Cerebral arteritis and bacterial meningitis.
Twelve cases of large- and medium-sized cerebral artery stenosis and/or occlusion associated with bacterial meningitis occurred. Neurological complication due to arterial involvement developed in seven patients on the third and fourth days of illness; in one patient, it developed on the fifth day, and in another it developed on the 14th day. In three cases, this could not be determined. Arterial stenosis is considered primarily to result from arterial spasm due to humoral factors that may be elaborated within the CSF or arterial wall, as in the cases of ruptured aneurysm; and secondarily, from to inflammatory involvement of major vessels at the base of the brain and from irritation by angiographic contrast material.


Actin-Interacting Amphidinolides: Syntheses and Mechanisms of Action of Amphidinolides X, J, and K.
Amphidinolides are a family of more than forty macrolides of varying sizes and complex structures isolated from dinoflagellates of the genus Amphidinium. Although all of them display potent-to-moderate cytotoxicity, their full bioactivity profile and mode of action have not been fully investigated. Access to enough material is needed for these studies, but samples of these compounds are limited due to the minute amounts that can only be obtained by either large-scale cultivation of the organism that produces them or by total synthesis. Of all the amphidinolides known to date, only the targets of five of them (B1, H1, J, K, and X) have been examined and all have been found to interact with actin, a crucial cytoskeletal protein. This paper reviews what is currently known about actin-interacting amphidinolides, with a focus on the research of our group. Amphidinolides J and X are F-actin destabilizers, whereas Amphidinolides H1 and K stabilize actin filaments, likely via different mechanisms. More precise details of the interaction between amphidinolides and actin are missing.


Soluble TNF-alpha-receptors I are prognostic markers in TIPS-treated patients with cirrhosis and portal hypertension.
TNFα levels are increased in liver cirrhosis even in the absence of infection, most likely owing to a continuous endotoxin influx into the portal blood. Soluble TNFα receptors (sTNFR type I and II) reflect release of the short-lived TNFα, because they are cleaved from the cells after binding of TNFα. The aims were to investigate the circulating levels of soluble TNFR-I and -II in cirrhotic patients receiving TIPS. Forty-nine patients with liver cirrhosis and portal hypertension (12 viral, 37 alcoholic) received TIPS for prevention of re-bleeding (n = 14), therapy-refractory ascites (n = 20), or both (n = 15). Portal and hepatic venous blood was drawn in these patients during the TIPS procedure and during the control catheterization two weeks later. sTNFR-I and sTNFR-II were measured by ELISA, correlated to clinical and biochemical characteristics. Before TIPS insertion, sTNFR-II levels were lower in portal venous blood than in the hepatic venous blood, as well as in portal venous blood after TIPS insertion. No significant differences were measured in sTNFR-I levels. Hepatic venous levels of sTNFR-I above 4.5 ng/mL (p = 0.036) and sTNFR-II above 7 ng/mL (p = 0.05) after TIPS insertion were associated with decreased survival. A multivariate Cox-regression survival analysis identified the hepatic venous levels of sTNFR-I (p = 0.004) two weeks after TIPS, and Child score (p = 0.002) as independent predictors of mortality, while MELD-score was not. Hepatic venous levels of sTNFR-I after TIPS insertion may predict mortality in patients with severe portal hypertension.


Role of CD4 and CD8 T-lymphocytes, B-lymphocytes and Natural Killer cells in the prediction of radiation-induced late toxicity in cervical cancer patients.
To analyse the role of in vitro radio-induced apoptosis of lymphocyte subpopulations as predictive test for late effects in cervical cancer patients treated with radiotherapy. Ninety-four consecutive patients and four healthy controls were included in the study. Toxicity was evaluated using the Late Effects Normal Tissue-Subjective, Objective, Management, and Analytic (LENT-SOMA) scale. Peripheral blood lymphocyte subpopulations were isolated and irradiated at 0, 1, 2 and 8 Gy, and then collected 24, 48 and 72 h after irradiation. Apoptosis was measured by flow cytometry. Radiation-induced apoptosis increased with radiation dose and time of incubation, and data fitted to a semi-logarithmic model defined by two constants: α (percentage of spontaneous cell death) and β (percentage of cell death induced at a determined radiation dose). Higher β values in cytotoxic T-lymphocytes (CD8) and bone cells (B-lymphocytes) were observed in patients with low bowel toxicity (hazard ratio (HR) = 0.96, p = 0.002 for B-cells); low rectal toxicity (HR = 0.96, p = 0.020; HR = 0.93, p = 0.05 for B and CD8 subpopulations respectively); low urinary toxicity (HR = 0.93, p = 0.003 for B-cells) and low sexual toxicity (HR = 0.93, p = 0.010 for CD8-cells). Radiation-induced CD8 T-lymphocytes and, for the first time, B-lymphocytes apoptosis can predict differences in late toxicity in cervical cancer patients.


Evaluation of German cockroach (Orthoptera:Blattellidae) allergen and seasonal variation in low-income housing.
Six apartments in a low-income housing project were evaluated for German cockroach. Blattella germanica (L.), infestation and concentration of an allergen derived from these cockroaches (Bla g II). Kitchen and living room samples were collected monthly for 1 yr. In addition, airborne sampling was carried out in 5 kitchens. The kitchen had the highest allergen concentration in 65% of visits and the highest number of cockroaches trapped in 69% of visits. In the kitchen, the highest cockroach levels were seen in June, whereas the values for Bla g II peaked in August. In keeping with this, the closest correlation was between Bla g II (microgram/g dust) and the number of cockroaches found 2 mo earlier. Airborne samples were assayed for 2 separate allergens. Bla g II and Bla g I. No allergen was detectable in the absence of disturbance. By contrast, during disturbance with a vacuum cleaner both Bla g II and Bla g I were detectable in the air of each apartment. Results suggest that immunochemical assay of a major allergen in dust samples from the kitchen floor may be used to monitor exposure to German cockroaches, also that cockroach levels may be used as an indicator or predictor of allergen in dust.


Chemical radioprotection to bone marrow stem cells after whole body gamma irradiation to mice.
Protection to mice bone marrow stem cells has been noted as early as two days after whole body gamma ray exposure by prior treatment with combination of hydroxytryptophan (HT) and one of the two thiol drugs viz., aminoethylisothiuronium bromide hydrobromide (AET) (20 mg/kg body weight) and B-mercaptopropionylglycine (MPG). The levels of protection to bone marrow stem cells thus obtained have been compared to that obtained by treating with the optimum radioprotecting dose of AET (200 mg/kg body weight). The study reports the bone marrow stem cells status after two days of 3 Gy, 5 Gy and 10 Gy whole body gamma irradiation in relation to the mentioned radioprotecting treatments as studied by spleen colony forming method.


Intravascular imaging for left main stem assessment: An update on the most recent clinical data.
Left main (LM) stem has different structural and anatomical characteristics compared to all of the other segments of the coronary tree, thus its management through percutaneous coronary intervention (PCI) is a challenge and is associated with worse clinical outcome and higher need for revascularization as compared to other lesion settings. Intravascular imaging, by means of intravascular ultrasound (IVUS) or optical coherence tomography (OCT), is an important tool for LM PCI guidance, aiming at improving the immediate performance and the long term outcome of this procedure. Following current guidelines and recent scientific findings, IVUS becomes important to firstly assess, and finally evaluate the result of LM stenting, according to the experience and preferences of the operator. The role of OCT still remains to be defined, but recent data is shedding light also on this imaging technique. The aim of this review is to highlight the latest scientific advancements regarding intravascular imaging in LM coronary artery disease.


Construct-Oriented or Goal-Motivated? Interpreting Test Preparation of a High-Stakes Writing Test From the Perspective of Expectancy-Value Theory.
Of the many possible individual factors bearing on test preparation, one is how individuals' motivational and cognitive perceptions affect test-driven preparation practices. This study reports an investigation into test preparation of a high-stakes writing test from the perspective of expectancy-value theory. Undergraduate students (n = 623) on their test preparation for the writing tasks of China's Graduate School Entrance English Examination (GSEEE) were recruited voluntarily from 11 universities in mainland China. The perceptions of GSEEE test takers, which included goal, task value, task demand, and expectation of success, were identified. Five types of preparation practices were identified for the GSEEE writing tasks: memorizing practice, test familiarization, comprehensive learning, skills development and drilling practice. Structural equation modeling revealed that the expectancy-value model held up well for the paths from test takers' perceptions to test-driven preparation practices, which were not construct-oriented but goal-motivated. The GSEEE test takers' goal, determined by the high-stakes nature of admission test, explained their motivation and determined their behavior toward test preparation. Results also indicated that task demand was inadequate to be termed a strong factor in affecting test preparation. As such, the findings of this study offer evidence regarding how an expectancy-value model fit into test preparation mechanism and provide insights into the nature and scope of test preparation for high-stakes writing tests.


[An analysis of four cases of misdiagnosed primary lymphocytic hypophysitis].
To improve the differential diagnosis of sellar region mass, 4 cases with sellar mass and misdiagnosed as lymphocytic hypophysitis (LYH) were reviewed retrospectively.The 4 patients (2 male and 2 female) aged 20-60 years old were all presented with symptoms of headache, polydipsia and polyuria.Biochemical studies confirmed the diagnoses of central diabetes insipidus and hypopituitarism.Head MRI scans showed LYH like image for all the cases, and, thus, high dose methylprednisolone pulse therapy (HDMPT) was applied to the patients.Their symptoms deteriorated and the sellar mass enlarged after a short period of partial improvement.Operations were performed in all the patients.Histology study showed craniopharyngioma with abscess, primary abscess, secondary hypophysitis caused by Wegener's granulomatosis, and germinoma with secondary hypophysitis, respectively.In conclusion, surgery or biopsy is necessary for those who presented with sellar region mass and was suspected to be with LYH, but with poor response or even worse after HDMPT.


