[The Ormond's disease: an intriguing obstructive nephrouropathy].
Idiopathic retroperitoneal fibrosis also known as Ormonds disease is a rare disorder characterized by the development of fibrotic tissue in the retroperitoneum involving the abdominal aorta and iliac arteries, ureters and the inferior vena cava. The aberrant tissue may compress ureters leading to obstructive nephrouropathy and renal failure, which are the most common clinical manifestations of this condition. The nephrologist is often consulted to make differential diagnosis for acute renal failure and obstructive uropathy. Ultrasounds may suggest the disease and the diagnosis will be confirmed by computed tomography or magnetic resonance, but biopsy is still the diagnostic gold standard. The aim of therapy is to remove the ureteral obstruction and prevent the progression and recurrence of the disease. After urine drainage by ureteral stents, medical long-term therapy is usually started whereas the open surgery is reserved as a last resort in selected patients. The pathophysiology of Ormond's disease is uncertain. For years the disease was considered reactive to local and /or systemic triggers with primarily involvement of abdominal aorta but at present is classified in the more broad spectrum of IgG4- Related- Disease, clinical pathological entity on autoimmune basis that can affect almost all of the body districts. This last concept has shed light on the understanding of the pathogenesis and opened new therapeutic perspectives with the use of biological agents. In this paper, on the basis of our paradigmatic clinical case of bilateral obstructive nephrouropathy associated with acute renal failure and examining the recent literature, we describe the clinical and therapeutic approach to Ormonds disease.


Cimetidine in elective Caesarean section. Effect on gastric acidity.
Aspiration pneumonitis, Mendelson's syndrome, continues to be an important cause of maternal morbidity and mortality in obstetric anaesthesia, despite widespread adoption of the practice of routine administration of alkalis. Histamine H2 receptor blocking drugs have been shown to reduce gastric secretion in non-obstetric patients. Cimetidine was given intravenously to fasting patients before elective Caesarean section. In all 10 patients who received cimetidine 200 mg intravenously at 60--80 minutes before anaesthesia, the pH of gastric contents at the time of induction was above 2.5. When the interval between administration of the drug and induction of anaesthesia was only 30--40 minutes (six patients) or was over 90 minutes (20 patients) then the pH was raised to above this value in only two-thirds of patients. By contrast eight of 10 untreated patients were found to have a gastric pH of less than 2.5. No adverse effects of cimetidine were seen in mothers or infants.


Testing whether macroevolution follows microevolution: are colour differences among swans (Cygnus) attributable to variation at the MCIR locus?
The MC1R (melanocortin-1 receptor) locus underlies intraspecific variation in melanin-based dark plumage coloration in several unrelated birds with plumage polymorphisms. There is far less evidence for functional variants of MC1R being involved in interspecific variation, in which spurious genotype-phenotype associations arising through population history are a far greater problem than in intraspecific studies. We investigated the relationship between MC1R variation and plumage coloration in swans (Cygnus), which show extreme variation in melanic plumage phenotypes among species (white to black). The two species with melanic plumage, C. atratus and C. melanocoryphus (black and black-necked swans respectively), both have amino acid changes at important functional sites in MC1R that are consistent with increased MC1R activity and melanism. Reconstruction of MC1R evolution over a newly generated independent molecular phylogeny of Cygnus and related genera shows that these putative melanizing mutations were independently derived in the two melanic lineages. However, interpretation is complicated by the fact that one of the outgroup genera, Coscoroba, also has a putative melanizing mutation at MC1R that has arisen independently but has nearly pure white plumage. Epistasis at other loci seems the most likely explanation for this discrepancy. Unexpectedly, the phylogeny shows that the genus Cygnus may not be monophyletic, with C. melanocoryphus placed as a sister group to true geese (Anser), but further data will be needed to confirm this. Our study highlights the difficulty of extrapolating from intraspecific studies to understand the genetic basis of interspecific adaptive phenotypic evolution, even with a gene whose structure-function relationships are as well understood as MC1R as confounding variation make clear genotype/phenotype associations difficult at the macroevolutionary scale. However, the identification of substitutions in the black and black-necked swan that are known to be associated with melanic phenotypes, suggests Cygnus may be another example where there appears to be convergent evolution at MC1R. This study therefore provides a novel example where previously described intraspecific genotype/phenotype associations occur at the macroevolutionary level.


Collagen-calcium phosphate cement scaffolds seeded with umbilical cord stem cells for bone tissue engineering.
Human umbilical cord mesenchymal stem cells (hUCMSCs) avoid the invasive procedure required to harvest bone marrow MSCs. The addition of collagen fibers into self-setting calcium phosphate cement (CPC) may increase the scaffold strength, and enhance cell attachment and differentiation. The objectives of this study were to develop a novel class of collagen-CPC composite scaffolds, and to investigate hUCMSC attachment, proliferation, and osteogenic differentiation on collagen-CPC scaffolds for the first time. Collagen fibers in CPC improved the load-bearing capability. Flow cytometry showed that the hUCMSCs expressed cell surface markers characteristic of MSCs, and were negative for hematopoietic and endothelial cell markers. hUCMSCs proliferated rapidly in all CPC composite scaffolds, with cell number increasing by sevenfold in 8 days. Cellular function was enhanced with collagen fibers in CPC scaffolds. Cell density increased from (645±60) cells/mm(2) on CPC with 0% collagen, to (1056±65) cells/mm(2) on CPC with 8% collagen (p<0.05). The actin stress fibers inside the hUCMSCs were stained, and the fluorescence intensity was doubled when the collagen in CPC was increased by 0% to 8%. RT-PCR showed that hUCMSCs on CPC with collagen had higher osteogenic expression than those on CPC without collagen. Alizarin Red S staining revealed a great increase in mineralization by hUCMSCs on CPC with collagen than that without collagen. In conclusion, hUCMSCs showed excellent proliferation, differentiation, and synthesis of bone minerals in collagen-CPC composite scaffolds for the first time. The novel hUCMSC-seeded collagen-CPC construct with superior cell function and load-bearing capability is promising to enhance bone regeneration in a wide range of orthopedic and craniofacial applications.


Mirror reversal and visual rotation are learned and consolidated via separate mechanisms: recalibrating or learning de novo?
Motor learning tasks are often classified into adaptation tasks, which involve the recalibration of an existing control policy (the mapping that determines both feedforward and feedback commands), and skill-learning tasks, requiring the acquisition of new control policies. We show here that this distinction also applies to two different visuomotor transformations during reaching in humans: Mirror-reversal (left-right reversal over a mid-sagittal axis) of visual feedback versus rotation of visual feedback around the movement origin. During mirror-reversal learning, correct movement initiation (feedforward commands) and online corrections (feedback responses) were only generated at longer latencies. The earliest responses were directed into a nonmirrored direction, even after two training sessions. In contrast, for visual rotation learning, no dependency of directional error on reaction time emerged, and fast feedback responses to visual displacements of the cursor were immediately adapted. These results suggest that the motor system acquires a new control policy for mirror reversal, which initially requires extra processing time, while it recalibrates an existing control policy for visual rotations, exploiting established fast computational processes. Importantly, memory for visual rotation decayed between sessions, whereas memory for mirror reversals showed offline gains, leading to better performance at the beginning of the second session than in the end of the first. With shifts in time-accuracy tradeoff and offline gains, mirror-reversal learning shares common features with other skill-learning tasks. We suggest that different neuronal mechanisms underlie the recalibration of an existing versus acquisition of a new control policy and that offline gains between sessions are a characteristic of latter.


Using signal-to-cutoff ratios of HIV screening assay to predict HIV infection.
The sensitivity of HIV screening assays often leads to a high rate of false-positive results, requiring retests and confirmatory tests. This study aimed to analyze the capability of signal-to-cutoff (S/CO) ratios of HIV screening assay to predict HIV infection. A retrospective study on the HIV screening-positive population was performed at Zhongshan Hospital, Xiamen University, the correlation between HIV screening assay S/CO ratios and HIV infection was assessed, and plotted Receiver Operating Characteristic (ROC) curves were generated to establish the optimal cutoff value for predicting HIV infection. Out of 396,679 patients, 836 were confirmed to be HIV-infected, with an HIV prevalence of 0.21%. The median S/CO ratios in HIV infection were significantly higher than that in non-HIV infection (296.9 vs. 2.41, P < 0.001). The rate of confirmed HIV infection was increased with higher S/CO ratios in the screening assay. The ROC curve based on the HIV screening assay S/CO ratio achieved a sensitivity of 93.78% and a specificity of 93.12% with an optimal cutoff value of 14.09. The area under the ROC curve was 0.9612. Further analysis of the ROC curve indicated that the S/CO ratio thresholds yielding positive predictive values of 99%, 99.5%, and 100% for HIV infection were 26.25, 285.7, and 354.5, respectively. Using HIV screening assay S/CO ratio to predict HIV infection can largely reduce necessitating retests and confirmatory tests. Incorporating the S/CO ratio into HIV testing algorithms can have significant implications for medical and public health practices.


High F-Content Perfluoropolyether-Based Nanoparticles for Targeted Detection of Breast Cancer by 19F Magnetic Resonance and Optical Imaging.
Two important challenges in the field of 19F magnetic resonance imaging (MRI) are the maintenance of high fluorine content without compromising imaging performance, and effective targeting of small particles to diseased tissue. To address these challenges, we have developed a series of perfluoropolyether (PFPE)-based hyperbranched (HBPFPE) nanoparticles with attached peptide aptamer as targeting ligands for specific in vivo detection of breast cancer with high 19F MRI sensitivity. A detailed comparison of the HBPFPE nanoparticles (NPs) with the previously reported trifluoroethyl acrylate (TFEA)-based polymers demonstrates that the mobility of fluorinated segments of the HBPFPE nanoparticles is significantly enhanced (19F T2 > 80 ms vs 31 ms), resulting in superior MR imaging sensitivity. Selective targeting was confirmed by auto- and pair correlation analysis of fluorescence microscopy data, in vitro immunofluorescence, in vivo 19F MRI, ex vivo fluorescence and 19F NMR. The results highlight the high efficiency of aptamers for targeting and the excellent sensitivity of the PFPE moieties for 19F MRI. Of relevance to in vivo applications, the PFPE-based polymers exhibit much faster clearance from the body than the previously introduced perfluorocarbon emulsions ( t1/2 ∼ 20 h vs up to months). Moreover, the aptamer-conjugated NPs show significantly higher tumor-penetration, demonstrating the potential of these imaging agents for therapeutic applications. This report of the synthesis of polymeric aptamer-conjugated PFPE-based 19F MRI CAs with high fluorine content (∼10 wt %) demonstrates that these NPs are exciting candidates for detecting diseases with high imaging sensitivity.


