Tibolone for the treatment of moderate to severe vasomotor symptoms and genital atrophy in postmenopausal women: a multicenter, randomized, double-blind, placebo-controlled study.
To demonstrate the safety and efficacy of tibolone (1.25 and 2.5 mg) in the treatment of moderate to severe vasomotor symptoms and symptoms associated with vaginal atrophy. A placebo-controlled, double-blind, randomized, multicenter study was conducted on 396 healthy postmenopausal women experiencing a minimum of 7 moderate to severe hot flashes per day (60 per week). Participants were randomized to receive tibolone 1.25 or 2.5 mg or placebo once daily for 12 weeks. Assessments were done at weeks 4, 8, and 12. The severity and frequency of hot flashes were recorded in patient diaries on a daily basis. Tibolone 2.5 mg significantly (P < 0.001) reduced the average number of hot flashes compared with placebo at week 4 (-7.82 vs -5.27), week 8 (-9.71 vs -5.86), and week 12 (-10.14 vs -5.85). The difference between tibolone 1.25 mg and placebo was significant (P < 0.001) at week 8 (-7.96) and week 12 (-8.32). Findings for the average daily severity of hot flashes were similar, with significantly greater reductions at week 4 (P < 0.05) and weeks 8 and 12 (P < 0.001) for tibolone 2.5 mg versus placebo and at weeks 8 and 12 for tibolone 1.25 mg versus placebo (P < 0.001). A menopausal atrophic symptom questionnaire revealed that tibolone 2.5 mg significantly (P < 0.05) reduced nocturia compared with placebo at weeks 4, 8, and 12 and urinary urgency at week 4. Compared with placebo, both doses of tibolone also significantly (P < 0.001) increased the vaginal maturation value from baseline. The overall incidence of adverse events was similar in all treatment groups. Tibolone is effective and well tolerated for the treatment of moderate to severe vasomotor symptoms and the effects of vaginal atrophy associated with menopause.


Young-onset rapidly progressive ALS associated with heterozygous FUS mutation.
We report a 36-years-old Cape Verdean man who presented with respiratory insufficiency due to rapidly progressive sporadic amyotrophic lateral sclerosis (ALS), in whom FUS mutation c.1551C > G (p.Hist517Gln) in heterozygosity was identified, a finding previously described as non-pathogenic. The only previous report on this mutation was in a family from Cape Verde in which four members developed ALS; all were homozygous for the mutation. This case shows that this FUS mutation presents a highly variable penetrance and expressivity.


Determining the amount of rumen-protected methionine supplement that corresponds to the optimal levels of methionine in metabolizable protein for maximizing milk protein production and profit on dairy farms.
The profitability of feeding rumen-protected Met (RPMet) sources to produce milk protein was estimated using a 2-step procedure: First, the effect of Met in metabolizable protein (MP) on milk protein production was estimated by using a quadratic Box-Cox functional form. Then, using these estimation results, the amounts of RPMet supplement that corresponded to the optimal levels of Met in MP for maximizing milk protein production and profit on dairy farms were determined. The data used in this study were modified from data used to determine the optimal level of Met in MP for lactating cows in the Nutrient Requirements of Dairy Cattle (NRC, 2001). The data used in this study differ from that in the NRC (2001) data in 2 ways. First, because dairy feed generally contains 1.80 to 1.90% Met in MP, this study adjusts the reference production value (RPV) from 2.06 to 1.80 or 1.90%. Consequently, the milk protein production response is also modified to an RPV of 1.80 or 1.90% Met in MP. Second, because this study is especially interested in how much additional Met, beyond the 1.80 or 1.90% already contained in the basal diet, is required to maximize farm profits, the data used are limited to concentrations of Met in MP above 1.80 or 1.90%. This allowed us to calculate any additional cost to farmers based solely on the price of an RPMet supplement and eliminated the need to estimate the dollar value of each gram of Met already contained in the basal diet. Results indicated that the optimal level of Met in MP for maximizing milk protein production was 2.40 and 2.42%, where the RPV was 1.80 and 1.90%, respectively. These optimal levels were almost identical to the recommended level of Met in MP of 2.40% in the NRC (2001). The amounts of RPMet required to increase the percentage of Met in MP from each RPV to 2.40 and 2.42% were 21.6 and 18.5 g/d, respectively. On the other hand, the optimal levels of Met in MP for maximizing profit were 2.32 and 2.34%, respectively. The amounts of RPMet required to increase the percentage of Met in MP from each RPV to 2.32 and 2.34% were 18.7 and 15.6 g/d, respectively. In each case, the additional daily profit per cow was estimated to be $0.38 and $0.29. These additional profit estimates were $0.02 higher than the additional profit estimates for maximizing milk protein production.


MicroRNA-532 and microRNA-3064 inhibit cell proliferation and invasion by acting as direct regulators of human telomerase reverse transcriptase in ovarian cancer.
Human telomerase reverse transcriptase (hTERT) plays a crucial role in ovarian cancer (OC) progression. However, the mechanisms underlying hTERT upregulation in OC, and the specific microRNAs (miRNAs) involved in the regulation of hTERT in OC cells, remains unclear. We performed a bioinformatics search to identify potential miRNAs that bind to the 3'-untranslated region (3'-UTR) region of the hTERT mRNA. We examined the expression levels of miR-532/miR-3064 in OC tissues and normal ovarian tissues, and analyzed the correlation between miRNA expression and OC patient outcomes. The impacts of miR-532/miR-3064 on hTERT expression were evaluated by western blot analysis and hTERT 3'-UTR reporter assays. We investigated the effects of miR-532/miR-3064 on proliferation and invasion in OC cells. We found that miR-532 and miR-3064 are down-regulated in OC specimens. We observed a significant association between reduced miR-532/miR-3064 expression and poorer survival of patients with OC. We confirmed that in OC cells, these two miRNAs downregulate hTERT levels by directly targeting its 3'-UTR region, and inhibited proliferation, EMT and invasion of OC cells. In addition, the overexpression of the hTERT cDNA lacking the 3'-UTR partially restored miR-532/miR-3064-inhibited OC cell proliferation and invasion. The silencing of hTERT by siRNA oligonucleotides abolished these malignant features, and phenocopied the effects of miR-532/miR-3064 overexpression. Furthermore, overexpression of miR-532/miR-3064 inhibits the growth of OC cells in vivo. Our findings demonstrate a miR-532/miR-3064-mediated mechanism responsible for hTERT upregulation in OC cells, and reveal a possibility of targeting miR-532/miR-3064 for future treatment of OC.


Psychometric validation of the Anticipated Effects of Alcohol Mixed with Energy Drinks Scale.
Young people are increasingly consuming alcohol mixed with energy drinks (AmEDs). As coingestion of these beverages results in greater adverse consequences than from drinking alcohol alone, we need to understand what factors contribute to and deter coingestion. Existing studies in this area have not utilized a theoretically based or empirically validated measure of outcome expectancies for drinking AmEDs. Our study modified Morean, Corbin, and Treat's (2012) Anticipated Effects of Alcohol Scale to assess the expected effects of drinking AmEDs. We evaluated the factor structure and concurrent validity of the Anticipated Effects of Alcohol Mixed with Energy Drinks (AEAMEDS) among 549 university students, aged 18-25, who had a lifetime history of consuming alcohol (231 had consumed AmEDs in the past 90 days). Exploratory and confirmatory factor analysis supported a 4-factor structure. Consistent with hypotheses, stronger high arousal/positive expectancies and weaker low arousal/negative expectancies were associated with greater AmED use. At the bivariate level, stronger low arousal/positive expectancies were associated with greater quantities of AmED use, but this relationship disappeared when taking into account other outcome expectancies. Moreover, students expected low arousal/positive expectancies to be less intense when consuming AmEDs than alcohol alone, but ratings for all other AmED expectancies were equivalent to consuming alcohol alone. These findings contribute to our knowledge of risk and protective factors for AmED use. (PsycINFO Database Record


Resistance to Chemotherapeutic 5-Fluorouracil Conferred by Modulation of Heterochromatic Integrity through Ino80 Function in Fission Yeast.
5-Fluorouracil (5-FU) is a conventional chemotherapeutic drug widely used in clinics worldwide, but development of resistance that compromises responsiveness remains a major hurdle to its efficacy. The mechanism underlying 5-FU resistance is conventionally attributed to the disruption of nucleotide synthesis, even though research has implicated other pathways such as RNA processing and chromatin dysregulation. Aiming to clarify resistance mechanisms of 5-FU, we tested the response of a collection of fission yeast (Schizosaccharomyces pombe) null mutants, which confer multiple environmental factor responsiveness (MER). Our screen identified disruption of membrane transport, chromosome segregation and mitochondrial oxidative phosphorylation to increase cellular susceptibility towards 5-FU. Conversely, we revealed several null mutants of Ino80 complex factors exhibited resistance to 5-FU. Furthermore, attenuation of Ino80 function via deleting several subunit genes reversed loss of chromosome-segregation fidelity in 5-FU in the loss-of-function mutant of the Argonaute protein, which regulates RNA interference (RNAi)-dependent maintenance of pericentromeric heterochromatin. Our study thus uncovered a critical role played by chromatin remodeling Ino80 complex factors in 5-FU resistance, which may constitute a possible target to modulate in reversing 5-FU resistance.


Technical Note: Diffusion-weighted MRI with minimal distortion in head-and-neck radiotherapy using a turbo spin echo acquisition method.
Diffusion-weighted (DW) MRI, showing high contrast between tumor and background tissue, is a promising technique in radiotherapy for tumor delineation. However, its use for head-and-neck patients is hampered by poor geometric accuracy in conventional echo planar imaging (EPI) DW-MRI. An alternative turbo spin echo sequence, DW-SPLICE, is implemented and demonstrated in patients. The DW-SPLICE sequence was implemented on a 3.0 T system and evaluated in 10 patients. The patients were scanned in treatment position, using a customized head support and immobilization mask. Image distortions were quantified at the gross tumor volume (GTV) using field map analysis. The apparent diffusion coefficient (ADC) was evaluated using an ice water phantom. The DW images acquired by DW-SPLICE showed no image distortions. Field map analysis at the gross tumor volumes resulted in a median distortion of 0.2 mm for DW-SPLICE, whereas for the conventional method this was 7.2 mm. ADC values, measured using an ice water phantom were in accordance with literature values. The implementation of DW-SPLICE allows for diffusion-weighted imaging of patients in treatment position with excellent geometrical accuracy. The images can be used to facilitate target volume delineation in RT treatment planning.


