Dietary spices as beneficial modulators of lipid profile in conditions of metabolic disorders and diseases.
Spices are valued for their medicinal properties besides their use as food adjuncts to enhance the sensory quality of food. Dietary garlic, onion, fenugreek, red pepper, turmeric, and ginger have been proven to be effective hypocholesterolemics in experimentally induced hypercholesterolemia. The hypolipidemic potential of fenugreek in diabetic subjects and of garlic and onion in humans with induced lipemia has been demonstrated. Capsaicin and curcumin - the bioactive compounds of red pepper and turmeric - are documented to be efficacious at doses comparable to usual human intake. Capsaicin and curcumin have been shown to be hypotriglyceridemic, thus preventing accumulation of fat in the liver under adverse situations by enhancing triglyceride transport out of the liver. Capsaicin, curcumin, fenugreek, ginger, and onion enhance secretion of bile acids into bile. These hypocholesterolemic spices/spice principles reduce blood and liver cholesterol by enhancing cholesterol conversion to bile acids through activation of hepatic cholesterol-7α-hydroxylase. Many human trials have been carried out with garlic, onion, and fenugreek. The mechanism underlying the hypocholesterolemic and hypotriglyceridemic influence of spices is fairly well understood. Health implications of the hypocholesterolemic effect of spices experimentally documented are cardio-protection, protection of the structural integrity of erythrocytes by restoration of membrane cholesterol/phospholipid profile and prevention of cholesterol gallstones by modulation of the cholesterol saturation index in bile.


Current developments and future prospects for HIV gene therapy using interfering RNA-based strategies.
Acquired immunodeficiency syndrome (AIDS) is a slow, progressive, degenerative disease of the human immune system, ultimately leading to premature death of the patient. This disease is primarily caused by human immunodeficiency virus type-1 (HIV-1). The major targets of HIV infection are blood cells, namely lymphocytes and macrophages. While the immune response fails to eliminate the infected cells, the virus continues to spread. The purpose of HIV gene therapy is to provide "anti-HIV" genes to cells that are susceptible to HIV infection. Anti-HIV genes may be designed to express RNAs or proteins that interfere with the function of viral or cellular RNA(s)/protein(s), thereby inhibiting virus replication. Whereas interfering proteins may be cytotoxic and/or immunogenic, interfering RNAs are not. Interfering protein-based strategies requiring inducible gene expression (under the control of HIV regulatory proteins) can only be designed to block steps subsequent to the viral regulatory protein production. In contrast, interfering RNAs can be produced in a constitutive manner, which further enhances their antiviral activity and allows one to design strategies to inhibit virus replication before viral regulatory protein production occurs. Thus, interfering RNAs are of particular interest and are the focus of this review. Genes expressing interfering RNAs were designed to inhibit syncytium formation to prevent the death of the gene-modified cells. Strategies may also be developed to prevent gene-modified cells from becoming infected by HIV or from supporting HIV replication. Genes expressing interfering RNAs have been designed to inhibit HIV-1 entry and to cleave the incoming virion RNA, thus blocking virus replication before provirus DNA synthesis can be completed. A number of genes were also designed to express interfering RNAs that inhibit HIV replication at a post-integration step, by inhibiting the function of HIV RNAs or proteins produced in the infected cell. Also in development are anti-HIV genes that produce RNAs that would not only inhibit HIV replication in the gene-modified cell, but also prevent HIV RNA packaging and/or reverse transcription such that the progeny virus produced would be non-infectious. Further refinements to these strategies may lead to the development of "self-propagating" anti-HIV genes. These genes would express interfering RNAs that not only inhibit virus replication in the cell and prevent HIV RNA packaging and/or reverse transcription in the progeny virus, but also make use of the HIV itself to deliver the anti-HIV gene(s) to other cells. Thus, more and more cells susceptible to HIV infection would become resistant. Such "self-propagation" of anti-HIV-1 genes would only occur in cells that are susceptible to HIV infection, and would continue to take place for as long as HIV exists in the body.


