced concentrations of kaempferol, quercetin and taxifolin as well as the late stage infection-induced concentrations of stilbenes and picein were negatively correlated with infection degree. We conclude that a combination of constitutive and inducible accumulation of phenolic compounds is associated with the lower susceptibility of individual trees to C. rhododendri. The potentially fungicidal flavonoid aglycones may limit hyphal growth and prevent development of infection symptoms, and high levels of stilbenes may impede the infection of older needles. The presented results underline a highly compound-specific seasonal accumulation and defense response of Norway spruce and may facilitate the selection of promising trees for breeding programs.


[Novelties and experience with tyrosine kinase inhibitor therapy in chronic myeloid leukemia].
The introduction of tyrosine kinase inhibitor (TKI) treatment has resulted in dramatically improved survival in chronic myeloid leukemia (CML). With the new generation of TKIs the majority of patients reach optimal molecular response. Due to the improving survival and the need for lifelong treatment, the safety profile of the various TKIs and the comorbidities of patients have to be considered. More than half of our CML patients had comorbidities that could have influenced the choice of therapy. Because of the high prevalence of cardiovascular comorbidities, cardiovascular risk assessment plays an important role in the care of CML patients. The aim of this article is to summarize the current national and international guidelines of the treatment in CML and to show the importance of comorbidities and cardiovascular risk assessment in our CML patients.


The importance of complete tissue homogenization for accurate stoichiometric measurement of myosin light chain phosphorylation in airway smooth muscle.
The standard method for measuring the phosphorylation of the regulatory myosin light chain (MLC20) in smooth muscle is extraction of the light chain using a urea extraction buffer, urea-glycerol gel electrophoresis of the soluble portion of the extract (supernatant) and Western blot analysis. The undissolved portion of the tissue during extraction (the pellet) is usually discarded. Because the pellet contains a finite amount of MLC20, omission of the pellet could result in inaccurate measurement of MLC20 phosphorylation. In this study we compared the level of tracheal smooth muscle MLC20 phosphorylation in the supernatant alone, with that in the complete tissue homogenate (supernatant and pellet) using the standard method. The supernatant fraction showed the well-known double bands representing phosphorylated and un-phosphorylated MLC20. The dissolved pellet fraction showed varying amounts of un-phosphorylated and phosphorylated MLC20. There was a small but statistically significant overestimation of the percent MLC20 phosphorylation if the pellet was not taken into consideration. The overestimation was 7% ± 2% (mean ± SEM) (p < 0.05) in unstimulated muscle and 2% ± 1% (p < 0.05) in acetylcholine (10(-6) mol/L) stimulated muscle. This finding suggests that for accurate estimation of the stoichiometry of MLC20 phosphorylation it is necessary to consider the contribution from the pellet portion of the muscle tissue homogenate.


Genuine Bayesian multiallelic significance test for the Hardy-Weinberg equilibrium law.
Statistical tests that detect and measure deviation from the Hardy-Weinberg equilibrium (HWE) have been devised but are limited when testing for deviation at multiallelic DNA loci is attempted. Here we present the full Bayesian significance test (FBST) for the HWE. This test depends neither on asymptotic results nor on the number of possible alleles for the particular locus being evaluated. The FBST is based on the computation of an evidence index in favor of the HWE hypothesis. A great deal of forensic inference based on DNA evidence assumes that the HWE is valid for the genetic loci being used. We applied the FBST to genotypes obtained at several multiallelic short tandem repeat loci during routine parentage testing; the locus Penta E exemplifies those clearly in HWE while others such as D10S1214 and D19S253 do not appear to show this.


Paramoguai kavieng, a new genus and species of camptandriid crab from Papua New Guinea (Crustacea: Brachyura).
Paramoguai kavieng is recognised as a new genus and species of camptandriid crab, recently discovered in Papua New Guinea. The new genus closely resembles Moguai Tan & Ng, 1999, from the western Pacific, sharing similar carapace and pereopod structure, but is distinguished chiefly by the fusion of the maxilliped 3 ischiomerus, features of the epistome and front, and position of the anterolateral margins of the carapace. The new genus is unique in the Camptandriidae Stimpson, 1858, in having an epistome with a bilobed buccal margin. Moguai pyriforme Naruse, 2005, from Japan, which differs from P. kavieng primarily in carapace ornamentation and gonopod morphology, is transferred to Paramoguai.


Pregnancy does not induce or worsen retinal and peripheral nerve dysfunction in insulin-dependent diabetic women.
In order to verify whether pregnancy induces or worsens diabetic retinopathy or somatic and autonomic neuropathy, 16 insulin-dependent diabetic (IDDM) pregnant women, 14 age-matched nondiabetic pregnant women, and 12 IDDM nonpregnant women matched for age and disease duration were studied. Plasma glucose, HbA1c, and fructosamine were repeatedly assayed during pregnancy. Retinopathic and neuropathic endpoints were evaluated through ophthalmoscopy, electrophysiology of left peroneal and sural nerves (motor and sensory conduction velocities), and cardiovascular autonomic tests (deep breathing, cough test, lying-to-standing). In the IDDM pregnant women, evaluations were performed three times during pregnancy and 6 months after delivery. Good metabolic control was achieved during pregnancy. At baseline, nine IDDM pregnant women did not show signs of retinopathy, and seven had nonproliferative retinopathy. Only one patient showed worsening during pregnancy, but she improved after delivery. Motor conduction velocity, significantly lower in IDDM pregnant women, progressively improved, and, in the third trimester, was not significantly different from that of nondiabetic pregnant women. At baseline, none of the IDDM pregnant women had abnormal responses to cardiovascular autonomic tests. During pregnancy, the response to deep breathing appeared temporarily reduced in all pregnant women, possibly due to lowered ventilatory excursion at the end of pregnancy. In IDDM women with minimal or no retinopathy, and subclinical or no peripheral neuropathy, pregnancy does not appear to induce or worsen these complications.


First measurements of inclusive muon neutrino charged current differential cross sections on argon.
The ArgoNeuT Collaboration presents the first measurements of inclusive muon neutrino charged current differential cross sections on argon. Obtained in the NuMI neutrino beam line at Fermilab, the flux-integrated results are reported in terms of outgoing muon angle and momentum. The data are consistent with the Monte Carlo expectation across the full range of kinematics sampled, 0°<θ(μ)<36° and 0<P(μ)<25 GeV/c. Along with confirming the viability of liquid argon time projection chamber technology for neutrino detection, the measurements allow tests of low-energy neutrino scattering models important for interpreting results from long baseline neutrino oscillation experiments designed to investigate CP violation and the orientation of the neutrino mass hierarchy.


[Psychological trauma in trauma medicine--the current status of psychological management of trauma victims in Germany].
A clinically significant amount of accident victims display psychological disorders as a reaction to the trauma. Outcome studies on multiple trauma emphasize that life quality following severe accidental injury is influenced by early diagnosis and treatment of psychic co-morbidity. In a nationwide survey concerning the state of the art in in-patient treatment of injury patients conducted in Germany, every surgical ward was contacted and physicians were asked about their standard procedures of detecting and treating psychotraumatic complications. The results of the survey indicate that surgeons pay close attention to signs of psychological comorbidity and have good basic knowledge of psychotraumatic disorders. Nevertheless, there are structural deficiencies caused by the fact that only a few wards have staff specially trained in psychotraumatological care. Only a minority of patients is treated for psychotraumatic symptoms. In view of the high prevalence rates for psychotraumatic disorders in the aftermath of severe accidental injuries, the article discusses the need for psychic diagnosis and support as well as the necessary cooperative structures required in the model of Integrative Posttraumatic Acute Care.


Renal handling of phenol red. II. The mechanism of substituted phenolsulphophthalein (PSP) dye transport in rabbit kidney tubules in vitro.
1. The uptake of various substituted phenolsulphophthalein dyes by cortical slices of rabbit kidney has been studied in detail in order to obtain more information on the secretory system for organic anions. 2. The rate of initial uptake of dyes and the accumulation after incubation for 2 hr under aerobic conditions increased in the order: phenol red (PR) greater than bromophenol blue (BPB) greater than bromocresol green (BCG) greater than bromothymol blue (BTB), while the reverse order of uptake was observed under anaerobic conditions. There was no difference between the uptake of BTB under aerobic and anaerobic conditions. 3. The accumulation of dyes under anaerobic conditions could be accounted for by binding to tissue constituents. In comparison with PR (Sheikh, 1972), the substituted dyes were found to interact extensively with the 700 G (cell membranes) and cytosol fractions of renal homogenates. 4. Low concentrations of the substituted dyes efficiently inhibited the accumulation of rho-aminohippurate (PAH). The concentration of dye resulting in 50% inhibition of PAH accumulation (KI) agreed well with concentrations estimated to sustain 50% of maximal dye transport (KM). On this basis the affinity of the dyes for the transport system increases in the order: PR less than BPB less than BCG less than BTB. 5. Probenecid, 2,4-dinitrophenol, PAH, octanoate and succinate affected to a smaller extent the uptake and binding of BPB and BCG by renal tissue than that previously shown for PR (Sheikh, 1972). No inhibitory effect of these substances on the accumulation of BTB by kidney tissue was observed. 6. The binding of PSP dyes by phospholipid vesicles (liposomes) and a representative binding protein, human serum albumin, exhibited close similarity to that of binding by renal tissue. Partition experiments involving octanol-water phases indicated that the hydrophobicity of the dyes increased in the order: PR less than BPB less than BCG less than BTB. 7. The results indicate that BTB, despite its inhibitory potency, is not transported by the organic anion system. BPB and BCG are transported to a lesser extent, and interact more strongly with the transport system than does PR. It is suggested that the substituted dyes by virtue of hydrophobic interaction with the transport system reduce the movement of the mobile part of the transport system.