Headache and Its Approach in Today's NeuroIntensive Care Unit.
Headache is a very common symptom in the neurointensive care unit (neuroICU). While headache in the neuroICU can be caused by worsening of a pre-existing primary headache disorder, most are secondary to another condition. Additionally, headache can be the presenting symptom of a number of conditions requiring prompt recognition and treatment including subarachnoid hemorrhage, ischemic and hemorrhagic stroke, central nervous system infection, pituitary apoplexy, and cerebral vasoconstriction. The neuroICU also has a unique postoperative population in which postcraniectomy and postcraniotomy headache, postintravascular intervention headache, hyperperfusion syndrome, ventriculitis, medication overuse or withdrawal headache, and hypercapnia may be encountered. Management varies dramatically depending on the etiology of the headache. Overreliance on opiate analgesics may produce significant adverse effects and lengthen ICU stays. However, nonnarcotic medications are increasingly being recognized as helpful in reducing the pain among various postsurgical and headache patients. Taken together, a multimodal approach targeting the underlying pathology and choosing appropriate systemic and local analgesic medications may be the best way to manage headache in critically ill patients.


Lifespan of gamma/delta T cells.
Information on the turnover and lifespan of murine gamma/delta cells was obtained by administering the DNA precursor, bromodeoxyuridine (BrdU), in the drinking water and staining lymphoid cells for BrdU incorporation. For TCR-gamma/delta (Vgamma2) transgenic mice, nearly all gamma/delta thymocytes became BrdU+ within 2 d and were released rapidly into the peripheral lymphoid tissues. These recent thymic emigrants (RTEs) underwent phenotypic maturation in the periphery for several days, but most of these cells died within 4 wk. In adult thymectomized (ATx) transgenic mice, only a small proportion of gamma/delta cells survived as long-lived cells; most of these cells had a slow turnover and retained a naive phenotype. As in transgenic mice, the majority of RTEs generated in normal mice (C57BL/6) appeared to have a restricted lifespan as naive cells. However, in marked contrast to TCR transgenic mice, most of the gamma/delta cells surviving in ATx normal mice had a rapid turnover and displayed an activated/memory phenotype, implying a chronic response to environmental antigens. Hence, in normal mice many gamma/delta RTEs did not die but switched to memory cells.


Selective EP2 and Cox-2 inhibition suppresses cell migration by reversing epithelial-to-mesenchymal transition and Cox-2 overexpression and E-cadherin downregulation are implicated in neck metastasis of hypopharyngeal cancer.
Cyclooxygenase-2 (Cox-2) has been shown to promote cancer initiation and progression through pleiotropic functions including induction of epithelial-to-mesenchymal transition (EMT) via its predominant product prostaglandin E2 that binds to the cognate receptor EP2. Hence, pharmacological inhibition at the level of EP2 is assumed to be a more selective alternative with less risk to Cox-2 inhibition. However, little is known regarding the anti-cancer effect of an EP2 antagonist on the malignant properties of cancers including hypopharyngeal squamous cell carcinoma (HPSCC). The present study found that both the Cox-2 inhibitor celecoxib and the EP2 antagonist PF-04418948 upregulated CDH-1 expression, restored membranous localization of E-cadherin, and reduced vimentin expression, by downregulating the transcriptional repressors of E-cadherin in BICR6 and FaDu cells. Such Cox-2 or EP2 inhibition-induced EMT reversal led to repressed migration ability in both cells. Immunohistochemical analysis of surgical HPSCC specimens demonstrated an inverse relationship in expression between Cox-2 and E-cadherin both in the context of statistics (P = 0.028) and of reciprocal immunolocalization in situ. Multivariate logistic regression revealed that overexpression of Cox-2 (P < 0.001) and downregulation of E-cadherin (P = 0.016) were both independently predictive of neck metastasis. These results suggest that suppression of cell migration ability via reversing EMT by inhibiting the Cox-2/EP2 signaling may contribute to preventing the development and progression of lymphatic metastasis. Collectively, targeting Cox-2/EP2, especially using EP2 antagonist, can be a promising therapeutic strategy by exerting an anti-metastatic effect via EMT reversal for improving the treatment outcomes of patients with various cancers including HPSCC.


Cigarettes and Water Pipe Smoking Prevalence, Knowledge, and Attitudes Among the Palestinian Physicians in the West Bank.
Tobacco use is one of the major public health threats nowadays. Smoking can affect everybody organ. Health professionals should play pivotal roles in tobacco control, and their attitude and practice toward tobacco use can affect the health of the community. Therefore, assessing and influencing physicians' attitudes and practice are one of the alternatives to reduce smoking prevalence in the community. We aimed to assess smoking status among medical physicians in the West Bank, Palestine to better understand their future role in any smoking cessation program. A cross-sectional study using the World Health Organization Global Health Professional Survey questionnaire was conducted. A non-probability sampling technique from a total of 6500 physicians registered in the Palestinian Medical Association in the West Bank was used. The age ranged from 23 to 78 years with a mean of 34.92 years. Current smokers represented 60.3%. Of them, 18.5% were both cigarettes and water pipe smokers. The main reason that motivates the physician to smoke is experimenting (57.9%). Also stress (31.8%) and social pressure (26.4%) were of the most common causes to start smoking. Almost all medical doctors have a high level of knowledge regarding the health consequences of smoking. Smokers were less likely to hold favorable attitudes toward smoking cessation and support tobacco control policy compared with non-smokers (P-values < .05). Physicians' degree of awareness and knowledge about their role in aiding patients to quit smoking are high. However, smokers' attitudes toward smoking cessation programs need to be improved to increase their involvement in such interventional programs.


Factors associated with the risk of gingival disease in patients with rheumatoid arthritis.
Gingival disase and rheumatoid arthritis (RA) are linked at both the epidemiologic and pathogenesis levels. In this study, we aimed to identify environmental factors associated with RA and gingival disease and to investigate factors that protect the gingival tissue in RA patients. This retrospective study analyzed 754 RA patients with gingival disease selected from the NHANES database who completed the mobile examination center interview/examination between 1999 and 2004. Data collected included demographics, lifestyle, dietary intake, and biomarkers. The study included 173 RA patients with gingival disease. Multivariate logistic regression analysis showed that the odds of gingival disease were significantly increased with male gender. However, the odds of gingival disease was significantly decreased with increased vitamin C intake (OR = 0.996, p = 0.041), and higher serum vitamin D levels (OR = 0.979, p = 0.011). Given the significant association between the prevalence of gingival disease and RA, identification of risk factors of gingival disease will be useful as a screening tool in national health surveys to improve the management of periodontal disease in patients with RA.


[T-lymphocyte precursor count in the thymus and the development of lymphomas in AKR/J-strain mice].
The content of T-cell precursors is increased in the thymus of AKR/J mice. Thymus also contains cells carrying markers of pre-T (SC-1-antigen) and T-(Thy-1-antigen) cells simultaneously. The level of SC-1+-cells grows just before the lymphoma appearance in the AKR/J thymus. Lymphoma cells express both SC-1 and Thy-1-antigens, i. e. they are a transitional form between pre-T- and T-cells. It is suggested that accumulation of SC-1+-Thy-1+ cells in the mouse thymus is an essential condition for the development of virus-induced lymphomas.


Cold-stored whole blood: A better method of trauma resuscitation?
Cold-stored whole blood (CWB) provides a balance of red blood cells, plasma, and platelets in less anticoagulant volume than standard blood component therapy (BCT). We hypothesize that patients receiving CWB along with BCT have improved survival compared with patients receiving only BCT. We performed a dual-center case-match study of trauma patients who received CWB and BCT at two urban, Level-I Trauma Centers. Criteria to receive CWB included boys 16 years of older, women older than 50 years, SBP less than 90 mm Hg, and identifiable source of hemorrhage. We performed a 2:1 propensity match against any trauma patient who received 1 unit or greater of packed red cells during their initial trauma bay resuscitation. Endpoints included trauma bay mortality, 30-day mortality, laboratory values at 4 hours and 24 hours, and overall blood product utilization. Comparisons were made with Wilcoxon-ranked sum and Fisher's exact test, p less than 0.05 was significant. Between both institutions, a total of 107 patients received CWB during the study period with 91 being matched to 182 BCT patients for analysis. Hemodynamic parameters of the patients in both groups at the time of presentation were similar. The CWB patients had higher mean hemoglobin (10 ± 2 g/dL vs. 11 ± 2 g/dL; p < 0.001) and hematocrit (29.2 ± 6.1% vs. 32.1 ± 5.8%; p < 0.001) at 24 hours. Importantly, trauma bay mortality was less in CWB patients (8.8% vs. 2.2%;p = 0.039). Thirty-day mortality was not different in CWB patients, and there were no differences in the total amount of blood products transfused at the 4-hour and 24-hour periods. Cold-stored whole blood offers the benefit of a balanced resuscitation with improved trauma bay survival and higher mean hemoglobin at 24 hours. A larger, prospective study is needed to determine whether it has a longer-term survival benefit for severely injured patients. Therapeutic, level III.


Clinical applications of free medial tibial flap with posterior tibial artery for head and neck reconstruction after tumor resection.
Tumor resection causes damage in the head and neck which creates problems in swallowing, chewing, articulation, and vision, all of which seriously affect patients' quality of life. In this work, we evaluated the application of a free medial tibial flap in reconstruction of head and neck defects after tumor resection. We discussed the anatomy, surgical technique, and the advantages and disadvantages of the flap. We found several benefits for the flap, such as, it is especially effective for the defects that require thin-layer epithelium to cover or the separated soft tissue defect; a two-team approach can be used because the donor site is far away from the head and neck; and the flap is easy to integrate because of the subcutaneous fat layer of the free medial tibial flap is thin and the flap is soft. Thus, the medial tibial flap could replace the forearm flap for certain applications.