[General profile of the nutrition surplus in Mexico from 1990-2013: An approach using the energy supplied by macronutrients and food groups].
This text analyzes the evolution of the excessive food energy supply in Mexico from 1990 to 2013. For each year, the energy and macronutrient requirements of the Mexican population were estimated and contrasted with the per capita energy supply. Discrepancies between requirement and supply were analyzed as a time series. The energy surplus ranged from 700 to 800 kcal per capita per day throughout the studied period and sugar/sweeteners contributed the highest above-requirement energy supply. Lipids excess increased steadily and intensely, mainly due to lipid increases from poultry and pork. Excess energy from alcoholic beverages tended to be concentrated into growing beer consumption. In summary, the energy supply and the corresponding surplus tended to be made up mainly of sugar/sweeteners and meat. This has direct implications for the prevalence of chronic non-communicable diseases as well as unsustainable use of land, water and energy.


Recent Updates on Outbreaks of Shiga Toxin-Producing Escherichia coli and Its Potential Reservoirs.
Following infection with certain strains of Shiga toxin-producing Escherichia coli (STEC), particularly enterohemorrhagic ones, patients are at elevated risk for developing life-threatening extraintestinal complications, such as acute renal failure. Hence, these bacteria represent a public health concern in both developed and developing countries. Shiga toxins (Stxs) expressed by STEC are highly cytotoxic class II ribosome-inactivating proteins and primary virulence factors responsible for major clinical signs of Stx-mediated pathogenesis, including bloody diarrhea, hemolytic uremic syndrome (HUS), and neurological complications. Ruminant animals are thought to serve as critical environmental reservoirs of Stx-producing Escherichia coli (STEC), but other emerging or arising reservoirs of the toxin-producing bacteria have been overlooked. In particular, a number of new animal species from wildlife and aquaculture industries have recently been identified as unexpected reservoir or spillover hosts of STEC. Here, we summarize recent findings about reservoirs of STEC and review outbreaks of these bacteria both within and outside the United States. A better understanding of environmental transmission to humans will facilitate the development of novel strategies for preventing zoonotic STEC infection.


Immunohistochemical localization of sex hormone receptors in two Raillietina tapeworms.
Sex hormone receptors play critical roles in development and reproduction. However, it is not known whether they exist in Raillietina tapeworms, and if they do, whether they have a similar function to that in vertebrates. We examined the immunohistochemical distributions of androgen receptors (ARs), estrogen receptors (ERs), and progesterone receptors (PRs) in the tissues of two tapeworm species: Raillietina echinobothrida and Raillietina tetragona. Immunopositive ARs were found in the entire reproductive system of R. echinobothrida, including the testes, ovaries, and oocysts, and weakly immunopositive ERs and PRs were found in the testes, ovaries, and oocysts. Immunopositive ARs were also found throughout the entire reproductive system of R. tetragona, including the testes, ovaries, and oocysts, and weakly immunopositive ERs were in the testes and oocysts; the PRs were distributed in an immunonegative manner. The results show that androgens and their receptors play critical roles in reproductive system development in the two tapeworms. The immunoreactivity and tissue localizations of the sex hormone receptors suggest that, in both species, they have similar functions as in vertebrates, and modulate reproduction.


Reengineering a pharmacist intervention program.
At the beginning of a period of rapid growth in clinical pharmacy services in our integrated health system, we realized that there was no mechanism to address how pharmacist interventions were processed, evaluated, and followed up. Interventions were inconsistently documented, and the documentation served no more purpose than to record workload statistics. There was little assessment of the value or quality of interventions, no peer review, and no reporting of aggregate data to improve system-related problems. How are others handling the documentation and assessment of pharmacist interventions?


Gender differences in characteristics and service use of public mental health patients with schizophrenia.
The study examined gender differences in sociodemographic, clinical, and mental health service use variables among patients with schizophrenia in a public mental health care system. Data from 1999 to 2000 for 4975 adult patients were analyzed. Women were older and more likely to be married and to have Medicaid insurance and less likely to have a diagnosis of substance abuse than men. More women were living independently, whereas more men resided in assisted living facilities or were homeless. Women were significantly more likely to have had a psychiatric hospitalization than men, which may be related to differential use of services by men and women with the worst level of functioning.


A long-term evaluation of abrasion of dental composite resins.
A long-term study was performed on the abrasion of dental composites stored in different solutions for six months. No difference in wear resistancewas noticeable between the water and lactic acid group. But the composite with regular filler showed reduced wear resistance when compared with a microfiller composite.


Granulocyte-colony stimulating factor in the treatment of colchicine poisoning.
1. Colchicine is a highly active alkaloid used in the treatment of gouty arthritis and pseudogout. In overdose colchicine inhibits cell division effecting organs with a high rate of cell turn-over, such as the gastrointestinal tract and bone marrow. Early fatality results from cardiovascular collapse and respiratory failure, however pancytopenia and overwhelming septicaemia can occur later. 2. We describe a case of suicidal ingestion of 25-30 mg of colchicine in a previously healthy 43-year-old woman. Initial symptoms were mainly gastrointestinal. By day 5 she had developed severe pancytopenia and early sepsis, which were successfully treated using granulocyte colony stimulating factor (G-CSF) 600 micrograms s.c. 3. In vitro G-CSF is produced by the haematopoietic system. However, G-CSF can now be produced by recombinant DNA cloning technology and thus is available clinically. 4. There is no recognised antidote for colchicine poisoning and treatment is symptomatic. Fab fragments may have a promising future in eliminating colchicine from the body, but are currently not clinically available. In those patients that survive the initial phase of poisoning, G-CSF offers an effective method of treating the pancytopenia and preventing overwhelming septicaemia. Daily monitoring of the patient's haematological status is strongly recommended.


Number, size, and transcriptional activity of nucleoli during different periods of interphase in antheridial filaments of Chara vulgaris L.
In antheridial filaments of Chara vulgaris the number of nucleoli within a single cell nucleus ranges from 3 to 12. The sizes of nucleoli vary from 0.2 to 3.5 micron in diameter. Mean number of micronucleoli, i.e. the smallest nucleoli of 0.2-0.5 micron in diameter which are distinguished after silver staining is higher than that estimated with the use of toluidine blue method according to Smetana et al. [34], the latter procedure resulting in a less contrasting visualization. Throughout the course of the whole period of interphase the mean number of nucleoli was found unchanged in successive phases and it equals some 6.5 per nucleus. Concurrently, the total volume of nucleoli increases progressively reaching maximum value by the end of the G2 phase which is attributed to the increase in number of largest nucleoli. On the basis of the analysis of 3H uridine incorporation and an in situ determination of RNA polymerase activity using the method adopted by Moore and Ringertz [25] it was evidenced that the mean transcriptional activity of nucleoli larger than 0.5 micron in diameter is not dependent upon nucleolar number within a single nucleus. It is concluded that the diverse appearance of nucleoli in cells being located precisely at the same stage of interphase reflects temporal changes of their sizes consisting in an asynchronous pulsation of individual nucleoli.


Kinetic roughening of ion-sputtered Pd(001) surface: beyond the Kuramoto-Sivashinsky model.
We investigate the kinetic roughening of Ar+ ion-sputtered Pd(001) surface both experimentally and theoretically. In situ real-time x-ray reflectivity and in situ scanning tunneling microscopy show that nanoscale adatom islands form and grow with increasing sputter time t. Surface roughness W(t) and lateral correlation length xi(t) follow the scaling laws W(t) approximately t(beta) and xi(t) approximately t(1/z) with the exponents beta approximately 0.20 and 1/z approximately 0.20, for an ion beam energy epsilon=0.5 keV, which is inconsistent with the prediction of the Kuramoto-Sivashinsky (KS) model. We thereby extend the KS model by applying the coarse-grained continuum approach of the Sigmund theory to the order of O(inverted Delta(4),h(2)), where h is the surface height, and derive a new term of the form inverted Delta(2)(inverted Delta h)(2) which plays a decisive role in describing the observed morphological evolution of the sputtered surface.


A green approach for the synthesis and thiol-ene modification of alkene functionalized poly(2-oxazoline)s.
The bulk polymerization of 2-(dec-9-enyl)-2-oxazoline (DecEnOx), a fatty acid-based monomer for the cationic ring-opening polymerization, is reported. Furthermore, under optimal conditions, namely microwave heating at 100 °C, the bulk copolymerization with 2-ethyl-2-oxazoline yielded well-defined copolymers. Due to its pendant alkene groups DecEnOx-based polymers possess the potential to be modified in efficient thiol-ene reactions. The functionalization with thiols, e.g., dodecanethiol and 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glycopyranose in "green" solvents is demonstrated.


Factors affecting plasma prolactin concentrations throughout gestation in high producing dairy cows.
The aim of the present study was to investigate possible relationships between plasma concentrations of prolactin and the following factors throughout gestation in lactating dairy cows: photoperiod, season, milk production, Neospora caninum-seropositivity, twin pregnancy, and plasma concentrations of pregnancy associated glycoproteins-1 (PAG-1), progesterone and cortisol. Pregnancy was diagnosed by trans-rectal ultrasonography on Day 40 post-insemination and by palpation per rectum on Days 90, 120, 150, 180 and 210 or until abortion in aborting cows. Blood samples were collected from each animal immediately before each pregnancy diagnosis. The study population was comprised of 73 non-aborting (54 Neospora-seropositive cows) and 20 aborting cows (all Neospora-seropositive) cows. In non-aborting cows, GLM repeated measures of analysis of variance revealed that lactation number and days in milk had no effect on plasma prolactin concentrations throughout gestation, whereas high plasma prolactin concentrations were significantly associated with high plasma levels of cortisol and PAG-1, with Neospora-seropositivity, positive photoperiod (increasing day length), twin pregnancy, and with low plasma progesterone concentrations. An interaction among plasma prolactin, plasma cortisol and milk production was observed in that plasma prolactin concentrations differed significantly throughout gestation and were highest in high-producing cows with high cortisol levels. In Neospora-seropositive non-aborting versus aborting cows, mean prolactin concentrations failed to differ on Days 40, 90, 120, 150 and 180 of pregnancy, whereas prolactin values were significantly lower (P=0.03) in aborting animals on Day 210 of pregnancy. Our results indicate that a positive photoperiod and Neospora-infection lead to increased plasma prolactin concentrations throughout gestation. Reduced prolactin concentrations detected in Neospora-seropositive aborting cows compared to non-aborting animals suggests a protective effect of prolactin in N. caninum infection.


Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine.
A 65-year-old man with chronic lymphocytic leukemia (CLL) diagnosed 11 years ago and treated with standard dose of fludarabine developed a rapidly fatal progressive neurological syndrome. Differential diagnoses included brain infiltration by CLL as opposed to progressive multifocal leukoencephalopathy (PML). A magnetic resonance imaging (MRI) scan showed a hyperintense T2-weighted signal in the left frontal region. Cerebro-spinal fluid polymerase chain reaction (PCR) was positive for virus JC (JCV). These findings were compatible with the diagnosis of PML. Fludarabine has been used to treat acute leukemias, CLL and follicular lymphomas. Its toxicity includes myelosuppression, immunosuppression and sporadic life-threatening neurotoxicity, although standard doses of it are considered safe. Late-onset fatal cerebral dysfunction caused by JCV after standard-dose fludarabine has been described previously. The widespread and increasing use of fludarabine makes it interesting to define the potential of standard doses of fludarabine for causing severe neurological side-effects such as PML.


Erythropoietin in very preterm infants.
Three neonates (a male and two females of gestational ages 27, 27 and 29 weeks with birthweight 985, 660 and 1130 g), born to parents who are Jehovah's Witnesses, were admitted to our neonatal intensive care unit over a 2 month period in 1992. Human recombinant erythropoietin (rHuEpo, 200 u/kg sc. on alternate days for 6-8 weeks) was started early in conjunction with strict control of blood sampling in an attempt to avoid the need for blood transfusion. The lowest haemoglobin recorded was 95 g/L at 35 days of age in the first infant. The amount of blood withdrawn for sampling was 21.4 mL, 20.7 mL and 5.5 mL, respectively. All were discharged near their expected birthdate, never having received a blood transfusion in the Nursery. It is possible to manage sick, very preterm, very low birthweight neonates in a neonatal intensive care setting without the use of blood transfusions by the early use of rHuEpo in conjunction with strict control of blood sampling.


Balancing the benefits and risks of drug treatment: a stated-preference, discrete choice experiment with patients with psoriasis.
To examine the extent to which the attributes of a treatment affect patients' choice of treatment for psoriasis and the magnitude and nature of trade-offs between risks and benefits of treatment. A questionnaire, including a stated-preference, discrete choice experiment, was used to elicit patients' preferences for the treatment of psoriasis. Dermatology clinics in England. A total of 126 patients with psoriasis. Preferences of patients for, and trade-offs between, the 6 attributes of time to moderate (50%) improvement, relapse, and risks of experiencing skin irritation, high blood pressure, liver damage, and skin cancer. The mean age of respondents was 47.6 years, and the mean duration of psoriasis was 23 years. All 6 attributes were important factors affecting choice of treatment. The results indicated that patients with psoriasis prioritized low risk of skin cancer (beta = -0.054; P < .01) and liver damage (beta = -0.054; P < .01) and preferred treatment that resulted in a shorter time to achieve a moderate improvement (beta = -0.034; P < .01) over a longer time to relapse (beta = 0.028; P < .01). Patients were most willing to wait longer for a treatment to work if the likelihood of skin cancer or liver damage was reduced. This study shows that treatment attributes influence patients with psoriasis in their choice of treatment. The results of the discrete choice experiment presented herein indicate that most respondents would be willing to trade between different aspects of treatment to achieve improvements in their psoriasis and minimize the risks of adverse events.


Superparamagnetic segmentation by excitable neural systems.
Magnetic modeling for clustering or segmentation purposes can either associate the image data to external quenched fields or to the interactions among a set of auxiliary variables. The latter gives rise to superparamagnetic segmentation and is usually done with Potts systems. We have used the superparamagnetic clustering technique to segment images, with the aid of different associated systems. Results using Potts model are comparable to those obtained using excitable FitzHugh-Nagumo and Morris-Lecar model neurons. Interactions between the associated system components are a function of the difference of luminosity on a gray scale of neighbor pixels and the difference of membrane potential.


Ancestral transfer of symbionts between cockroaches and termites: an unlikely scenario.
Thorne's (Proc. R. Soc. Lond. B 241, 37 (1990] studies of the laboratory behaviour of extant woodroaches (Cryptocercus) and termites (Zootermopsis) suggest that transfaunation of hindgut protozoans potentially could occur by aggression and consumption in the field. However, existing literature suggests no overlap in protozoan species composition for these two taxa. Furthermore, it is doubtful that transfaunation would occur in the solitary ancestral 'termitoid' and 'roachoid' lines proposed by Thorne: not only is it unlikely that such insects would encounter each other, but it is doubtful that they would show the degree of aggression exhibited by the termite soldiers in her study. Inheritance from an ancestor common to Cryptocercus and the lower termites remains the most logical explanation for the presence of the unique cellulolytic oxymonad, trichomonad and hypermastigote flagellates in these two groups.


High-performance liquid chromatographic analysis of resveratrol analog 3,5,4'-trimethoxystilbene in rat plasma.
(E)-3,5,4'-Trimethoxystilbene (BTM-0512), the analog of resveratrol, is potentially useful for the treatment of human diseases. This is the first study to use high-performance liquid chromatography (HPLC) for the determination of the resveratrol analog in rat plasma. Plasma proteins (0.1 mL) were precipitated with acetonitrile after the addition of the internal standard chlorzoxazone. The analysis used a BDS HYPERSIL C(18) analytical column (5 microm, 4.6 x 250 mm) with acetonitrile/water as the mobile phase. The UV-detection wavelength was 303 nm. The calibration curve was linear over the range of 0.025-10 microg/mL with a correlation coefficient of 0.9958. This concentration range corresponds well with the plasma concentrations of BTM-0512 in pharmacokinetic studies. There was a recovery of 102.2%, 95.3% and 103.7% from 0.05, 5 and 10 microg/mL plasma samples, respectively. The relative standard deviation of intra- and interday assay variations was all less than 13%. This HPLC assay is a quick, precise and reliable method for the analysis of BTM-0512 in pharmacokinetic studies.


Mutational inactivation of two distinct negative RNA elements in the human papillomavirus type 16 L2 coding region induces production of high levels of L2 in human cells.
Here we show that the 5' end and the middle region of the L2 coding sequence of human papillomavirus type 16 contain strong inhibitory RNA sequences termed inhibitory regions I and II. This is in contrast to L1, which contains one inhibitory region in the 5' end of the coding region. Inhibitory regions I and II acted in cis to reduce L2 mRNA levels and to inhibit the use of the mRNA. In tandem, the two regions reduced L2 mRNA production to undetectable levels. Specific mutational inactivation of the two inhibitory elements in the 5' end and in the middle region of L2 by the introduction of nucleotide substitutions that changed the nucleotide sequence but not the protein sequence resulted in production of high levels of L2 mRNA and protein. In contrast to L2, a partial L1 mutant in which only the first one third of L1 was mutated produced levels of L1 mRNA and protein similar to those in a full L1 mutant. In addition, the constitutive transport element of simian retrovirus type 1 overcomes the effect of the inhibitory sequences of L1 but not L2.


Dyke-Davidoff-Masson Syndrome. An unusual cause of status epilepticus.
The Dyke-Davidoff-Masson Syndrome (DDMS) results from an insult to the growing brain in utero or early infancy, which lead to loss of neurons compromising the growth of the brain. Clinical presentation includes seizures, hemiparesis, facial asymmetry, and learning disability. Radiological findings include cerebral atrophy on one side. Here, we present a case with status epilepticus who had underlying DDMS. It is a rare syndrome and uncommon cause for status epilepticus. Infections of CNS, hypoxic ischemic encephalopathy, intracranial bleed, trauma, congenital vascular malformations are the common causes of this syndrome. Diagnosis is established after clinical history, examination, and MRI. Intractable seizures can be controlled with appropriate anticonvulsants. Subsequently, these children may require physiotherapy, speech therapy, and occupational therapy in addition to the anticonvulsant medication. Outcome is better if the seizures are controlled.


Vibrational spectra and fragmentation pathways of size-selected, D2-tagged ammonium/methylammonium bisulfate clusters.
Particles consisting of ammonia and sulfuric acid are widely regarded as seeds for atmospheric aerosol nucleation, and incorporation of alkylamines has been suggested to substantially accelerate their growth. Despite significant efforts, little direct experimental evidence exists for the structures and chemical processes underlying multicomponent particle nucleation. Here we are concerned with the positively charged clusters of ammonia and sulfuric acid with compositions H(+)(NH3)m(H2SO4)n (2 ≤ m ≤ 5, 1 ≤ n ≤ 4), for which equilibrium geometry structures have been reported in recent computational searches. The computed harmonic vibrational spectra of such minimum energy structures can be directly compared with the experimental spectra of each cluster composition isolated in the laboratory using cryogenic ion chemistry methods. We present one-photon (i.e., linear) infrared action spectra of the isolated gas phase ions cryogenically cooled to 10 K, allowing us to resolve the characteristic vibrational signatures of these clusters. Because the available calculated spectra for different structural candidates have been obtained using different levels of theory, we reoptimized the previously reported structures with several common electronic structure methods and find excellent agreement can be achieved for the (m = 3, n = 2) cluster using CAM-B3LYP with only minor structural differences from the previously identified geometries. At the larger sizes, the experimental spectra strongly resemble that observed for 180 nm ammonium bisulfate particles. The characteristic ammonium- and bisulfate-localized bands are clearly evident at all sizes studied, indicating that the cluster structures are indeed ionic in nature. With the likely (3,2) structure in hand, we then explore the spectral and structural changes caused when methylamine is substituted for ammonia. This process is found to occur with minimal perturbation of the unsubstituted cluster. The thermal decomposition pathways were also evaluated using multiple-photon induced dissociation and are, in all cases, dominated (>100:1) by evaporation of a neutral ammonia molecule rather than methylamine. Spectra obtained for the product cluster ions resulting from this evaporation are consistent with the formation of a single hydrogen bond between two neighboring bisulfate ions, partially regenerating a sulfuric acid molecule. These results provide critical experimental benchmarks for ongoing theoretical efforts to understand the early stages of aerosol growth.


Analysis of luteolin in Elsholtzia blanda Benth. by RP-HPLC.
The total luteolin content in Elsholtzia blanda Benth. extracts (EBBE) was determined using reversed phase HPLC. C18 was used as the packing material and 0.01 M phosphate buffer (pH 2)-tetrahydrofuran-isopropanol (70:30:5) as the mobile phase with detection wavelength 360 nm. The recovery of the method was 96.4%-101.8%, and the assay was linear at concentrations from 5 to 200 microg/ml (r = 0.9999). The results indicated that the content of luteolin in EBBE extracted under different conditions varied significantly. This method can be used to optimize the extraction procedure and determine the content of luteolin in Elsholtzia blanda Benth. extracts.