Zinc regulates Nox1 expression through a NF-κB and mitochondrial ROS dependent mechanism to induce senescence of vascular smooth muscle cells.
The role of oxidative stress and inflammation in the development and progression of cardiovascular diseases (CVD) is well established. Increases in oxidative stress can further exacerbate the inflammatory response and lead to cellular senescence. We previously reported that angiotensin II (Ang II) and zinc increase reactive oxygen species (ROS) and cause senescence of vascular smooth muscle cells (VSMCs) and that senescence induced by Ang II is a zinc-dependent process. Zinc stimulated NADPH oxidase (Nox) activity; however, the role of Nox isoforms in zinc effects was not determined. Here, we show that downregulation of Nox1, but not Nox4, by siRNA prevented both Ang II- and zinc-induced senescence in VSMCs. On the other hand, overexpression of Nox1 induced senescence, which was associated with reduced proliferation, reduced expression of telomerase and increased DNA damage. Zinc increased Nox1 protein expression, which was inhibited by chelation of zinc with TPEN and by overexpression of the zinc exporters ZnT3 and ZnT10. These transporters work to reduce cytosolic zinc, suggesting that increased cytosolic zinc mediates Nox1 upregulation. Other metals including copper, iron, cobalt and manganese failed to upregulate Nox1, suggesting that this pathway is zinc specific. Nox1 upregulation was inhibited by actinomycin D (ACD), an inhibitor of transcription, by inhibition of NF-κB, a known Nox1 transcriptional regulator and by N-acetyl cysteine (NAC) and MitoTEMPO, suggesting that NF-κB and mitochondrial ROS mediate zinc effects. Supporting this idea, we found that zinc increased NF-κB activation in the cytosol, stimulated the translocation of the p65 subunit to the nucleus, and that zinc accumulated in mitochondria increasing mitochondrial ROS, measured using MitoSox. Further, zinc-induced senescence was reduced by inhibition of NF-κB or reduction of mitochondrial ROS with MitoTEMPO. NF-κB activity was also reduced by MitoTEMPO, suggesting that mitochondrial ROS is upstream of NF-κB. Our data demonstrate that altered zinc distribution leading to accumulation of zinc in the mitochondria increases mitochondrial ROS production causing NF-κB activation which in turn upregulates Nox1 expression inducing senescence of VSMCs.


The lncRNA MALAT1 acts as a competing endogenous RNA to regulate KRAS expression by sponging miR-217 in pancreatic ductal adenocarcinoma.
The long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) has been shown to play an important role in tumourigenesis. The aim of this study was to investigate the role of MALAT1 in pancreatic ductal adenocarcinoma. MALAT1 is expressed at higher levels in pancreatic ductal adenocarcinoma (PDAC) tissues than in nontumour tissues and in metastatic PDAC than in localized tumours. Patients with PDAC and high MALAT1 expression levels have shorter overall survival than patients with PDAC and low MALAT1 expression levels. Knocking down MALAT1 reduces pancreatic tumour cell growth and proliferation both in vitro and in vivo. Moreover, MALAT1 knockdown inhibits cell cycle progression and impairs tumour cell migration and invasion. We found that miR-217 can bind MALAT1 and regulate its expression in PDAC cell lines. We also found MALAT1 knockdown attenuates the protein expression of KRAS, a known target of miR-217. After MALAT1 knockdown, KRAS protein expression levels can be rescued through inhibition of miR-217 expression. More importantly, MALAT1 knockdown does not directly affect cellular miR-217 expression but decreases the miR-217 nucleus/cytoplasm ratio, suggesting that MALAT1 inhibits the translocation of miR-217 from the nucleus to the cytoplasm.


[Morphometric analysis of the spleen].
Present possibilities of morphometric analysis of the spleen have been studied. We have compared possibilities provided by stereological calculation and by computer image analysators a) Telemet II (Tesla, Piestany) and b) CUE-2 GALAI (Israel). In both latter cases equidensitometric evaluation and image processing methods were used. Stereological calculations are not technically demanding but time consuming. Computer image processing on the base of equidensitometric measurements is more effective that stereological calculations. The difference between used equipments is based on access to appropriate microscopic and computer technique and software equipment.


Mitochondrial autophagy protects against heat shock-induced apoptosis through reducing cytosolic cytochrome c release and downstream caspase-3 activation.
Autophagy is an evolutionarily conserved process for bulk degradation of cytoplasmic components, including large molecules and organelles. It can either help to enhance or to resist apoptosis, depending on the circumstances. The mechanism of how autophagy impacts apoptosis and the subsequent cellular events upon heat shock remains unclear. In this study, we demonstrate for the first time that mitochondrial membrane permeability transition (MPT)-sensitive mitochondrial autophagy can protect against heat-induced apoptosis through reduction of cytosolic cytochrome c release and downstream caspase-3 activation. With confocal microscopy, it was revealed that as autophagosomes increased, mitochondrial content was mass decreased after heat shock. Detailed analysis shows that a single swelling mitochondrion could be entrapped into autophagosome. The depolarization of mitochondria preceded the mitochondrial loss, and both could be abolished by MPT inhibitor cyclosporine (CsA). In addition, along with the decrease of mitochondrial content, the level of total cytochrome c was also reduced, resulting in a reduction of its release to cytoplasm. When heat shock was combined with 3-methyladenine (3-MA), an inhibitor of autophagy, the mitochondrial loss and the reduction of total cytochrome c were both inhibited, and then caspase-3 activation and cell apoptosis were increased. Thus, it is reasonable to believe that, heat shock-induced cellular events can be modulated by controlling autophagy, and this may represent a novel approach to enhance the efficacy of hyperthermia.


Small subunit ribosomal metabarcoding reveals extraordinary trypanosomatid diversity in Brazilian bats.
Bats are a highly successful, globally dispersed order of mammals that occupy a wide array of ecological niches. They are also intensely parasitized and implicated in multiple viral, bacterial and parasitic zoonoses. Trypanosomes are thought to be especially abundant and diverse in bats. In this study, we used 18S ribosomal RNA metabarcoding to probe bat trypanosome diversity in unprecedented detail. Total DNA was extracted from the blood of 90 bat individuals (17 species) captured along Atlantic Forest fragments of Espírito Santo state, southeast Brazil. 18S ribosomal RNA was amplified by standard and/or nested PCR, then deep sequenced to recover and identify Operational Taxonomic Units (OTUs) for phylogenetic analysis. Blood samples from 34 bat individuals (13 species) tested positive for infection by 18S rRNA amplification. Amplicon sequences clustered to 14 OTUs, of which five were identified as Trypanosoma cruzi I, T. cruzi III/V, Trypanosoma cruzi marinkellei, Trypanosoma rangeli, and Trypanosoma dionisii, and seven were identified as novel genotypes monophyletic to basal T. cruzi clade types of the New World. Another OTU was identified as a trypanosome like those found in reptiles. Surprisingly, the remaining OTU was identified as Bodo saltans-closest non-parasitic relative of the trypanosomatid order. While three blood samples featured just one OTU (T. dionisii), all others resolved as mixed infections of up to eight OTUs. This study demonstrates the utility of next-generation barcoding methods to screen parasite diversity in mammalian reservoir hosts. We exposed high rates of local bat parasitism by multiple trypanosome species, some known to cause fatal human disease, others non-pathogenic, novel or yet little understood. Our results highlight bats as a long-standing nexus among host-parasite interactions of multiple niches, sustained in part by opportunistic and incidental infections of consequence to evolutionary theory as much as to public health.


Study on early markers of death in patients with COVID-19.
Coronavirus disease 2019 (COVID-19) was first discovered in December 2019, and since then rapidly spread worldwide. Our study aimed to investigate the early indicators of death in patients suffering from severe and critical COVID-19. A retrospective cohort study was conducted on patients with severe and critical COVID-19, admitted to the Seventh Hospital of Wuhan. Clinical information was collected from electronic medical records according to standardized data collection tables. Patients were divided into non-survival and survival groups based on the disease outcome. Using univariate and multivariate logistic regression analysis, and calculating odds ratios (OR) and 95% confidence intervals (CI), independent risk factors for death in severe and critically ill COVID-19 patients were identified. The median age of 162 patients (57.4% males) was 67.5 years old. Patients in the non-survival group had significantly higher white blood cell count, decreased lymphocyte count, anemia and thrombocytopenia compared to patients in the survival group (p < 0.05). A 28-day mortality rate of the study cohort was 31.5%. Multivariate logistic regression analysis showed that underlying heart disease, lymphocyte count < 1.0 × 109/L, glomerular filtration rate < 66, lactate > 2.2 mmol/L, higher Sequential Organ Failure Assessment (SOFA) score, lower oxygenation index (OR 1.748; 95% CI 1.024-2.984; p=0.041) and higher "multi-lobar infiltration, hypo lymphocytosis, bacterial co-infection, smoking history, hypertension and age" (MuLBSTA) score (OR 1.601; 95% CI 1.062-2.415; p=0.025) were risk factors associated with death in patients with severe and critical COVID-19. Underlying heart disease, lymphocyte count, glomerular filtration rate, lactate, oxygenation index, SOFA score, and MuLBSTA score were associated with the risk of death in severe and critical COVID-19 patients.


Gene transfer of the vascular endothelial growth factor receptor flt-1 suppresses pulmonary metastasis associated with lung growth.
Growth of solid tumor metastases is critically dependent on angiogenesis. We hypothesized that an "angiogenic-rich" milieu, as in pneumonectomy-induced lung growth, would be conducive to growth of pulmonary metastases, and that transfer of an antiangiogenic gene would suppress tumor growth. Two weeks after left pneumonectomy in BALB/c mice, right lung mass increased 1.5-fold compared with controls (P < 0.0001). Our pulmonary metastases model, intravenous administration of beta-galactosidase (betagal)-marked CT26.CL25 colon carcinoma cells, resulted in diffuse metastases at 12 d after administration. However, if left pneumonectomy was performed 1 d before tumor cell administration, right lung mass was increased 1.7-fold after 12 d (P < 0.001 compared with the right + left lung of controls), and betagal activity was greater (2.8-fold, P < 0.05). To assess antiangiogenesis therapy, tumor cells were administered 1 d after pneumonectomy and 1 d later, 5 x 10(8) plaque-forming units of Adsflt (an Ad vector expressing the extracellular portion of the flt-1 vascular endothelial growth factor [VEGF] receptor) was administered. Compared with controls, mice receiving Adsflt via intranasal or intravenous routes showed suppression of pneumonectomy-induced tumor growth (P < 0.01, both routes compared with controls). Postpneumonectomy lung growth enhances growth of lung metastases, but this can be suppressed with Adsflt antiangiogenesis therapy.