Lipidomic analysis of Toxoplasma gondii reveals unusual polar lipids.
Analysis of the polar lipids of Toxoplasma gondii by electrospray ionization tandem mass spectrometry provides a detailed picture of the lipid molecular species of this parasitic protozoan. Most notably, T. gondii contains a relatively high level, estimated to about 2% of the total polar lipid, of ceramide phosphoethanolamine. The ceramide phosphoethanolamine has a fatty amide profile with only 16- and 18-carbon species. Compared with the host fibroblasts in which it was grown, T. gondii also has higher levels of phosphatidylcholine but lower levels of sphingomyelin and phosphatidylserine. Analysis at the molecular species level indicated that T. gondii has greater amounts of shorter-chain fatty acid in its polar lipid molecular species than the host fibroblasts. Shorter-chain fatty acids with a combined total of 30 or fewer acyl carbons make up 21% of Toxoplasma's, but only 3% of the host's, diacyl phosphatidylcholine. Furthermore, diacyl phosphatidylcholine with two saturated acyl chains with 12, 14, or 16 carbons make up over 11% of parasite phosphatidylcholine but less than 3% of the host phosphatidylcholine molecular species. The distinctive T. gondii tachyzoite lipid profile may be particularly suited to the function of parasitic membranes and the interaction of the parasite with the host cell and the host's immune system. Combined with T. gondii genomic data, these lipidomic data will assist in elucidation of metabolic pathways for lipid biosynthesis in this important human pathogen.


Predictors of compliance with community-directed ivermectin treatment in Uganda: quantitative results.
In order to identify the factors influencing compliance with mass ivermectin treatment for onchocerciasis control, a cross-sectional study was carried out in Bushenyi District, Uganda. Data were collected by interviewing 839 individuals who were randomly selected from 30 clusters where onchocerciasis is endemic. Information was collected on compliance with ivermectin treatment, socio-demographic characteristics, perception of personal susceptibility to onchocerciasis, knowledge about cause/transmission of onchocerciasis, knowledge of signs and symptoms of onchocerciasis, treatment of onchocerciasis, benefits and dangers of taking ivermectin, organization of distribution of ivermectin, work and selections of community drug distributors (CDDs), social influence and support to take ivermectin and on barriers and supports towards compliance with ivermectin treatment. The major factors favouring compliance were: perceiving CDDs as doing their work well, believing that measuring height is the best way to determine one's dose of ivermectin, having social support from one's family, saying that ivermectin treatment costs nothing, perceiving personal risk of onchocerciasis, believing that ivermectin prevents onchocerciasis and perceiving radios as supporting treatment with ivermectin. The strongest predictor of compliance with ivermectin treatment is perceiving CDDs as doing their work well with adjusted odds ratios of 5.54 (95% CI: 3.19-9.62). In order to improve compliance with ivermectin treatment, CDDs need to be well-facilitated and ivermectin distribution should be free. Health education is necessary so that people perceive themselves to be at risk of onchocerciasis and to understand the rationale of using height for dose determination. The health education should target the family and use radios.


Atomic arrangements at metal surfaces.
The termination of a solid induces changes in the locations of the outermost atoms of the solid. The changes can be minor or as dramatic as the rearrangement of the atoms into a different crystallographic group. Surface crystallography studies have determined that all surfaces are altered by forces induced at the solid-vacuum interface. At the least, the outermost atomic layers are displaced away from positions that they would have had in the bulk environment. Results from experimental and theoretical investigations for the Al(110) surface are discussed to illustrate present understanding of the surface atomic displacements. Some effects that the truncation- induced forces have on the surfaces of binary metal alloys are also discussed.


Sex-specific differences and developmental programming for diseases in later life.
Epidemiological data indicate that developmental programming of various non-communicable diseases (NCDs) occurs as a consequence of altered maternal metabolic and physiological status due to a number of environmental insults during pregnancy. Sex-specific differences have also been reported in most NCDs. Evidence suggests that beginning from conception, the maternal and neonatal metabolic environment, including hormones, contributes to sex-specific placental development. The placenta then regulates the sex-specific differences in NCDs via the epigenetic mechanisms that are further affected by hormones. Male and female embryos have been reported to exhibit sex-specific transcriptional regulation, and it is suggested that their development can be considered as separate processes beginning from conception. This review summarises various animal and human studies examining sex-specific differences in NCDs due to differential placental epigenetic developmental programming. An overview of possible mechanisms underlying this is also discussed. Further, the review describes sex-specific changes in the structure and function of the placenta in pregnancies complicated by fetal growth restriction, pre-eclampsia and preterm birth. Thus, because sex-specific differences are associated with fetal outcome and survival, future studies need to take into consideration the sex of the fetus while explaining the concept of the developmental origins of health and disease.


Specific inhibitor of Wnt/beta-catenin pathway can alter behavioral responses in young rats with malformed cortices.
The Wnt/beta-catenin pathway plays a crucial role in regulating cellular processes and has been implicated in neural activity-dependent learning as well as anxiety. However, the role of this pathway in young children with abnormal cortical development is unknown. Cortical malformations at early development, behavioral abnormalities, and a susceptibility to seizures have been reported in rats prenatally exposed to methylazoxymethanol. In this study, we aimed to investigate whether we could improve the behavioral deficits in young rats with malformed cerebral cortices by modulation of the Wnt/beta-catenin pathway. We found a small molecule Wnt/beta-catenin inhibitor (CWP) that increased exploratory behavior in the open field test (P9, CWP 100 ug treatment, peripheral exploration, P = 0.011) and social behavior test (P12, CWP 250 ug treatment, distance traveled in center, P = 0.033) and decreased anxiety in fear conditioning. However, it did not reduce the susceptibility to seizures. After high dose (250 ug) CWP treatment at P12, phosphocreatine and glutathione (GSH) were decreased in the cortex at P15 (P = 0.021). These findings suggest that the role of Wnt/beta-catenin signaling in exploratory behavior and anxiety during early development warrants further investigation.


Effects of Shexiangbaoxin pills on the expression of cardiac α₁- and β-adrenergic receptor subtypes in rat hearts with heart failure induced by myocardial infarction.
Chronic heart failure (CHF) had been characterized as an activated sympathetic system leading to the alteration of adrenergic receptor (AR) levels in the heart. Thus far, not much research has been done with regard to traditional Chinese medical treatment for CHF. We investigated the effect of Shexiangbaoxin pills (SXBXP) on the function of the heart and the expression of a(1)-AR and b-AR subtypes in the messenger RNA (mRNA) levels and protein levels of non-infarction left ventricular tissue from rats with CHF induced by myocardial infarction. Models of CHF were established by left anterior descending coronary artery ligature. Fifty-four Wistar rats were randomly divided into five groups: normal control group (group A), sham operation group (group B), CHF model group (group C), positive medicine control group (group D), and small-dose SXBXP group (group E) and large-dose SXBXP group (group F), deployed intragastrically. Cardiac function was examined by echocardiography before and after therapy; mRNA expressed levels were measured by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) for b(1)-AR, b(2)-AR, b(3)-AR, a(1A)-AR, a(1B)-AR, and a(1D)-AR; protein levels were measured by Western blotting analysis for b(1)-AR, b(2)-AR, a(1A)-AR, a(1B)-AR, and a(1D)-AR in non-infarction left ventricular tissue. There was no significant difference in the left ventricular ejection fraction (LVEF) between groups A and B. Compared to group B, LVEF of groups C, D, E, and F were significantly decreased (P < 0.01) before therapy. After therapy, compared to group C, LVEF of group F was significantly improved (P < 0.05). Compared to group B, b(1)-AR and a(1B)-AR expressed levels were markedly decreased (P < 0.05), a(1A)-AR and b(3)-AR were significantly increased (P < 0.01) in group C, and in both mRNA and protein expressed levels b(2)-AR had no significant difference between groups B and C (P > 0.05). a(1D)-AR mRNA levels were unchanged in each group (P > 0.05), but a(1D)-AR protein level was significantly decreased in group C (P < 0.05). After treatment, compared to group C, mRNA levels of b(1)-AR and a(1B)-AR were significantly increased (P < 0.05 and P < 0.01), and a(1A)-AR was markedly decreased in groups D, E, and F (P < 0.05). b(3)-AR level significantly declined in both groups D and F (P < 0.01), but b(2)-AR and a(1D)-AR expressed levels remained unchanged in each group (P > 0.05). Protein levels, compared to group C, b(1)-AR was significantly increased (P < 0.01, P < 0.05, and P < 0.01) and a(1A)-AR was markedly decreased in groups D, E, and F (P < 0.05, P < 0.01, and P < 0.01). b(2)-AR expressed level was significantly increased in group F (P < 0.05). a(1B)-AR expressed level was significantly increased in both groups E and F (P < 0.05), and a(1D)-AR was remarkably increased in both groups D and F (P < 0.05). After SXBXP treatment, LVEF was increased and cardiac function was significantly ameliorated in rats with CHF. The therapeutic effect of SXBXP may be related to better blood supply for myocardium and up-regulation of b(1)-AR and a(1B)-AR, and down-regulation of a(1A)-AR and b(3)-AR. The results show that SXBXP can be used in treatment of CHF and the therapeutic effect of large-dose SXBXP is superior to small-dose SXBXP.


Particulate air pollution: possible relevance in asthma.
The relative importance of air pollution in the pathogenesis of bronchial asthma has been of interest for several decades. Numerous studies on the role of gaseous air pollution containing ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide have been published. Very little attention has been focused on the role of respirable particles in the causation of asthma. In this article we summarize some of our ongoing investigations into the sources and composition of airborne particles in the Los Angeles and Pasadena atmosphere, including the search for biologically active particles that may induce asthma attacks. If is found that the urban atmosphere contains not only combustion-derived particles from diesel engine exhaust and gasoline-powered motor vehicle exhaust, but also particles formed from biological starting materials including plant debris, cigarette smoke, wood smoke, and meat smoke as well as tire debris containing some natural rubber and paved road dust. Paved road dust is a very complex mixture of particles including garden soil, tire dust, plant fragments, redeposited atmospheric particles of all types, and pollen fragments presumably ground up by passing traffic. We have shown previously that latex allergen can be extracted from tire dust, from roadside dust, and from respirable air samples taken at Los Angeles and Long Beach. At present, work is underway to identify the larger range of allergens that may be contributed by the entrainment of paved road dust into the atmosphere. The possible importance of pollen fragments present in paved road dust in very small particle sizes is discussed as well as their potential relevance in asthma.