Learning from parental experience in a neonatal surgical unit: a qualitative service evaluation.
Patient experience is directly related to health outcomes, and parental experience can be used as a proxy for this in neonatal care. This project was designed to assess parental experience of neonatal surgical care to inform future service developments and improve the care we provide. This was a qualitative study using rapid qualitative analysis. The study was carried out in a large neonatal surgical intensive care unit in the UK. Parents of infants treated by the neonatal surgical team between March 2020 and February 2021, during the COVID-19 pandemic were included. Purposive sampling was used to ensure that a representative range of parents were interviewed. A semistructured interview was created and tested in a previous phase of work. This questionnaire was used to ask parents open questions about different aspects of their infants' healthcare journey from the antenatal phase through to discharge from the neonatal unit (NUU). Rapid qualitative analysis was employed, and parental experiences were grouped into five main categories: before admission to the NNU, initial admission to NNU, information and support, COVID-19 and discharge. Within these five groups, we highlighted positive experiences to be fed back to the healthcare teams to reinforce good practice, areas that warranted improvement and suggestions for service development. The wealth of data generated from the interviews has been summarized and shared with healthcare teams who are putting the service improvement suggestions into practice. The tool is available for services that wish to measure parental experience.


[Iodine and thyroid autoimmunity].
The pathogenetic mechanisms leading to the development of autoimmune disease of the thyroid are based on several different factors. The resultant immune response is related to both the genetic predisposition and other influencing factors such as iodine intake, a very important modulator of thyroid autoimmunity. To a large extent, the details of the mechanisms that induce the immune response and lead to chronic autoimmune thyroid reactions are still poorly understood. In genetically predisposed individuals the iodine intake modulates autoimmune thyroid reactions. Especially with acute or chronic increase of iodine intake it leads to a significant increase in the incidence and intensity of autoimmune thyroid disease. There is a need to further investigate whether the results of experimental animal studies can be generalised to humans. Epidemiological data from countries with sufficient or high nutritional iodine intake clearly show that in comparison to countries with iodine deficiency there is an increase in the incidence of autoimmune thyroid disease and a change in the pattern of manifestation, e.g. in the proportion of autoimmune thyroiditis and hyperthyroidism due to Graves' disease. At the same time, thyroid diseases related to iodine deficiency significantly decrease, which is to be expected with a continuously higher iodine intake.


Agouti Signaling Protein and Its Receptors as Potential Molecular Markers for Intramuscular and Body Fat Deposition in Cattle.
Transcriptome analyses of bovine muscle tissue differing in intramuscular fat (IMF) content identified agouti signaling protein (ASIP) as a promising candidate gene for fat deposition. The protein is secreted from adipocytes and may serve as a signaling molecule in cross-talk between adipocytes and muscle fibers or other cells. Known receptors for ASIP are the melanocortin receptors (e.g., MC4R) and attractin (ATRN). The present study was conducted to determine relationships between the expression of ASIP and its receptors in different bovine tissues with fat deposition. Adipose tissues, liver, and longissimus muscle tissue were collected from 246 F2-generation bulls (Charolais × Holstein cross) and gene expression was measured with RT-qPCR. During analysis of subcutaneous fat (SCF) of all bulls, 17 animals were identified with a transposon-derived transcript (Exon2C) inserted in the ASIP gene and dramatically increased ASIP mRNA levels. Significant correlations between normalized mRNA values of SCF and phenotypic traits related to fat deposition were found in bulls without Exon2C. Three retrospectively assigned groups [Exon2C, n = 17; high carcass fat (HCF), n = 20; low carcass fat (LCF), n = 20] were further analyzed to verify expression differences and elucidate molecular reasons. Expression of ASIP could be detected in isolated muscle fibers and adipocytes of Exon2C bulls in contrast to HCF and LCF bulls, indicating ectopic ASIP expression if the transposon is present. Among adipose tissues, highest ASIP mRNA levels were measured in SCF with significantly higher values in HCF compared to LCF bulls (1.6-fold, P < 0.05). However, the protein abundance was below the detection limit in all bulls. Potential ASIP receptors were detected in most investigated tissues. The expression of MC4R was higher and of ATRN was lower in several tissues of LCF compared to HCF bulls, whereas MC1R was not differentially expressed. Bulls of the Exon2C group had lower ATRN mRNA values than HCF and LCF bulls in perirenal fat (PF), but higher (P < 0.05) values in muscle. Receptors were also expressed in tissues where ASIP mRNA was not detected. Consequently, those tissues could be targets for ASIP if it circulates.


Ticks as vectors: taxonomy, biology and ecology.
Ticks are prominent parasites and competent vectors of pathogens that affect both humans and animals. This review outlines and illustrates the main features of the morphology of ticks of the families Ixodidae and Argasidae, and summarises the basic components of their life cycles. It focuses mainly on development processes and mortality among tick populations so as to provide an overview of how they are regulated in nature and how pathogens can be transmitted under such a framework. The effects of the weather on these life cycles are reviewed. The author also examines how landscape structure and biotic factors, such as the presence and abundance of hosts, may shape the density of tick populations. The uncertainty inherent in dealing with the transmission of pathogens by ticks is highlighted; this results from the sometimes complex relationships among the vectors, the climate and the presence and density of host populations. The need to obtain reliable field estimations of such relationships before drawing conclusions about the effects of the isolated components of the system is stressed. A section is devoted to addressing the expected (and not yet totally understood) effects of trends in climate on the spread of ticks, and how these can be analysed and tracked.


Effects of immunization and checkpoint inhibition on amodiaquine-induced liver injury.
If idiosyncratic drug-induced liver injury (IDILI) is immune-mediated, it is possible that an individual's prior exposure to antigens may affect their susceptibility to IDILI. An individual's repertoire of memory immune cells is shaped by every past exposure to antigens. Subsequent drug-induced adverse drug reactions may therefore involve an immune cell's cross reactivity between a prior antigen and resulting drug-modified proteins. Therefore in this experiment, mice were immunized with amodiaquine (AQ)-modified hepatic proteins to mimic a previous exposure; treated with a RIBI adjuvant and anti-CD40 antibodies to stimulate an immune response; and, treated with anti-PD1 and anti-CTLA-4 antibodies prior to AQ treatment in order to overcome immune tolerance. This treatment led to greater liver injury than treatment with AQ alone. However, the mice did not develop serious liver injury. PD1-/- mice were then immunized and treated with AQ and anti-CTLA-4 antibodies so that immune tolerance would be impaired, both during immunization and also during AQ treatment. However, even this did not result in liver failure, and the liver injury was not significantly increased relative to un-immunized PD1-/- mice treated with anti-CTLA-4 and AQ. From these results we conclude that, although previous antigen exposure may affect the risk of IDILI, it appears that a very strong stimulus is required, and impairing immune tolerance remains the most effective method for producing an animal model of IDILI.


The Estrogen-Induced miR-19 Downregulates Secretory Leucoprotease Inhibitor Expression in Monocytes.
Compared to females, males are more susceptible to acute viral and other respiratory tract infections that display greater severity and higher mortality. In contrast, females tend to fare worse with chronic inflammatory diseases. Circulating 17β-estradiol (E2) is a female-specific factor that may influence the progression of human lung diseases. Here we hypothesize that E2 modulates the inflammatory response of monocytes through microRNA (miRNA)-based modulation of secretory leucoprotease inhibitor (SLPI), an antiprotease with immunomodulatory effects. Monocytic cells were treated ± E2, and differentially expressed miRNAs were identified using PCR profiling. Cells were transfected with miRNA mimics or antimiRs and SLPI mRNA and protein levels were quantified. Luciferase activity assay using wildtype and ΔmiR-19a/b-SLPI3'UTR reporter constructs and chromatin immunoprecipitation on E2-treated monocytes were performed. E2 downregulated SLPI and upregulated miR-19 expression in monocytes. Transfection with premiR-19b reduced SLPI mRNA and protein levels and this effect was abrogated using antimiRs against miR-19b. miR-19b directly binds the SLPI 3'UTR. The mechanism responsible for E2-mediated upregulation of miR-19 occurs via increased MIR17HG promoter activity mediated by c-MYC. Overall E2 decreases SLPI expression in human monocytic cells, via changes in miRNA expression and highlights the potential for estrogen to modulate the innate immune system.


Mycobacterium bovis tuberculosis: from animal to man and back.
Rare cases of tuberculosis due to Mycobacterium bovis have been described in humans who have been exposed to cattle or other infected animals. We report a case of tuberculosis in cattle exposed to a patient infected with M. bovis, where the strain isolated in the cattle and the patient were identical. As the patient is reported to have been exposed and contaminated during childhood, this seems to be the first documented case of transmission of M. bovis from animal to man and back to animal.


Antigen-specific T lymphocyte clones. III. Papain splits purified T suppressor molecules into two functional domains.
Purified molecules (70,000 mol wt) from a T-suppressor (Ts) clone bind to sheep erythrocyte glycophorin and specifically suppress the response to this antigen. Papain splits purified 70,000-mol wt Ts molecules into two peptides: mol wt 45,000 and 24,000. The 45,000-mol wt peptide nonspecifically suppresses antibody response to several antigens and lacks antigen-binding activity. The 24,000-mol wt peptide does not suppress but retains antigen-binding activity. The results indicate that papain splits the Ts molecule into a "constant" region responsible for function and a "variable" region responsible for antigen-binding. Since binding of the 70,000-mol wt molecule to antigen also results in release of the 45,000 mol wt subunit, this cleavage may allow Ts molecules specific for one determinant to suppress immunity to complex foreign proteins.


IDIOPATHIC FULL-THICKNESS MACULAR HOLE IN AN 8-YEAR-OLD BOY.
To report a case of idiopathic full-thickness macular hole in a young boy, which was managed surgically with good visual and anatomical outcomes. Single case report. An 8-year-old boy presented for defective vision in the left eye noticed for the past 2 weeks with best-corrected visual acuity of 6/24. A large full-thickness macular hole was diagnosed clinically and was confirmed on optical coherence tomography. There was no clinical or tomographic findings suggestive of trauma or retinal degeneration. After observation for 8 weeks, the patient underwent macular hole surgery in the left eye including internal limiting membrane peeling and C3F8 gas tamponade. Intraoperatively abnormally tight vitreoretinal adherence was noted during the induction of posterior vitreous detachment. Optical coherence tomography at 1 month after surgery showed decrease in the size of macular hole suggestive of incomplete closure. Repeat optical coherence tomography at 3 months showed closed macular hole with mild foveal thinning and ellipsoid zone discontinuity with best-corrected visual acuity improving to 6/18. The tomographic features and best-corrected visual acuity remained stable at 6-month follow-up. We hereby report the first case, to the best of our knowledge, of a truly idiopathic full-thickness macular hole in an 8-year-old boy. Surgical treatment offers the best outcomes in these cases and should be considered at the earliest without waiting for spontaneous closure unlike in the case of traumatic full-thickness macular hole.