Long-Term Survival and Local Relapse Following Surgery Without Radiotherapy for Locally Advanced Upper Rectal Cancer: An International Multi-Institutional Study.
Controversy remains regarding whether preoperative chemoradiation protocol should be applied uniformly to all rectal cancer patients regardless of tumor height. This pooled analysis was designed to evaluate whether preoperative chemoradiation can be safely omitted in higher rectal cancer.An international consortium of 7 institutions was established. A review of the database that was collected from January 2004 to May 2008 identified a series of 2102 patients with stage II/III rectal or sigmoid cancer (control arm) without concurrent chemoradiation. Data regarding patient demographics, recurrence pattern, and oncological outcomes were analyzed. The primary end point was the 5-year local recurrence rate.The local relapse rate of the sigmoid colon cancer (SC) and upper rectal cancer (UR) cohorts was significantly lower than that of the mid/low rectal cancer group (M-LR), with 5-year estimates of 2.5% for the SC group, 3.5% for the UR group, and 11.1% for the M-LR group, respectively. A multivariate analysis showed that tumor depth, nodal metastasis, venous invasion, and lower tumor level were strongly associated with local recurrence. The cumulative incidence rate of local failure was 90.6%, 92.5%, and 94.4% for tumors located within 5, 7, and 9 cm from the anal verge, respectively.Routine use of preoperative chemoradiation for stage II/III rectal tumors located more than 8 to 9 cm above the anal verge would be excessive. The integration of a more individualized approach focused on systemic control is warranted to improve survival in patients with upper rectal cancer.


Vascular endothelial growth factor G1612A (rs10434) gene polymorphism and neuropsychiatric manifestations in systemic lupus erythematosus patients.
To investigate the relation between vascular endothelial growth factor (VEGF) gene polymorphism in systemic lupus erythematosus (SLE) patients and lupus related neuropsychiatric manifestations. Sixty adult SLE patients recruited from the Rheumatology and Neurology departments of Cairo University hospitals were classified into two groups; Group A: 30 patients with neuropsychiatric manifestations (NPSLE) and Group B: 30 patients without. For both groups the SNP G1612A (rs10434) of the VEGF gene was genotyped by real time polymerase chain reaction (RT-PCR). Statistically significant difference was found in genotype and allele frequencies between both groups (AA [70% vs 13.3%, p<0.001] and GG [10% vs 66.7%, p<0.001]). Polymorphism in the gene coding for VEGF may be associated with increased incidence of neuropsychiatric lupus in SLE patients.


Keap1-Nrf2 activation in the presence and absence of DJ-1.
The molecular mechanisms leading to neurodegeneration in Parkinson's disease remain elusive. Deletion and mutations of DJ-1 (PARK7) have been reported to cause autosomal recessive familial Parkinson's disease. Wildtype DJ-1 scavenges H(2)O(2) by cysteine oxidation in response to oxidative stress, and thus confers neuroprotection. Activation of the transcription factor NF-E2-related factor-2 (Nrf2) has also been shown to be important for protection against oxidative stress in many models of neurodegenerative diseases. Previous data indicate that DJ-1 affects the transcriptional functions and stability of Nrf2. However, this observation has not been confirmed. In the current study, the role of DJ-1 in the regulation of Nrf2 is examined in primary cultured neurons, astrocytes and in vivo. The prototypical Nrf2 activator tBHQ protected primary cortical neurons derived from DJ-1-knockout (KO) as well as DJ-1 wildtype mice by activation of Nrf2-ARE pathway. Nrf2 nuclear translocation, robust increases in canonical Nrf2-driven genes and proteins, and dramatic activation of the ARE reporter gene, hPAP, were observed after tBHQ treatment. These results were further confirmed by siRNA-mediated DJ-1 knockdown in primary cortical astrocytes from ARE-hPAP mice and tBHQ administration into the striatum of mouse brain. In addition, overexpression of Nrf2 with adenovirus preferentially in astrocytes from DJ-1-KO mice enhanced survival of neurons under oxidative insults. These findings indicate that activation of the Nrf2-ARE pathway is independent of DJ-1, and Nrf2 activation is a potential therapeutic target to prevent neurodegeneration in sporadic and DJ-1 familial Parkinson's disease.


Two-dimensional millisecond analysis of intracellular Ca2+ sparks in cardiac myocytes by rapid scanning confocal microscopy: increase in amplitude by isoproterenol.
Two dimensional images of myocardial Ca2+ sparks, non-propagating local rises in cytoplasmic Ca2+ concentration, were obtained at 4 msec intervals with a rapid-scanning confocal laser microscope, Nikon RCM 8000, and fluo-3. Spontaneous Ca2+ sparks were observed at apparently random sites throughout the cytoplasm of rat ventricular cells. The duration of sparks was 30 to 40 msec and the time to peak intensity about 10 msec. Ryanodine (1 microM) completely inhibited Ca2+ sparks while nicardipine (3 microM) had no effect. Isoproterenol (1 microM) had no effect on the frequency and distribution of Ca2+ sparks but significantly increased their amplitude. These results suggest that myocardial Ca2+ sparks are the result of spontaneous release of Ca2+ from the sarcoplasmic reticulum and that beta-adrenergic stimulation may result in functional modification of the ryanodine receptor channel.


Airborne ragweed (Ambrosia artemisiifolia L.) pollen content in the city of Zagreb and implications on pollen allergy.
The increasing problem of sensitization to Ambrosia pollen in Europe has stimulated studies on Ambrosia pollen occurrence and pollinosis in Croatia. The aim of this study was to analyze the ragweed pollen pattern in Zagreb and to determine the incidence of sensitization to this pollen types in patients with seasonal respiratory allergy. The study was performed in the city of Zagreb during the 2002-2005 seasons. Skin prick test were performed on a total of 750 patients aged 18-80 in Zagreb between 2 January - 31 December 2004. The mean 4-year rate of ragweed pollen in the Zagreb atmosphere was 14.8% of all plant pollen. The highest rate of airborne ragweed pollen was recorded in August and September. 365 patients were allergic to ragweed pollen; 20.3% of them monosensitized; 10.9% allergic to Ambrosia and Artemisia pollen. Almost all study patients suffered the most severe symptoms in August and September. The highest proportion of allergic patients were recorded in the 31-50 age group and the lowest proportion in the >50 age group. Forecasting of allergenic pollen season in an area is a crucial pursuit for all developed countries, in order to minimize clinical symptoms in patients suffering from respiratory allergy. This can be achieved through public announcements by mass media (radio, television, internet, etc.) aiming to protect allergic individuals.


Paclitaxel-induced sickle cell crisis.
A case of paclitaxel-induced painful crisis in a patient with breast cancer and hemoglobin sickle cell disease (SCD) is reported. A 55-year-old postmenopausal African-American woman had stage IIB invasive ductal carcinoma of the left breast. She was not taking any medications and did not report a history of cancer or other diseases. She had mild microcytic anemia, but the rest of her blood counts and liver function test values were normal. Bone scans and computed tomography scans of her chest and abdomen did not reveal any metastatic disease. She underwent a routine left segmental mastectomy and axillary lymph node dissection that revealed a 4-cm invasive cancer with 1 of 10 axillary lymph nodes positive for metastatic disease. Her treatment plan included chemotherapy with weekly paclitaxel, followed by fluorouracil, epirubicin, and cyclophosphamide and radiation. The first cycle of paclitaxel was well tolerated until one week after initiation when the patient woke up in the middle of the night with a sudden onset of excruciating back pain and muscle spasms. Other symptoms that developed included fatigue, left-sided rib pain, and shortness of breath. The patient recalled being told that she had sickle cell trait but said that she never had a sickle cell crisis. Laboratory tests during her 13-day hospitalization revealed hemolysis. The patient was diagnosed with hemoglobin SCD and later discharged with as-needed, low-dose oxycodone and baclofen, antibiotics, and folic acid. A patient with breast cancer and SCD had a painful crisis after receiving paclitaxel as part of her chemotherapy regimen.


Confinement effects of P3HT in nanochannels and their implications for bulk heterojunction solar cells.
We studied the properties of regioregular P3HT conducting polymers with three different molecular weights infiltrated into the pores of mesoporous titania thin films. The titania thin films, prepared by self-organization of titania species with a non-ionic triblock copolymer F127 followed by calcination to remove organics, have arrays of 7 nm vertical nanochannels. The UV-Vis spectra of the P3HT-titania nanocomposite films revealed that the interstrand interactions between P3HT chains were weakened by the infiltration. Such an effect increases as the molecular weight of P3HT increases and as the infiltration temperature increases. Consequently, the efficiency of the solar cells, assembled by using the P3HT infiltrated mesoporous titania thin films, was the highest with the smallest P3HT, contrary to the generally accepted practice of using high molecular weight P3HT for forming bulk heterojunction solar cells.


CBP7 codes for a co-factor required in conjunction with a mitochondrial maturase for splicing of its cognate intervening sequence.
Maturases are required for the processing of their cognate intervening sequences in the mitochondrial cytochrome beta pre-mRNA. In this paper we characterize a nuclear gene, CBP7, already known to be required for the translation of the cytochrome b transcript; we present further evidence that it is also required as a co-factor in conjunction with the maturases for the efficient processing of their intervening sequences. Results are based on Northern blot analyses which show that in cbp7 mutants with the short cytochrome b gene the maturase encoding intervening sequence fails to be excised although, at the same time, at least wild-type levels of the maturase are present as indicated by antibodies specific to it in Western blot analyses.


Characterization of stroma from Fuchs' endothelial dystrophy corneas.
Fuchs' endothelial dystrophy is commonly regarded as an endothelial cell disorder. In the present study we compared glycoconjugates of Fuchs' and normal corneas using FITC conjugated lectins [peanut agglutinin (PNA), castor bean agglutinin (RCA120), soybean agglutinin (SBA), and wheat germ agglutinin (WGA)]. Our results showed increased staining with RCA120 and PNA in the posterior region of the Fuchs' corneas, indicating an accumulation of terminal beta-galactose and B-D-galactose (1-3)-D-N-acetylgalactosamine residues. The stromal and epithelial regions of normal and Fuchs' corneas exhibited similar staining patterns with all lectins tested. Our collagen studies showed an increased extractability and abnormal amino acid analyses of collagen from Fuchs' corneas as compared with normals. The purified collagens did have similar banding patterns by sodium dodecyl sulfate gels. However, further characterization by 125(1) two-dimensional peptide mapping revealed that Fuchs' alpha 1-sized chains contained fingerprints that were distinctly different from normal cornea stromal collagen. These data suggest that in addition to abnormal accumulation of RCA120- and PNA-specific glycoconjugates in the posterior cornea, Fuchs' corneas contained stromal collagens with altered biochemical properties. We postulate that the characteristic deterioration of endothelial function in Fuchs' dystrophy may compromise the microenvironment of the stroma and its keratocytes, and thereby lead to an altered collagenous extracellular matrix.