Genotyping by sequencing reveals contrasting patterns of population structure, ecologically mediated divergence, and long-distance dispersal in North American palms.
Comparative studies can provide powerful insights into processes that affect population divergence and thereby help to elucidate the mechanisms by which contemporary populations may respond to environmental change. Furthermore, approaches such as genotyping by sequencing (GBS) provide unprecedented power for resolving genetic differences among species and populations. We therefore used GBS to provide a genomewide perspective on the comparative population structure of two palm genera, Washingtonia and Brahea, on the Baja California peninsula, a region of high landscape and ecological complexity. First, we used phylogenetic analysis to address taxonomic uncertainties among five currently recognized species. We resolved three main clades, the first corresponding to W. robusta and W. filifera, the second to B. brandegeei and B. armata, and the third to B. edulis from Guadalupe Island. Focusing on the first two clades, we then delved deeper by investigating the underlying population structure. Striking differences were found, with GBS uncovering four distinct Washingtonia populations and identifying a suite of loci associated with temperature, consistent with ecologically mediated divergence. By contrast, individual mountain ranges could be resolved in Brahea and few loci were associated with environmental variables, implying a more prominent role of neutral divergence. Finally, evidence was found for long-distance dispersal events in Washingtonia but not Brahea, in line with knowledge of the dispersal mechanisms of these palms including the possibility of human-mediated dispersal. Overall, our study demonstrates the power of GBS together with a comparative approach to elucidate markedly different patterns of genomewide divergence mediated by multiple effectors.


Symmetry and asymmetry of the RING-RING dimer of Rad18.
The human ubiquitin-conjugating enzyme Rad6 (E2), with ubiquitin ligase enzyme Rad18 (RING E3), monoubiquitinates proliferating cell nuclear antigen at stalled replication forks in DNA translesion synthesis. Here, we determine the structure of the homodimeric Rad18 RING domains by X-ray crystallography and classify it to RING-RING dimers that dimerize through helices adjacent to the RING domains and through the canonical RING domains. Using NMR spectroscopy and site-directed mutagenesis, we demonstrate that the Rad6b binding site, for the Rad18 RING domain, strongly resembles that of other E2/E3 RING/U-box complexes. We show that the homodimeric Rad18 RING domain can recruit two Rad6b E2 enzymes, whereas the full-length Rad18 homodimer binds only to a single Rad6b molecule. Such asymmetry is a common feature of RING-RING heterodimers and has been observed for the CHIP U-box homodimer. We propose that asymmetry may be a common feature of dimeric RING E3 ligases.


[Chiasma frequencies in the meiocytes of anther diametrical sections in Capsicum species].
Investigations concerning chiasma frequencies in meiocytes of three anther zones (free end, middle, base) in the cultivated and wild species of Capsicum genus have been carried out. It is revealed that maximum indices of total chiasma frequency were observed in the anther free end in comparison with its middle part and base. The conclusion is drawn that regularities of distribution of recombination indices are the result of the anther anatomy structure.


Axial and appendicular pneumaticity in Archaeopteryx.
From the time of its discovery in 1860 to this day Archaeopteryx has been essential to our understanding of avian evolution. Despite the great diversity of plesiomorphic avialan (sensu Gauthier 1986) taxa discovered within the last decade, Archaeopteryx remains the most basal avialan taxon. A very unusual feature of extant birds is their lung structure, in which air diverticulae penetrate the bones. This has previously been reported in Archaeopteryx as well, in the cervical vertebrae of the Berlin specimen and in an anterior thoracal vertebra of the Eichstätt specimen. This indicates the presence of a cervical air sac. We show that the London specimen also has pneumatized anterior thoracal vertebrae, and, thus, that this feature was present in the most archaic avialans, as the London and Eichstätt specimens are different species. Furthermore, the pelvis of the London specimen shows clear signs of the presence of an abdominal air sac, indicating that at least two of the five air sacs present in modern birds were also present in Archaeopteryx. Evidence of pubic pneumaticity was also found in the same position in some extant ratites.


Oral hygiene awareness among female Saudi school children.
To evaluate the oral hygiene habits and utilization of professional dental health services by all the children in the primary schools, and to compare the differences in oral hygiene awareness (OHA) and dental health status of schoolchildren who are exposed to dental health education and those who are not. Participants included 400 Saudi children, randomly selected from the primary female schools in Al-Kharj, Kingdom of Saudi Arabia on April 2007. Two hundreds children (age 9-11) from the 25 schools, who were exposed to the dental health education program on April 2006, were randomly selected as the study group. Two hundred children (age 9-11) from the schools, which were not exposed to such program were also randomly selected as the control group. The required information about oral hygiene awareness was collected through an especially designed questionnaire. Tooth brushing for 2 times a day or after meals were more common among schoolchildren of study group, than schoolchildren of control group. A significant difference (p=0.00) was observed between study group and control group, with regard to never brush their teeth. There was no significant difference between study group and control group with respect to using dental floss, using mouthwash, and in relation to never visiting a dentist for check up. The main reason cited by study group, and by control group for visiting the dentist was that they had severe toothache. Both groups presently consume more sweetened soft drinks. A significant (p=0.00) higher frequency of good dental status was observed in the study group, as compared with that of the control group. The school which applied this program, showed improved OHA of children as compared with the control group. Systematic school-based oral health promotion programs are urgently needed in the Kingdom to target lifestyles and health needs of children.


Are there parallel processes in psychotherapy supervision? An empirical examination.
Parallel processes in supervision occur when (1) the therapist brings the interaction pattern that occurs between the therapist and client into supervision and enacts the same pattern but with the therapist trainee in the client's role, or (2) the trainee takes the interaction pattern in supervision back into the therapy session as the therapist, now enacting the supervisor's role. We examined these processes in the interactions of 17 therapy/supervision triads (i.e., supervisor, therapist/trainee, and client). Each session was rated for dominance and affiliation, and the similarity of these dimensions across equal status pairs (supervisor-therapist and trainee-client) was examined. It was hypothesized that if parallel process existed, there would be more similarity in dominance and affiliation between equal status pairs in contiguous sessions than would be true relative to general responses; the dominance and affiliation would be more closely matched than would be expected given general response tendencies. This was examined separately for each supervision triad using single-case randomization tests. Significant results were obtained for each dyad indicating the presence of parallel processes in each supervision triad. Additionally, the relation between parallel processes over the course of treatment and client outcome was examined using hierarchical Bayesian modeling. Results indicate that a positive client outcome was associated with increasing similarity of therapist behavior to the supervisor over time on both affiliation and dominance (increasing parallel process) and an inverted U pattern of high-low-high similarity of client behavior to trainee behavior over time. This study provides support for the existence of bidirectional parallel processes at the level of interpersonal interaction. Implications for therapist training and supervision are discussed.


Lunar true polar wander inferred from polar hydrogen.
The earliest dynamic and thermal history of the Moon is not well understood. The hydrogen content of deposits near the lunar poles may yield insight into this history, because these deposits (which are probably composed of water ice) survive only if they remain in permanent shadow. If the orientation of the Moon has changed, then the locations of the shadowed regions will also have changed. The polar hydrogen deposits have been mapped by orbiting neutron spectrometers, and their observed spatial distribution does not match the expected distribution of water ice inferred from present-day lunar temperatures. This finding is in contrast to the distribution of volatiles observed in similar thermal environments at Mercury's poles. Here we show that polar hydrogen preserves evidence that the spin axis of the Moon has shifted: the hydrogen deposits are antipodal and displaced equally from each pole along opposite longitudes. From the direction and magnitude of the inferred reorientation, and from analysis of the moments of inertia of the Moon, we hypothesize that this change in the spin axis, known as true polar wander, was caused by a low-density thermal anomaly beneath the Procellarum region. Radiogenic heating within this region resulted in the bulk of lunar mare volcanism and altered the density structure of the Moon, changing its moments of inertia. This resulted in true polar wander consistent with the observed remnant polar hydrogen. This thermal anomaly still exists and, in part, controls the current orientation of the Moon. The Procellarum region was most geologically active early in lunar history, which implies that polar wander initiated billions of years ago and that a large portion of the measured polar hydrogen is ancient, recording early delivery of water to the inner Solar System. Our hypothesis provides an explanation for the antipodal distribution of lunar polar hydrogen, and connects polar volatiles to the geologic and geophysical evolution of the Moon and the bombardment history of the early Solar System.


Effects of tri-iodothyronine on testicular interstitial cells and androgen secretory capacity of the prepubertal Rat.
The main objective of the study was to investigate the effects of hyperthyroidism on the rat testis interstitium during prepuberty, which is not well understood at present. Male Sprague Dawley rats were injected subcutaneously daily with saline (controls) or tri-iodothyronine (T(3), 50 microg/kg body weight; hyperthyroids) from postnatal Day 1. Rats were killed at Days 5, 7, 9, 12, 16, and 21. One testis of each rat was used to determine LH-stimulated (100 ng/ml) testicular androgen secretory capacity in vitro. The other testis was used either for morphometric studies (n = 5) or for immunolocalization of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) to identify steroidogenic cells (n = 3) and 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1) to differentially identify adult Leydig cells. Daily T(3) injections resulted in significant reductions in body and testis weights. Morphometric analysis revealed that lower testis weights in rats treated with T(3) were mainly the result of reductions of total volume of seminiferous cords/tubules. The number of interstitial mesenchymal cells (MCs) was lower (P < 0.05) in T(3) rats compared with age-matched controls. The number of fetal Leydig cells (FLCs) was not different between the two groups; however, FLC hypotrophy was detected in T(3) rats at Day 16 in contrast to Day 21 in control rats. In both groups, morphologically identifiable adult Leydig cells (ALCs) were observed at Day 12 and thereafter; however, the ALC number per testis in T(3) rats was twice as much as those of controls. Positive immunolabeling for 3beta-HSD was first detected in MC/progenitor cells on Day 9 in rats in the T(3) group (cells were still spindle-shaped) and on Day 12 in rats in the control group. Testicular testosterone production in vitro was lower (P < 0.05) in T(3) rats compared with controls at each age tested and further reductions (<0.05) were observed in T(3) rats at Days 16 and 21. Testicular androstenedione production was also lower (P < 0.05) in T(3) rats at Days 5 and 7, but increased (P < 0.05) thereafter, than in control rats. These findings support that there are more newly formed ALCs in T(3) testes than in those of controls. Moreover, these results demonstrate that hyperthyroidism stimulates premature hypotrophy of FLCs and early differentiation of increased numbers of MCs to ALCs in the prepubertal rat testis, further supporting the view that thyroid hormone has a regulatory role in initiating MC differentiation into ALCs in the prepubertal rat testis.