Coexisting carcinoid tumor and Crohn's disease.
Several malignancies have been described occurring simultaneously with regional enteritis. Only four examples of coexistent carcinoid and Crohn's disease have been described worldwide. In this report, two new cases of simultaneous Crohn's disease and carcinoid tumor, diagnosed and treated within a single month, are presented. In one instance, a segment of terminal ileum contained regional enteritis, carcinoid tumor, and a small focus of adenocarcinoma.


LncRNA MAGI2-AS3 Affects Cell Invasion and Migration of Cervical Squamous Cell Carcinoma (CSCC) via Sponging miRNA-233/EPB41L3 Axis.
The incidence of cervical squamous cell carcinoma (CSCC) has expanded in recent years. However, the function of long non-coding RNA (lncRNA) MAGI2-AS3 in the occurrence and progression of CSCC remains unclear. Therefore, the role of lncRNA MAGI2-AS3 in cervical squamous cell carcinoma (CSCC) was investigated in our study. We used qRT-PCR analysis to identify the level of MAGI2-AS3 mRNA expression in CSCC clinical samples and cell lines. We investigated cell migration and invasion of CSCC cells transfected with MAGI2-AS3, miR-233 mimic, or EPB41L3 with transwell assays. Bioinformatics analysis and a luciferase reporter assay were employed to predict the interaction between MAGI2-AS3 and miR-233. We found that MAGI2-AS3 and EPB41L3 were both downregulated in CSCC and the expression of this two was positively correlated. Bioinformatics analysis showed that MAGI2-AS3 might bind to miR-233, which could directly target EPB41L3. In CSCC cells, overexpression of MAGI2-AS3 led to upregulated, while overexpression of miRNA-233 led to downregulated expression of EPB41L3. However, MAGI2-AS3 and miR-233 did not affect the expression of each other. In addition, overexpression of MAGI2-AS3 and EPB41L3 led to inhibited cancer cell invasion and migration, while overexpression of miR-233 played an opposite role and attenuated the effects of overexpressing MAGI2-AS3. MAGI2-AS3 may sponge miR-233 to upregulate EPB41L3, thereby inhibiting CSCC cell invasion and migration.


Alternative wetting boundary condition for the chemical-potential-based free-energy lattice Boltzmann model.
The free-energy lattice Boltzmann (LB) method is a multiphase LB approach based on the thermodynamic theory. Compared with traditional free-energy LB models, which employ a nonideal thermodynamic pressure tensor, the chemical-potential-based free-energy LB model has attracted much attention in recent years as it avoids computing the thermodynamic pressure tensor and its divergence. In this paper, we propose an improved wetting boundary condition for the chemical-potential-based free-energy LB model. Different from the original wetting boundary condition in the literature, the improved wetting boundary condition utilizes a surface chemical potential that is compatible with the chemical potential of the fluid domain. Accordingly, the thermodynamic consistency of the chemical-potential-based free-energy LB model can be retained by the improved wetting boundary condition. Numerical simulations are performed for droplets resting on flat and cylindrical surfaces with different contact angles. The numerical results show that the improved wetting boundary condition yields more reasonable results and the maximum spurious velocities are found to be smaller by 2 ∼ 3 orders of magnitude than those produced by the original wetting boundary condition.


UPLC-MS-MS method for simultaneous determination of caffeine, tolbutamide, metoprolol, and dapsone in rat plasma and its application to cytochrome P450 activity study in rats.
A specific ultra-performance liquid chromatography tandem mass spectrometry method has been described for the simultaneous determination of caffeine, tolbutamide, metoprolol and dapsone in rat plasma, which are the four probe drugs of the four cytochrome P450 (CYP450) isoforms CYP1A2, CYP2C9, CYP2D6 and CYP3A4. The chromatographic separation was achieved using a Waters Acquity UPLC BEH HILIC C(18) column (2.1 × 50 mm, 1.7 µm). The mobile phase consisted of acetonitrile and water (containing 0.1% formic acid) (15:85, v/v). The triple quadrupole mass spectrometric detection was operated by positive electrospray ionization. Phenacetin was chosen as internal standard. Plasma samples were extracted with dichloromethane-butanol (10:1, v/v). The recoveries ranged from 67.5% to 98.5%. The calibration curves in plasma were linear in the range of 2.5-1,000 ng/mL for caffeine and dapsone, 5-5,000 ng/mL for tolbutamide and 2.5-250 ng/mLfor metoprolol, with correlation coefficient (r(2)) of 0.9936, 0.9966, 0.9990 and 0.9998, respectively. The method was successfully applied to pharmacokinetic studies of the four probe drugs of the four CYP450 isoforms and used to evaluate the effects of breviscapine on the activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in rats.


RAF Kinase Inhibitory Protein Expression and Phosphorylation Profiles in Oral Cancers.
Raf Kinase Inhibitory Protein (RKIP) expression has been profiled for a number of unique tissue cancers. However, certain tissues have not been explored, and oral and oropharyngeal cancers stand out as high priority targets, given their relatively high incidence, high morbidity rate, and in many cases, preventable nature. The purpose of this study was to examine changes in RKIP expression and phosphorylation in tissues resected from oral cancer patients, and compare to results generated from immortalized cell lines raised from primary oral cancer tissues, including oral squamous cell carcinoma line 4 (SCC4) and human squamous cell carcinoma line 3 (HSC3). Out of 4 human samples collected from male and female patients across various ages with variable risk factors, we observed an across the board reduction in RKIP expression. Two human samples demonstrated a significant increase in phosphorylated RKIP when normalized to total RKIP, however all 4 were increased when normalized to total cellular protein. The immortalized oral cancer cell culture HSC3 revealed significant increases in phosphorylated RKIP with no change in total RKIP expression, while line SCC4 demonstrated an increase in both total and phosphorylated RKIP. Results presented here indicate that oral cancers behave similarly to other cancers in terms of changes in RKIP expression and phosphorylation, although immortalized cell line expression profiles significantly differ from human tissue biopsies.


Autocatalytic backbone N-methylation in a family of ribosomal peptide natural products.
Peptide backbone N-methylation, as seen in cyclosporin A, has been considered to be exclusive to nonribosomal peptides. We have identified the first post-translationally modified peptide or protein harboring internal α-N-methylations through discovery of the genetic locus for the omphalotins, cyclic N-methylated peptides produced by the fungus Omphalotus olearius. We show that iterative autocatalytic activity of an N-methyltransferase fused to its peptide substrate is the signature of a new family of ribosomally encoded metabolites.


[Treatment of patients after myocardial infarction].
During the first year after myocardial infarction 15-20% of patients die and about 50% because of sudden death. Appropriate therapy is essential to prevent arrhythmias and heart failure. Some pharmacological methods are discussed in main clinical aspects.


Older Adults' Interpretation of Nurses' Nonverbal Communication in Cameroon: A Grounded Theory Inquiry.
Communication is central to nursing care. Yet, the nonverbal aspect of communication tends to be neglected or underestimated in nursing studies. Research has shown that older patients interpret nurses' communication messages during the clinical encounter. This article conceptualizes older adults' interpretation of and need for nonverbal communication (NVC) to enhance patient-centered communication advocated by the World Health Organization. The Corbin and Strauss (2015) inductive Grounded Theory approach was used to collect data from 3 hospital units in Cameroon using in-depth interviews with eight older adults, thirteen nurses, and four student nurses between July 2018 and January 2020. Open coding, axial coding, and selective coding were used for analysis, which reveals that interpretations of NVC can be positive or negative. It means that older adults view nurses either as angels or as difficult persons, depending on the nurses' positive or negative NVC and behaviors. These interpretations lead to consequences ranging from a preference for some nurses to noncompliance with care. The results further show that older adults need active listening, humor, and affection from nurses. Information regarding older adults' interpretation of and need for NVC can be used to improve curriculum content and to develop skills in and awareness of NVC with older adults. It is recommended that further research expand on effective nonverbal techniques during COVID-19 times where the meaning of facial expressions and voice inflection can be disrupted.


Exhaled nitric oxide measurements: correction equation to compare hand-held device to stationary analyzer.
Exhaled nitric oxide (FE(NO)) is a reliable non-invasive marker of airway inflammation. In 2003 FE(NO) chemiluminescence analyzer (NIOX; Aerocrine AB, Solna, Sweden) was approved by U.S. Food and Drug Administration for monitoring asthma therapy. Recently, the same company developed a portable device using electrochemical sensors (NIOX-MINO; Aerocrine AB). The aim of our study was to compare NIOX-MINO FE(NO) values to those obtained by NIOX and to calculate a correction equation. Two adequate measurements obtained by NIOX and NIOX-MINO were recorded in 32 subjects (16 females, mean age 41 years). FE(NO) values measured by NIOX-MINO were systematically higher than those obtained by NIOX (47.1ppb, IC 95% 35.2-59.1 and 36.9ppb, IC 95% 25.0-49.0, respectively). There was a significant correlation (r=0.998, p<0.001) between FE(NO) measured by the two analyzers and the following conversion equation was calculated as: FE(NO(NIOX))=-1.656(SE=0.61)+0.808(SE=0.009)x FE(NO(NIOX-MINO)) DISCUSSION: FE(NO) values measured by the portable nitric oxide analyzer are reliable and strongly correlated with values obtained by the standard stationary device, with a systematic difference observed between the two instruments' values that can be described by the conversion equation we provided. This equation will help clinicians and researchers to compare data obtainable by the two analyzers.


Studies on the mechanism of bile salt-induced liposomal membrane damage.
The damage of phosphatidylcholine membranes by bile salts such as cholate, deoxycholate (DC), chenodeoxycholate (CDC), ursodeoxycholate (UDC), as well as their glyco- and tauroconjugates, and lithocholate (LC) were studied. The permeabilities of liposomes differing in size (700 and 1,700 A in diameter) were determined at increasing bile salt concentrations. The release of entrapped raffinose (3H) (MW: 594) or inulin (3H) (MW: 5,000) was measured by pelleting of the liposomes and subsequent determination of the radioactivities in the supernatant. The release of these uncharged volume markers of different size points to a formation of membrane leaks increasing in size with increasing bile salt concentration. Determination of the membrane damaging threshold concentrations of bile salts demonstrated a higher stability of the smaller liposomes. Incubation of the smaller liposomes with increasing DC concentrations results in a successive substitution of lecithin by DC. The predominantly DC-containing vesicles are of remarkable stability against higher DC concentrations. The damaging properties of bile salts increase with decreasing number of hydroxy groups, with the exception of UDC and its conjugates which are much less membrane toxic than the other dihydroxy bile salts. Conjugation with glycine or taurine slightly enhances the membrane toxicity of bile salts with the exception of UDC. Sulfation of the 3-alpha-hydroxy group of LC reduces the damaging effect to about 10%.