Maize tumors caused by Ustilago maydis require organ-specific genes in host and pathogen.
Infection of maize by corn smut (Ustilago maydis) provides an agronomically important model of biotrophic host-pathogen interactions. After penetration of the maize epidermis, fungal colonization of host tissue induces tumor formation on all aerial maize organs. We hypothesized that transformation of different primordia into plant tumors would require organ-specific gene expression by both host and pathogen and documented these differences by transcriptome profiling. Phenotypic screening of U. maydis mutants deleted for genes encoding secreted proteins and maize mutants with organ-specific defects confirmed organ-restricted tumorigenesis. This is the foundation for exploring how individual pathogen effectors, deployed in an organ-specific pattern, interact with host factors to reprogram normal ontogeny into a tumor pathway.


Classification of intertrochanteric fractures with computed tomography: a study of intraobserver and interobserver variability and prognostic value.
The purpose of this prospective study was to determine the level of interobserver and intraobserver agreement among orthopedic surgeons and radiologists when computed tomography (CT) scans are used with plain radiographs to evaluate intertrochanteric fractures. In addition, the prognostic value of current classifications systems concerning quality of life was evaluated. Sixty-one patients who presented with intertrochanteric fractures received open reduction and internal fixation with compression hip screw. Three orthopedic surgeons and 2 radiologists independently classified the fractures according to 2 systems: Evans-Jensen and AO (Arbeitsgemeinschaft für Osteo-synthesefragen). Fractures were initially graded with plain radiographs and then again in conjunction with CT. Results were analyzed using the (kappa) kappa coefficient. The 36-item Short-Form Health Survey was administered at baseline, 3 months, and 1 year, and results were correlated with fracture grade. Mean kappa coefficients when comparing radiography alone with radiography and CT scan were 0.63 for the AO system and 0.59 for the Evans-Jensen system. Both represent "fair" agreements. Mean overall interobserver kappa coefficients were 0.67 for radiologists and 0.57 for orthopedic surgeons. Radiologists also had higher intraobserver kappa coefficients. No significant relationships were found between follow-up Short Form Health Survey results and intraoperative grading of fractures. When these classification schemes are compared, interobserver agreement does not appear to change dramatically when information from CT scans is added. This may suggest that (1) more data have been provided by CT with greater possibilities for misinterpretation and (2) these classification schemes may not be comprehensive in describing fracture pattern and displacement. Finally, both systems failed to provide any prognostic value.


[Inflammatory granuloma of the face with a malignant course. Atypical Hodgkin's disease (author's transl)].
A case of Hodgkin's disease beginning in the skin of the face with local lymph node involvement is reported. This was a lymphogranulomatous form without characteristic Reed-Sternberg cells in skin biopsy specimens, rendering the diagnosis difficult. There was a combination of granulomatous inflammation, plaques of necrosis and lesions of fibrinoid necrosis in the vessel walls. This form entered the classification of clinical Stage IV, with its associated serious prognosis.


Protein Arginine Methyltransferase 5 Inhibition Upregulates Foxp3+ Regulatory T Cells Frequency and Function during the Ulcerative Colitis.
Ulcerative colitis (UC) pathogenesis is related to imbalance of immune responses, and the equilibrium between inflammatory T cells and Foxp3+ regulatory T cells (Tregs) plays an important role in the intestinal homeostasis. Protein arginine methyltransferases (PRMTs) regulate chromatin remodeling and gene expression. Here, we investigated whether inhibition of PRMTs affects colitis pathogenesis in mice and inflammatory bowel disease patients and further explored the underlying mechanisms. In this study, we found that protein arginine N-methyltransferase inhibitor 1 (AMI-1) treatments increased Tregs frequency, function, and reduced colitis incidence. Adoptive transfer of AMI-1-treated Tregs could reduce the colitis incidence. Colitis was associated with increased local PRMT5 expression, which was inhibited by AMI-1 treatment. Additionally, PRMT5 knockdown T cells produced a better response to TGFβ and promoted Tregs differentiation through decreased DNA methyltransferase 1 (DNMT1) expression. PRMT5 also enhanced H3K27me3 and DNMT1 binding to Foxp3 promoter, which restricted Tregs differentiation. Furthermore, PRMT5 knockdown led to decreased Foxp3 promoter methylation during Tregs induction. PRMT5 expression had a negative relationship with Tregs in UC patients, knockdown of PRMT5 expression increased Tregs frequency and decreased TNFα, IL-6, and IL-13 levels. Our study outlines a novel regulation of PRMT5 on Tregs development and function. Strategies to decrease PRMT5 expression might have therapeutic potential to control UC.


The effects of ionic liquids on the ethanolysis of a chloroacenaphthene. Evaluation of the effectiveness of nucleofugality data to predict reaction outcome.
The reaction of a chlorobenzene in mixtures containing ethanol and eight different ionic liquids was investigated in order to understand the effects of varying proportions and constituent ions of an ionic liquid on the rate constant of the process. The results were found to be generally consistent with previously studied reactions of the same type, with small proportions of an ionic liquid resulting in a rate constant increase compared to ethanol and large proportions causing a rate constant decrease. Temperature dependent kinetic studies were used to interpret the changes in reaction outcome, particularly noting an entropic cost on moving to high proportions of ionic liquid, consistent with organisation of solvent around the transition state. While attempts to use empirical solvent parameters to correlate outcome with the ionic liquid used were unsuccessful, use of recently acquired nucleofugality data for chloride and estimations for the electrofuge allowed for excellent prediction of the effects of ionic liquids, with rate constants quantitatively predicted in systems containing both different proportions of ionic liquid (mean absolute error (MAE) log(k1) = 0.11) and different ionic liquids (MAE log(k1) = 0.33). Importantly, this demonstrates the ready application of these quantitative reactivity parameters.


Clinically relevant fluoroquinolone resistance due to constitutive overexpression of the PatAB ABC transporter in Streptococcus pneumoniae is conferred by disruption of a transcriptional attenuator.
Constitutive overexpression of patAB has been observed in several unrelated fluoroquinolone-resistant laboratory mutants and clinical isolates; therefore, we sought to identify the cause of this overexpression. Constitutive patAB overexpression in two clinical isolates and a laboratory-selected mutant was investigated using a whole-genome transformation approach. To determine the effect of the detected terminator mutations, the WT and mutated patA leader sequences were cloned upstream of a GFP reporter. Finally, mutation of the opposing base in the stem-loop structure was carried out. We identified three novel mutations causing up-regulation of patAB. All three of these were located in the upstream region of patA and affected the same Rho-independent transcriptional terminator structure. Each mutation was predicted to destabilize the terminator stem-loop to a different degree, and there was a strong correlation between predicted terminator stability and patAB expression level. Using a GFP reporter of patA transcription, these terminator mutations led to increased transcription of a downstream gene. For one mutant sequence, terminator stability could be restored by mutation of the opposing base in the stem-loop structure, demonstrating that transcriptional suppression of patAB is mediated by the terminator stem-loop structure. This study showed that a mutation in a Rho-independent transcriptional terminator structure confers overexpression of patAB and fluoroquinolone resistance. Understanding how levels of the PatAB efflux pump are regulated increases our knowledge of pneumococcal biology and how the pneumococcus can respond to various stresses, including antimicrobials.


Audiovisual Integration of Time-to-Contact Information for Approaching Objects.
Previous studies of time-to-collision (TTC) judgments of approaching objects focused on effectiveness of visual TTC information in the optical expansion pattern (e.g., visual tau, disparity). Fewer studies examined effectiveness of auditory TTC information in the pattern of increasing intensity (auditory tau), or measured integration of auditory and visual TTC information. Here, participants judged TTC of an approaching object presented in the visual or auditory modality, or both concurrently. TTC information provided by the modalities was jittered slightly against each other, so that auditory and visual TTC were not perfectly correlated. A psychophysical reverse correlation approach was used to estimate the influence of auditory and visual cues on TTC estimates. TTC estimates were shorter in the auditory than the visual condition. On average, TTC judgments in the audiovisual condition were not significantly different from judgments in the visual condition. However, multiple regression analyses showed that TTC estimates were based on both auditory and visual information. Although heuristic cues (final sound pressure level, final optical size) and more reliable information (relative rate of change in acoustic intensity, optical expansion) contributed to auditory and visual judgments, the effect of heuristics was greater in the auditory condition. Although auditory and visual information influenced judgments, concurrent presentation of both did not result in lower response variability compared to presentation of either one alone; there was no multimodal advantage. The relative weightings of heuristics and more reliable information differed between auditory and visual TTC judgments, and when both were available, visual information was weighted more heavily.


[Fast determination of pericarpium papaveris illegally added in foods by TurboFlow online purification-ultra performance liquid chromatography-triple quadrupole/linear ion trap mass spectrometry].
A fast confirmation method was developed for the determination of the six markers of pericarpium papaveris, morphine, codeine, narcotine, papavarine, thebaine and protopine in foods, by TurboFlow online purification-ultra performance liquid chromatography-triple quadrupole/linear ion trap mass spectrometry (TF-UPLC-QTRAP MS). The sample was extracted with 0.10 mol/L HCl. After the procedure of removal of lipid with hexane, the extraction solution was analyzed by TF-UPLC-QTRAP MS. The main factors influencing the purification efficiency including TurboFlow column, mobile phase and elution solution were optimized. The six opium alkaloids were detected by positive electrospray ionization tandem mass spectrometry in the multiple reaction monitoring-information-dependent acquisition-enhanced product ion (MRM-IDA-EPI) mode, and quantified by solvent standard internal standard method. The limits of detection were 0.05-0.5 μg/kg and the limits of quantification were 0.2-2 μg/kg for the six opium alkaloids. The recoveries were in the range of 81.1%-98.6% with the relative standard deviations ranging from 2.9% to 15.7% (n=6). The method is sensitive and accurate, and has been successfully applied to the detection of pericarpium papaveris illegally added in foods.