Multiphoton excitation of autofluorescence for microscopy of glioma tissue.
Intraoperative detection of residual tumor tissue in glioma surgery remains an important challenge because the extent of tumor removal is related to the prognosis of the disease. Multiphoton excited fluorescence tomography of living tissues provides high-resolution structural and photochemical imaging at a subcellular level. In this conceptual study, we have used multiphoton microscopy and fluorescence lifetime imaging (4D microscopy) to image cultured glioma cell lines, solid tumor, and invasive tumor cells in an experimental mouse glioma model and human glioma biopsy specimens. A laser imaging system containing a mode-locked 80 MHz titanium:sapphire laser with a tuning range of 710 to 920 nm, a scan unit, and a time correlated single photon counting board was used to generate autofluorescence intensity images and fluorescence lifetime images of cultured cell lines, experimental intracranial gliomas in mouse brain, and biopsies of human gliomas. Multiphoton microscopy of native tumor bearing brain provided structural images of the normal brain anatomy at a subcellular resolution. Solid tumor, the tumor-brain interface, and single invasive tumor cells could be visualized. Fluorescence lifetime imaging demonstrated significantly different decay of the fluorescent signal in tumor versus normal brain, allowing a clear definition of the tumor-brain interface based on this parameter. Distinct fluorescence lifetimes of endogenous fluorophores were found in different cellular compartments in cultured glioma cells. The analysis of the relationship between the laser excitation wavelength and the lifetime of excitable fluorophores demonstrated distinct profiles for cells of different histotypes. Multiphoton excited fluorescence of endogenous fluorophores allows structural imaging of tumor and central nervous system histo-architecture at a subcellular level. The analysis of the decay of the fluorescent signal within specific excitation volumes by fluorescent lifetime imaging discriminates glioma cells and normal brain, and the excitation/lifetime profiles may further allow differentiation of cellular histotypes. This technology provides a noninvasive optical tissue analysis that may potentially be applied to an intraoperative analysis of resection plains in tumor surgery.


Decision makers conceive of their choices as interventions.
Causal considerations must be relevant for those making decisions. Whether to bring an umbrella or leave it at home depends on the causal consequences of these options. However, most current decision theories do not address causal reasoning. Here, the authors propose a causal model theory of choice based on causal Bayes nets. The critical ideas are (a) that people decide using causal models of the decision situation and (b) that people conceive of their own choice as an intervention. Four corroborating experiments are reported. The first 2 experiments showed that participants chose on the basis of the causal structure underlying a choice scenario rather than the statistical relation among actions and outcomes. Experiments 3 and 4 showed that participants treated choices and interventions similarly. They also suggest that decision makers use causal models to derive inferences about expected outcomes. Boundary conditions on causal decision making and examples of faulty causal inferences in choice (e.g., self-deception) are discussed. (PsycINFO Database Record (c) 2009 APA, all rights reserved).


Adaptations in corticospinal excitability and inhibition are not spatially confined to the agonist muscle following strength training.
We used transcranial magnetic stimulation (TMS) to determine the corticospinal responses from an agonist and synergist muscle following strength training of the right elbow flexors. Motor-evoked potentials were recorded from the biceps brachii and flexor carpi radialis during a submaximal contraction from 20 individuals (10 women, 10 men, aged 18-35 years; training group; n = 10 and control group; n = 10) before and after 3 weeks of strength training at 80% of 1-repetition maximum (1-RM). To characterise the input-output properties of the corticospinal tract, stimulus-response curves for corticospinal excitability and inhibition of the right biceps brachii and flexor carpi radialis were constructed and assessed by examining the area under the recruitment curve (AURC). Strength training resulted in a 29% (P < 0.001) increase in 1-RM biceps brachii strength and this was accompanied by a 19% increase in isometric strength of the wrist flexors (P = 0.001). TMS revealed an increase in corticospinal excitability AURC and a decrease in silent period duration AURC for the biceps brachii and flexor carpi radialis following strength training (all P < 0.05). However, the changes in corticospinal function were not associated with increased muscle strength. These findings show that the corticospinal responses to strength training of a proximal upper limb muscle are not spatially restricted, but rather, results in a change in connectivity, among an agonist and a synergistic muscle relevant to force production.


Microscopic origin of the fast blue-green luminescence of chemically synthesized non-oxidized silicon quantum dots.
The microscopic origin of the bright nanosecond blue-green photoluminescence (PL), frequently reported for synthesized organically terminated Si quantum dots (Si-QDs), has not been fully resolved, hampering potential applications of this interesting material. Here a comprehensive study of the PL from alkyl-terminated Si-QDs of 2-3 nm size, prepared by wet chemical synthesis is reported. Results obtained on the ensemble and those from the single nano-object level are compared, and they provide conclusive evidence that efficient and tunable emission arises due to radiative recombination of electron-hole pairs confined in the Si-QDs. This understanding paves the way towards applications of chemical synthesis for the development of Si-QDs with tunable sizes and bandgaps.


Gambling in the Mist of Economic Crisis: Results From Three National Prevalence Studies From Iceland.
In October 2008 all three major banks in Iceland went bankrupt with serious consequences for Icelandic society. The national currency lost more than half of its value and there was a sharp increase in household debts and prices for domestic goods. Very little is known about the potential effects of economic recessions on gambling participation and problem gambling. This study reports on the results of three national prevalence studies conducted before and after the economic collapse in Iceland. The same methodology and measures were used in all three studies to ensure their comparability and the studies included in total N = 8.249 participants. There was an increase in past year gambling participation which extended across most gambling types. Only participation on EGMs declined significantly after the economic collapse. Past year prevalence of problematic gambling increased but further examination revealed that this increase is most probably explained by an increase in card and internet gambling among young men. Moreover, those who experienced financial difficulties due to the economic recession were 52% more likely to have bought a lottery ticket during the recession compared to those who were not affected financially. Overall, the results indicate that serious national economic recessions have differential effects on gambling behavior.


Pediatric heat-related illness: recommendations for prevention and management
Infants, children, and adolescents are at increased risk for heat-related illness due to their inability to remove themselves from dangerous environments. Evidence shows that morbidity and mortality from heat illness is related to the length of time core temperature is elevated, so rapid reduction and accurate serial measurements are crucial to prevention of organ system damage and death. The primary methods of patient cooling are conduction (ice-water immersion, cold packs) and convection (moisture and moving air). The choice of method used may depend on availability of equipment, but there is evidence that can guide optimal use of resources. This issue presents evidence-based recommendations and best practices in heat-illness resuscitation, including managing children who are obese, have special needs or take medications, and advocacy for prevention strategies.


Testing for neutrality in samples with sequencing errors.
Many data sets one could use for population genetics contain artifactual sites, i.e., sequencing errors. Here, we first explore the impact of such errors on several common summary statistics, assuming that sequencing errors are mostly singletons. We thus show that in the presence of those errors, estimators of can be strongly biased. We further show that even with a moderate number of sequencing errors, neutrality tests based on the frequency spectrum reject neutrality. This implies that analyses of data sets with such errors will systematically lead to wrong inferences of evolutionary scenarios. To avoid to these errors, we propose two new estimators of theta that ignore singletons as well as two new tests Y and Y* that can be used to test neutrality despite sequencing errors. All in all, we show that even though singletons are ignored, these new tests show some power to detect deviations from a standard neutral model. We therefore advise the use of these new tests to strengthen conclusions in suspicious data sets.


Generalizing evidence from randomized clinical trials to target populations: The ACTG 320 trial.
Properly planned and conducted randomized clinical trials remain susceptible to a lack of external validity. The authors illustrate a model-based method to standardize observed trial results to a specified target population using a seminal human immunodeficiency virus (HIV) treatment trial, and they provide Monte Carlo simulation evidence supporting the method. The example trial enrolled 1,156 HIV-infected adult men and women in the United States in 1996, randomly assigned 577 to a highly active antiretroviral therapy and 579 to a largely ineffective combination therapy, and followed participants for 52 weeks. The target population was US people infected with HIV in 2006, as estimated by the Centers for Disease Control and Prevention. Results from the trial apply, albeit muted by 12%, to the target population, under the assumption that the authors have measured and correctly modeled the determinants of selection that reflect heterogeneity in the treatment effect. In simulations with a heterogeneous treatment effect, a conventional intent-to-treat estimate was biased with poor confidence limit coverage, but the proposed estimate was largely unbiased with appropriate confidence limit coverage. The proposed method standardizes observed trial results to a specified target population and thereby provides information regarding the generalizability of trial results.