Weaning practices in peri-urban low socioeconomic groups.
To assess the current weaning practices in infants (children under one year of age) in a low socioeconomic peri-urban area in Karachi. Cross-sectional study. 'Well Baby Clinic" in Jinnah Medical College Hospital situated in Korangi Industrial area of Karachi from October 2003 to March 2004. One hundred and fifty infants were included in the study. Their feeding pattern and weaning practices were studied using a questionnaire. They were grouped in three categories according to their age of commencement of weaning. Ninety (60%) infants were receiving semi-solids/solids (weaning foods) in addition to milk. The recommended age (between 4 to 6 months) was noted in 37 (25%) cases, while early weaning was present in 9 (6%) cases and delayed weaning in 44 (29 %) cases. Even if weaning was started at the correct age, several problems were noted. These included infrequent feeding, use of expensive commercial cereals given in diluted form as compared to home-made foods, and improper food preparation. The quality, type and choice of food was not ideal for adequate growth. Incorrect weaning practices is an issue of public health in developing countries. The identification and analysis of weaning practices prevalent in low socioeconomic households can lead to remedial strategies for improving the nutrition status of infants and, thereby, help reduce infant and morbidity rate.


Okadaic acid inhibits relaxant neural transmission in rat gastric fundus in vitro.
The aim of the present study was to characterize the influence of the phosphatase type 1 and 2A inhibitor okadaic acid on non-adrenergic, non-cholinergic (NANC) neurotransmission in the rat gastric fundus. Okadaic acid (10-6 M), an inhibitor of protein phosphatases 1 and 2A, did not show any influence on the basal tonus or on a contraction plateau induced by 5-HT (10-7 M) within 30 min of observation. When okadaic acid (10-6 M) was applied 10 min prior to 5-HT (10-7 M), the contraction plateau of serotonin was unchanged. To investigate the inhibitory neurotransmission, the muscle strips were pre-contracted using 5-HT (10-7 M), and inhibitory stimuli were applied at the contraction plateau, which was stable over 30 min. The inhibitory effects of vasoactive intestinal peptide (VIP), nitric oxide (NO) and electrical field stimulation (EFS, 40 V, 0.5 ms, frequencies ranging from 0.5 to 16 Hz) were examined. When okadaic acid (10-6 M) was applied prior to EFS-induced NANC relaxation, significant attenuation of the inhibitory response was demonstrated (16 Hz: control: -92.4 +/- 1.9%; okadaic acid 10-7 M: -60.7 +/- 6.1%; okadaic acid 10-6 M: -25.3 +/- 3.4%; n=11; P < 0.01). By contrast, neither the concentration-dependent inhibitory actions of VIP (10-11-10-8 M) (VIP 10-8 M: -100%; VIP 10-8 M + okadaic acid 10-6 M: -89.9 +/- 8.3%; n=8; n.s) nor that of diethylamine nitric oxide (DEA-NO) (3 x 10-7-10-4 M) (DEA-NO 10-4 M: -95.3 +/- 8.4%; DEA-NO 10-4 M + okadaic acid 10-7 M: -98.3 +/- 6.3%; DEA-NO 10-4 M + okadaic acid 10-6 M: 96.5 +/- 7.6%; n=9; n.s.) on 5-HT induced contraction were altered by pre-incubation with okadaic acid (10-6 M). This is the first report that supports the concept that protein phosphatases 1 and 2A may contribute to the regulation of rat gastric fundus motility. The protein phosphatase inhibitor okadaic acid significantly reduces electrically induced inhibitory NANC responses, while leaving direct muscular effects of the inhibitory NANC neurotransmitters VIP and NO unaffected - suggesting a neural site of action. The potential roles of protein phosphatases on NANC neurotransmission remain to be clarified in detail, as this might offer a new pathway for modulating smooth-muscle function.


Potential New Approaches for Diagnosis of Alzheimer's Disease and Related Dementias.
Dementia is an umbrella term-caused by a large number of specific diagnoses, including several neurodegenerative disorders. Alzheimer's disease (AD) is now the most common cause of dementia in advanced countries, while dementia due to neurosyphilis was the leading cause a century ago. Many challenges remain for diagnosing dementia definitively. Some of these include variability of early symptoms and overlap with similar disorders, as well as the possibility of combined, or mixed, etiologies in some cases. Newer technologies, including the incorporation of PET neuroimaging and other biomarkers (genomics and proteomics), are being incorporated into revised diagnostic criteria. However, the application of novel diagnostic methods at clinical sites is plagued by many caveats including availability and access. This review surveys new diagnostic methods as well as remaining challenges-for clinical care and clinical research.


Testing the suffocation false alarm theory of panic disorder.
The need for hypotheses concerning the nature of those functions that have been impaired in stereotyped psychiatric syndromes is emphasized. With regard to panic disorder, the key role of the spontaneous panic attack became apparent from several viewpoints. However, panics seem to be a type of misreleased fear, which guided the thinking concerning the nature of possible psychological or physiological malfunctions. We indicate that spontaneous panic cannot be fear, but must represent some other malfunction and suggest that the spontaneous panic is a suffocation false alarm. The development of this idea is outlined, and attempts to develop tests of this hypothesis are indicated. In particular, studies of children with congenital central hypoventilation syndrome, patients with Chronic Obstructive Pulmonary Disease, dyspnea, field measures of panic, pregnancy, childbirth and the postpartum period, as well as the premenstrual syndrome afford pointed opportunities, new information and potential tests of the theory. A recent challenge to the theory from acetazolamide infusion is discussed. Developing a possible antecedent for the pathologically depressed threshold for the suffocation alarm, in the form of a phasic endorphinergic deficiency, is presented.


Cardiovascular genomics and sudden cardiac death in the young.
Sudden cardiac death (SCD) in the young is a rare but tragic consequence of a number of genetic cardiovascular disorders. The care of survivors of cardiac arrest and families affected by SCD seeks to prevent further SCD events through family screening. The aim of this article is to review the genetic basis of SCD in the young and outline the clinical aspects of caring for families affected by SCD. Inherited cardiomyopathies and primary arrhythmia syndromes are important causes of SCD in young people. Over the past 30 years, there has been an explosion of knowledge regarding the underlying genetic mechanisms of these disorders and dramatic advances in genetic testing technologies. Family screening with thorough multidisciplinary clinical assessment and genetic testing allows for the initiation of preventive strategies in high-risk relatives and ultimately a reduction in SCD events.


Use of pulsatile intravenous administration of gonadotropin-releasing hormone to induce fertile estrus in bitches.
The pulsatile IV administration of gonadotropin-releasing hormone (GnRH) was evaluated as a method to induce fertile estrus in 8 anestrous Beagle bitches. Bitches received 1.25 micrograms of GnRH every 90 minutes for 11 to 13 days. Gonadotropin-releasing hormone was delivered by use of an automatic pump. Reproductive history was known for all bitches, 4 of which, on the basis of 3 or 4 preceding cycles, had an interestrous interval of 219 +/- 14 days (mean +/- SEM). Estrus induction was attempted during early anestrus in 6 bitches (ie, 148 +/- 10 days since the preceding estrus) and late anestrus in 1 bitch (ie, 260 days since the preceding estrus); another bitch had not had an estrous cycle for nearly 2 years before GnRH administration. Signs of estrus were seen within 16 days after the start of GnRH administration in the bitches with regular estrous cycles (group 1, n = 7), and within 23 days in the bitch (group 2) with prolonged anestrus. All bitches were bred, and 7 of 8 (87.5%) became pregnant, with a mean litter size of 4.5 +/- 0.75. A normal hormonal response pattern was observed in group-1 bitches--a peak increase in plasma estrogen concentration of 22.3 +/- 2 pg/ml immediately before the onset of estrus. Peak plasma progesterone concentration (17.3 +/- 3 ng/ml) was observed 1 to 14 days after the onset of diestrus in the group-1 bitches that ovulated, and adequate plasma progesterone concentration was maintained throughout gestation.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of Fungicides and Spray Application Interval on Controlling Marssonina Blotch of Apple in the Loess Plateau Region of China.
Marssonina blotch, caused by the fungus Marssonina coronariae, is a serious foliar disease on apple in East Asia as well as in other moist temperate regions in Asia, Europe, and South America. Several fungicides were investigated for their toxicity to mycelial growth and conidial germination of the pathogen in vitro. Tebuconazole, kresoxim-methyl, hexaconazole, propiconazole, and a mixture of tebuconazole and benziothiazolinone sharply inhibited mycelial growth but had less effect on conidial germination. Field tests were conducted in a commercial orchard in Baishui County, Shaanxi Province, China, during 2012, 2013, 2014, and 2015 in order to develop recommendations for apple growers. Three applications of tebuconazole, hexaconazole, propiconazole, or a mixture of tebuconazole and benziothiazolinone at 20-day intervals from early July to late August resulted in defoliation incidence of <5%. When sprays of Bordeaux mixture + tebuconazole, Bordeaux mixture + propiconazole, and Bordeaux mixture + tebuconazole and benziothiazolinone were alternated, the spray interval was extended to 25 days and defoliation incidence remained <5%. Based on historical records and our results, scouting for symptoms should begin in mid-June. We recommend commencing the spray period in early July in years with normal rainfall patterns, and spraying in mid- to late June in years with much rainfall. The findings of this study create a foundation for implementation of an efficient spray program against Marssonina leaf blotch in apple orchards in the Loess Plateau Region of China.


Metabolism of MK-499, a class III antiarrhythmic agent, in rats and dogs.
MK-499 [(+)-N-[1'-(6-cyano-1, 2, 3, 4-tetrahydro-2(R)-naphthalenyl)-3, 4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2, 4'-piperidin)-6-yl]methanesulfonamide] monohydrochloride is an investigational class III antiarrhythmic agent for treatment of malignant ventricular tachyarrhythmias. The disposition of [3H]MK-499 and [14C]MK-499 was studied in rats and dogs after oral and iv administration. MK-499 was concentrated in organs of excretion and the heart. In the rat, urinary radioactivity elimination values after iv (0.5 mg/kg) and oral (6.25 mg/kg) doses were 21 +/- 3% and 10 +/- 2%, respectively. Corresponding fecal recoveries were 68 +/- 6% and 78 +/- 7%. Similar results were found after corresponding doses of [14C]MK-499. In dogs, urine and feces accounted for 16 +/- 3% and 75 +/- 4% of recovered radioactivity after a [3H]MK-499 iv dose (0.1 mg/kg). Corresponding recoveries after an oral dose (1 mg/kg) were 12 +/- 2% and 76 +/- 3%. Biliary (0-24 hr) excretion accounted for 39 +/- 5% and 41 +/- 18% of [3H] and [14C] oral doses in rats, respectively. Dogs excreted 34% of [3H] oral dose in (0-24 hr) bile. The data indicated that a substantial amount of MK-499 was absorbed by rats and dogs. MK-499, metabolite I (formed by loss of N-substitution), and metabolite II (an acid formed by metabolic scission across the benzopyran ring) each represented 30% of rat urinary label. Rat bile contained MK-499 (10%), II (20%), and IV (10%), which was formed by carbon-4 hydroxylation of the tetralin ring. Additionally, rat bile included glutathione (V) and N-acetyl-1-cysteine (VI) conjugates of a ring-opened metabolite. Metabolite III, a positional isomer of IV, was excreted in rat urine. The major labeled species excreted in dog bile were unchanged MK-499 and its glucuronide (VII), which, respectively, represented 50% and 30% of the biliary radioactivity. MK-499 and a small amount of I represented dog urinary radioactivity. The bioavailability of MK-499 was high in dogs (100%) but low in rats (17%). This difference was probably due to the more extensive presystemic metabolism of MK-499 in rats.