Interface Engineering with Quaternary Ammonium-Based Ionic Liquids toward Efficient Blue Perovskite Light-Emitting Diodes.
Perovskite light-emitting diodes (PeLEDs) have become a hot research topic in recent years and can now achieve an external quantum efficiency (EQE) of over 22% for green and red devices. However, the efficiency of blue PeLEDs, which are essential for display applications, lags far behind their green and red counterparts. The interface of the PeLEDs has a critical influence on the carrier transport and exciton recombination dynamics, and interface engineering is considered to be an effective strategy to improve the device performance. Herein, quaternary ammonium-based ionic liquids serve as an interfacial modification layer to significantly improve the device efficiency and stability. The interaction of quaternary ammonium cations with Pb(Br/Cl)6 octahedra promotes nucleation sites, which significantly improves the morphology of perovskite films and reduces the formation of defects in films. In addition, ion migration is also effectively suppressed in the device. As a result, with tributylmethylammonium bromide (TMAB) used as the interface layer, the EQE of the device is successfully increased from 3.5 to 6.7%, and the operational stability with a half-lifetime (T50) is increased by over 12 times. Our work provides a new class of interface modification materials toward high-performance blue PeLEDs.


Acid mucopolysaccharide and one of its glomerular degrading enzymes beta-glucuronidase in experimental and human glomerulonephritis.
In 1962, when the immune complex in nephritic glomerular basement membrane (GBM) was clarified as being a type of GBM thickening, Amon and Gayer reported a different type of thickening in the rabbit administered hyaluronidase (an enzyme to degrade hyaluronic acid) and named it 'herniation' of the GBM. As we have been interested for a long time in the disappearance of normally present nonsulfated AMPS, presumably hyaluronic acid (HA), from the glomeruli in humans and experimental animals with chronic glomerulonephritis, we wanted to observe the activity of the enzyme in these conditions. Since a suitable histochemical method for the precise evaluation of hyaluronidase is unavailable, we instead chose beta-glucuronidase(beta-Gase), which is also an enzyme which degrades HA. The principal study was performed by means of light- and electron-microscopic histochemistry of chronic glomerulonephritis produced experimentally in rats and compared the obtained results to those in human chronic glomerulonephritis. The high activity of beta-Gase with a coincidental decrease of AMPS in the glomeruli was observed both in experimental and human chronic glomerulonephritis. The herniation type GBM thickening in the rat was coincidental with the enzyme localization with the disappearance of AMPS from foot processes of epithelial cells overlaying the lesion. The results might suggest the key role of beta-Gase in the deformation of GBM in chronic glomerulonephritis in general.


Influence of Different Irradiation Protocols on Vascularization and Bone Formation Parameters in Rat Femora.
Aim of the present study was the establishment of an efficient and reproducible model for irradiation of rat femora as a model for impaired osteogenesis and angiogenesis. Four different irradiation protocols were compared: single irradiation of the left femur with 20 Gy and explantation after 4 or 8 weeks (group A, B) and three irradiation fractions at 3-4 days intervals with 10 Gy and explantation after 4 or 8 weeks (group C, D). The contralateral, unirradiated femur served as control. Evaluation included histology, microcomputertomography (μCT), and real-time polymerase chain reaction. Histology showed a pronounced increase of vacuoles in bone marrow after irradiation, especially after 4 weeks (group A and C), demonstrating bone marrow edema and fatty degeneration. Irradiation provoked a decrease of total cell numbers in cortical bone and of hypoxia-inducible factor 1 alpha (HIF1α)-positive cells in bone marrow. The expression of several markers (osteocalcin [OCN], runt-related transcription factor 2 [RUNX2], transforming growth factor beta 1 [TGFβ1], tumor necrosis factor alpha [TNFα], vascular endothelial growth factor A [VEGFA], and HIF1α) was decreased in group A after irradiation. This might suggest a decreased metabolism after irradiation. A significant decrease in small-sized vessels was seen in μCT evaluation in group A and D. Single irradiation with 20 Gy had the most severe and reproducible impact on osteogenesis and angiogenesis after 4 weeks while being well tolerated by all animals, thus making it an excellent model for evaluation of bone healing and vascularization in irradiated tissue.


The effect of a flexible thoracolumbar brace on neuromuscular scoliosis: A prospective observational study.
Neuromuscular scoliosis is a common deformity seen in patients with neuromuscular diseases. Although rigid thoracolumbosacral orthosis is the most frequently used brace, it has low compliance rates and can lead to complications including skin ulcers. Thus, alternative methods for treating neuromuscular scoliosis are needed. The purpose of this study is to evaluate the clinical effects of a novel flexible brace to prevent the progression of neuromuscular scoliosis.This study is a prospective observational study. Twenty-three patients with neuromuscular scoliosis were enrolled in the study. Among patients diagnosed with neuromuscular disease, spine radiographs were checked for a neuromuscular scoliosis diagnosis. The participants were treated with a novel flexible brace for 6 months. The control group (n = 46) was selected using propensity score matching method from a clinical data warehouse. The Cobb angle was measured and compared between the study and control groups.In the study group, the average Cobb's angle significantly decreased from 47.22 ± 18.9° to 31.8 ± 20.0 when wearing the flexible brace (P < .001). Thus, the correction rate was 36.9%. The annual progression rate was significantly lower in the study group than in the control group (P < .05).The flexible brace showed a significant correction rate of scoliosis in patients with severe neuromuscular diseases. The flexible brace is an alternative treatment modality for patients with neuromuscular scoliosis. Daily application of the flexible brace during the growing period can reduce the degree of fixed deformity in the long term.


Leprosy in Southern Brazil: a twenty-year epidemiological profile.
This study evaluated leprosy rates in Rio Grande do Sul, an area with a historically low prevalence. However, recent studies are lacking. Data extracted from a National Database were analyzed for clinical features and compared to 1980s data. Tendency was assessed via stationarity analysis. Between 1990 and 2011, 4,770 cases were reported (0.21/10,000 inhabitants; 95% CI = 0.19-0.24). Detection was slightly higher among males, 1.9% cases were among children and most multibacillary (74.7%) at diagnosis. Leprosy is controlled in RS, but most cases are multibacillary. Early identification is important to avoid disabilities due to late diagnosis.


Timing of resection of liver metastases synchronous to colorectal tumor: proposal of prognosis-based decisional model.
Timing of hepatectomy for synchronous metastases of colorectal cancer is still debated. The aim of this retrospective study was to analyze prognostic factors after synchronous and delayed liver resections to define selection criteria for choosing timing of hepatectomy. The study was performed on 127 patients with synchronous metastases undergoing radical hepatectomy. We divided patients according to the timing of hepatectomy: 70 synchronous (group A) and 57 delayed (group B). Overall survival was similar between the two groups (5-year survival 30.8% vs. 32.0% A vs. B, P = .406). The multivariate analysis evidenced four independent prognostic factors in group A: male sex (P = .04), T4 (P = .0035), more than three metastases (P = .0001), and metastatic infiltration of nearby structures (P < .0001). There were no statistically significant prognostic factors in group B. Patients with more than three metastases had a significantly worse survival in group A than in group B (3-year survival, 15.0% vs. 34.3%, P = .007); similarly, borderline significant difference was encountered in patients with T4 primary tumor (3-year survival, 16.7% vs. 60%, P = .064) Patients with liver metastases synchronous with colorectal cancer with T4 primary tumor, metastasis infiltration of neighboring structures, and especially with more than three metastases should receive neoadjuvant chemotherapy before liver resection.


Comparison of tropisetron and chlorpromazine combinations in the control of nausea and vomiting of patients with advanced cancer.
The single-institution, prospective, randomized trial was performed to evaluate the efficacy of tropisetron and chlorpromazine in the management of nausea and vomiting of terminal cancer patients. Patients had no recent chemotherapy or radiotherapy, and emesis was not due to bowel obstruction, electrolytic or metabolic disturbances, drug intake, or intracranial disease. One hundred and sixty patients randomly received either (a) chlorpromazine (CLO) (50 mg/day) plus dexamethasone (DEX) (2 mg/day), (b) chlorpromazine (25 mg/day) plus tropisetron (TRO) (5 mg/day), (c) chlorpromazine (25 mg/day plus tropisetron (5 mg/day) plus dexamethasone (2 mg/day), or (d) tropisetron (TRO) (5 mg/day). Patients were monitored from day 1 to day 15. No nausea or vomiting was defined as "total" control. On day 15, total vomiting control was achieved in 33.3% of the patients receiving CLO + DEX, 84.6% of the patients receiving CLO + TRO, 92.5% of the patients receiving CLO + TRO + DEX, and 78.9% of the patients receiving TRO. Total control of nausea was achieved in 18.0% of the patients receiving CLO + DEX, 74.4% of the patients receiving (CLO + TRO), 85.0% of the patients receiving CLO + TRO + DEX, and 65.8% of the patients receiving TRO. Tropisetron-containing combinations produced significant control of nausea and vomiting from the third day onward. All antiemetic drugs were well tolerated. These data suggest that tropisetron-containing combinations or tropisetron as a single agent are much more effective in the control of emesis in patients with advanced cancer than the conventional antiemetic combination of chlorpromazine plus dexamethasone. Tropisetron is well tolerated and may be the best choice for controlling persistent nausea and vomiting in terminal cancer patients.


Multicenter COMPACT study of COMplications in patients with sickle cell disease and utilization of iron chelation therapy.
Over the past few decades, lifespans of sickle cell disease (SCD) patients have increased; hence, they encounter multiple complications. Early detection, appropriate comprehensive care, and treatment may prevent or delay onset of complications. We collected longitudinal data on sickle cell disease (SCD) complication rates and associated resource utilization relative to blood transfusion patterns and iron chelation therapy (ICT) use in patients aged ≥16 years to address a gap in the literature. Medical records of 254 SCD patients ≥16 years were retrospectively reviewed at three US tertiary care centers. We classified patients into cohorts based on cumulative units of blood transfused and ICT history: <15 units, no ICT (Cohort 1 [C1]), ≥15 units, no ICT (Cohort 2 [C2]), and ≥15 units with ICT (Cohort 3 [C3]). We report SCD complication rates per patient per year; cohort comparisons use rate ratios (RRs). Cohorts had 69 (C1), 91 (C2), and 94 (C3) patients. Pain led to most hospitalizations (76%) and emergency department (ED) (82%) visits. Among transfused patients (C2+C3), those receiving ICT were less likely to experience SCD complications than those who did not (RR [95% CI] C2 vs. C3: 1.33 [1.25-1.42]). Similar trends (RR [95% CI]) were observed in ED visits and hospitalizations associated with SCD complications (C2 vs. C3, ED: 1.94 [1.70-2.21]; hospitalizations: 1.61 [1.45-1.78]), but not in outpatient visits. Although the most commonly reported SCD complication among all patients was pain, patients who received ICT were less likely to experience pain and other complications than those who did not. These results highlight the need for increased patient and provider education on the importance of comprehensive disease management.