Perceived control and frailty: The role of affect and perceived health.
Mechanisms underlying prospective associations of perceived control with frailty and other health outcomes are not well understood. In the present study we used 3 waves of data from the Health and Retirement Study (N = 2,127) to test potential psychological and biological pathways linking perceived control with frailty over an 8-year period, and whether 4-year change in control predicts frailty independent of initial control. Lower odds of increasing frailty were associated with higher initial levels of perceived control (odds ratio [OR] = .74, p < .001, 95% confidence interval [CI] [.65, .83]) and a more positive change in perceived control (OR = .82, p = .006, 95% CI [.73, .92]), independent of the personality traits neuroticism and conscientiousness. In cross-lagged mediation models, the association of initial perceived control with frailty was partially mediated by positive affect, negative affect, and self-rated health, but not C-reactive protein or allostatic load. Associations of perceived control with positive and negative affect were bidirectional, with mediation in both directions. Initial frailty status was not related to 4-year change in perceived control. Perceived control may affect frailty risk through influences on affective states as well as perceived health. Findings also extend evidence that changes in perceived control may be prognostic of future health outcomes in older adults. (PsycINFO Database Record


Transition metal-catalyzed couplings of alkynes to 1,3-enynes: modern methods and synthetic applications.
The metal-catalyzed coupling of alkynes is a powerful method for the preparation of 1,3-enynes, compounds that are of broad interest in organic synthesis. Numerous strategies have been developed for the homo- and cross coupling of alkynes to enynes via transition metal catalysis. In such reactions, a major issue is the control of regio-, stereo-, and, where applicable, chemoselectivity. Herein, we highlight prominent methods for the selective synthesis of these valuable compounds. Further, we illustrate the utility of these processes through specific examples of their application in carbocycle, heterocycle, and natural product syntheses.


Pathways to violent behavior during first-episode psychosis: a report from the UK National EDEN Study.
Although many studies have explored the correlates of violence during first-episode psychosis (FEP), most have simply compared violent psychotic individuals with nonviolent psychotic individuals. Accumulating evidence suggests there may be subgroups within psychosis, differing in terms of developmental processes and proximal factors associated with violent behavior. To determine whether there are subgroups of psychotic individuals characterized by different developmental trajectories to violent behavior. The National EDEN (Evaluating the Development and Impact of Early Intervention Services in the West Midlands) Study longitudinal cohort assessed premorbid delinquency (premorbid adjustment adaptation subscale across childhood and adolescence), age at illness onset, duration of untreated psychosis, past drug use, positive symptoms, and violent behavior. Group trajectories of premorbid delinquency were estimated using latent class growth analysis, and associations with violent behavior were quantified. This study included 6 early intervention services in 5 geographical locations across England, with violent behavior information available for 670 first-episode psychosis cases. Violent behavior at 6 or 12 months following early intervention services entry. Four groups of premorbid delinquency were identified: stable low, adolescent-onset high to moderate, stable moderate, and stable high. Logistic regression analysis, with stable low delinquency as the reference group, demonstrated that moderate (odds ratio, 1.97; 95% CI, 1.12-3.46) and high (odds ratio, 3.53; 95% CI, 1.85-6.73) premorbid delinquency trajectories increased the risk for violent behavior during FEP. After controlling for confounders, path analysis demonstrated that the increased risk for violence in the moderate delinquency group was indirect (ie, partially mediated by positive symptoms) (probit coefficient [β] = 0.12; P = .002); while stable high delinquency directly increased the risk for violence (β = 0.38; P = .05). There appear to be diverse pathways to violent behavior during FEP. Stable high premorbid delinquency from childhood onwards appears to directly increase the risk for violent behavior, independent of psychosis-related risk factors. In addition to tackling illness-related risks, treatments should directly address antisocial traits as a potent risk for violence during FEP.


Suicide in Dublin: II. The influence of some social and medical factors on coroners' verdicts.
This paper presents an analysis of the factors which influence coroners in their decision to classify some deaths as suicides and others as accidental or "open". The most important influence on coroners' behaviour was seen to be the manner by which the person died. Those who died by cutting, hanging, drugs or gas were significantly more likely to receive a suicide verdict than those whose deaths were due to drowning, jumping, shooting or poisoning. If the deceased left any intimation of a suicidal intent, this increased the likelihood that a suicide verdict would be returned. Finally, persons aged under 40 were significantly more likely to be returned as suicides than older victims, especially those aged over 70. All of these results show that coroners operate by observing the law as it defines suicide, that is, by looking for evidence of intent of self-inflicted death. Our findings concerning the factors associated with the suicide verdict help to clarify the meaning of the official data on suicides in Ireland, and illuminate the reasons why, using clinical rather than legal criteria, a much higher rate is obtained.


Assessing colour preference in Aldabra giant tortoises (Geochelone gigantea).
Tortoises perceive different colours and rely on the visual system to find food. However, few studies have considered colour preference in tortoises, especially in land species. The aim of this study is to investigate whether Aldabra giant tortoises (Geochelone gigantea) housed in Parco Natura Viva (VR), an Italian zoological garden, show a specific colour preference in their social context. The study was divided into two different periods in which red and yellow balls of the same size were scattered around in the outdoor enclosure. In the first period, pieces of carrots were placed behind each ball whereas in the second period, carrots were replaced with apples. Data on the frequencies of interaction with red and yellow balls were collected. First, tortoises interacted more with the balls when pieces of apples rather than carrots were hidden behind them. No significant group-level colour preference was found; however, individual-level variation in colour preference was reported. In addition, tortoises interacted significantly more with the yellow balls in the second than in the first period. Food typology seems therefore to play an important role in determining colour preference in chelonians. Research aimed at identifying individual differences in animal preferences might be valuable to improve captive animal husbandry (e.g.: development of enrichment programmes, diets and rewards).


Clopidogrel and Low-Dose Aspirin, Alone or Together, Reduce Risk of Colorectal Cancer.
The antiplatelet effect of low-dose aspirin, via inhibition of cyclooxygenase-1, might contribute to its ability to reduce the risk of colorectal cancer (CRC). Antiplatelet agents with a different mechanism, such as clopidogrel, might have the same effects. We aimed to quantify the effects of low-dose aspirin and clopidogrel on the risk of CRC in a Mediterranean population. We performed a nested case-control study using a primary care database (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria) in Spain. We collected data, from 2001 through 2014, on 15,491 incident cases of CRC and 60,000 randomly selected individuals (controls), frequency-matched to cases by age, sex, and year. To estimate the association between exposure to different antiplatelet agents and the risk of colorectal cancer, we built multiple logistic regression models and computed the adjusted-odds ratios (AORs) and their respective 95% CIs. Use of low-dose aspirin was associated with a reduced risk of CRC overall (AOR, 0.83; 95% CI, 0.78-0.89) and in patients receiving treatment for more than 1 year (AOR, 0.79; 95% CI, 0.73-0.85). Use of clopidogrel was associated with a decreased risk of CRC overall (AOR, 0.8; 95% CI, 0.69-0.93) and in patients receiving treatment for more than 1 year (AOR, 0.65; 95% CI, 0.55-0.78). Dual antiplatelet therapy had the same effect as either drug taken as monotherapy. No modification by sex or age was observed. In a nested case-control study of a primary care database in Spain, we found clopidogrel use, alone or in combination with low-dose aspirin, to reduce the risk of CRC by 20% to 30%, a magnitude similar to that of low-dose aspirin alone. These data support the concept that inhibiting platelets is an effective strategy for prevention of CRC.


DC expressing transgene Foxp3 are regulatory APC.
Tolerogenic DC and suppressive Foxp3(+) Treg play important roles in preventing autoimmunity and allograft rejection. We report that (adenovirus mediated) ectopic expression of Foxp3 in human DC (i.e. DC.Foxp3) yields an APC that severely limits T-cell proliferation and type-1 immune responses from the naïve, but not memory, pool of responder T cells in vitro. In marked contrast, the frequencies of type-2 and Treg responses were dramatically increased after stimulation of naïve T cells with DC.Foxp3 versus control DC. DC.Foxp3-induced CD4(+)CD25(+) Treg cells potently suppressed the proliferation of, and IFN-gamma production from, CD4(+) and CD8(+) responder T cells. Notably, the immunosuppressive biology of DC.Foxp3 was effectively normalized by addition of 1-methyl-tryptophan or neutralizing anti-TGF-beta1 Ab during the period of T-cell priming. These data suggest the potential utility of regulatory DC.Foxp3 and/or DC.Foxp3-induced CD4(+)CD25(+) Treg as translational agents for the amelioration or prevention of pathology in the setting of allograft transplantation and/or autoimmunity.


Dynamics of insertion sequence element IS629 inactivation of verotoxin 2 genes in Escherichia coli O157:H7.
There are several anecdotal reports of insertion sequence (IS) element inactivation of verotoxin genes among enterohaemorrhagic Escherichia coli of the serotype O157:H7, a pathogen causing severe gastrointestinal disease in infected humans. These insertions can be expected to drastically reduce the virulence of the bacteria. IS element inactivation has been shown to be reversible in model systems, suggesting the possibility of spontaneous restoration of virulence. In this study, traditional and high-throughput sequencing was used to characterise three patterns of IS629 inactivation of verotoxin 2 genes in EHEC O157:H7, caused by insertion or insertion followed by partial deletion. At least one of the patterns of inactivation appears to have persisted several years among cattle O157:H7, indicating it has no major effect on fitness in the animal reservoir. Digital PCR was used to directly quantify the reversal rates of the insertional inactivation of a selected isolate under laboratory conditions. Inserts were found to be absent from in the order of 1/105 of individual genomes, with significantly higher loss frequencies observed in cultures under nutrient-poor conditions. We conclude that strains with this type of inactivation found in food or animal samples should be considered a threat to human health, and may pose a challenge for PCR-based detection methods.


Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay.
The Rho GTPase family belongs to the Ras superfamily and includes approximately 20 members in humans. Rho GTPases are important in the regulation of diverse cellular functions, including cytoskeletal dynamics, cell motility, cell polarity, axonal guidance, vesicular trafficking, and cell cycle control. Changes in Rho GTPase signaling play an essential regulatory role in many pathological conditions, such as cancer, central nervous system diseases, and immune system-dependent diseases. The posttranslational modification of Rho GTPases (i.e., prenylation by mevalonate pathway intermediates) and GTP binding are key factors which affect the activation of this protein. In this paper, two essential and simple methods are provided to detect a broad range of Rho GTPase prenylation and GTP binding activities. Details of the technical procedures that have been used are explained step by step in this manuscript.