Real-time quaking-induced conversion assays for prions: Applying a sensitive but imperfect test in clinical practice.
Real-time quaking-induced conversion (RT-QuIC) assays offer a sensitive and specific means for detection of prions, although false negative results are recognized in clinical practice. We profile the clinical, laboratory, and pathologic features associated with false negative RT-QuIC assays and extend these to frame the diagnostic approach to patients with suspected prion disease. A total of 113 patients with probable or definite prion disease were assessed at Mayo Clinic (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) or Washington University School of Medicine (Saint Louis, MO) from 2013 to 2021. RT-QuIC testing for prions was performed in cerebrospinal fluid (CSF) at the National Prion Disease Pathology Surveillance Center (Cleveland, OH). Initial RT-QuIC testing was negative in 13 of 113 patients (sensitivity = 88.5%). RT-QuIC negative patients were younger (median = 52.0 years vs. 66.1 years, p < 0.001). Other demographic and presenting features, and CSF cell count, protein, and glucose levels were similar in RT-QuIC negative and positive patients. Frequency of 14-3-3 positivity (4/13 vs. 77/94, p < 0.001) and median CSF total tau levels were lower in RT-QuIC negative patients (2517 vs. 4001 pg/mL, p = 0.020), and time from symptom onset to first presentation (153 vs. 47 days, p = 0.001) and symptomatic duration (710 vs. 148 days, p = 0.001) were longer. RT-QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when evaluating patients with suspected prion disease. Patients with negative RT-QuIC had lower markers of neuronal damage (CSF total tau and protein 14-3-3) and longer symptomatic duration of disease, suggesting that false negative RT-QuIC testing associates with a more indolent course.


The changing nature of the protein folding transition state: implications for the shape of the free-energy profile for folding.
According to landscape theory proteins do not fold by localised pathways, but find their native conformation by a progressive organisation of an ensemble of partly folded structures down a folding funnel. Here, we use kinetics and protein engineering to investigate the shape of the free-energy profile for two-state folding, which is the macroscopic view of the funnel process for small and rapidly folding proteins. Our experiments are based mainly on structural changes of the transition state of chymotrypsin inhibitor 2 (CI2) upon destabilisation with temperature and GdnHCl. The transition state ensemble of CI2 is a localised feature in the free-energy profile that is sharply higher than the other parts of the activation barrier. The relatively fixed position of the CI2 transition state on the reaction coordinate makes it easy to characterise but contributes also to overshadow the rest of the free-energy profile, the shape of which is inaccessible for analysis. Results from mutants of CI2 and comparison with other two-state proteins, however, point at the possibility that the barrier for folding is generally broad and that localised transition states result from minor ripples in the free-energy profile. Accordingly, variabilities in the folding kinetics may not indicate different folding mechanisms, but could be accounted for by various degrees of ruggedness on top of very broad activation barriers for folding. The concept is attractive since it summarises a wide range of folding data which have previously seemed unrelated. It is also supported by theory. Consistent with experiment, broad barriers predict that new transition state ensembles are exposed upon extreme destabilisation or radical mutations.


Normal development, growth and reproduction in cellular retinoic acid binding protein-I (CRABPI) null mutant mice.
We have generated mouse null mutants for the cellular retinoic acid (RA) binding protein type I (CRABPI), a protein whose spatio-temporal expression pattern coincides with the target tissues for RA action. Inactivation of the CRABPI gene was accomplished via homologous recombination in embryonic stem cells. Cells carrying the correctly targeted gene were injected into blastocysts and the resulting chimaeras yielded offspring heterozygous for the knockout mutation. Subsequent breeding programs resulted in normal litter sizes containing viable and fertile CRABPI deficient mice. Homozygous mice carrying the knockout mutation were studied in detail to detect possible organ and skeletal anomalies and/or abnormalities of the hematopoietic system. No overt phenotype was evident indicating that a deficiency for CRABPI does not seem to interfere with normal development, growth and reproduction.


Correlation of Fentanyl Positive Drug Screens with Other Medications in Patients from Pain, Rehabilitation and Behavioral Programs.
Fentanyl has been associated with many drug overdose deaths; its presence in many street drugs has been postulated to be increasing. We examined 1.3 million urine drug tests from April 2016 to April 2019 for fentanyl and other drugs. The highest relationship was observed with heroin. Approximately 30%-40% of the drug tests positive for the heroin metabolite 6-monacetylmorphine (6-MAM) were also positive for fentanyl. There was a large variance over time, but the percent positive in 2016 and 2019 were similar. In contrast, there was a definite increase in the presence of fentanyl with cocaine and methamphetamine. There was not a large increase over time associated with methadone, buprenorphine, and marijuana.


Collection of bone grafts from the tuber coxae of the horse.
Autogenous bone grafts were obtained from the tuber coxae of 9 horses. The method used involved an oblique incision to expose the lateral aspect of the tuber coxae. The periosteum was incised and reflected in order to make a 5- by 2.5-cm opening in the lateral cortex for graft retrieval. The method provided good visualization, ample grafting material, and freedom from postsurgical complications.


Antiangiogenic drugs used with chemotherapy for patients with recurrent ovarian cancer: a meta-analysis.
The value of antiangiogenic inhibitors for patients with recurrent ovarian cancer has not been completely affirmed. Therefore, we aimed to assess the effectiveness and toxicities of various antiangiogenic drugs for the treatment of recurrent ovarian cancer. In this meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases for complete randomized controlled trials. The searches were extended to May 15, 2016. The risk of bias of the included studies was evaluated via a Cochrane systematic evaluation, and the statistical analyses were performed using RevMan 5.2 software. In total, we included 8 randomized controlled trials involving 3,211 patients and divided them into 3 groups, vascular endothelial growth factor receptor inhibitors (VEGFRIs), vascular endothelial growth factor (VEGF) inhibitors (bevacizumab), and angiopoietin inhibitors (trebananib). The progression-free survival improved significantly in all the groups being given antiangiogenic drugs (hazard ratio [HR]: 0.55, 95% confidence interval [CI]: 0.45-0.67, I2=0%, P<0.00001 for the VEGFRI group; HR: 0.53, 95% CI: 0.45-0.63, I2=51%, P<0.00001 for the VEGF inhibitor group; HR: 0.67, 95% CI: 0.58-0.77, I2=0%, P<0.00001 for the trebananib group). Overall survival was obviously prolonged in the VEGFRI (HR: 0.76, 95% CI: 0.59-0.97, I2=0%, P=0.03), the VEGF inhibitor (HR: 0.87, 95% CI: 0.77-0.99, I2=0%, P=0.03), and trebananib groups (HR: 0.81, 95% CI: 0.67-0.99, I2=0%, P=0.04). The incidence of grade 3/4 side effects was different among the 3 groups, for example, proteinuria, hypertension, gastrointestinal perforation, and arterial thromboembolism were presented in the VEGF inhibitor group. Increased incidences of fatigue, diarrhea, and hypertension were seen in the VEGFRI group, and the trebananib group had a higher incidence of hypokalemia. This meta-analysis showed that antiangiogenic drugs improved the progression-free survival. The VEGFRI, bevacizumab, and trebananib groups showed increased overall survival. Adding antiangiogenic drugs to chemotherapy treatment resulted in a higher incidence of grade 3/4 side effects, but these were manageable.


Improved single-cell genome amplification by a high-efficiency phi29 DNA polymerase.
Single-cell genomic whole genome amplification (WGA) is a crucial step in single-cell sequencing, yet its low amplification efficiency, incomplete and uneven genome amplification still hinder the throughput and efficiency of single-cell sequencing workflows. Here we introduce a process called Improved Single-cell Genome Amplification (iSGA), in which the whole single-cell sequencing cycle is completed in a high-efficient and high-coverage manner, through phi29 DNA polymerase engineering and process engineering. By establishing a disulfide bond of F137C-A377C, the amplification ability of the enzyme was improved to that of single-cell. By further protein engineering and process engineering, a supreme enzyme named HotJa Phi29 DNA Polymerase was developed and showed significantly better coverage (99.75%) at a higher temperature (40°C). High single-cell genome amplification ability and high coverage (93.59%) were also achieved for commercial probiotic samples. iSGA is more efficient and robust than the wild-type phi29 DNA polymerase, and it is 2.03-fold more efficient and 10.89-fold cheaper than the commercial Thermo Scientific EquiPhi29 DNA Polymerase. These advantages promise its broad applications in large-scale single-cell sequencing.


Why are several inhibitory transmitters present in the innervation of pituitary melanotrophs? Actions and interactions of dopamine, GABA and neuropeptide Y on secretion from neurointermediate lobes of Xenopus laevis.
The aim of the present experiments was to determine whether some rationale for the presence of the several inhibitory neurotransmitters in the innervation to the toad melanotroph might be found in differences in their individual effects or in possible cooperative interactions affecting secretion. Measurements of peptide release from isolated, perifused neurointermediate lobes of the toad Xenopus laevis showed that each of the three identified inhibitory transmitters, dopamine, GABA and NPY, was able to inhibit secretion profoundly and no less effectively than omission of Ca. Moreover, the inhibitory effects were rather similar in onset, duration and recovery. Furthermore, there was no evidence of any cooperative interactions when the transmitters were given in various combinations. And finally, the inhibitory response to each of the transmitters was abolished by pretreatment with pertussis toxin. While not excluding differential postsynaptic effects on other parameters of melanotroph function, the similarities observed have encouraged alternative speculations on the significance of the apparent redundancy of inhibitory transmitters.