Two doses of MMR vaccine--sufficient to eradicate measles, mumps and rubella?
A review has been done of the available literature on measles, mumps, rubella and vaccines against these diseases. So far, 17 studies on the same virus strains as those in M-M-R II have been published. The rate of seroconversion is practically 100% for rubella, generally more than 90% for measles and between 40 and 100% for mumps. Immediate side effects of vaccination are mild in infants and negligible in schoolchildren. However, the follow-up periods are short. In the only 10-year follow-up published, 14 subjects remained at the end of the period, and the vaccine studied differed from M-M-R II. Large, well-documented studies of MMR vaccination in unselected populations are rare. It must be of crucial importance that the immunity situation is followed up continuously for both vaccinated and non-vaccinated individuals when a mass vaccination programme has been introduced as there will be a risk of outbreaks of diseases mostly among young adults.


Scaffolding the coronary arteries: intracoronary stenting.
Stenting is a new method for treating coronary artery stenosis. This article presents an overview of the rationale for the implantation of stents, the various types of stents available, and roles the home care nurse assumes in caring for these patients.


Assessing the assessors: The feasibility and validity of clinicians as a source for personality disorder research.
The use of knowledgeable informants is a particularly valuable tool for the diagnosis and assessment of personality disorder (PD). This review details the use of one particular type of informant-practicing clinicians-in PD research. We detail a wide variety of studies that have employed clinicians as an assessment source, including those focused on interrater agreement, comparative validity with other methods, cognitive factors of diagnosis, and opinion surveys. We demonstrate limitations, such as potential biases and limited convergent validity, which caution against the assumption that clinicians' ratings should be considered a gold-standard. Nonetheless, we also highlight the potential value of research that focuses on clinicians due to its external validity to real-world practice settings. Finally, we outline several issues to consider when sampling clinicians, such as participation rate and sample size, and call for future research that collects ratings from clinicians using systematic, well-validated measures. (PsycINFO Database Record


Combinatorial regulation of a signal-dependent activator by phosphorylation and acetylation.
In the fasted state, increases in catecholamine signaling promote adipocyte function via the protein kinase A-mediated phosphorylation of cyclic AMP response element binding protein (CREB). CREB activity is further up-regulated in obesity, despite reductions in catecholamine signaling, where it contributes to the development of insulin resistance. Here we show that obesity promotes the CREB binding protein (CBP)-mediated acetylation of CREB at Lys136 in adipose. Under lean conditions, CREB acetylation was low due to an association with the energy-sensing NAD(+)-dependent deacetylase SirT1; amounts of acetylated CREB were increased in obesity, when SirT1 undergoes proteolytic degradation. Whereas CREB phosphorylation stimulated an association with the KIX domain of CBP, Lys136 acetylation triggered an interaction with the CBP bromodomain (BRD) that augmented recruitment of this coactivator to the promoter. Indeed, coincident Ser133 phosphorylation and Lys136 acetylation of CREB stimulated the formation of a ternary complex with the KIX and BRD domains of CBP by NMR analysis. As disruption of the CREB:BRD complex with a CBP-specific BRD inhibitor blocked effects of CREB acetylation on target gene expression, our results demonstrate how changes in nutrient status modulate cellular gene expression in response to hormonal signals.


Use of the Optimality Index-United States in perinatal clinical research: a validation study.
The objective of this study was to assess the validity and observed effect size of a new instrument, the Optimality Index-United States (OI-US), for use in perinatal clinical research. Using a large, hospital-based, midwifery service clinical database that included complete obstetric data for 3425 women, we examined discriminant validity and the effects of two different scoring methods used with the OI-US. Discriminant validity was confirmed by comparing OI scores for women who remained low risk and did not require physician involvement in their care (OI score mean = 84%; standard deviation [SD] = 8%) compared to those whose condition changed to require physician involvement in their care (mean = 71%; SD = 10%; P < .001). Two methods of scoring the OI-US were compared, finding no significant difference and suggesting that the types of data available and the research question can drive this decision. Finally, effect size was calculated by two methods: Cohen's d (-1.4) and the effect size correlation (r = -0.548), the latter of which corresponds to a d of -1.3, both resulting in a similarly large effect size estimation. The OI-US is a new instrument that shows promise for use in perinatal clinical research, particularly when assessing more subtle clinical differences in outcomes between study groups.


Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its major metabolites in squirrel monkeys at plasma concentrations of MDMA that develop after typical psychoactive doses.
At certain doses, the psychoactive drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") destroys brain serotonin axon terminals. By causing increases in plasma MDMA concentrations that exceed those predicted by the increase in dose, nonlinear pharmacokinetics has the potential to narrow the range between safe and neurotoxic doses of MDMA. The present study sought to determine whether the pharmacokinetics of MDMA in nonhuman primates are nonlinear and, if they are, to identify plasma concentrations of MDMA at which nonlinear accumulation of MDMA occurs. Four different oral doses of MDMA were tested in the same six squirrel monkeys in random order. At each dose, pharmacokinetic parameters for MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 3,4-methylenedioxyamphetamine were determined. Doses were selected to be equivalent to 0.4, 0.8, 1.6, and 2.8 mg/kg doses in humans. The maximal concentration (C(max)) and area under the curve (AUC) of MDMA increased nonlinearly with dose, whereas the C(max) and AUC of the metabolites HHMA and HMMA remained relatively constant. Nonlinear MDMA pharmacokinetics occurred at plasma MDMA concentrations of 100 to 300 ng/ml and above. The half-life (T(1/2)) of MDMA and its metabolites also increased with dose. These results firmly establish nonlinear pharmacokinetics for MDMA in squirrel monkeys and indicate that nonlinear MDMA accumulation occurs at plasma MDMA concentrations that develop in humans taking typical doses. By raising MDMA concentrations and prolonging its action, nonlinear pharmacokinetics and T(1/2) prolongation, respectively, may influence the likelihood and severity of MDMA toxicities (including brain serotonin neurotoxicity).


Prenatal testing: Does reproductive autonomy succeed in dispelling eugenic concerns?
Traditionally, two main rationales for the provision of prenatal testing and screening are identified: the expansion of women's reproductive choices and the reduction of the burden of disease on society. With the number of prenatal tests available and the increasing potential for their widespread use, it is necessary to examine whether the reproductive autonomy model remains useful in upholding the autonomy of pregnant women or whether it allows public health considerations and even eugenic aims to be smuggled in under the smokescreen of autonomy. In this article I argue that if we are serious about upholding women's autonomy in the context of prenatal testing, what is needed is a model based on a more robust conception of reproductive autonomy, such as the one defended by Josephine Johnston and Rachel Zacharias as 'reproductive autonomy worth having'. While Johnston and Zacharias put forward a basic outline of this conception, I apply it to the specific case of prenatal testing and show how it responds to objections levelled against the reproductive autonomy model. I argue that adopting this kind of conception is necessary to avoid fundamental challenges to women's autonomy when it comes to prenatal screening and testing.


The influence of microtiter plates from different suppliers on lymphocyte proliferation.
Microtiter plates have been popularly used for lymphocyte culture, but the influence of culture plates from different sources has not been investigated. In this study, the degree of mitogen-induced cell proliferation was investigated using six different brands of flat-bottomed plates. Lymphocytes from twelve normal donors were cultured for 96 hours with several mitogens including PHA, Con A and PWM. Spontaneous cell proliferation was slow and it did not differ significantly among the different plates. However, mitogen-induced cell proliferation showed a wide variation among the six types of plates used. The importance of selecting certain kinds of plates for specific purposes is emphasized.


The use of stereotactic radiosurgery in the management of meningiomas.
This is a systematic review of a consecutive series of 309 meningiomas treated with gamma knife stereotactic radiosurgery between 1994 and 2000. There was an extreme selection bias towards lesions unfavourable for surgery, determined by the patients referred for treatment: 70% of tumours involved the skull base, 47% specifically the cavernous sinus: 15% of patients had multiple meningiomatosis or type 2 neurofibromatosis. Tumour histology was the main determinant of growth control (p < 0.001), the 5-year actuarial control rates being 87% for typical meningiomas, 49% for atypical tumours and 0% for malignant lesions. Complications from radiosurgery were rare, occurring in 3% of tumours, and were most frequently trigeminal and eye movement disturbances treating cavernous sinus meningiomas. Given the problems inherent in managing these tumours, radiosurgery is a valuable strategy and adjuvant treatment for these meningiomas.


Review: The international consensus classification of Focal Cortical Dysplasia - a critical update 2018.
The Diagnostic Methods commission of the International League against Epilepsy (ILAE) released a first international consensus classification of Focal Cortical Dysplasia (FCD) in 2011. Since that time, this FCD classification has been widely used in clinical diagnosis and research (more than 740 papers cited in Pubmed between 1/1/2012 and 7/1/2017). Herein, we review the new data that will inform and revise the FCD classification. Many recent papers described molecular-genetic characteristics in FCD type II including multiple mutations in the mTOR pathway. In addition, the electro-clinico-imaging phenotype and surgical outcomes of FCD type II (in particular type IIb) were further defined and validated. These results pave the way for the design of an integrated clinico-pathological and genetic classification system, as recently recommended by the WHO for the classification of malignant brain tumours. On the other hand, little new information was acquired on FCD types I and III. Focal cortical dysplasia type I subtypes are still lacking a comprehensive description of clinical phenotypes, reproducible imaging characteristics, and specific molecular/genetic biomarkers. Associated FCD III subtypes also became rare in published literature. Despite temporal lobe epilepsy being the most common focal epilepsy in adults, we have not identified neurophysiological, imaging, histopathological and/or genetic biomarkers to reliably classify FCD III with or without hippocampal sclerosis. In respect of pathogenesis, FCD adjacent to a non-developmental, postnatally acquired lesion is difficult to explain and perhaps does not exist. This update may help foster shared efforts towards a better understanding of FCD, potential future updates of classification and novel targeted treatments.