Behaviors of children who are exposed and not exposed to intimate partner violence: an analysis of 330 black, white, and Hispanic children.
To compare the behaviors of black, white, and Hispanic children who were 18 months to 18 years of age and exposed to intimate partner violence with an age- and ethnically similar sample of children who were not exposed to violence and to compare both exposed and nonexposed children to normative samples. As part of a study on treatments for abused women in primary care public health clinics and Women, Infants and Children clinics in a large urban area, 258 abused mothers completed the Child Behavior Checklist (CBCL) on 1 of their randomly selected children between the ages of 18 months and 18 years. An ethnically similar sample of 72 nonabused mothers also completed the CBCL. The CBCL is a standardized instrument that provides a parental report of the extent of a child's behavioral problems and social competencies. The CBCL consists of a form for children 18 months to 5 years and a version for ages 6 to 18 years. The CBCL is orally administered to a parent, who rates the presence and frequency of certain behaviors on a 3-point scale (0 = not true, 1 = somewhat or sometimes true, and 2 = very true or often true). The time period is the last 6 months for the child 6 to 18 years of age and 2 months for the child 18 months to 5 years of age. Examples of behaviors for the child age 6 to 18 years include "gets in many fights," "truancy, skips school." Examples of behaviors for the child 18 months to 5 years of age include "cruel to animals," "physically attacks people," and "doesn't want to sleep alone." Both forms of the CBCL consist of 2 broadband factors of behavioral problems: internalizing and externalizing with mean scale scores for national normative samples as well as clinically referred and nonreferred samples of children. Internalizing behaviors include anxiety/depression, withdrawal, and somatic complaints. Externalizing behaviors include attention problems, aggressive behavior, and rule-breaking actions. Behavior scales yield a score of total behavioral problems. Scores are summed and then converted to normalized T scores. T scores >or=60 are within the borderline/clinical referral range-higher scores represent more deviant behavior. Multivariate analyses of variance (MANOVAs) were used to determine whether children from abused mothers differed significantly in their internalizing behaviors, externalizing behaviors, and total behavior problems from children of nonabused mothers. One sample t tests were used to compare children from abused and nonabused mothers to the matched clinically referred and nonreferred normative sample. Four pair-wise comparisons were considered: 1) children from abused women to referred norm, 2) children from abused women to nonreferred norm, 3) children from nonabused women to referred norm, and 4) children from nonabused to nonreferred norm. The internal, external, and total behavior problem T scores were dichotomized into a referral status: nonreferred = T score < 60, referred = T score >or= 60. Frequencies and percentages were used to describe the distribution of referral status among the children from the abused and nonabused women, and chi(2) tests of independence were used to determine whether the groups were significantly different. No significant differences in demographic characteristics between children from the abused women and nonabused women were observed. The sample consisted of a large number of Hispanic children (68.9%) and slightly more girls (53.6%), and nearly half (45.2%) had annual household incomes <10,000 dollars. Means, standard deviations, and results from the MANOVAs performed on internal, external, and total behavior problem scores between children from abused and nonabused women revealed no significant differences (F[3,139] = 1.21) for children ages 18 months through 5 years. Results from the MANOVA performed for ages 6 through 18 years revealed a significant group difference (F[3,183] = 3.13). Univariate tests revealed significant group differences for internalizing behavior (F[1,185] = 6.81), externalizing behav = 6.81), externalizing behavior (F[1,185] = 7.84), and total behavior problems (F[1,185] = 9.45). Overall, children of abused mothers had significantly higher internalizing (58.5 +/- 12.1), externalizing (55.5 +/- 12.4), and total behavior problems (57.6 +/- 12.3) scores than the internalizing (52.9 +/- 13.7), externalizing (49.7 +/- 10.6), and total behavior problems (51.0 +/- 13.0) scores exhibited for children of nonabused mothers. Most comparisons of children from the abused women to the referred and nonreferred norms are significant. The mean internal, external, and total behavior problem scores from children of abused women were significantly higher than the nonreferred norms and significantly lower than the referred norms. In contrast, all comparisons for children from nonabused women were not significantly different from the nonreferred norms. Children, ages 6 to 18 years, of abused mothers exhibit significantly more internalizing, externalizing, and total behavior problems than children for the same age and sex of nonabused mothers. In addition, the mean internalizing behavior score for boys 6 to 11 years of age as well as girls and boys 12 to 18 years of age of abused mothers were not significantly different from the clinical referral norms. Internalizing behaviors of anxiety, withdrawal, and depression are consistent with suicidal risk. The association of a child's exposure to intimate partner violence and subsequent attempted and/or completed suicide demands research. Our data demonstrate that children of abused mothers have significantly more behavioral problems than the nonclinically referred norm children but also, for most children, display significantly fewer problems than the clinically referred children. These children of abused mothers are clearly suspended above normal and below deviant, with children ages 6 to 18 being at the greatest risk. If abused mothers can be identified and treated, then perhaps behavior problems of their children can be arrested and behavioral scores improved. The American Academy of Pediatrics Committee on Child Abuse and Neglect recommends routine screening of all women for abuse at the time of the well-child visit and implementation of a protocol that includes a safety plan for the entire family. Clinicians can use this research information to assess for intimate partner violence during child health visits and inform abused mothers of the potential effects on their children's behavior. Early detection and treatment for intimate partner violence against women has the potential to interrupt and prevent behavioral problems for their children.