Curative resection of a duodenal gastrointestinal stromal tumor in the setting of von Willebrand's disease.
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract and usually presents with gastrointestinal hemorrhage. The diagnosis of GIST is typically made with upper endoscopy after excluding other causes of bleeding. The surgical management of GIST can be challenging depending upon the location of the tumor. We present a unique case of duodenal GIST in the setting von Willebrand's disease diagnosed after emergent laparotomy for massive gastrointestinal hemorrhage. Key strategies in curing our patient were treating the underlying bleeding disorder, collaborating with radiology and gastroenterology teams, and early exploratory laparotomy for refractory hemorrhage. This case demonstrates the challenges of diagnosing and managing GIST in patients with underlying coagulopathies.


Reference limit of thyrotropin (TSH) and free thyroxine (FT4) in thyroperoxidase positive and negative subjects: a population based study.
Current reference values for thyroid function tests are based on data from different ethnicities and geographical areas. The aim of the present study was to determine reference intervals for thyrotropin (TSH) and free T4 (FT4), based on the criteria of the National Academy of Clinical Biochemistry (NACB) in an Iranian population. This study was conducted within the framework of Tehran Thyroid Study (TTS), an ongoing prospective cohort of 5704 randomly selected individuals, age ≥ 20 yr. A total of 2199 individuals (43.3% male, 56.7% female), based on NACB criteria were included in this study. Reference limit analysis was performed for the negative thyroid peroxidase antibody (TPOAb) group. After applying all exclusion criteria except TPOAb positivity (10.5%), data of 2459 participants remained for analysis. Of these, 953 (43.3%) were males and 1246 (56.7%) were females; the mean ± SD age was 43.53 ± 14.16 yr. The mean ± SD and median+IQR for TSH were 1.77 mU/l ± 1.24 and 1.46 (0.93-2.23) mU/l, respectively. The 2.5th and 97.5th percentiles TSH were 0.32 mU/l and 5.06 mU/l respectively. The mean ± SD and median (IQR) for FT4 for all negative TPOAb subjects were 1.19 ± 0.16 and 1.18 (1.08-1.31) ng/dl respectively. Reference ranges for thyroid function tests need to be derived from national databases. This study determined age and sex specific TSH and FT4 reference ranges in a Tehranian population, which could eventually enable clinicians to classify patients more appropriately.


Local activation of mammalian separase in interphase promotes double-strand break repair and prevents oncogenic transformation.
Separase halves eukaryotic chromosomes in M-phase by cleaving cohesin complexes holding sister chromatids together. Whether this essential protease functions also in interphase and/or impacts carcinogenesis remains largely unknown. Here, we show that mammalian separase is recruited to DNA double-strand breaks (DSBs) where it is activated to locally cleave cohesin and facilitate homology-directed repair (HDR). Inactivating phosphorylation of its NES, arginine methylation of its RG-repeats, and sumoylation redirect separase from the cytosol to DSBs. In vitro assays suggest that DNA damage response-relevant ATM, PRMT1, and Mms21 represent the corresponding kinase, methyltransferase, and SUMO ligase, respectively. SEPARASE heterozygosity not only debilitates HDR but also predisposes primary embryonic fibroblasts to neoplasia and mice to chemically induced skin cancer. Thus, tethering of separase to DSBs and confined cohesin cleavage promote DSB repair in G2 cells. Importantly, this conserved interphase function of separase protects mammalian cells from oncogenic transformation.


Dichotic listening to speech: background and preliminary data for digits, sentences, and nonsense syllables.
Three tests of dichotic listening utilizing speech signals as stimuli are included on the VA-CD Tonal and Speech Materials for Auditory Perceptual Assessment, Disc 1.0. They include a dichotic monosyllabic digits task, a dichotic synthetic sentences task, and a dichotic nonsense syllable (CV) task. Since the materials were specially recorded or created and recorded for use on the VA-CD, normative data were collected at nine universities/medical centers in the United States involving 120 young listeners. Data revealed that these listeners had little difficulty correctly identifying digits or synthetic sentences when they were presented at 50-70 dB HL in a dichotic format requiring two responses to each trial. At the same presentation levels and under two onset-time conditions (0- and 90-msec onset stagger), correct responsiveness was less frequent when the stimuli were dichotic CVs. However, scores fell in ranges consistent with previous studies and useful for seeking lesion effects. Although careful definition of stimuli, standardization of materials, and the relative stability offered by audio compact disc technology were prime reasons for making the VA-CD, another goal was to offer the clinician-researcher a range of difficulty among the procedures on the disc. Data from the normative trials using dichotic speech signals suggest that the goal has been accomplished.


A liquid metal flume for free surface magnetohydrodynamic experiments.
We present an experiment designed to study magnetohydrodynamic effects in free surface channel flow. The wide aspect ratio channel (the width to height ratio is about 15) is completely enclosed in an inert atmosphere to prevent oxidization of the liquid metal. A custom-designed pump reduces entrainment of oxygen, which was found to be a problem with standard centrifugal and gear pumps. Laser Doppler velocimetry experiments characterize velocity profiles of the flow. Various flow constraints mitigate secondary circulation and end effects on the flow. Measurements of the wave propagation characteristics in the liquid metal demonstrate the surfactant effect of surface oxides and the damping of fluctuations by a cross-channel magnetic field.


Hepatitis C virus nonstructural protein 5A inhibits thapsigargin-induced apoptosis.
We previously reported that the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) down-regulates TLR4 signaling and lipopolysaccharide-induced apoptosis of hepatocytes. There have been several reports regarding the association between HCV infection and endoplasmic reticulum (ER) stress. Here, we examined the regulation of HCV NS5A on the apoptosis of hepatocytes induced by thapsigargin, an inducer of ER stress. The apoptotic response to thapsigargin and the expression of molecules involved in human hepatocyte apoptotic pathways were examined in the presence or absence of HCV NS5A expression. HCV JFH1 infection induced ER stress in the Huh7 cell line. HCV NS5A protected HepG2 cells against thapsigargin-induced apoptosis, the effect of which was linked to the enhanced expression of the 78-kDa glucose-regulated protein/immunoglobulin heavy-chain binding protein (GRP78). Consistent with a conferred pro-survival advantage, HCV NS5A reduced poly(adenosine diphosphate-ribose) polymerase cleavage and activation of caspases-3, -7 and -9, and Bax expression, while increasing the expressions of the anti-apoptotic molecules XIAP and c-FLIP. HCV NS5A weakly interacts with GRP78 and enhances GRP78 expression in hepatocytes. HCV NS5A enhances GRP78 expression, resulting in the inhibition of apoptotic properties, and inhibits thapsigargin-induced apoptotic pathways in human hepatocytes, suggesting that disruption of ER stress-mediated apoptosis may have a role in the pathogenesis of HCV infection. Thus, HCV NS5A might engender the survival of HCV-infected hepatocytes contributing to the establishment of persistent infection.


[Prevention of accidental poisonings in the household with children under 6 years of age].
Children under six years of age are most frequently involved in poisoning accidents at home. They are caused by medications, household cleaners and plants. Socio-economic factors have an influence on the risk of poisoning. Passive and active measures are useful for the prevention of poisoning. This study shows the precautionary measures and their effectiveness in relation to the risks and the factors of poisoning accidents. A literature review searched in relevant databases for studies that relate to the risk of poisoning on children under six years and that represent the effectiveness of prevention measures. Solely education of the parents is not enough, therefore it is combined with prevention programs, followed by home visits or with child resistant containers. The combination with home visits is effective because the parents get encouraged to make their household safe for children. The education has to be directly with the parents, because the measures can be customized. Short education programs with specific objectives, in written form, are more effective than longer ones. They contain informations about the correct storage and use of child resistant containers, and the behavior in case of emergency. This safety measures must be already implemented at the birth of the child. It's not clear if public education through mass media is effective. Nurses have to educate parents and to advise them to all dangers in the household. The education programs must be carried out individually with the parents. In families with several children, the implementation of passive prevention strategies is more effective. The nurse plays an important role in relation to the poisoning prevention.


SOX7 inhibits tumor progression of glioblastoma and is regulated by miRNA-24.
Sex-determining region Y-box 7 (SOX7) is a putative tumor suppressor in various types of human cancers. In the present study, the expression and function of SOX7 was investigated in human glioblastoma (GBM) cells. Real-time PCR and western blot were carried out to reveal the expression of SOX7 in GBM specimens and cultured cell lines. A short interfering RNA (siRNA) targeting SOX7 was synthesized and transfected into U87 cells. 3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay was performed to valuate the cell proliferation ability in U87 cells. Bioinformatics analysis further predicted its regulation by microRNA-24 (miR-24). Luciferase reporter assay was performed to prove this regulation. SOX7 was downregulated in GBM specimens and cell lines. Inhibition of SOX7 in cultured U87 cells resulted in a slower growth rate. Mechanically, SOX7 was a target of miR-24, demonstrated by reporter assay. SOX7 was a strong tumor suppressor regulated by miR-24 in human GBM cells.


Analysis of swine leukocyte antigen class I gene profiles and porcine endogenous retrovirus viremia level in a transgenic porcine herd inbred for xenotransplantation research.
Molecular characterization of swine leukocyte antigen (SLA) genes is important for elucidating the immune responses between swine-donor and human-recipient in xenotransplantation. Examination of associations between alleles of SLA class I genes, type of pig genetic modification, porcine endogenous retrovirus (PERV) viral titer, and PERV subtypes may shed light on the nature of xenograft acceptance or rejection and the safety of xenotransplantation. No significant difference in PERV gag RNA level between transgenic and non-transgenic pigs was noted; likewise, the type of applied transgene had no impact on PERV viremia. SLA-1 gene profile type may correspond with PERV level in blood and thereby influence infectiveness. Screening of pigs should provide selection of animals with low PERV expression and exclusion of specimens with PERV-C in the genome due to possible recombination between A and C subtypes, which may lead to autoinfection. Presence of PERV-C integrated in the genome was detected in 31.25% of specimens, but statistically significant increased viremia in specimens with PERV-C was not observed. There is a need for multidirectional molecular characterization (SLA typing, viremia estimation, and PERV subtype screening) of animals intended for xenotransplantation research in the interest of xeno-recipient safety.