The cardinal principle of like attracting like generates many ubiquitous oligopeptides shared by divergent proteins.
Actual protein amino acid sequences are very different from random assemblages of 20 varieties of amino acids. The separate survey of 20 unrelated proteins in two steps that included eight of the 18 discussed in this paper, revealed that at the level of 5000 total residues, one out of every 32 tetrapeptides appeared in two or more identical copies, whereas at the level of 10,000 total residues, the frequency was elevated to one out of every 29. It would thus appear that only 60,000 or so, out of the possible 160,000 (20(4)) varieties of tetrapeptides, are regularly used by all proteins. These shall be defined as ubiquitous tetrapeptides. Those tetrapeptides occasionally found to be stray which did not belong to the above group of 60,000 must have been generated by new mutations. Thus, they are expected to return to the group by subsequent mutations. The above ubiquity is due to the cardinal principle of protein construction which is like attracting like. On the average, 28% of each residue is devoted to the formation of homodipeptides such as Leu-Leu, Asn-Asn and Trp-Trp. Consequently, homo-oligopeptides, pentapeptidic and longer, are readily found in two or more proteins unrelated to each other. The next in line among the ubiquitous oligopeptides are those made of similar residues. They usually contain palindromic cores such as Leu-Val-Leu, Ala-Gly-Ala and Lys-Arg-Lys.(ABSTRACT TRUNCATED AT 250 WORDS)


Role of DRAM1 in mitophagy contributes to preeclampsia regulation in mice.
Preeclampsia (PE) is a complication during pregnancy that is diagnosed by a new onset of hypertension and proteinuria. Although the pathogenesis of PE is not fully understood, a growing body of evidence indicates that oxidative stress and mitochondrial dysfunction might contribute to the progression of PE. Therefore, the aim of the present study was to determine the role of mitophagy in mitochondrial dysfunction and oxidative stress in PE, and to evaluate the role of DNA damage‑regulated autophagy modulator 1 (DRAM1) in the development of PE. First, a mouse model of PE induced by hypoxia‑inducible factor 1α was established, and high levels of oxidative stress, apoptosis and mitochondrial dysfunction were found in the placentas of PE mice. Additionally, the placentas of PE mice exhibited decreased mitophagy and significantly decreased DRAM1 expression. To further explore the role of DRAM1 in mitophagy, DRAM1 was overexpressed in the placental tissues of PE mice, and this overexpression effectively improved the symptoms of PE mice and significantly reduced blood lipid and urine protein levels. DRAM1 overexpression also improved mitochondrial function and reduced oxidative stress in the placentas of PE mice. In addition, the overexpression of DRAM1 improved mitochondrial fusion and fission, and enhanced mitophagy. Altogether, these results indicated a key role for DRAM1 in mitophagy that contributed to the regulation of PE. To the best of the authors' knowledge, the present study provided the first evidence of a role for DRAM1 in PE, and offered novel insight into the pathophysiological mechanisms of PE.


Rehabilitation of cognitive and motor functions in younger and older patients with vascular brain damage, rheumatologic illness and in post-surgery patients.
This study presents results of inpatient rehabilitation (as monitored by Functional Independence Measure (FIM)) of patients with vascular brain damage (n = 78), post surgery patients (n = 62) and of patients with rheumatologic illness (n = 45). These patients were divided into two age groups (cut off point 65 years). There were significant differences in the FIM scores in all three diagnosis groups between the younger and the older patients at discharge, the younger patients reaching a higher FIM score. However, there were no substantial differences between the two age groups in FIM gains the length of stay in any of the diagnosis groups. This study indicates that although younger patients reach higher FIM score at admission and at discharge the patients older than 65 improved in a comparable way during the same length of stay thus requiring comparable financial resources.


Signal transduction via the beta 1 integrins is a required intermediate in interleukin-1 beta induction of alkaline phosphatase activity in human osteosarcoma cells.
In this report data are presented which demonstrate that the induction of an osteoblastic phenotype by interleukin-1 beta (IL-1 beta) requires an intermediate step involving signal transduction via the beta 1 family of integrin glycoproteins. Recombinant human IL-1 beta inhibits human osteosarcoma cell proliferation, stimulates integrin expression, and induces alkaline phosphatase activity, a marker of osteoinductive and osteoblastic phenotype. The approximately 10-fold stimulation of expression of the beta 1 integrins occurs rapidly (within 20 to 40 h), whereas the alkaline phosphatase activity is not induced until at least 5 days after the addition of IL-1 beta. To determine whether the early stimulation of integrin expression is required for the subsequent expression of alkaline phosphatase activity, polyclonal as well as monoclonal antibodies directed against the alpha 5 and beta 1 integrin subunits were added to cultures at the same time as IL-1 beta. These antibodies inhibited by 55 to 82% the longer term induction of the osteoblastic differentiation marker, alkaline phosphatase activity, but did not however affect the IL-1 beta-induced stimulation of integrin expression or the inhibition of cell proliferation. In addition, at the concentrations used, there was no effect of the antibodies on cell attachment. These data suggest that the stimulation of integrin expression by IL-1 beta, and the resulting enhanced integrin-extracellular matrix interactions, is a required intermediate event in the IL-1 beta regulation of osteoblastic cell differentiation. The data also suggest that the integrins are capable of signal transduction resulting in altered gene expression, and may also play a crucial role in modulating cytokine-mediated effects on cell differentiation.


Water-fat MRI for assessing changes in bone marrow composition due to radiation and chemotherapy in gynecologic cancer patients.
To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy. Thirteen women with gynecologic malignancies who were to receive radiation and/or chemotherapy were recruited for this study. Subjects were imaged on a 3T magnetic resonance (MR) scanner at baseline (after surgery but before radiation or chemotherapy), 6 months, and 12 months after treatment. Water-fat imaging was used to generate high-resolution, 3D signal fat fraction (sFF) maps extending from mid-femur to L3. Treatment changes were assessed by measuring marrow sFF in the L4 vertebra, femoral necks, and control tissues. Pretreatment and 6-month scans were compared in nine women. sFF increased significantly in both the L4 vertebral marrow (P = 0.04) and the femoral necks (P = 0.03), while no significant change was observed in control regions. Qualitatively, chemotherapy changes were more uniform in space, whereas the radiation-induced changes were largest in marrow regions inside and close to the target radiation field. Water-fat MRI is sensitive to changes in red/yellow marrow composition, and can be used for quantitative and qualitative assessment of treatment-induced marrow damage.


Clindamycin releasing bionanocomposite hydrogels as potential wound dressings for the treatment of infected wounds.
The bionanocomposite hydrogels based on polyvinyl alcohol and egg white (as the matrix) and montmorillonite nanoclay (as reinforcement) were fabricated via the freezing-thawing technique. The prepared bionanocomposite hydrogels were loaded with clindamycin, as an effective antibiotic, to attain new potential wound dressings for healing the infected wounds. The microstructural properties of the bionanocomposite hydrogel wound dressings were characterized using the X-ray diffractometry, transmission electron microscopy, atomic force microscopy and gel fraction measurement. It was shown that all of the bionanocomposite hydrogel wound dressings had an exfoliated morphology and the montmorillonite layers acted as additional crosslinking zones to interconnect the polyvinyl alcohol and egg white chains. The characteristics of the prepared wound dressings were investigated using different experiments, including the water content, drying, water vapor transmission rate (WVTR), transparency and in vitro drug release tests. It was found that the equilibrium water content and WVTR were tended to decrease by increasing the loading level of montmorillonite in samples. The results showed that the drying period of bionanocomposite hydrogel wound dressings was prolonged by increasing the content of the incorporated montmorillonite. In vitro drug delivery experiments showed the cumulative fractional release of clindamycin and the clindamycin diffusion coefficient were decreased either by increasing the weight percentage of the incorporated montmorillonite into the wound dressings or by decreasing the pH of the release medium. It was also shown that the mechanism governing the release of clindamycin in all examined samples was the non-Fickian (anomalous) transport.


Amendments to regulations regarding withdrawal of applications and voluntary suspension of benefits. Final rule with request for comments.
We are modifying our regulations to establish a 12-month time limit for the withdrawal of old-age benefits applications, allow one withdrawal per lifetime, and limit the voluntary suspension of benefits for purposes of receiving delayed retirement credits to months for which you have not received a payment. We are making these changes to revise current policies that have the potential for misuse.


15N-1H HSQC NMR evidence for distinct specificity of two active sites in Escherichia coli glyoxalase I.
Much remains to be elucidated concerning the selectivity mechanism of supposedly identical active sites in oligomeric proteins. Glyoxalase I (GlxI) catalyzes the glutathione-dependent conversion of 2-oxoaldehydes to S-2-hydroxyacylglutathione derivatives. The E. coli GlxI is a Ni(2+)/Co(2+)-activated homodimeric protein containing two symmetric, and dually metallated active sites as characterized by X-ray structure determination. Nevertheless, kinetics and isothermal titration calorimetric (ITC) studies indicate that dimeric GlxI binds to metal ions in a ratio of 1:1 (one metal ion/one dimer) [ Clugston , S. L. , Yajima , R. , and Honek , J. F. ( 2004 ) Biochem. J. 377 , 309 - 316 ]. In the current study, we provide spectroscopic evidence for the nonequivalent metallation of GlxI by use of (15)N-(1)H HSQC NMR titration experiments. (15)N-(1)H HSQC NMR spectra reveal that the local conformations of the two active sites in homodimeric GlxI are initially asymmetric in the apo-form, resulting in functional differentiation, wherein only one active site binds to the Ni(2+) ion, and another active site is observed to be more selective for a potent inhibitor. The current results enhance our understanding of GlxI structure-function relationships and provide a potential new strategy for the development of small molecule inhibitors for this enzyme system.


Identification of mutation sites on delta5 desaturase genes from Mortierella alpina 1S-4 mutants.
The mutation sites on delta5 desaturase genes in delta5 desaturase-defective mutants derived from arachidonic acid-producing Mortierella alpina 1S-4 were identified. The mutations resulted in an amino acid replacement (G189E or W301Stop) and uncorrected transcription caused by recognition of an AG-terminal newly created on C207A gene mutation, resulting in low or no delta5 desaturase activity in these mutants.