Distribution of sasX, pvl, and qacA/B genes in epidemic methicillin-resistant Staphylococcus aureus strains isolated from East China.
Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. Various virulence and antiseptic-resistant factors increase the pathogenicity of MRSA strains and allow for increased infection rates. The purpose of this study was to investigate the prevalence and distribution of virulence-associated and antiseptic-resistant genes from epidemic MRSA strains isolated from East China. A newly designed multiplex PCR assay was used to assess whether the virulence-associated genes sasX and pvl and the chlorhexidine tolerance gene qacA/B were present in 189 clinical isolates of MRSA. Multilocus sequence typing (MLST) and Staphylococcal protein A (spa) typing of these isolates were also performed. The frequency of these genes in isolates with epidemic sequence types (STs) was investigated. Twenty STs and 36 spa types with five epidemic clones (ST5-t311, ST59-t437, ST5-t002, ST239-t030, and ST239-t037) were identified. The prevalence of sasX, pvl, and qacA/B in all isolates was 5.8%, 10.1%, and 20.1%, respectively. The prevalences of these genes in isolates with ST5, ST59, ST239, and other ST genetic backgrounds were all significantly different (P<0.001). Isolates that had the highest frequency of sasX, pvl, or qacA/B were ST239 (33.3%), ST59 (28.9%), and ST5 (34.1%), respectively. The gene distribution pattern from all of the isolates showed that sasX-pvl-qacA/B+, sasX-pvl+qacA/B-, and sasX+pvl-qacA/B- were closely associated with epidemic clones ST5-t311, ST59-t437, and ST239-t037, respectively. There are significant differences in the prevalence of virulence-associated and antiseptic-resistant genes in epidemic MRSA strains. Using this information, more effective control and prevention strategies for nosocomial MRSA infections can be developed.


Importance of TRF1 for functional telomere structure.
Telomeres are comprised of telomeric DNA sequences and associated binding molecules. Their structure functions to protect the ends of linear chromosomes and ensure chromosomal stability. One of the mammalian telomere-binding factors, TRF1, localizes telomeres by binding to double-stranded telomeric DNA arrays. Because the overexpression of wild-type and dominant-negative TRF1 induces progressive telomere shortening and elongation in human cells, respectively, a proposed major role of TRF1 is that of a negative regulator of telomere length. Here we report another crucial function of TRF1 in telomeres. In conditional mouse TRF1 null mutant embryonic stem cells, TRF1 deletion induced growth defect and chromosomal instability. Although no clear telomere shortening or elongation was observed in short term cultured TRF1-deficient cells, abnormal telomere signals were observed, and TRF1-interacting telomere-binding factor, TIN2, lost telomeric association. Furthermore, another double-stranded telomeric DNA-binding factor, TRF2, also showed decreased telomeric association. Importantly, end-to-end fusions with detectable telomere signals at fusion points accumulated in TRF1-deficient cells. These results strongly suggest that TRF1 interacts with other telomere-binding molecules and integrates into the functional telomere structure.


Sexual activity and knowledge of safe sex reported by HIV-infected persons receiving home care.
Sexual activity and knowledge of safe sex were assessed for 57 human immunodeficiency virus (HIV)-infected persons on admission to home care. More than one third of the individuals providing information were sexually active; 72% of the sexually active persons reported that they practiced safe sex. Definitions of safe sex were inconsistent, particularly regarding safety of oral sex. Needs for counseling on safe sex of HIV-infected persons receiving home care practices were clearly evident.


Pharmacokinetics of atazanavir/ritonavir once daily and lopinavir/ritonavir twice and once daily over 72 h following drug cessation.
We investigated the pharmacokinetics of atazanavir/ritonavir once daily and lopinavir/ritonavir twice and once daily over 72 h following drug intake cessation. This was an open-label, three-session, pharmacokinetic trial. Healthy volunteers received atazanavir/ritonavir 300/100 mg once daily and lopinavir/ritonavir 400/100 mg twice daily and 800/200 mg once daily separately for 10 days. Pharmacokinetic profiles were assessed for each phase on day 10 over 72 h. Pharmacokinetic parameters were determined over 12 or 24 h and to the last measurable concentration by non-compartmental methods. Sixteen participants completed the study. Geometric mean terminal elimination half-life to 72 h of atazanavir was 8.35 h and not different from the 0-24 h half-life (9.91 h). Terminal elimination halflife of lopinavir was 2.33 h (twice daily) and 2.44 h (once daily). These values were lower compared with the half-life over the respective dosing intervals (7.15 and 4.88 h for 0-12 and 0-24 h, respectively). No participant on atazanavir had concentrations below the minimum effective concentration (MEC) of 150 ng/ml at 24 h. In total, 44% of the participants on lopinavir once daily had concentrations below the MEC of 1,000 ng/ml at 24 h. At 16 h and 20 h, 13% and 63% of participants were below target for twice daily lopinavir, respectively. At 36 h, all participants on lopinavir and 31% on atazanavir were below target. Ritonavir area under the plasma concentration-time curve was 30% lower and 26% higher when dosed at 100 mg or 200 mg with lopinavir versus atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Whereas the decline in lopinavir concentrations occured rapidly as the boosting effect of ritonavir diminished, the rate of decline of atazanavir remained constant to 72 h.


Studying the protein-protein interactions in the postsynaptic density by means of immunoabsorption and chemical crosslinking.
Postsynaptic densities (PSDs), isolated from porcine cerebral cortices, are large disk-shaped aggregates consisting of hundreds of different proteins. To study the protein-protein interactions in such complex supramolecules, we developed a procedure to break up the PSD's overall structure, while preserving some interactions between individual proteins. Using the resulting PSD sample and an indirect immunoabsorption procedure, PSD-95 was isolated along with the α- and β-subunits of calcium calmodulin-dependent protein kinase II (CaMKIIα and CaMKIIβ), α-tubulin, β-tubulin, and Chapsyn110. Similarly, CaMKIIα was isolated along with CaMKIIβ, α-tubulin, β-tubulin, and small amounts of PSD-95. The proteins isolated from PSDs treated with a cleavable bifunctional crosslinking reagent were further subjected to diagonal gel electrophoresis analysis, and the results indicated that CaMKIIα resides next to α-tubulin in the PSD. Overall, the results obtained here suggest that within the PSD, large aggregates of CaMKIIα, CaMKIIβ, α-tubulin, and β-tubulin may occur that indirectly associate with PSD-95 and Chapsyn110. Such a protein organization would allow interactions with F-actin in the cytoplasm and with proteins, such as N-methyl-D-aspartate receptors, which reside on the postsynaptic membrane. Furthermore, it would facilitate binding to proteins such as the various microtubule-associated proteins that reside in the core region of the PSD.


Mood Instability Is a Precursor of Relationship and Marital Difficulties: Results from Prospective Data from the British Health and Lifestyle Surveys.
The DSM system implies that affective instability is caused by reactivity to interpersonal events. We used the British Health and Lifestyle Survey that surveyed community residents in 1984 and again in 1991 to study competing hypotheses: that mood instability (MI) leads to interpersonal difficulties or vice versa. We analyzed data from 5,352 persons who participated in both waves of the survey. Factor analysis of the Eysenck Personality Inventory neuroticism scale was used to derive a 4-item scale for MI. We used depression measures that were previously derived by factor analyzing the General Health Questionnaire. We tested the competing hypotheses by regressing variables at follow-up against baseline variables. The results showed that MI in 1984 clearly predicted the development of interpersonal problems in 1991. After adjusting for depression, depression becomes the main predictor of spousal difficulties, but MI remains a predictor of interpersonal difficulties with family and friends. Attempts to investigate the reverse hypothesis were ambiguous. The clinical implication is that when MI and interpersonal problems are reported, the MI should be treated first, or at least concurrently.


Telemedicine in Orthopaedic Surgery: Challenges and Opportunities.
Improvements in technology and a push toward value-based health care have poised the telemedicine industry for growth; however, despite the benefits of virtual care, widespread implementation had not occurred until the coronavirus 2019 (COVID-19) pandemic. Powerful barriers have hindered the widespread adoption of telemedicine, including lack of awareness, implementation costs, inefficiencies introduced, difficulty performing physical examinations, overall lack of perceived benefit of virtual care, negative financial implications, concern for medicolegal liability, and regulatory restrictions. Some of these challenges have been addressed with temporary state and federal mandates in response to the COVID-19 pandemic; however, continued investment in systems and technology as well as refinement of regulations around telemedicine are needed to sustain widespread adoption by patients and providers.


Yeast prt1 mutations alter heat-shock gene expression through transcript fragmentation.
The inhibition of translation initiation by modification or mutation of initiation factors can lead to disproportionate effects on gene expression. Here we report disproportionate decreases in gene expression in cells with mutated Prt1 activity. The PRT1 gene product of the budding yeast Saccharomyces cerevisiae is necessary for translation initiation and is thought to be a component of initiation factor 3. At a restrictive temperature the prt1-1 mutation, in addition to decreasing global protein synthesis, caused disproportionate decreases of the synthesis of the Ssa1 and Ssa2 members of the hsp70 heat-shock gene family, and of the Hsp82 and Hsc82 heat-shock proteins. Quantification of pulse-labelled, immunoprecipitated lacZ fusion proteins showed that synthesis of each of these proteins was disproportionately decreased in prt1-1 mutant cells. Although the mRNAs of affected genes were shown to be polysomal in mutant cells, they were fragmented and of decreased abundance, as indicated by transcript analysis and in vitro translation. Thus the mRNAs of these hsp genes become degraded under the conditions of limited translation initiation that are imposed by the prt1-1 mutation. This untimely mRNA degradation accounts for the disproportionate decreases in polypeptide synthesis in prt1 mutant cells. We propose that sequences at the translation initiation site of SSA2 mRNA bring about the observed mRNA fragmentation.


Effects of subgingival chlorhexidine irrigation on peri-implant maintenance.
To evaluate the effect of irrigation with 0.06% chlorhexidine (PerioGard) (CHX) using a powered oral irrigator (Water Pik) with a special subgingival irrigating tip (Pik Pocket Subgingival Tip) compared to rinsing with 0.12% chlorhexidine gluconate once daily. Following a prophylaxis, patients were randomly assigned to an irrigation or a rinse group. The following clinical parameters were measured at baseline and at the 3-month end of the study: Modified Gingival Index (MGI), Plaque Index (PI), Bleeding Index (BI), and Calculus Index (CI). Also, a Stain Index (SI) was measured at 3 months. Patients irrigating with diluted CHX showed a statistically significant reduction (P < 0.05) from their baseline in the MGI, PI, BI, and CI scores at 3 months. In the rinse group both MGI and BI showed statistically significant reduction from their baseline (P < 0.05) at 3 months. The rinse group showed a nonsignificant (P > 0.05) increase from baseline in CI and a nonsignificant decrease in PI. Intergroup comparisons showed that CHX irrigation produced statistically significantly greater reductions than CHX rinsing in the PI, MGI, and SI. The irrigation group also showed a greater reduction in BI and CI than the rinsing group but these differences were not statistically significant (P = 0.12). The results of this study suggest that use of diluted 0.06% CHX when used in a powered irrigator may be a valuable adjunct to oral health in patients with implants.