Observations on the techniques used in the qualitative and quantitative diagnosis of schistosomiasis.
For many years, the Visser filter has been used in various laboratories in South Africa for the qualitative and quantitative diagnosis of human schistosomiasis. In the present study, the effectiveness of the Visser filter was compared with those of the urinalysis method for urine (involving the use of small transparent filters in Millipore filter holders attached to 10-ml syringes) and the Kato-Katz thick smear method for faeces. The Visser filter was the most sensitive in detecting ova in human excreta. Furthermore, there was little agreement between the egg counts obtained using the Visser filter and those obtained with the other two techniques. The Visser filter owes its effectiveness and superior sensitivity to the fact that, compared with the other two techniques, larger quantities of urine (total bladder contents) and stool (up to 5 g) can be easily processed.


Frontal plane knee and hip kinematics during sit-to-stand and proximal lower extremity strength in persons with patellofemoral osteoarthritis: a pilot study.
Increased joint stress and malalignment are etiologic factors in osteoarthritis. Static tibiofemoral frontal plane malalignment is associated with patellofemoral osteoarthritis (PFOA). Patellofemoral joint stress is increased by activities such as sit-to-stand (STS); this stress may be even greater if dynamic frontal plane tibiofemoral malalignment occurs. If hip muscle or quadriceps weakness is present in persons with PFOA, aberrant tibiofemoral frontal plane movement may occur, with increased patellofemoral stress. No studies have investigated frontal plane tibiofemoral and hip kinematics during STS in persons with PFOA or the relationship of hip muscle and quadriceps strength to these motions. Eight PFOA and seven control subjects performed STS from a stool during three-dimensional motion capture. Hip muscle and quadriceps strength were measured as peak isometric force. The PFOA group demonstrated increased peak tibial abduction angles during STS, and decreased hip abductor, hip extensor, and quadriceps peak force versus controls. A moderate inverse relationship between peak tibial abduction angle and peak hip abductor force was present. No difference between groups was found for peak hip adduction angle or peak hip external rotator force. Dynamic tibiofemoral malalignment and proximal lower extremity weakness may cause increased patellofemoral stress and may contribute to PFOA incidence or progression.


Providing mental health first aid in the workplace: a Delphi consensus study.
Mental health problems are common in the workplace, but workers affected by such problems are not always well supported by managers and co-workers. Guidelines exist for the public on how to provide mental health first aid, but not specifically on how to tailor one's approach if the person of concern is a co-worker or employee. A Delphi consensus study was carried out to develop guidelines on additional considerations required when offering mental health first aid in a workplace context. A systematic search of websites, books and journal articles was conducted to develop a questionnaire with 246 items containing actions that someone may use to offer mental health first aid to a co-worker or employee. Three panels of experts from English-speaking countries were recruited (23 consumers, 26 managers and 38 workplace mental health professionals), who independently rated the items over three rounds for inclusion in the guidelines. The retention rate of the expert panellists across the three rounds was 61.7 %. Of the 246 items, 201 items were agreed to be important or very important by at least 80 % of panellists. These 201 endorsed items included actions on how to approach and offer support to a co-worker, and additional considerations where the person assisting is a supervisor or manager, or is assisting in crisis situations such as acute distress. The guidelines outline strategies for a worker to use when they are concerned about the mental health of a co-worker or employee. They will be used to inform future tailoring of Mental Health First Aid training when it is delivered in workplace settings and could influence organisational policies and procedures.


Comparison of results from novice and trained personnel using the Macintosh laryngoscope, Pentax AWS®, C-MAC™ and Bonfils intubation fibrescope: a manikin study.
Indirect laryngoscopes offer improved laryngeal view and higher success rates of intubation, particularly for difficult airways. We hypothesised that: (a) the time required for intubation, overall success rates and ease of intubation with indirect laryngoscopes would be better than with the Macintosh laryngoscope; and (b) novices may achieve higher success rates and intubate faster using indirect laryngoscopes. In a cross-sectional observational study, 13 novices and 13 skilled anaesthetists were recruited. Participants were compared when intubating a manikin simulating normal and difficult airway scenarios using the Macintosh laryngoscope, Pentax Airway Scope® (AWS), C-MAC[TM] and Bonfils intubation fibrescope. There was no significant difference in intubation success rates between the groups. Skilled anaesthetists intubated faster than novices with Pentax AWS in the difficult airway scenario (22 s vs. 33 s, p = 0.047). The mean intubation times for C-MAC and Pentax AWS were shorter than for the Macintosh laryngoscope and Bonfils intubation fibrescope in both difficult (C-MAC: 24 s, Pentax AWS: 28 s, Macintosh: 80 s, Bonfils: 61 s; p < 0.001) and normal (C-MAC: 17 s, Pentax AWS: 19 s, Macintosh: 39 s, Bonfils: 38 s; p = 0.002) airway scenarios. We found that intubation success was more than 85% with all indirect laryngoscopes compared to 69% for the Macintosh laryngoscope. Both C-MAC and Pentax AWS achieved faster intubation times compared to the Macintosh laryngoscope and Bonfils intubation fibroscope for both airway scenarios. Skilled anaesthetists were 33% faster than novices when intubating a difficult airway using Pentax AWS.


[Giant paraurethral leiomyoma in the female: a case report].
We report a case of giant paraurethral leiomyoma weighing more than 100 g in a 19-year-old woman. She had been complaining of micturition pain and a mass at the external genitals. Magnetic resonance imaging showed a 5 cm mass surrounding the urethra, which appeared low intensity on T1-weighted images and higher intensity than that of the surrounding muscles in the pelvis on T2-weighted images. Biopsy was performed and the pathological diagnosis was leiomyoma. The mass was removed transvaginally and transperitoneally, which did not invade to urethra or vaginal wall. The resected specimen exhibited 8 x 7.5 x 3.6 cm in size and 105 g in weight. Pathological diagnosis was leiomyoma with no invasion to surrounding tissue. This is the 132nd case of female paraurethral leiomyoma in Japan, and there were only five cases (6%) of giant paraurethral leiomyoma weighing more than 100 g. We discuss the clinical and pathological features of this disease.


Lessons Learned in Posttraumatic Reconstruction of Labial Defects in Children.
There is no universal technique for reconstructing the different types of labial defects. The etiology, the size and location, the layers compromised and the depth of the defect are the main determinants of the technique to be chosen. The aesthetic form and the function recovery must be the main objective of the therapeutic process.Scarce studies concentrate into the pediatric population and the operational resolution of complex, full-depth defects. The oral contingence, articulation and facial expression (mimicking) are amongst the most important functions of the lower third of the face, and, in terms of reconstruction, they represent a difficult task for the plastic surgeon. In our case, the experience has taught us about new tools, useful and potentially replicable to guide the reconstruction of our infantile population. The authors present different techniques from five different cases, using loco-regional options that spare microsurgical solutions.


Temperature Dependence of the Thermo-Optic Coefficient of SiO2 Glass.
This paper presents a thorough analysis on the temperature dependence of the thermo-optic coefficient, dn/dT, of four bulk annealed pure-silica glass samples (type I-natural quartz: Infrasil 301; type II-quartz crystal powder: Heraeus Homosil; type III-synthetic vitreous silica: Corning 7980 and Suprasil 3001) from room temperature down to 0 K. The three/four term temperature dependent Sellmeier equations and respective coefficients were considered, which results from fitting to the raw data obtained by Leviton et al. The thermo-optic coefficient was extrapolated down to zero Kelvin. We have obtained dn/dT values ranging from 8.16 × 10-6 up to 8.53 × 10-6 for the four samples at 293 K and for a wavelength of 1.55 μm. For the Corning 7980 SiO2 glass, the thermo-optic coefficient decreases monotonically, from 8.74 × 10-6 down to 8.16 × 10-6, from the visible range up to the third telecommunication window, being almost constant above 1.3 μm. The Ghosh's model was revisited, and it was concluded that the thermal expansion coefficient only accounts for about 2% of the thermo-optic coefficient, and we have obtained an expression for the temperature behavior of the silica excitonic bandgap. Wemple's model was also analyzed where we have also considered the material dispersion in order to determine the coefficients and respective temperature dependences. The limitations of this model were also discussed.


The Ensembl Variant Effect Predictor.
The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.


[Transglutaminase 2 inhibits the proliferation of H1 subtype influenza virus in MDCK cells].
Transglutaminase 2 (TGM2) is a ubiquitous multifunctional protein, which is related to the adhesion of different cells and tumor formation. Previous studies found that TGM2 is involved in the interaction between host cells and viruses, but the effect of TGM2 on the proliferation of influenza virus in cells has not been reported. To explore the effect of TGM2 during H1N1 subtype influenza virus infection, a stable MDCK cell line with TGM2 overexpression and a knockout cell line were constructed. The mRNA and protein expression levels of NP and NS1 as well as the virus titer were measured at 48 hours after pot-infection with H1N1 subtype influenza virus. The results showed that overexpression of TGM2 effectively inhibited the expression of NP and NS1 genes of H1N1 subtype influenza virus, while knockout of TGM2 up-regulated the expression of the NP and NS1 genes, and the expression of the NP at protein level was consistent with that at mRNA level. Virus proliferation curve showed that the titer of H1N1 subtype influenza virus decreased significantly upon TGM2 overexpression. On the contrary, the virus titer in TGM2 knockout cells reached the peak at 48 h, which further proved that TGM2 was involved in the inhibition of H1N1 subtype influenza virus proliferation in MDCK cells. By analyzing the expression of genes downstream of influenza virus response signaling pathway, we found that TGM2 may inhibit the proliferation of H1N1 subtype influenza virus by promoting the activation of JAK-STAT molecular pathway and inhibiting RIG-1 signaling pathway. The above findings are of great significance for revealing the mechanism underlying the interactions between host cells and virus and establishing a genetically engineering cell line for high-yield influenza vaccine production of influenza virus.


Distribution of urocortins and corticotropin-releasing factor receptors in the cardiovascular system.
Urocortins are human homologues of urotensin I, a fish corticotropin-releasing-factor- (CRF-) like peptide secreted from the urophysis. There are three urocortins: urocortin 1, urocortin 2, and urocortin 3 in mammals. We have shown that urocortin 1 and urocortin 3 are endogenously synthesized in the myocardial cells of human heart and may act on CRF type 2 receptor (CRFR2) expressed in the heart. Expression levels of urocortin 1 in the heart and plasma urocortin 1 levels are elevated in patients with heart failure. Recent studies have shown that urocortins have various biological actions in the cardiovascular system, such as a vasodilator action, a positive inotropic action, a cardioprotective action against ischemia/reperfusion injury, and suppressive actions against the renin angiotensin system and the sympathetic nervous system. Urocortins and CRFR2 may therefore be a potential therapeutic target for cardiovascular diseases, such as congestive heart failure, hypertension, and myocardial infarction.