Spleen enlargement following recombinant human granulocyte colony-stimulating factor administration for peripheral blood stem cell mobilization.
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to mobilize peripheral blood stem cells (PBSC) for autologous or allogeneic transplants. Such treatment may cause spleen enlargement; exceptionally, spontaneous spleen rupture has been reported. We investigated changes in spleen size during stem cell mobilization. We evaluated spleen size, comparing palpation with ultrasound (US)-evaluated longitudinal diameter and volume, in 13 healthy donors and 22 patients with a hematological malignancy who were undergoing PBSC mobilization with rhG-CSF-including regimens. Intraobserver and interobserver variability of US-calculated spleen volume was very low; the correlation between the volume calculated by US and that measured by 3-dimensional computed tomography was excellent. During mobilization, spleen enlargement was detected by palpation in 17% of subjects, by US-measured longitudinal diameter in 60%, and by US-calculated volume in 91%. The median increase in spleen volume was 300 mL (range, 54-820; p<0.001) in healthy donors and 135 mL (range, 0-413; p=0.004) in the group of patients; the enlargement correlated with white blood cell count elevation (p=0.016) but not with circulating CD34+ cells. One month after the last administration of rhG-CSF, the median decrease was 160 mL (range, 35-800) in healthy donors and 58 mL (range, 0-310) in patients. When evaluated by sensitive methods, rhG-CSF caused spleen enlargement in almost all individuals treated. US-calculated volume proved to be an excellent method, much better than longitudinal diameter, for detecting non-palpable splenomegaly induced by rhG-CSF.


Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma.
Oral tyrosine kinase inhibitor has been shown to prolong progression-free survival (PFS) in estimated glomerular filtration rate (EGFR) mutation positive adenocarcinoma; however, the comparator arm has not included the current standard adenocarcinoma regimen (pemetrexed carboplatin induction followed by maintenance pemetrexed) and patients from Indian subcontinent. Hence, this study was carried out in Indian patients to compare gefitinib with the above-mentioned chemotherapy regimen. This was an open-labelled, randomised, parallel group study comparing gefitinib (250 mg orally daily) with pemetrexed (500 mg/m2) and carboplatin (area under the curve 5) doublet intravenous induction chemotherapy regimen followed by maintenance pemetrexed (500 mg/m2) in patients with EGFR-activating mutation-positive stage IIIB or stage IV adenocarcinoma lung in the first-line setting. The primary endpoint for the study was PFS. 260 patients were required to demonstrate a 50% improvement in PFS of gefitinib over chemotherapy, with 80% power and 5% type 1 error. With an expected 5% dropout rate, the sample size was 290 patients. The median PFS in gefitinib arm was 8.4 months (95% CI 6.3 to 10.5 months) compared with 5.6 months (95% CI 4.2 to 7.0 months) in pemetrexed-carboplatin arm (HR: 95% CI 0.513 to 0.851; p -0.001). The impact of gefitinib on PFS was seen across all subgroups.There was no statistically significant difference in overall survival between the two arms. Haematologicalgrade3-4toxicities likeanaemia,neutropaenia and thrombocytopaenia were common in the pemetrexed-carboplatin arm while grade3-4 acneiform rash and diarrhoeawere common in the gefitinib arm. The study confirms the superiority of gefitinib in prolonging PFS against the most active chemotherapy regimen of pemetrexed-carboplatin followed by maintenance pemetrexed in EGFR-mutated lung adenocarcinoma. The median PFS in Indian patients in gefitinib arm is similar to that reported in east Asians and Caucasians.


Near infrared spectro-interferometer using femtosecond laser written GLS embedded waveguides and nano-scatterers.
Guided optics spectrometers can be essentially classified into two main families: based on Fourier transform or dispersion. In the first case, an interferogram generated inside an optical waveguide and containing the spectral information is sampled using spatially distributed nanodetectors. These scatter quasi-non-perturbingly light into the detector that is in contact with the waveguide, helping to reconstruct the stationary wave. A dedicated FFT processing is needed in order to recover the spectrum with high resolution but limited spectral range. Another way is to directly disperse the different wavelengths to different pixels, either introducing differential optical path in the same propagation plane (multiple Mach-Zehnder interferometers or Arrayed Waveguides Gratings), or using a periodic structure to perpendicularly extract the optical signal confined in a waveguide (photonic crystals or surface gratings), and by means of a relay optics, generate the spectrum on the Fourier plane of the lens, where the detector is placed. Following this second approach, we present a laser-fabricated high-resolution compact dispersive spectro-interferometer (R>2500, 30nm spectral range at λ = 1560nm), using four parallel waveguides that can provide up to three non-redundant interferometric combinations. The device is based on guided optics technology embedded in bulk optical glass. Ultrafast laser photoinscription with 3D laser index engineering in bulk chalcogenide Gallium Lanthanium Sulfide glass is utilized to fabricate large mode area waveguides in an evanescently-coupled hexagonal multicore array configuration, followed by subsequent realization of nanoscaled scattering centers via one dimensional nanovoids across the waveguide, written in a non-diffractive Bessel configuration. A simple relay optics, with limited optical aberrations, reimages the diffracted signal on the focal plane array, leading to a robust, easy to align instrument.


Effects of Sake lees (Sake-kasu) supplementation on the quality characteristics of fermented dry sausages.
Sake lees (Sake-kasu) are the sediments of Japanese sake brewing process from fermented rice with Aspergillus oryzae and yeasts. Sake lees contain various enzymes and metabolites derived from the Sake starter culture, and expected to add aroma, flavor and softness to sausages. We investigated the effects of Sake lees supplementation on fermented dry sausage characteristics over an aging period of 35 days. Sake lees supplementation significantly accelerated sarcoplasmic and myofibrillar protein decomposition and increased peptide and free amino acid content compared to untreated sausage meat. Sake lees significantly acidified the sausages, enhanced their sour taste, and influenced their acceptability. Sake lees supplementation also significantly improved the hardness of the final product and conferred a preferable flavor to it. These results suggest that the various enzymes and compounds in Sake lees improve the flavor and texture of fermented dry sausages.


Over the counter non-steroidal anti-inflammatory drugs and risk of gastrointestinal bleeding.
Independent analyses of data from a case-control study conducted by the American College of Gastroenterology (ACG) were performed to evaluate and quantify potential risks of gastrointestinal (GI) bleeding associated with use of analgesics at over the counter (OTC) doses. Information on recent (within the past week) use of multiple analgesics, plus data on tobacco, alcohol and other factors, were obtained from 627 patients enrolled in the ACG GI bleeding registry and from 590 procedure-matched controls. Odds ratios (OR) were calculated as the measure of association between GI bleeding and the exposures of interest. Risk of GI bleeding was increased 2-3 fold among recent users of aspirin, ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) at OTC doses, with risk increasing in a dose-related manner. In contrast, no excess was found among acetaminophen (paracetamol) users. Alcohol consumption was also a risk factor, with doubled risks of GI bleeding among drinkers. While these study results are not definitive, the findings are consistent with limited other data also reviewed, and suggest the need for further epidemiologic research to clarify the association between use of NSAIDs at OTC levels and risk of GI bleeding, and to determine whether NSAIDs and alcohol may interactively combine to enhance risk.


Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas.
The prognosis for patients with recurrent high-grade gliomas is poor and treatment options are limited. Current chemotherapeutic regimens can improve clinical outcomes, but extend survival by only a few months. Temozolomide is a methylating agent that is typically administered once daily. Because preclinical studies suggested that a twice-daily dosing schedule might be more effective, the safety and efficacy of twice-daily dosing of temozolomide were studied in patients with recurrent gliomas at their first, second, or third recurrence. This multi-institutional trial enrolled 120 patients with recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO). An initial oral dose of 200 mg/m(2) of temozolomide was followed by 9 consecutive doses of 90-mg/m(2) every 12 hours. Treatment cycles were repeated every 28 days. Doses were escalated to 100 mg/m(2) twice daily in the absence of unacceptable toxicity or were reduced if unacceptable toxicity occurred. For GBM, AA, and AO patients, respectively, the median progression-free survival (PFS) was 4.2 months, 5.8 months, and 7.7 months, whereas the median overall survival (OS) was 8.8 months, 14.6 months, and 18 months. The overall response rate (partial and complete) for the GBM, AA, and AO patients was 31%, 46%, and 46%, respectively. Grade 3/4 toxicities included neutropenia (1.1%), thrombocytopenia (3.6%), and anemia (0.3%) (graded according to the World Health Organization grading system). Twice-daily dosing may enhance the efficacy of temozolomide in the treatment of recurrent gliomas without increasing toxicity. This regimen compares favorably with other dosing schedules of temozolomide reported in the literature.


Dietary restriction and aging, 2009.
Dietary restriction (DR) is a robust nongenetic, nonpharmacological intervention that is known to increase active and healthy lifespan in a variety of species. Despite a variety of differences in the protocols and the way DR is carried out in different species, conserved relationships are emerging among multiple species. 2009 saw the field of DR mature with important mechanistic insights from multiple species. A report of lifespan extension in rapamycin-treated mice suggested that the TOR pathway, a conserved mediator of DR in invertebrates, may also be critical to DR effects in mammals. 2009 also saw exciting discoveries related to DR in various organisms including yeast, worms, flies, mice, monkeys and humans. These studies complement each other and together aim to deliver the promise of postponing aging and age-related diseases by revealing the underlying mechanisms of the protective effects of DR. Here, we summarize a few of the reports published in 2009 that we believe provide novel directions and an improved understanding of dietary restriction.


Association between Beckwith-Wiedemann syndrome and assisted reproductive technology: a case series of 19 patients.
An association between assisted reproductive technique (ART) and specific imprinting mutations, such as Beckwith-Wiedemann syndrome (BWS), has recently been documented. Based on experiments in farm animals that demonstrated an association between alterations in culture media during ART and large offspring syndrome, we hypothesized that the culture media could be implicated as a common factor among the children with BWS conceived after ART. Retrospective case series. Registry from Academic Medical Center. Nineteen children born after ART were identified within the registry. Demographics of patients, type of ART, culture media, IVF parameters. Twelve of the 19 medical records from the reproductive endocrine centers were successfully obtained. Ten of 12 mothers of children with BWS had IVF, but no single, consistent culture media was used in this group. Half of the patients underwent IVF with intracytoplasmic sperm injection (ICSI; n = 5), whereas the other half had routine IVF. One child was conceived through clomiphene citrate (CC) stimulation and artificial insemination, whereas another patient conceived through gonadotropin stimulation with intrauterine insemination (IUI). The gonadotropin dosage and quantity of embryos transferred also varied significantly. The only consistent finding was that all 12 women received some type of ovarian stimulation medication. Large epidemiologic studies are needed to further study the association between BWS and ART.