Substance use, substance use disorders, and treatment in adolescent and young adult cancer survivors-Results from a national survey.
Substance use can exacerbate cancer-related morbidity and mortality in adolescent/young adult (AYA) cancer survivors and place them at increased risk for adverse health outcomes. The objective of this study was to assess substance use, misuse, and substance use disorders [SUDs], as well as receipt of treatment for SUDs, among AYA cancer survivors. The authors used data from the National Survey of Drug Use and Health (2015-2018) to identify a nationally representative sample of AYAs aged 12 to 34 years. Outcomes assessed past-year tobacco, alcohol, marijuana, and illicit drug use; misuse of prescription opioids; SUDs; and SUD treatment. Multiple logistic regression was estimated to compare outcomes between 832 AYAs who reported a cancer history (survivors) and 140,826 AYAs who did not, adjusting sequentially for sociodemographic characteristics and health status. In regressions adjusting for sociodemographic characteristics, survivors were more likely than a noncancer comparison group of peers to use alcohol (6% relative increase; P = .048) and illicit drugs (34% relative increase; P = .012), to misuse prescription opioids (59% relative increase; P < .001), and to have a marijuana (67% relative increase; P = .011), illicit drug (77% relative increase; P < .001), or prescription opioid (67% relative increase; P = .048) SUD. When further adjusting for health status, survivors were still 41% more likely (P < .001) to misuse prescription opioids than noncancer peers. Among those with SUDs, survivors were more likely than peers to receive treatment (unadjusted, 21.5% vs 8.0%; adjusted, P < .05). AYA survivors were as likely as or more likely than noncancer peers to report substance use problems. These findings underscore the importance of interventions to reduce substance use and improve SUD treatment among AYA cancer survivors. The authors assessed substance use, misuse, and substance use disorders, as well as the receipt of treatment for substance use disorders, among adolescent and young adult (AYA) cancer survivors. In a nationally representative AYA sample, cancer survivors, despite their increased risk for morbidity and early mortality, were as likely as or more likely than peers without cancer to experience substance use problems. In particular, survivors had a significantly higher rate of prescription opioid misuse than peers. However, only 1 in 5 AYA survivors who experienced substance use disorders received treatment. These findings underscore the importance of interventions toward reducing substance use and improving access to treatment among AYA survivors.


Sources of alcohol for underage drinkers.
We assessed the extent to which various sources of alcoholic beverages are used by early, middle and older teenagers, the extent to which teenagers perceive alcohol to be available from different sources and factors related to use of alternative sources. Ninth graders (n = 2,269), twelfth graders (n = 2,377) and youth aged 18-20 (n = 1,738) were surveyed in 15 upper-midwestern communities using a nested cross-sectional design. Analyses were based on mixed-model regressions, with both the individual and community treated as random effects, taking into account the intraclass correlation for each dependent variable. Analyses focused on current (last 30 day) drinkers to avoid recall bias for drinking events in the distant past. A person aged 21 or over was the most common source of alcohol for current drinkers in all three age groups; 46% of 9th graders, 60% of 12th graders and 68% of those aged 18-20 obtained alcohol from a person age 21 or older for their last drinking occasion. A person under age 21 was the second most prevalent source for 9th and 12th graders (29% of each group obtained alcohol from someone under age 21 for their last drinking occasion). A commercial outlet was the second most prevalent source for those aged 18-20 (14% obtained alcohol directly from an outlet for their last drinking occasion). Perceived availability, binge drinking and several demographic characteristics were independently related to source of alcohol used, and age interacted with several factors in predicting source of alcohol. We conclude that increased attention to sources of alcohol used by youths would facilitate efforts to reduce underage drinking.