Inadequate intake of nutrients essential for neurodevelopment in children with fetal alcohol spectrum disorders (FASD).
This study evaluated dietary intake in children with fetal alcohol spectrum disorders (FASD). Pre-clinical research suggests that nutrient supplementation may attenuate cognitive and behavioral deficits in FASD. Currently, the dietary adequacy of essential nutrients in children with FASD is unknown. Dietary data were collected as part of a randomized, double-blind controlled trial of choline supplementation in FASD. Participants included 31 children with FASD, ages 2.5-4.9 years at enrollment. Dietary intake data was collected three times during the nine-month study via interview-administered 24-hour recalls with the Automated Self-Administered 24-hour Recall. Dietary intake of macronutrients and 17 vitamins/minerals from food was averaged across three data collection points. Observed nutrient intakes were compared to national dietary intake data of children ages 2-5 years (What we Eat in America, NHANES 2007-2008) and to the Dietary Reference Intakes. Compared to the dietary intakes of children in the NHANES sample, children with FASD had lower intakes of saturated fat, vitamin D, and calcium. The majority (>50%) of children with FASD did not meet the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) for fiber, n-3 fatty acids, vitamin D, vitamin E, vitamin K, choline, and calcium. This pattern of dietary intake in children with FASD suggests that there may be opportunities to benefit from nutritional intervention. Supplementation with several nutrients, including choline, vitamin D, and n-3 fatty acids, has been shown in animal models to attenuate the cognitive deficits of FASD. These results highlight the potential of nutritional clinical trials in FASD.


Super-resolution Reflection Microscopy via Absorbance Modulation.
In recent years, fluorescence microscopy has been revolutionized. Reversible switching of fluorophores has enabled circumventing the limits imposed by diffraction. Thus, resolution down to the molecular scale became possible. However, to the best of our knowledge, the application of the principles underlying super-resolution fluorescence microscopy to reflection microscopy has not been experimentally demonstrated. Here, we present the first evidence that this is indeed possible. A layer of photochromic molecules referred to as the absorbance modulation layer (AML) is applied to a sample under investigation. The AML-coated sample is then sequentially illuminated with a one-dimensional (1D) focal intensity distribution (similar to the transverse laser mode TEM01) at wavelength λ1 = 325 nm to create a subwavelength aperture within the AML, followed by illumination with a Gaussian focal spot at λ2 = 633 nm for high-resolution imaging. Using this method, called absorbance modulation imaging (AMI) in reflection, we demonstrate a 2.4-fold resolution enhancement over the diffraction limit for a numerical aperture (NA) of 0.65 and wavelength (λ) of 633 nm.


Clinical and endocrinological investigation of possible ovulatory failure in a dairy cow.
Ovulatory failure was diagnosed in a cow by repeated rectal palpation. The follicle continued to increase in size accompanied by a thickening of the wall and retention of fluid in the central cavity. Plasma hormone profiles showed normal preovulatory oestradiol and luteinising hormone peaks. Four days later progesterone concentrations rose and were maintained for 14 days before falling to baseline concentrations as in a normal luteal phase. Twenty-two days after the luteinising hormone peak, the animal returned to oestrus.


Demethylation demystification.
The ability of the DNA methyltransferase inhibitors (DNMTi) to induce terminal differentiation in fibroblasts was first noted by Taylor and Jones in 1979; Silverman and Holland reported hematologic improvement in patients with myelodysplastic syndrome (MDS) in 1993. That azacitidine improves survival in patients with high-risk MDS and acute myeloid leukemia with MDS features compared with a combined comparator group of supportive care, low-dose cytarabine, and intensive cytarabine plus anthracycline, while inducing trilineage normalization in approximately 15% of patients makes the development of more potent, more specific drugs that behave like azacitidine imperative. The question is, how do the azanucleosides behave?


[Reactions to vaccinations against tetanus and tick-borne encephalitis caused by merthiolate (thiomersal)].
Thirty patients with suspected adverse reactions to tetanus- or tick-borne encephalitis-vaccines were subjected to allergy tests. In 8 of 30 patients epicutaneous and/or intracutaneous tests with merthiolate were positive. Testing anorganic mercury, formaldehyde, aluminium hydroxide, gentamycin and egg white (i.c. and RAST), no positive reactions were found. After vaccination - prior to testing - merthiolate - positive patients had suffered from local inflammatory reactions at the injection site, fever and lymphadenopathy (four patients), urticarial (three patients) or lichenoid exanthemas (one patient). Reviewing the literature it is suggested that alternatively merthiolate-free vaccines be provided for sensitized individuals.


Factors Affecting Physician Satisfaction and Wisconsin Medical Society Strategies to Drive Change.
Physicians' dissatisfaction in their work is increasing, which is affecting the stability of health care in America. The Wisconsin Medical Society (Society) surveyed 1016 Wisconsin physicians to determine the source of their dissatisfaction. The survey results indicate Wisconsin physicians are satisfied when it comes to practice environment, work-life balance, and income. In addition, they are extremely satisfied when it comes to rating their ability to provide high quality care, and they have identified some benefits related to the adoption of electronic health records. However, they are feeling burned out, very unsatisfied with the amount of time spent in direct patient care compared to indirect patient care, and that they are spending too much time on administrative and data entry tasks. In terms of future workforce, many physicians are either unsure or would not recommend the profession to a prospective medical student. Electronic health records serve as both a satisfier and dissatisfier and as a potential driver for future physician satisfaction interventions. Changes at the institutional, organizational, and individual levels potentially could address the identified dissatisfiers and build upon the satisfiers. The Society identifies 12 strategies to improve upon the physician experience.


A green and efficient vortex-assisted liquid-phase microextraction based on supramolecular solvent for UV-VIS determination of nitrite in processed meat and chicken products.
This paper describes a simple, efficient and rapid analytical method for extraction and determination of nitrite in meat and chicken products by vortex-assisted supramolecular solvent-based liquid phase microextraction (VA-SUPRAS-LPME) prior to spectrophotometric detection. The SUPRAS was rapidly formed by the addition of a colloidal decanoic acid suspension to tetrahydrofuran (THF). The validation studies were carried out in terms of linearity, limit of detection (LOD), limit of quantitation (LOQ), matrix effects, robustness, uncertainty measurement, precision, accuracy, and certified reference material (CRM) analysis using optimized experimental conditions. The LOD, LOQ, linearity and matrix effect were 0.035 ng mL-1, 0.1 ng mL-1, 0.1-300 ng mL-1, and 9.6% respectively, with high preconcentration factor (200). The method was successfully applied for the determination of nitrite in processed products. Moreover, the results obtained by the proposed method were compared to the standard Griess method, and showed no significant differences in term of Student's t-test.


Adaptation of cardiac myosin and creatine kinase to chronic hypoxia: role of anorexia and hypertension.
The effects of chronic hypobaric hypoxia (CHH, 28 days, simulated altitude 5,500 m) on the cardiac expression of myosin heavy chain (MHC) and creatine kinase (CK) was studied in rat left (LV) and right (RV) ventricle. To separate the effects of hypoxia from its associated perturbations, anorexia and pulmonary hypertension (resulting in RV hypertrophy), CHH animals were compared with normoxic controls (C) and with rats restricted in food supply (pair fed, PF). In RV, the increased proportion of beta-MHC in CHH (20 +/- 3%) vs. C (7 +/- 2%, P < 0.01) and vs. PF (12 +/- 2%, P < 0.05) rats was mainly attributed to hypertension. In contrast, the higher beta-MHC of CHH (23 +/- 2%) vs. C (13 +/- 2%, P < 0.05) in LV was mainly ascribed to anorexia (PF = 21 +/- 3%, not significant). A major contribution of anorexia was also evidenced in the isozymic profile of CK; anorexia accounted for a 25% decrease in mito-CK specific activity in LV, whereas hypertension partly accounted for the threefold increase in BB-CK in RV. CHH specifically induced a twofold rise in LV BB-CK. This suggests that both the expression of slow myosin, improving the economy of contraction, and the changes in CK isozymic profile could provide a biochemical basis for the CHH resistance to ischemia.


[Epilepsy of the developmental age and control of seizure-releasing factors].
On the basis of an analysis of a paediatric material the author discusses the most important elements influencing the pattern of developmental age epilepsy calling attention to the significance of early aetiological diagnosis since in this early period of life many processes can be treated causatively before epilepsy develops into a chronic disease. The dynamic course of epilepsy and classification difficulties resulting from clinical and electroencephalographic variability of childhood epilepsy are discussed explaining these facts by differences in structural maturity and functional organization at the age of development. It is indispensable to know the classification of seizure circuits for selection of possibly effective symptomatic treatment for prevention of seizures and their sequelae in the neuropsychiatric and social aspects. In the clinical course of a given case there are also individual differences between the seizure-releasing factors and their knowledge helps to avoid the critical threshold of seizure readiness releasing seizures in a given child. Acceptance of certain rules for observation in the everyday life of patients permits an individual prophylaxis of seizures. This shows that prevention of epileptic seizures includes not only causative and symptomatic treatment but also the knowledge of individual seizure-releasing factors which cannot be controlled pharmacologically.


Gait and cognitive impairments in multiple sclerosis: the specific contribution of falls and fear of falling.
Our goal was to identify the specific contribution of fear of falling (FoF) and falls with quantitative gait impairments and cognition capabilities in multiple sclerosis (MS) patients. Patients were separated into four individual subgroups as to the presence of FoF and falls (i.e., fearless/non-fallers, fearless/fallers, FoF/non-fallers and FoF/fallers). The Falls Efficacy Scale International questionnaire was used to assess the level of concern of falling. Participants were defined as "fallers" and "non-fallers" based on their fall history. Spatio-temporal parameters of gait were analyzed using an electronic mat. Cognitive performance was assessed by a computerized cognitive battery of tests. The study included 540 MS patients, 47% were defined as fallers and 61.9% reported a FoF. Non-significant differences were found between the fearless/non-fallers and fearless/fallers in all clinical, gait and cognitive scores. FoF/non-fallers walked significantly slower compared to fearless MS individuals who had previously fallen. Furthermore, the same patient group exhibited a poorer performance in the motor skills cognitive subdomain. A significant reverse relationship was found between FoF and cognitive motor skills in the fallers and non-fallers groups. FoF characterizes a more disabling symptom than falling in the MS population.