SHAPING QUALITY THROUGH VISION, STRUCTURE, AND MONITORING OF PERFORMANCE AND QUALITY INDICATORS: IMPACT STORY FROM THE QUEBEC TRAUMA NETWORK.
The Quebec Trauma Care Continuum (TCC) was initiated in 1991 with the objective of providing accessible, continuous, efficient, and high quality services for all injury cases in the province. The TCC design relied on three key components: (i) the designation of a network of acute care and rehabilitation facilities with specific mandates and responsibilities; (ii) the elaboration of transfer protocols, standing agreements, and governing structures to ensure fluid and optimal patient flow; and (iii) the close monitoring of several indicators to facilitate the continuous evaluation and improvement of the network. Between 1992 and 2002, in-hospital mortality following major trauma decreased from 51.8 percent to 8.6 percent, followed by an additional 24 percent drop between 1999 and 2012. We also observed a 16 percent decrease in average LOS but no change in the incidence of complications or unplanned readmissions. These changes translate into 186 lives saved per year and cost savings, due to shorter LOS, of 6.3 million CD$ per year. The risk-adjusted incidence of in-hospital mortality following major injury between 2006 and 2012 (7 percent) was the lowest of all Canadian provinces. Strategic transformation of a network's structure and processes, supported by continuous monitoring of validated quality indicators, can lead to significant and sustainable improvements in clinical outcomes. It is hoped that the Quebec trauma story will inspire other jurisdictions and other healthcare sectors.


[About the Geserick sign--a literature study].
Fractures of the medial and basal orbital wall as well as the petrous part of the temporal bone were described first in 1980 by a Berlin-based study group led by Geserick as new cranium findings resulting from a contrecoup mechanism. Experimental and comparative examinations revealed that indirect fractures of the orbital walls are caused by a coup action of the eyeballs, whereas the mechanogenesis of the petrous bone fractures continues to be unclear. The frequently combined occurrence with the orbital sign nonetheless permits an allocation to the contrecoup mechanism. Both signs are important criteria for forensic and clinical assessment of craniocerebral injuries.


[Adaptation of water-electrolytes metabolism to space flight and in its imitation].
50-years study of water-electrolytes exchange, the condition of water environments of the organism and the hormonal regulation in space flights, and also in postflight period or in its on ground modeling (hypokinesia, bed rest, immersion etc.) has shown the important role of the water-salt homeostasis in adaptation of the human and animal organisms to weightlessness. It has been revealed, that in weightlessness conditions for development of negative balance of a liquid (hypohydration) and the basic electrolytes are created. After the termination of long space flights attributes of development adaptive reactions compensating for extracellular liquid's volume come to light. In order to assess the state of the kidneys and water-electrolyte metabolism in cosmonauts and investigators, functional load tests and especial methods of diagnostic were developed. This is the basis for researches directed on improvement of the scheme of correction hydrogenous the status of an organism of the cosmonauts at the different stages of flight.


iTRAQ-Based Proteomics of Chronic Renal Failure Rats after FuShengong Decoction Treatment Reveals Haptoglobin and Alpha-1-Antitrypsin as Potential Biomarkers.
Background. Chronic renal failure (CRF) has become a global health problem and bears a huge economic burden. FuShengong Decoction (FSGD) as traditional Chinese medicine has multiple pharmacological effects. Objectives. To understand the underlying molecular mechanism and signaling pathway involved in the FSGD treatment of CRF and screen differentially expressed proteins in rats with CRF treated with FSGD. Methods. Thirty-three male Sprague-Dawley rats were randomly divided into control group, CRF group, and FSGD group. Differentially expressed proteins were screened by iTRAQ coupled with nanoLC-MS/MS, and these identified proteins were later analyzed by GO, KEGG, and STRING. Additionally, haptoglobin (HP) and alpha-1-antitrypsin (AAT) were finally verified by ELISA, Western blot, and real time PCR. Results. A total of 417 proteins were identified. Nineteen differentially expressed proteins were identified in the FSGD group compared with the model group, of which 3 proteins were upregulated and 16 proteins were downregulated. Cluster analysis indicated that inflammatory response was associated with these proteins and complement and coagulation cascade pathways were predominantly involved. The validation methods further confirmed that the levels of HP and AAT were significantly increased. Conclusions. HP and AAT may be the important biomarkers in the pathogenesis of CRF and FSGD therapy.


Formulation, release characteristics and bioavailability of novel monolithic hydroxypropylmethylcellulose matrix tablets containing acetaminophen.
Effect of incorporating pharmaceutical excipients on the in vitro release profiles and the release mechanism of monolithic hydroxypropylmethylcellulose (4000 cps) matrix tablets (m-HPMC tablets) in terms of mimicking the dual drug release character of bi-layered Tylenol ER tablets was studied. We also compared the in vitro release profiles of optimized m-HPMC matrix tablet and Tylenol ER tablet in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid, and in vivo drug bioavailabilities in healthy human volunteers. Acetaminophen was used as the model drug. The m-HPMC tablets were prepared using a wet granulation method followed by direct compression. Release profiles and swelling rates of m-HPMC tablets were found to be highly influenced by the types and amounts of pharmaceutical excipients incorporated. Starch 1500 (Prejel) and sodium lauryl sulfate (SLS) played a key role in determining the dissolution rate of m-HPMC tablets. Additional excipients, i.e., microcrystalline cellulose (Avicel PH101) and NaH2PO4 were used to tune the release profiles of m-HPMC tablets. The effect of pharmaceutical excipients on drug release from HPMC-based matrix tablets was found to be mainly due to a change in hydrophilic gel expansion and on physical interactions between the drug and HPMC. The optimized m-HPMC tablet with a balanced ratio of Prejel, SLS, Avicel PH101, and NaH2PO4 in the formulation showed dual release profiles in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid in vitro. Dual release was defined as immediate drug release within few minutes followed by extended release over 8 h. The similarity factors of m-HPMC tablets and bi-layered Tylenol ER tablets were 79.8, 66.1, and 82.7 in water, gastric fluid and intestinal fluid, respectively, indicating the equivalence of the two release profiles. No significant in vivo bioavailability differences were observed in healthy human volunteers. The developed m-HPMC tablet with dual release characteristics can be easily prepared using a conventional high-speed tablet machine and could provide an alternative to commercially available bilayered Tylenol ER tablets.


Chemometric analysis reveals links in the formation of fragrant bio-molecules during agarwood (Aquilaria malaccensis) and fungal interactions.
Fragrant agarwood, arguably the costliest wood in the world, is formed by plant-fungal interactions in Aquilaria spp. However, very little is known about this fragrant outcome of interaction. Therefore, mimicking the ancient traditions of agarwood production in Assam (Northeast India), a chemometric assessment of the agarwood-fungus interaction was made by chemical profiling (GC-MS) coupled with statistical analysis (principal component, correlation network analysis) across three platforms, viz. callus, juvenile plants and resinous wood-chips with an associated Fusarium. In the study of callus-fungus interaction, increased accumulation of key aroma compounds such as pentatriacontane {fold change (log2FC) = 3.47)}, 17-pentatriacontene (log2FC = 2.95), tetradecane, 2-methyl- (log2FC = 1.10) over callus and activation of pathways related to defense and secondary metabolism indicated links to aroma production. Study on fungal interactions in juvenile plants and resinous wood-chips indicated formation of terpenoid precursors (e.g. farnesol, geranylgeraniol acetate) and agarwood sesquiterpenes (e.g. agarospirol, γ-eudesmol). Correlation network analysis revealed the possible regulation of sesquiterpene biosynthesis involving squalene. Also a direct role of fungus in aroma (e.g. dodecane, 4-methyl-, tetracosane) was highlighted. Appearance of fragrant molecules unknown to agarwood during interaction featured as a new possibility for future research.


ABCB1 1199G>A polymorphism (rs2229109) affects the transport of imatinib, nilotinib and dasatinib.
ABCB1 (or P-glycoprotein) is implicated in the multidrug-resistance phenotype, including the resistance toward anticancer drugs such as tyrosine kinase inhibitors (TKIs). The purpose of this study was to evaluate in vitro the influence of the ABCB1 1199G>A SNP on ABCB1 transport activity toward selected TKIs (imatinib, nilotinib and dasatinib) that are currently used in chronic myelogenous leukemia. Two different cell lines, HEK293 and K562, were stably transfected with ABCB1 1199G wild-type or ABCB1 1199A variant allele. The impact of this polymorphism on accumulation and antiproliferative effects of imatinib, nilotinib and dasatinib was evaluated. In K562 models, the expression of Asn400 variant protein was associated with lower antiproliferative effects of imatinib, nilotinib and dasatinib compared with Ser400 wild-type protein. Moreover, in HEK293 cells, imatinib and nilotinib intracellular accumulation were lower in variant compared with wild-type models. Imatinib, nilotinib and dasatinib are transported more efficiently by the ABCB1 variant (Asn400) compared with the wild-type (Ser400) protein. The impact of ABCB1 1199G>A SNP on TKI response should be further investigated in chronic myelogenous leukemia patients.


B7-H4 expression is elevated in human U251 glioma stem-like cells and is inducible in monocytes cultured with U251 stem-like cell conditioned medium.
Previous studies indicated that B7-H4, the youngest B7 family, negatively regulates T cell-mediated immunity and is significantly overexpressed in many human tumors. Tumor stem cells are purported to play a role in tumor renewal and resistance to radiation and chemotherapy. However, the link between B7-H4 and tumor stem cells is unclear. In this study, we investigated B7-H4 expression in the medium of human glioma U251 cell cultures. Immunofluorescence results showed that U251 cells cultured in serum-free medium (supplemented with 2% B27, 20 ng/mL epidermal growth factor, 20 ng/mL basic fibroblast growth factor) maintained stem-like cell characteristics, including expression of stem cell marker CD133 and the neural progenitor cell markers nestin and SOX2. In contrast, U251 cells cultured in serum-containing medium highly expressed differentiation marker glial fibrillary acidic protein. Flow cytometry analysis showed serum-free medium-cultured U251 cells expressed higher intracellular B7-H4 than serum-containing medium-cultured U251 cells (24%-35% vs. 8%-11%, P < 0.001). Immunofluorescence in purified monocytes from normal human peripheral blood mononuclear cells revealed moderate expression of B7-H4 after stimulation with conditioned medium from U251 cells cultured in serum-containing medium. Moreover, conditioned medium from U251 stem-like cells had a significant stimulation effect on B7-H4 expression compared with serum-containing conditioned medium (P < 0.01). Negative costimulatory molecule B7-H4 was preferentially expressed in U251 stem-like cells, and conditioned medium from these cells more effectively induced monocytes to express B7-H4 than conditioned medium from U251 cells cultured in the presence of serum. Our results show that U251 stem-like cells may play a more crucial role in tumor immunoloregulation with high expression of B7-H4.