Dual-functional analogous cis-platinum complex with high antitumor activities and two-photon bioimaging.
Here we have designed and synthesized a novel analogous cis-platinum complex (TDPt) with strong two-photon absorption properties and higher stability upon laser irradiation. Interestingly, a higher cytotoxicity against three types of cancer cells compared to that of commercial cis-platinum was observed. The initial confocal micrographs showed that lysosomes may be the biological targets of such TDPt, except the conventional presumed DNA. This hypothesis was further confirmed by the two-photon microscopy and transmission electron microscopy micrograph. These results form an important basis for future "on-site observation" of the anticancer mechanism of the Pt(II) complex.


Catecholamines in prevention of hypoglycemia during exercise in humans.
To assess the role of catecholamines in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal humans were studied with combined alpha- and beta-adrenergic blockade and with adrenergic blockade while changes in insulin and glucagon were prevented with the islet clamp technique (somatostatin infusion with insulin and glucagon infused at fixed rates). The results were compared with those from an islet clamp alone study. In contrast to a comparison study (saline infusion), adrenergic blockade resulted in a small initial decrease in plasma glucose during exercise, from 5.0 +/- 0.2 to 4.4 +/- 0.2 mmol/l (P less than 0.01), but the level then plateaued. There was a substantial exercise-associated decrement in plasma glucose when insulin and glucagon were held constant, i.e., from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.0001), but the level again plateaued. However, when insulin and glucagon were held constant and catecholamine actions were blocked simultaneously, progressive hypoglycemia, to 2.6 +/- 0.6 mmol/l (P less than 0.001), developed during exercise. Hypoglycemia was the result of an absent increase in glucose production and an exaggerated initial increase in glucose utilization. Thus we conclude that sympathochromaffin activation plays a minor role when insulin and glucagon are operative, but a catecholamine, probably epinephrine, becomes critical to the prevention of hypoglycemia during exercise when changes in insulin and glucagon do not occur.


P21 v-ras inhibits induction of c-myc and c-fos expression by platelet-derived growth factor.
The viral oncogene v-ras inhibited the platelet-derived growth factor (PDGF)-induced upregulation of c-myc and c-fos proto-oncogene expression in fibroblast monolayers. These v-ras-containing cells proliferated in the absence of c-myc induction and no longer required PDGF to support growth. Fibroblasts expressing v-ras continued to express the same number of functional PDGF receptors on their surface as uninfected cells, yet the usual induction of transcription of the genes c-myc, c-fos, and JE in response to PDGF stimulation did not occur in the presence of newly introduced v-ras or chronic v-ras gene expression, and synthesis of c-myc protein did not occur. This inhibitory effect on growth factor-mediated induction of cellular proto-oncogenes was specific for PDGF in that induction of the c-myc and c-fos genes by certain other factors was not impaired.


Energy Level Alignment of N-Doping Fullerenes and Fullerene Derivatives Using Air-Stable Dopant.
Doping has been proved to be one of the powerful technologies to achieve significant improvement in the performance of organic electronic devices. Herein, we systematically map out the interface properties of solution-processed air-stable n-type (4-(1,3-dimethyl-2,3-dihydro-1H-benzoimidazol-2-yl)phenyl) doping fullerenes and fullerene derivatives and establish a universal energy level alignment scheme for this class of n-doped system. At low doping levels at which the charge-transfer doping induces mainly bound charges, the energy level alignment of the n-doping organic semiconductor can be described by combining integer charger transfer-induced shifts with a so-called double-dipole step. At high doping levels, significant densities of free charges are generated and the charge flows between the organic film and the conducting electrodes equilibrating the Fermi level in a classic "depletion layer" scheme. Moreover, we demonstrate that the model holds for both n- and p-doping of π-backbone molecules and polymers. With the results, we provide wide guidance for identifying the application of the current organic n-type doping technology in organic electronics.