Cholecystokinin-8S increases dynorphin B, aspartate and glutamate release in the fronto-parietal cortex of the rat via different receptor subtypes.
The effect of sulphated cholecystokinin-8 (CCK-8S) on extracellular dynorphin B, aspartate, glutamate and GABA levels in the rat fronto-parietal cortex was investigated with in vivo microdialysis. The peptide was infused through the microdialysis probe trying to mimic local CCK-8S release. Basal levels of dynorphin B were around 20 pM, aspartate 100 nM, glutamate 600 nM and GABA 30 nM. CCK-8S (10 microM) induced a approximately 3-fold increase in extracellular dynorphin B, aspartate and glutamate levels, while GABA levels were only slightly increased. The effect of CCK-8S was restricted to the stimulated neocortex. Systemic pretreatment with the CCKB antagonist, L-365, 260, but not with the CCKA antagonist, L-364, 718, significantly antagonised the effect of CCK-8S on cortical dynorphin B and aspartate release. However, both CCKA and CCKB antagonists inhibited the increase in cortical glutamate levels. Thus, the present results indicate that cortical CCK release exerts a stimulatory modulation on cortical dynorphin B and aspartate release via the CCKB receptor subtype, and on glutamate release via both CCKA and CCKB receptor subtypes. Considering electrophysiological evidence that CCK increases neuronal firing rates in many brain regions, it may be suggested that CCK represents a stimulatory system modulating the function of the neocortex.


Kratom Alkaloids, Cannabinoids, and Chronic Pain: Basis of Potential Utility and Role in Therapy.
Introduction: Chronic neuropathic pain is as a severe detriment to overall quality of life for millions of Americans. Current pharmacological treatment options for chronic neuropathic pain are generally limited in efficacy and may pose serious adverse effects such as risk of abuse, nausea, dizziness, and cardiovascular events. Therefore, many individuals have resorted to methods of pharmacological self-treatment. This narrative review summarizes the existing literature on the utilization of two novel approaches for the treatment of chronic pain, cannabinoid constituents of Cannabis sativa and alkaloid constituents of Mitragyna speciosa (kratom), and speculates on the potential therapeutic benefits of co-administration of these two classes of compounds. Methods: We conducted a narrative review summarizing the primary motivations for use of both kratom and cannabis products based on epidemiological data and summarize the pre-clinical evidence supporting the application of both kratom alkaloids and cannabinoids for the treatment of chronic pain. Data collection was performed using the PubMed electronic database. The following word combinations were used: kratom and cannabis, kratom and pain, cannabis and pain, kratom and chronic pain, and cannabis and chronic pain. Results: Epidemiological evidence reports that the self-treatment of pain is a primary motivator for use of both kratom and cannabinoid products among adult Americans. Further evidence shows that use of cannabinoid products may precede kratom use, and that a subset of individuals concurrently uses both kratom and cannabinoid products. Despite its growing popularity as a form of self-treatment of pain, there remains an immense gap in knowledge of the therapeutic efficacy of kratom alkaloids for chronic pain in comparison to that of cannabis-based products, with only three pre-clinical studies having been conducted to date. Conclusion: There is sufficient epidemiological evidence to suggest that both kratom and cannabis products are used to self-treat pain, and that some individuals actively use both drugs, which may produce potential additive or synergistic therapeutic benefits that have not yet been characterized. Given the lack of pre-clinical investigation into the potential therapeutic benefits of kratom alkaloids against forms of chronic pain, further research is warranted to better understand its application as a treatment alternative.


Incorporating bioinformatics into biological science education in Nigeria: prospects and challenges.
The urgency to process and analyze the deluge of data created by proteomics and genomics studies worldwide has caused bioinformatics to gain prominence and importance. However, its multidisciplinary nature has created a unique demand for specialist trained in both biology and computing. Several countries, in response to this challenge, have developed a number of manpower training programmes. This review presents a description of the meaning, scope, history and development of bioinformatics with focus on prospects and challenges facing bioinformatics education worldwide. The paper also provides an overview of attempts at the introduction of bioinformatics in Nigeria; describes the existing bioinformatics scenario in Nigeria and suggests strategies for effective bioinformatics education in Nigeria.


[Psychological management of heart patients and their relatives in the pre- and postoperative phases: experiences from a 2 year model trial].
The psychological and neurological disorders as well as psychosocial problems experienced by cardiac patients and their relatives while waiting for coronary artery bypass surgery are outlined, as well as their intrapsychic situation following the operation. With a view to providing long-term psychological support and care of cardiac bypass patients and their relatives, a care model has been developed which emphasizes the following: (1) initial contact and individual counselling immediately following establishment of the indication for surgery (2) client-centered groups to prepare for the operation, involving both the patients and their partners (3) client-centered (therapy)/relaxation groups for postoperative patients. This model trial is described, covering its development, structure, and contents in some detail. An evaluation is given, as is an explanatory case presentation. The results obtained from 48 cardiac bypass patients in a follow-up study of their views concerning the psychological care provided, are presented in a summary account. Concluding, the authors outline future emphases for practical work and research.


Antigen Loss Variants: Catching Hold of Escaping Foes.
Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.


In vitro and in vivo regulation of the expression of the tyrosine hydroxylase gene.
Preganglionic nerve stimulation has been shown to induce delayed or long term changes in the neuron. Different models were used to study the trans-synaptic regulation of the tyrosine hydroxylase (TH): the rat adrenal medulla (AM) and the superior cervical ganglia (SCG). Northern blot analysis, western blot and enzymatic assays demonstrated that the TH mRNA paralleled both an increase in the protein amount and its enzymatic activity. Results of in vitro transcription on nuclei isolated from AM or from SCG after treatment with reserpine suggest that this increase in TH expression is due to an effect on the transcriptional activity of the TH gene. Other gene, cfos, is also induced by reserpine indicating that the TH transcription in these neurons may be mediated by "third messengers". Several putative regulatory elements, in particular an octamer sequence AP1 has been localized in the promoter of TH gene. Gel shift assays with nuclear extracts from untreated and phorbol ester treated cells strongly suggest that a protein complex binds to this AP1 like sequence. Comparative analysis of gel shift assays with AM nuclear extracts exhibit a similar pattern suggesting that this AP1 site could be involved in the trans-synaptic regulation of TH.


New targets in endocrine-resistant hormone receptor-positive breast cancer.
Endocrine-based treatments are the backbone of initial therapy for advanced hormone receptor-positive breast cancers. Developing new therapeutic strategies to address resistance to endocrine therapy is an area of active research. In this review, we discuss targeted therapies that are currently the standard of care, as well as agents that are at present under investigation as potential treatments for advanced hormone receptor-positive breast cancer.


[The possible drawbacks of applying the DRG classification].
The objective of this article is to present the difficulties linked to the measure and use of the Diagnosis Related Group (DRG) as part of a hospital's production and management accounting evaluation system. We will present here all the criticisms brought forth in management literature against DRG classifications. The article isn't intended to argue against and to push people to reconsider the tool but rather to attract the attention of politicians and hospital managers to all the possible difficulties and outcomes that could be generated by the DRG, this in terms of either the AP-DRG or the German-DRG, the latter being the classification that has been adopted in Switzerland as the basis for the construction of the future Swiss-DRG.


Bone marrow metastases. A review.
Although bone marrow examination is a common procedure in the evaluation of patients with cancer, its role and contribution have been questioned in recent years. This review deals with the clinical and biologic aspects of metastasis to the bone marrow. The discussion is focused on the common tumor types that involve marrow and the application of newer techniques for tumor detection in the marrow. Therapeutic and prognostic implications of bone marrow metastasis are significant in several clinical settings. The mechanisms by which tumor cells affect marrow function have not been completely defined.


Quantifying Autophagic Structures in Mammalian Cells Using Confocal Microscopy.
Autophagy relies on the sequential, hierarchical association of proteins with phagophores, and forming autophagosomes to allow completion of the process. Additionally, the trafficking of the unique transmembrane autophagy-related protein ATG9 is vital for autophagy progression. In this chapter, we discuss methods to monitor autophagosome number using confocal microscopy, by following the association of different autophagosomal markers with the phagophore and completed autophagosome. We also discuss methods to monitor the trafficking of ATG9 in mammalian cells under starvation conditions.


The phosphotransferase system of Streptomyces coelicolor.
We have investigated the crr gene of Streptomyces coelicolor that encodes a homologue of enzyme IIAGlucose of Escherichia coli, which, as a component of the phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) plays a key role in carbon regulation by triggering glucose transport, carbon catabolite repression, and inducer exclusion. As in E. coli, the crr gene of S. coelicolor is genetically associated with the ptsI gene that encodes the general phosphotransferase enzyme I. The gene product IIACrr was overproduced, purified, and polyclonal antibodies were obtained. Western blot analysis revealed that IIACrr is expressed in vivo. The functionality of IIACrr was demonstrated by phosphoenolpyruvate-dependent phosphorylation via enzyme I and the histidine-containing phosphoryl carrier protein HPr. Phosphorylation was abolished when His72, which corresponds to the catalytic histidine of E. coli IIAGlucose, was mutated. The capacity of IIACrr to operate in sugar transport was shown by complementation of the E. coli glucose-PTS. The striking functional resemblance between IIACrr and IIAGlucose was further demonstrated by its ability to confer inducer exclusion of maltose to E. coli. A specific interaction of IIACrr with the maltose permease subunit MalK from Salmonella typhimurium was uncovered by surface plasmon resonance. These data suggest that this IIAGlucose-like protein may be involved in carbon metabolism in S. coelicolor.


[Pain of autonomic nervous system origin].
Reflex sympathetic dystrophy (algodystrophy) is a descriptive term used to designate a clinical phenomenology, which appears after a trauma, often a minor one; it is thought that the sympathetic nervous system plays an important role in its physiopathology. The same applies to sympathetic maintained pain appearing after a lesion of a peripheral nerve (causalgia). There is no agreement as to which are the criteria necessary to make the diagnosis and as to what is the physiopathology of these syndromes. Research in this field is very active today.