Neuromelanin and Parkinson's disease.
Neuromelanin is closely linked to Parkinson's disease, but is it the cause of the illness? The main pathology of Parkinson's disease is a loss of pigmented brain-stem neurones, and neuromelanin or its precursors might be cytotoxic. However, the cellular marker of Parkinsonian pathology, the Lewy body, is not confined to neurones containing neuromelanin. There are areas of the brain, of which the substantia innominata is a good example, which contain no neuromelanin or catecholaminergic neurones, but whose cells are packed with Lewy bodies and die. It is concluded that it is not neuromelanin, but the Lewy body which holds the key to Parkinson's disease.


Selenium-Containing Nanocomplexes Achieve Dual Immune Checkpoint Blockade for NK Cell Reinvigoration.
The blockade of immune checkpoints has emerged as a promising strategy for cancer immunotherapy. However, most of the current approaches focus on T cells, leaving natural killer (NK) cell-mediated therapeutic strategies rarely explored. Here, a selenium-containing nanocomplex is developed that acts as a dual immune checkpoint inhibitor to reinvigorate NK cell-based cancer immunotherapy. The Se nanocomplex can deliver and release siRNA that targets programmed death ligand-1 (PD-L1) in tumor cells, thereby silencing the checkpoint receptor PD-L1. The intracellular reactive oxygen species generated by porphyrin derivatives in the nanocomplexes can oxidize the diselenide bond into seleninic acid, which blocks the expression of another checkpoint receptor, human leukocyte antigen E. The blockade of dual immune checkpoints shows synergistic effects on promoting NK cell-mediated antitumoral activity. This study provides a new strategy to reinvigorate NK cell immunity for the development of combined cancer immunotherapy.


Telomerase RNA expression during progression of gastric cancer.
Telomerase, an enzyme associated with cellular immortality and malignancy, is stringently repressed in most normal somatic cells but is reactivated in malignant tumor cells and immortal cell lines, indicating that activation of telomerase may play an important role in tumorigenesis and immortalization. The pattern of human telomerase RNA (hTR) expression during progression of gastric cancer was investigated by a radioactive in situ hybridization (ISH) assay. Paraffin-embedded sections of 85 archival samples from Korean patients with benign and various malignant stages of gastric carcinomas as well as normal and regenerative tissues were studied. In normal gastric mucosae and regenerative lesions such as chronic peptic ulcer and hyperplastic polyps, only a weak degree of hTR expression was noted, and the expression was limited to basal cells of the gastric glands. Also, a moderate degree of hTR expression was present in the germinal centers of lymphoid follicles present in the submucosa. In tubular adenomas, the degree of hTR expression was also generally weak, but, unlike normal gastric mucosa, the expression was rather diffuse and occasionally focal in distribution. However, moderate to intense and usually diffuse hTR expression was present in all cancerous tissues at different stages. Although some heterogeneity of hTR expression was noted, there was a tendency for intensity of hTR expression to increase gradually as the cancer progressed to a more advanced stage. Our results indicate that upregulation of telomerase expression is associated with gastric cancer development or plays some role in gastric carcinogenesis. Upregulation of hTR expression detected by ISH assay may be a useful marker or tool for the early detection of gastric cancer.


CETP and APOA2 polymorphisms are associated with weight loss and healthy eating behavior changes in response to digital lifestyle modifications.
Response to digital healthcare lifestyle modifications is highly divergent. This study aimed to examine the association between single nucleotide polymorphism (SNP) genotypes and clinical efficacy of a digital healthcare lifestyle modification. We genotyped 97 obesity-related SNPs from 45 participants aged 18-39 years, who underwent lifestyle modification via digital cognitive behavioral therapy for obesity for 8 weeks. Anthropometric, eating behavior phenotypes, and psychological measures were analyzed before and after the intervention to identify their clinical efficacy. CETP (rs9939224) SNP significantly predict "super-responders" with greater body mass index (BMI) reduction (p = 0.028; GG - 2.91%, GT - 9.94%), while APOA2 (rs5082) appeared to have some potential for predicting "poor-responders" with lower BMI reduction (p = 0.005; AA - 6.17%, AG + 2.05%, and GG + 5.11%). These SNPs was also associated with significant differences in eating behavior changes, healthy diet proportions, health diet diversity, emotional and restrained eating behavior changes. Furthermore, classification using gene-gene interactions between rs9939224 and rs5082 significantly predicted the best response, with a greater decrease in BMI (p = 0.038; - 11.45% for the best response group (CEPT GT/TT × APOA2 AA) vs. + 2.62% for the worst response group (CEPT GG × APOA2 AG/GG)). CETP and APOA2 SNPs can be used as candidate markers to predict the efficacy of digital healthcare lifestyle modifications based on genotype-based precision medicine.Trial registration: NCT03465306, ClinicalTrials.gov. Registered March, 2018.


Estimation of potency of HERG channel blockers: impact of voltage protocol and temperature.
The HERG channel is widely used for the assessment of proarrhythmic risk for new drugs. HERG channel blockers obstruct channel functions through various mechanisms, which usually show time dependence, voltage dependence, and state dependence. The voltage protocol and temperature may affect the estimation of drug potency, but limited information is available in this regard. The purpose of this study was to evaluate the influence of voltage protocol and temperature on predicting the potency of HERG channel blockers, and to determine electrophysiological approaches for new drugs screening studies. Whole-cell patch-clamp electrophysiology was carried out by utilizing different voltage step protocols to examine the potency of compounds known to preferentially block the channel in the closed (ketoconazole and BeKm-1), open, and/or inactivated states (E-4031, astemizole, and terfenadine) in HEK293 cells transfected with HERG cDNA at room temperature and near-physiological temperature. Drug potency determined using different voltage protocols varied dependent on the mechanisms of drug actions. For most compounds, the IC(50) values obtained with a long pulse step protocol at room temperature were close to those determined with the voltage protocols designed to disclose their intrinsic potency. Relative to room temperature, the potency of E-4031, terfenadine, and ketoconazole was not changed at approximately 35 degrees C, but potency of astemizole was reduced. The long pulse step protocol with room temperature can be selected for HERG channel safety screening studies. Alternative voltage protocols or temperatures should be considered if HERG study results are not consistent with other cardiac safety assessments.


Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats.
We previously showed that the molecule interacting with Ang II type 1 receptor (AT1R), ATRAP, promotes AT1R internalization and attenuates AT1R-mediated pathological responses. In this study we examined whether the regulation of renal ATRAP expression is related to the development of salt-induced hypertension and renal injury as well as to the beneficial effects of AT1R blockade. Dahl Iwai salt-sensitive hypertensive and Dahl Iwai salt-resistant rats were divided into six groups for the administration of vehicle or olmesartan either continuously from 3 to 16 weeks, or transiently from weaning to puberty (3-10 weeks), and fed high salt diet from 6 to 16 weeks. In Dahl Iwai salt-sensitive rats, not only continuous, but also prepubertal olmesartan treatment improved hypertension at 15 weeks. Renal ATRAP expression was suppressed in vehicle-treated Dahl Iwai salt-sensitive rats, concomitant with up-regulation of renal oxidative stress, inflammation and fibrosis-related markers such as p22phox, TGF-β, fibronectin, monocyte chemotactic protein-1 and type 1 collagen. However, prepubertal as well as continuous olmesartan treatment recovered the suppressed renal ATRAP expression and inhibited the renal activation of p22phox, TGF-β, fibronectin, MCP-1 and type 1 collagen. In Dahl Iwai salt-resistant rats, such suppression of renal ATRAP expression or induction of renal pathological responses by salt loading was not observed. These results indicate that prepubertal transient blockade of AT1R signaling exerts a long-term therapeutic effect on salt-induced hypertension and renal injury in Dahl Iwai salt-sensitive rats, partly through a sustained enhancement of renal ATRAP expression, thereby suggesting ATRAP a novel molecular target in salt-induced hypertension and renal injury.


[Relationship between cholecystokinin gene -45C/T polymorphism and schizophrenia and its application in forensic medicine].
To investigate the polymorphism of cholecystokinin (CCK) gene -45C/T of schizophrenia and its application in forensic medicine. Bidirectional allele specific PCR was used to detect CCK gene -45C/T polymorphisms in 207 schizophrenic patients (case group) and 202 healthy individuals (control group) of the Han population in northern China. The chi2 test was used to identify Hardy-Weinberg equilibrium of the genotype distribution in control group. The differences of genotype and allele frequencies distributions were compared between two groups. Distributions of the genotype frequencies satisfied the law of Hardy-Weinberg equilibrium in control group. The differences between genotypic frequencies and allele frequencies were not statistical significance in case group and control groups (P > 0.05). Gender-stratified analysis showed that frequency of allele T in female case group was statistically higher than that in female control group (P = 0.044). CCK gene -45C/T locus T allele may be positively associated with schizophrenia in female population and useful in schizophrenia identification.


Using the 12-item short form health survey (SF-12) to assess self rated health of an engaged population impacted by hurricane Harvey, Houston, TX.
In the last decade there has been an increase in community-based organizations providing support and educational outreach to populations effected by hazards. Prior research has demonstrated various roles that community social capital can play in both the enhancement of disaster preparedness and the mitigation of physical and mental health impacts following a natural disaster. To assess self-reported health of residents of South Houston, Texas impacted by Hurricane Harvey, attendees of a community event completed a survey that included the 12 item short form health survey version 2 (SF-12v2). Although survey participants were older and more likely to be African-American than the overall population of Houston, they had higher mental health composite scores that the national average, with increases in mental wellbeing associated with a longer length of residence in their neighborhood. The City of Houston, with highly segregated, socially vulnerable populations at high risk from natural hazards, should consider ways to support community engagement around disaster preparedness, response, and recovery that may build community cohesion and improve post-disaster mental health.