Virus RNA species in kirsten murine sarcoma virus-transformed mink cells.
The nuclear and cytoplasmic RNAs from Kirsten murine sarcoma virus (KiMuSV)-transformed non-producer mink cells were studied for the species of virus-specific RNA by fractionation in agarose gels, transfer to diazotized aminophenylthioether paper and hybridization to complementary DNA probe. In both nuclei and cytoplasm, only genome-length KiMuSV-specific RNA was detected. No subgenomic virus RNA species was detected in poly(A+) or poly(A-) RNA fractions. The same observations were made in KiMuSV-transformed mink cells superinfected with feline leukaemia viruses. The significance of these findings is discussed.


Decreased PITX1 gene expression in human cutaneous malignant melanoma and its clinicopathological significance.
The pituitary homeobox 1 (PITX1) protein is a member of the bicoid-related homeobox transcription factors and has essential roles in human development. Recently, the PITX1 gene has been considered as a tumor suppressor gene in various human cancers. This study examined the expression of PITX1 in the development and progression of human cutaneous malignant melanoma. Immunohistochemical and/or immunofluorescence analyses were performed to examine the histological expression of PITX1 in healthy skin and 40 cutaneous malignant melanoma cases, including 10 melanoma in situ cases. Expression of PITX1 was shown in nuclei of melanocytes in normal skin. PITX1 expression was positive (labeling index: ≥10%) in 21 (52.5%) cases and negative (labeling index: <10%) in 19 (47.5%) of 40 cases of primary cutaneous malignant melanoma. The mean tumor thickness in PITX1-negative cases (7.11 ± 10.3 mm) was significantly higher than that in the positive cases (1.90 ± 3.19 mm) (P<0.01). The numbers of cases showing metastasis were 1 (4.76%) of 21 cases in PITX1-positive cases and 7 (36.8%) of 19 cases in PITX1-negative cases; the frequency was significantly higher in PITX1-negative cases than the positive cases (P = 0.012). Moreover, the reduction in PITX1 expression correlated significantly with clinical stage (P<0.001). Interestingly, PITX1 expression was inversely correlated with cell proliferation of cutaneous malignant melanoma (P<0.001). Down-regulation of PITX1 expression might contribute to the progression of cutaneous malignant melanoma via promoting cell proliferative activity.


Treatment of Taenia saginata infection with mixture of areca nuts and pumpkin seeds.
In January and February 1974, 32 adults (20 males and 12 females) and a 13-year-old girl with taeniasis saginata were treated with the mixture of boiled areca nuts and pumpkin seeds at Mastoban, Jen-ai District, Nantou County, Taiwan. A total of 48 worms including 42 scolices were recovered from 29 cases. Side-effects were observed in 4 cases including 3 with complaints of dizziness, tinnitus, nausea and vomiting, and one with coma and abdominal pain. Mixtures of 75-150 g areca nuts and 50-100 g pumpkin seeds were judged effective and safe.


Comparative Cost-Effectiveness of Clinic, Home, or Ambulatory Blood Pressure Measurement for Hypertension Diagnosis in US Adults.
Previous cost-effectiveness models found ambulatory blood pressure monitoring (ABPM) to be a favorable strategy to diagnose hypertension; however, they mostly focused on older adults with a positive clinic blood pressure (BP) screen. We evaluated the cost-effectiveness of 3 methods of BP measurement for hypertension diagnosis in primary care settings among 14 age- and sex-stratified hypothetical cohorts (adults ≥21 years of age), accounting for the possibility of both false-positive (white-coat hypertension) and false-negative (masked hypertension) clinic measurements. We compared quality-adjusted life-years and lifetime costs ($US 2017 from the US healthcare perspective) associated with clinic BP measurement, home BP monitoring, and ABPM under 2 scenarios: positive and negative initial screen. Model parameters were obtained from published literature, publicly available data sources, and expert input. In the screen-positive scenario, ABPM was the dominant strategy among all age and sex groups. Compared with clinic BP measurement, ABPM was associated with cost-savings ranging from $77 (women 80 years of age) to $5013 (women 21 years of age). In the screen-negative scenario, ABPM was the dominant strategy in all men and women <80 years of age with cost-savings ranging from $128 (women 70 years of age) to $2794 (women 21 years of age). Sensitivity analyses showed that results were sensitive to test specificity and antihypertensive medication costs. ABPM is recommended as the diagnostic strategy of choice for most adults in primary care settings regardless of initial screening results.