Use of a multidimensional assessment tool in a psychiatric adolescent care unit.
Adolescent mental health problems require treatment and care that are adapted to their needs. To evaluate this issue, it was decided to implement a multidimensional instrument focused on a global approach to adolescent social and behavioural functioning, combined with the ICD-10 classification. The combination of an assessment interview and a classification tool enabled the method to integrate the measurement of several domains of patient-based outcome rather than focus on the measurement of symptoms. A group of 68 adolescents from an inpatient unit were compared with 67 adolescents from the general population. Results suggest that adolescents from the care unit adopt significantly riskier behaviour compared with adolescents from the control group. As expected, the main problems identified refer to the psychological and familial areas. A cluster analysis was performed and provided three different profiles: a group with externalizing disorders and two groups with internalizing disorders. On the basis of a structured interview it was possible to obtain information in a systematic way about the adolescents' trajectory (delinquency, physical and sexual abuse, psychoactive substance use). It was shown that treatment and care should not focus exclusively on mental health symptoms, but also upon physical, psychological and social aspects of the adolescent. A global approach helps in the consideration of the multitude of factors which must be taken into account when working with people with serious mental health problems and may help to turn the care unit's activity more specifically towards the needs of these adolescents.


ROM Plus(®): accurate point-of-care detection of ruptured fetal membranes.
Accurate and timely diagnosis of rupture of fetal membranes is imperative to inform and guide gestational age-specific interventions to optimize perinatal outcomes and reduce the risk of serious complications, including preterm delivery and infections. The ROM Plus is a rapid, point-of-care, qualitative immunochromatographic diagnostic test that uses a unique monoclonal/polyclonal antibody approach to detect two different proteins found in amniotic fluid at high concentrations: alpha-fetoprotein and insulin-like growth factor binding protein-1. Clinical study results have uniformly demonstrated high diagnostic accuracy and performance characteristics with this point-of-care test that exceeds conventional clinical testing with external laboratory evaluation. The description, indications for use, procedural steps, and laboratory and clinical characterization of this assay are presented in this article.


[Molecular mechanisms of senescence in cell culture].
Clones of non-transformed human cells are mortal, that is, the cells divide only a limited number of times before they approach a state of proliferative senescence. This state has long been regarded as a cellular model of organismal aging or as aging in vitro because of its close relationship to the aging process of the donor of the cells. The underlying molecular mechanisms of this particular aging process have only been recently understood and are reviewed in the present paper. Cell division is accompanied by progressive telomere shortening, which is due both to properties of the replicative apparatus (the "end-replication problem") and to oxidative damage to telomere DNA under conventional cell culture conditions. If shortening of telomeres reaches a certain critical level, it is recognized as DNA damage by the cell's "guardian of the genome", the tumor suppressor p53. Stabilization of p53 activates the well characterized cell cycle checkpoint at the G1/S phase boundary and blocks the cell cycle irreversibly. Two recent results prove that telomere shortening is in fact the trigger of the checkpoint control in cellular senescence: First, acceleration of telomere shortening by increased oxidative stress results in accelerated proliferative senescence. Second, stabilization of telomere length, typically by activation of telomere, appears to be a necessary prerequisite for the immortalization of cells. Proliferative senescence, therefore, should be understood as an important means to counteract genetic instability and cancer.


Strawberries from integrated pest management and organic farming: phenolic composition and antioxidant properties.
Consumer awareness, pesticide and fertilizer contaminations and environmental concerns have resulted in significant demand for organically grown farm produce. Consumption of berries has become popular among health-conscious consumers due to the high levels of valuable antioxidants, such as anthocyanins and other phenolic compounds. The present study evaluated the influence that organic farming (OF) and integrated pest management (IPM) practise exert on the total phenolic content in 22 strawberry samples from four varieties. Postharvest performance of OF and IPM strawberries grown in the same area in the centre of Portugal and harvested at the same maturity stage were compared. Chemical profiles (phenolic compounds) were determined with the aid of HPLC-DAD/MS. Total phenolic content was higher for OF strawberry extracts. This study showed that the main differences in bioactive phytochemicals between organically and IPM grown strawberries concerned their anthocyanin levels. Organically grown strawberries were significantly higher in antioxidant activity than were the IPM strawberries, as measured by DPPH and FRAP assays.


How number line estimation skills relate to neural activations in single digit subtraction problems.
The Number Line (NL) task requires judging the relative numerical magnitude of a number and estimating its value spatially on a continuous line. Children's skill on this task has been shown to correlate with and predict future mathematical competence. Neurofunctionally, this task has been shown to rely on brain regions involved in numerical processing. However, there is no direct evidence that performance on the NL task is related to brain areas recruited during arithmetical processing and that these areas are domain-specific to numerical processing. In this study, we test whether 8- to 14-year-old's behavioral performance on the NL task is related to fMRI activation during small and large single-digit subtraction problems. Domain-specific areas for numerical processing were independently localized through a numerosity judgment task. Results show a direct relation between NL estimation performance and the amount of the activation in key areas for arithmetical processing. Better NL estimators showed a larger problem size effect than poorer NL estimators in numerical magnitude (i.e., intraparietal sulcus) and visuospatial areas (i.e., posterior superior parietal lobules), marked by less activation for small problems. In addition, the direction of the activation with problem size within the IPS was associated with differences in accuracies for small subtraction problems. This study is the first to show that performance in the NL task, i.e. estimating the spatial position of a number on an interval, correlates with brain activity observed during single-digit subtraction problem in regions thought to be involved in numerical magnitude and spatial processes.


Modulation of cPKCγ on Synapsin-Ia/b-Specific Phosphorylation Sites in the Developing Visual Cortex of Mice.
To explore the role of synapsin-Ia/b in visual cortical plasticity, the dynamic changes in total protein expression (T-) and conventional protein kinase C (cPKC)γ-modulated phosphorylation (P-) levels of synapsin-Ia/b were observed in the developing visual cortex of mice. The Western blot analysis was used to determine the levels of T- and P-synapsin-Ia/b at site of Ser9, 549, and 603; the cPKCγ gene wild-type (cPKCγ+/+) and knockout (cPKCγ-/-) mice were applied to explore the modulation of cPKCγ on synapsin-Ia/b phosphorylation status in visual cortex of mice at postnatal 7 to 60 days (P7-P60, n = 6 per group). The results showed that T-synapsin-Ia/b protein levels significantly increased at P14 to P35 and peaked at P42 to 60 (P < 0.001) in visual cortex when compared with that of P7 cPKCγ+/+ mice, and cPKCγ-/- did not affect this pattern of T-synapsin-Ia/b protein expressions. For synapsin-Ia/b phosphorylation status, the levels of P-Ser9 and 603 synapsin-Ia/b significantly elevated at P21 to P28 (P < 0.05 or 0.001), and then went down and maintained at lower levels at P35 to P60 (P < 0.05 or 0.001) compared with P7 cPKCγ+/+ mice. In addition, the cPKCγ gene knockout could significantly (P < 0.001) inhibit both the increase and decrease of P-Ser9 and 603 synapsin-Ia/b levels when compared with cPKCγ+/+ mice at P7 to P60. However, there were no significant changes of P-Ser549 synapsin-Ia/b in the developing visual cortex of both cPKCγ+/+ and cPKCγ-/- mice at P7 to P60. These results suggested that both protein expression levels and cPKCγ-modulated phosphorylation status at Ser9 and 603 of synapsin-Ia/b may play important role in developing visual cortex of mice.


Early Preventive Treatment With Enalapril Improves Cardiac Function and Delays Mortality in Mice With Arrhythmogenic Right Ventricular Cardiomyopathy Type 5.
Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in TMEM43 (transmembrane protein 43). There is no cure for ARVC5 and palliative treatment is started once the phenotype is present. A transgenic mouse model of ARVC5 expressing human TMEM43-S358L (TMEM43mut) recapitulates the human disease, enabling the exploration of preventive treatments. The aim of this study is to determine whether preventive treatment with heart failure drugs (β-blockers, ACE [angiotensin-converting enzyme] inhibitors, mineralocorticoid-receptor antagonists) improves the disease course of ARVC5 in TMEM43mut mice. TMEM43mut male/female mice were treated with metoprolol (β-blockers), enalapril (ACE inhibitor), spironolactone (mineralocorticoid-receptor antagonist), ACE inhibitor + mineralocorticoid-receptor antagonist, ACE inhibitor + mineralocorticoid-receptor antagonist + β-blockers or left untreated. Drugs were initiated at 3 weeks of age, before ARVC5 phenotype, and serial ECG and echocardiograms were performed. TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; P=0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; P=0.004), shorter QRS duration and reduced left ventricle fibrosis. Combined regimens including enalapril also showed positive effects. Metoprolol decreased QRS voltage prematurely and resulted in a nonsignificant decrease in left ventricular ejection fraction compared with untreated TMEM43mut mice. Preventive enalapril-based regimens reduced fibrosis, improved ECG, echocardiographic parameters and survival of ARVC5 mice. Early metoprolol did not show positive effects and caused premature ECG abnormalities. Our findings pave the way to consider prophylactic enalapril in asymptomatic ARVC5 genetic carriers.


Observation of half-quantum defects in superfluid 3He-B.
In the course of high-precision measurements of the relation between the superflow current J through a weak link in 3He-B and the difference in order parameter phase between each side of the link phi in a flexible wall Helmholtz resonator equipped with a rotation pickup loop, we have observed the signature of a stable textural defect that sustains a change of the phase by pi across it. "Cosmiclike" solitons, proposed by Salomaa and Volovik and hitherto thought unstable, can constitute such a defect.


Surgical resection of hepatocellular carcinoma in the cirrhotic liver.
A total of 80 patients with asymptomatic small hepatocellular carcinoma (HCC) associated with liver cirrhosis underwent a liver resection. The patients were divided into 4 groups according to the location of their tumor: group A (n = 9): left lateral segmentectomy or left hepatectomy, group B (n = 42): atypical partial hepatectomy on the lateral aspect of the right lobe, group C (n = 25): subsegmentectomy on either the anterior or the posterior surface of the right lobe, group D (n = 4): subsegmentectomy in the hilar area. There were two postoperative deaths (both in group D) and five cases of hospital mortality (1 case due to myocardial infarction in group C; 1 case due to bleeding esophageal varices in group B and 2 cases in group C; and 1 case due to fulminating hepatitis in group B). There was no any significant difference in tumor size, the preoperative serum bromosulfaphthalein retention rate or the postoperative peak serum conjugated bilirubin level among all the groups (p less than 0.05). The weights of the resected specimens were higher in groups A and B (259 +/- 58 g, 230 +/- 154 g) than in groups C and D (54 +/- 32 g, 37.5 +/- 15.0 g) (p less than 0.05). The amount of blood required for transfusion during surgery in group D (3,625 +/- 3,146 mL) was significantly greater than in the other three, groups (p less than 0.05); and was also greater in groups B and C (1,649 +/- 880 mL, 1,635 +/- 1,156 mL), than in group A (444 +/- 273 mL; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)