A Mobile App to Improve Self-Management of Individuals With Type 2 Diabetes: Qualitative Realist Evaluation.
The increasing use of Web-based solutions for health prevention and promotion presents opportunities to improve self-management and adherence to guideline-based therapy for individuals with type 2 diabetes (T2DM). Despite promising preliminary evidence, many users stop using Web-based solutions due to the burden of data entry, hidden costs, loss of interest, and a lack of comprehensive features. Evaluations tend to focus on effectiveness or impact and fail to evaluate the nuanced variables that may interact to contribute to outcome success (or failure). This study aimed to evaluate a Web-based solution for improving self-management in T2DM to identify key combinations of contextual variables and mechanisms of action that explain for whom the solution worked best and in what circumstances. A qualitative realist evaluation was conducted with one-on-one, semistructured telephonic interviews completed at baseline, and again toward the end of the intervention period (3 months). Topics included participants' experiences of using the Web-based solution, barriers and facilitators of self-management, and barriers and facilitators to effective use. Transcripts were analyzed using thematic analysis strategies, after which the key themes were used to develop statements of the relationships between the key contextual factors, mechanisms of action, and impact on the primary outcome (glycated hemoglobin, HbA1c). Twenty-six interviews (14 baseline, 12 follow-up) were completed with 16 participants with T2DM, and the following 3 key groups emerged: the easiest fit, the best fit, and those who failed to activate. Self-efficacy and willingness to engage with the solution facilitated improvement in HbA1c, whereas competing priorities and psychosocial issues created barriers to engagement. Individuals with high baseline self-efficacy who were motivated, took ownership for their actions, and prioritized diabetes management were early and eager adopters of the app and recorded improvements in HbA1c over the intervention period. Individuals with moderate baseline self-efficacy and no competing priorities, who identified gaps in understanding of how their actions influence their health, were slow to adopt use but recorded the greatest improvements in HbA1c. The final group had low baseline self-efficacy and identified a range of psychosocial issues and competing priorities. These participants were uncertain of the benefits of using a Web-based solution to support self-management, ultimately resulting in minimal engagement and no improvement in HbA1c. Self-efficacy, competing priorities, previous behavior change, and beliefs about Web-based solutions interact to determine engagement and impact on the clinical outcomes. Considering the balance of these patient characteristics is likely to help health care providers identify individuals who are apt to benefit from a Web-based solution to support self-management of T2DM. Web-based solutions could be modified to incorporate the existing screening measures to identify individuals who are at risk of suboptimal adherence to inform the provision of additional support(s) as needed.


Home-literacy environments and language development in toddlers with Down syndrome.
The present study aimed to (1) characterize the home-literacy environments (HLE) of toddlers with Down syndrome (DS) and (2) examine if richness of the HLE, child engagement during shared storybook reading activities, quality of a caregiver-child shared storybook reading activity, and exposure to language in the home environment predicted child receptive vocabulary concurrently (Time 1) and 6 months later (Time 2). Participants were toddlers with DS (n = 13 at Time 1, 11-29 months of age; n = 10 at Time 2) and their mothers. Mothers completed a Home Literacy Environment Questionnaire at Time 1, which was used to characterize the HLE and to calculate two composite variables: richness of the HLE and child engagement in shared storybook reading. Also at Time 1, the home language environment was measured using adult word count from the LENA Recorder DLP©. The LENA was also used to audio-record and capture the quality of a caregiver-child storybook reading task in the child's home using the book Dear Zoo. At both time points, mothers completed the MacArthur-Bates Communicative Development Inventories, and the number of words understood variable was used to measure receptive vocabulary. Results indicated that toddlers with DS experience rich HLEs and interactive shared storybook reading encounters with their mothers. A multiple linear regression revealed that child engagement and the home language environment correlated with both toddlers' concurrent and later receptive vocabularies, while the richness of the HLE and the shared storybook reading task emerged as moderate predictors of receptive vocabulary 6 months later.


A practical aryl unit for azlactone dynamic kinetic resolution: orthogonally protected products and a ligation-inspired coupling process.
The first strategy for bringing about enantioselective azlactone dynamic kinetic resolution to generate orthogonally protected amino acids has been developed. In the presence of a C2-symmetric squaramide-based catalyst, benzyl alcohol reacts with novel yet readily prepared tetrachloroisopropoxycarbonyl-substituted azlactones to generate trapped phthalimide products of significant synthetic interest with excellent enantiocontrol. These materials are masked amino acids which are demonstrably orthogonally protected: cleavage of the phthalimide can be achieved in the presence of the ester and vice versa. This process could be utilized to bring about a highly stereoselective ligation-type coupling of protected serines (at stoichiometric loadings) with racemic azlactones derived from both natural and abiotic amino acids. After deprotection, a subsequent base-mediated O→N acyl transfer occurs to form a dipeptide.


[Effects of piperazine ferulate on connective tissue growth factor and extracellular matrix in TGF-beta1 induced mesangial cells].
To observe the effects of piperazine ferulate (PF) on synthesis of extracellular matrix and expression of connective tissue growth factor (CTGF) in transforming growth factor-betal (TGF-beta1) induced rat glomerular mesangial cells (GMC), and to investigate its mechanism on the prevention of glomerulosclerosis. Rat HBZY-1 GMCs were cultured in vitro and divided into 5 groups: Normal control group, TGF-beta1-stimulated group, TGF-beta1 plus 50, 100, 200 ng/mL PF group. The level of CTGF protein expression induced by TGF-beta1 was measured by immunocytochemistry, The mRNA expression of CTGF was evaluated by quantitative real time fluroscent polymerase chain reaction. The expressions of fibronectin and collagen I were analyzed by enzyme linked immunosorbent assay (ELISA). With the stimulation of TGF-beta1, the expression of of CTGF protein and mRNA, as well as fibronectin and collagen I were markly increased (P < 0.05), which then were decreased by the treatment of PF. (P < 0.05). PF can partly inhibit synthesis of the extracellular matrix and CTGF. PF may take part in the prevention of glomerulosclerosis through the inhibition of CTGF expression.


Stereoselective Construction of Acyclic β,β-Disubstituted Enesulfinamides via Conjugate Addition of Organocuprates to α-Substituted α,β-Unsaturated N-Sulfinyl Ketimines.
In the presence of boron trifluoride, conjugate addition of organocuprates to α-substituted α,β-unsaturated N-tert-butanesulfinyl ketimines provides facile access to acyclic β,β-disubstituted enesulfinamides with high ratios of geometric isomers. Diverse and challenging to synthesize, multisubstituted aza-enolates bearing two electronically and sterically similar β-substituents, which are important precursors for asymmetric construction of the less accessible acyclic quaternary or tetrasubstituted stereocenters at the α-position of ketimines, can be efficiently prepared in good yields with high stereocontrol.


Solitary lumbar osteochondroma presenting with foot-drop: a case report.
Although osteochondroma is the most common benign bone tumor, the lumbar spine is anuncommon localization for solitary osteochondroma. Solitary lumbar osteochondromas rarely affect the neurological structures, because most of the lesions grow out of the spinal canal. We report a 48-year-old patient suffering from right foot-drop due to acute compression of right L4 nerve root by a lesion expanding into the spinal canal, originating from the right inferior articular facet of the third lumbar vertebrae. The symptoms improved after surgical removal of the lesion and histopathological examination of the lesion confirmed the diagnosis of osteochondroma. To the best of our knowledge, this is a unique case report in the literature.


Depletion of TIAR impairs embryogenesis via inhibiting zygote genome transcribe.
T cell intracellular antigen 1 related protein (TIAR), an RNA-binding protein (RBP), regulates pre-messenger RNA (pre-mRNA) alternative splicing, has been suggested to affect the maturation of primordial germ cells and early mouse embryo development. However, the underlying mechanism remains elusive. In this study, we revealed that TIAR was primarily located in the nucleus at the 2-cell stage embryo, accompanied by highly active transcription. Using immunofluorescence staining and western blotting, we first described the localization and expression level of TIAR during the whole period of oocyte matured and embryogenesis. Knocked down of TIAR could significantly inhibit transcribed and blocked the early mouse embryo development. Combined with RNAP II inhibitor and pre-RNA splicing inhibitor treatment, we further supposed that TIAR might affect transcription at 2-cell via regulating pre-mRNA splicing, and then regulate early mouse embryo development. Collectively, our results provided a novel and potential understanding of TIAR in embryogenesis, suggesting TIAR is required for transcription and embryonic development.


Systematic evaluation of apoptotic pathway gene polymorphisms and lung cancer risk.
We adopted a two-stage study design to screen 927 single nucleotide polymorphisms (SNPs) located in 73 apoptotic-pathway genes in a case-control study and then performed a fast-track validation of the significant SNPs in a replication population to identify sequence variations in the apoptotic pathway modulating lung cancer risk. Fifty-five SNPs showed significant associations in the discovery population comprised of 661 lung cancer cases and 959 controls. Six of these SNPs located in three genes (Bcl-2, CASP9 and ANKS1B) were validated in a replication population with 1154 cases and 1373 controls. Additive model was the best-fitting model for five SNPs (rs1462129 and rs255102 of Bcl-2, rs6685648 of CASP9 and rs1549102, rs11110099 of ANKS1B) and recessive model was the best fit for one SNP (rs10745877 of ANKS1B). In the analysis of joint effects with subjects carrying no unfavorable genotypes as the reference group, those carrying one, two, and three or more unfavorable genotypes had an odds ratio (OR) of 2.22 [95% confidence interval (CI) = 1.08-4.57, P = 0.03], 2.70 (95% CI = 1.33-5.49; P = 0.006) and 4.13 (95% CI = 2.00-8.57; P = 0.0001), respectively (P for trend = 6.05E-06). The joint effect of unfavorable genotypes was also validated in the replication population. The SNPs identified are located in or near key genes known to play important roles in apoptosis regulation, supporting the strong biological relevance of our findings. Future studies are needed to identify the causal SNPs and elucidate the underlying molecular mechanisms.