[Evaluation of bevacizumab combined with irinotecan-based regimen as the first-line treatment for patients with metastatic colorectal cancer].
To assess the efficacy and safety of bevacizumab plus irinotecan-based regimen for the first line treatment in metastatic colorectal cancer (mCRC) patients, and to investigate the correlation between serum tumor markers including CEA and CA19-9 and response as well as prognosis. From May 2007 to July 2008, 67 previously untreated mCRC patients received treatment of IFL (n = 25), IFL plus Bevacizumab (n = 20) or FOLFIRI (n = 22). The treatment continued until disease progression or unacceptable toxicity. The data were retrospectively analyzed. All patients were evaluable for response, survival and toxicity analysis. The objective response rate of IFL, IFL plus Bevacizumab or FOLFIRI regimen groups was 16.0% (4/25), 35.0% (7/20) and 18.2% (4/22), respectively (χ(2) = 6.026, P = 0.049). The median progression-free survival (PFS) of IFL plus bevacizumab group was 7.5 months, significantly improved as compared with 3.7 months in the IFL group and 4 months in FOLFIRI group (χ(2) = 11.97, P = 0.003). Of all 67 cases, the one-year survival rate was 47.0%, two-year survival rate was 27.0%, and the median overall survival (OS) was 13.0 months, with no significant difference among the three treatment groups (χ(2) = 3.42, P = 0.18). The serum CEA and CA19-9 levels were decreased after treatment, but with no significant difference among the three groups (P > 0.05). The common toxicity profiles of IFL and FOLFIRI regimens were diarrhea and neutropenia, while the toxicity related to bevacizumab was consistent with that documented in previous literature, such as hypertension, hemorrhage, cardiac toxicity and delayed wound healing. The addition of bevacizumab to irinotecan-based regimen significantly improves the response rate and PFS in first-line treatment for patients with mCRC and its toxicity is well tolerated.


Globalisation and global health: issues for nursing.
'Globalisation' is the term used to describe the increasing economic and social interdependence between countries. Shifting patterns of health and disease are associated with globalisation. Global health refers to a health issue that is not contained geographically and that single countries cannot address alone. In response to globalisation and global health issues, nurses practise in new and emerging transnational contexts. Therefore, it is important that nurses respond proactively to these changes and understand the effects of globalisation on health worldwide. This article aims to increase nurses' knowledge of, and confidence in, this important area of nursing practice.


Predictive value of temporal retinal disease in retinopathy of prematurity.
Screening examinations for retinopathy of prematurity (ROP) can be stressful to the premature infant. The temporal retina is the most easily visualized area of the peripheral retina. This study was undertaken to determine whether evaluation of the temporal peripheral retina provides a reliable indicator of the ROP status of the entire retina. A total of 690 ROP eye examinations were performed on 156 premature infants. Eye examinations of 95 patients were reviewed retrospectively and of 61 patients prospectively. All patients were born at less than 34 weeks estimated gestational age (EGA) and had a birth weight less than 1600 g. No examinations were performed prior to 4 weeks of age. Each eye examination was considered independently. The fundus examination was recorded using the International Classification of Retinopathy of Prematurity. The temporal four clock hours of retina were classified as the "temporal" retina. The remainder of the peripheral retina was classified as "nontemporal." A highly significant correlation (Pearson correlation coefficient = 0.88) between the severity (ie, stage) of temporal ROP and the severity of nontemporal ROP was noted. The status of temporal ROP was found to be more advanced or the same as nontemporal retina in 91.2% of the examinations. Nontemporal disease was found to be more severe than temporal disease in 8.8% of the examinations, but only 0.4% of examinations indicated nontemporal disease that was worse than temporal disease by more than one stage. The temporal retinal disease status in ROP is strongly predictive of the disease status of the entire retina. An abbreviated retinal examination of the temporal clock hours provides a reliable indicator of the highest stage of ROP present in the entire retina. Such a screening examination, although not recommended for routine screening, may be useful when a complete ROP examination cannot be performed because of physiologic instability or poor visibility.


Photophysics of organometallic platinum(II) derivatives of the diketopyrrolopyrrole chromophore.
A pair of diketopyrrolopyrrole (DPP) chromophores that are end-functionalized with platinum containing "auxochromes" were subjected to electrochemical and photophysical study. The chromophores contain either platinum acetylide or ortho-metalated 2-thienylpyridinyl(platinum) end-groups (DPP-Pt(CC) and DPP-Pt(acac), respectively). The ground state redox potentials of the chromophores were determined by solution electrochemistry, and the HOMO and LUMO levels were estimated. The chromophores' photophysical properties were characterized by absorption, photoluminescence, and time-resolved absorption spectroscopy on time scales from sub-picoseconds to microseconds. Density functional theory (DFT) computations were performed to understand the molecular orbitals involved in both the singlet and triplet excited state photophysics. The results reveal that in both platinum DPP derivatives the organometallic auxochromes have a significant effect on the chromophores' photophysics. The most profound effect is a reduction in the fluorescence yields accompanied by enhanced triplet yields due to spin-orbit coupling induced by the metal centers. The effects are most pronounced in DPP-Pt(acac), indicating that the orthometalated platinum auxochrome is able to induce spin-orbital coupling to a greater extent compared to the platinum acetylide units.


Phase Transformation, Vibrational and Electronic Properties of K2Ce(PO4)2: A Combined Experimental and Theoretical Study.
Herein we report the high-temperature crystal chemistry of K2Ce(PO4)2 as observed from a joint in situ variable-temperature X-ray diffraction (XRD) and Raman spectroscopy as well as ab initio density functional theory (DFT) calculations. These studies revealed that the ambient-temperature monoclinic (P21/n) phase reversibly transforms to a tetragonal (I41/amd) structure at higher temperature. Also, from the experimental and theoretical calculations, a possible existence of an orthorhombic (Imma) structure with almost zero orthorhombicity is predicted which is closely related to tetragonal K2Ce(PO4)2. The high-temperature tetragonal phase reverts back to ambient monoclinic phase at much lower temperature in the cooling cycle compared to that observed at the heating cycle. XRD studies revealed the transition is accompanied by volume expansion of about 14.4%. The lower packing density of the high-temperature phase is reflected in its significantly lower thermal expansion coefficient (αV = 3.83 × 10-6 K-1) compared to that in ambient monoclinic phase (αV = 41.30 × 10-6 K-1). The coexistences of low- and high-temperature phases, large volume discontinuity in transition, and large hysteresis of transition temperature in heating and cooling cycles, as well as drastically different structural arrangement are in accordance with the first-order reconstructive nature of the transition. Temperature-dependent Raman spectra indicate significant changes around 783 K attributable to the phase transition. In situ low-temperature XRD, neutron diffraction, and Raman spectroscopic studies revealed no structural transition below ambient temperature. Raman mode frequencies, temperature coefficients, and reduced temperature coefficients for both monoclinic and tetragonal phases of K2Ce(PO4)2 have been obtained. Several lattice and external modes of rigid PO4 units are found to be strongly anharmonic. The observed phase transition and structures as well as vibrational properties of both ambient- and high-temperature phases were complimented by DFT calculations. The optical absorption studies on monoclinic phase indicated a band gap of about 2.46 eV. The electronic structure calculations on ambient-temperature monoclinic and high-temperature phases were also carried out.


New mtDNA Association Model, MutPred Variant Load, Suggests Individuals With Multiple Mildly Deleterious mtDNA Variants Are More Likely to Suffer From Atherosclerosis.
The etiology of common complex diseases is multifactorial, involving both genetic, and environmental factors. A role for mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation has been suggested in the pathogenesis of common complex traits. The aim of this study was to investigate a potential role of mtDNA variants in the development of obesity, diabetes, and atherosclerosis in the Polish population. Whole mtDNA sequences from 415 Polish individuals representing three disease cohorts and a control group were obtained using high-throughput sequencing. Two approaches for the assessment of mtDNA variation were applied, traditional mitochondrial haplogroup association analysis and the mutational or variant load model using the MutPred pathogenicity prediction algorithm for amino acid substitutions in humans. We present a possible association between mildly deleterious mtDNA variant load and atherosclerosis that might be due to having more than one likely mildly deleterious non-synonymous substitution. Moreover, it seems largely dependent upon a few common haplogroup associated variants with MutPred score above 0.5.


Anticancer compound XL765 as PI3K/mTOR dual inhibitor: A structural insight into the inhibitory mechanism using computational approaches.
The PI3K-AKT-mTOR pathway is often a commonly disrupted pathway in human cancer and, therefore, it is widely exploited for cancer therapy. The inhibitors for the important proteins of the pathway including PI3K and mTOR have been increasingly designed. The dual inhibitors targeting PI3K and mTOR both have proven to be more effective than those targeting single protein only. An orally-active compound XL765 is well established as PI3K/mTOR dual inhibitor and have shown in vitro and in vivo anticancer activity against a variety of cancer types and is undergoing clinical trials. The present study explored the exact binding pose and the the interactive forces holding XL765 within the active sites of PI3Kγ and mTOR using molecular docking analyses. The XL765 interacting residues of both the proteins were delineated and the degree of participation in binding was estimated by various methods. In the process, among the interacting residues of PI3Kγ, the Lys-890 and the Met-953 were recognized as the key residues involved in XL765 binding. While, in mTOR case, the Trp-2239 was recognized as the key residue playing role in the XL765 binding. In order to explore the better inhibitors, the study also generated combinatorial chemical library by modifying the scaffold considered from XL765. The virtual screening of the generated compound library led to identification of six novel promising compounds proposed as PI3K/mTOR dual inhibitors. Thus, the present work will through light on the drug inhibitory mechanism of XL765 for PI3K and mTOR, and will also assist in designing novel efficacious drug candidates.


Identification of discrete functional domains of HIV-1 integrase and their organization within an active multimeric complex.
HIV-1 integrase protein possesses the 3' processing and DNA strand transfer activities that are required to integrate HIV DNA into a host chromosome. The N-, C-terminal and core domains of integrase are necessary for both activities in vitro. We find that certain pairs of mutant integrase proteins, which are inactive when each protein is assayed alone, can support near wild type levels of activity when both proteins are present together in the reaction mixture. This complementation implies that HIV-1 integrase functions as a multimer and has enabled us to probe the organization of the functional domains within active mixed multimers. We have identified a minimal set of functional integrase domains that are sufficient for 3' processing and DNA strand transfer and find that some domains are contributed in trans by separate monomers within the functional complex.