Bond strength evaluation of the veneering-core ceramics bonds.
The purpose of this study was to determine whether the bond of veneering porcelain to a ceramic core in bilayered ceramics was similar to that of the metal ceramic control of well known behaviour. Six groups of nine specimens each were fabricated, whose dimensions were 15 mm long and 8 mm in diameter at the core, and 2 mm long and 8 mm in diameter for the veneer. The groups were GR. 1 (control group): CrNi alloy/d.SIGN (Ivoclar), GR. 2: IPS e.maxPress/IPS e.maxCeram (Ivoclar), GR. 3: IPS e.maxZirCad/IPS e.maxZirPress (Ivoclar), GR. 4: IPS e.maxZirCad/IPS e.maxCeram (Ivoclar), GR. 5: Lava Frame (3M ESPE)/Lava Ceram (3M ESPE) and GR. 6: Lava Frame (3M ESPE)/IPS e.maxCeram (Ivoclar). A shear strength test was used in all samples with a universal testing machine. The chosen crosshead speed was of 0.50 mm/min. The obtained results were analyzed using a one way analysis of variance test (ANOVA) to determine whether significant differences existed between the groups (p<0.05). A Student Newman-Keuls multiple comparisons test was used. GR. 1: 13.45 MPa, GR. 2: 24.20 MPa, GR. 3: 12.70 MPa, GR. 4: 7.86 MPa, GR. 5: 10.20 Mpa and GR. 6: 4.62 Mpa. The bond strength of group 1 (control) was similar to groups 3 and 5. Group 2, whose core and veneer are both porcelains with a similar chemical composition, with silica as their main component, achieved the best adhesive results between both porcelains. The technique on zirconia cores that showed the higher results was the pressed technique. The lowest results were for the group using porcelains from different manufacturers.


A common signal detection model accounts for both perception and discrimination of the watercolor effect.
Establishing the relation between perception and discrimination is a fundamental objective in psychophysics, with the goal of characterizing the neural mechanisms mediating perception. Here, we show that a procedure for estimating a perceptual scale based on a signal detection model also predicts discrimination performance. We use a recently developed procedure, Maximum Likelihood Difference Scaling (MLDS), to measure the perceptual strength of a long-range, color, filling-in phenomenon, the Watercolor Effect (WCE), as a function of the luminance ratio between the two components of its generating contour. MLDS is based on an equal-variance, gaussian, signal detection model and yields a perceptual scale with interval properties. The strength of the fill-in percept increased 10-15 times the estimate of the internal noise level for a 3-fold increase in the luminance ratio. Each observer's estimated scale predicted discrimination performance in a subsequent paired-comparison task. A common signal detection model accounts for both the appearance and discrimination data. Since signal detection theory provides a common metric for relating discrimination performance and neural response, the results have implications for comparing perceptual and neural response functions.


New Metaphors for New Understandings of Genomes.
New techniques have made genome modification cheaper, easier, and faster, leading to a boom in research, especially for biomedical uses. Given the scope and potential power of this research and its applications, people need accurate information about what is being done or proposed, and why, and what the social and political implications might be. Metaphors can be useful in explaining complex topics, as they present the new in terms of the familiar. However, they can also misrepresent both how genomes and bodies work and the social and political implications of research and applications. Existing research shows that this is happening and that we need new language. However, it is not always easy to decide whether an alternative does rhetorical work that will empower publics, patients, biologists, and physicians alike. This article offers a conceptual framework for developing, analyzing, critiquing, and choosing new metaphors that will help improve communication about genomes and genomic research.


Depressive symptoms are associated with analgesic use in people with Alzheimer's disease: Kuopio ALSOVA study.
Neuropsychiatric symptoms of Alzheimer's disease (AD) such as depression may be associated with pain, which according to the literature may be inadequately recognized and managed in this population. This study aimed to identify the factors associated with analgesic use in persons with AD; in particular, how AD severity, functional status, neuropsychiatric symptoms of AD, co-morbidities and somatic symptoms are associated with analgesic use. 236 community-dwelling persons with very mild or mild AD at baseline, and their caregivers, were interviewed over five years as part of the prospective ALSOVA study. Generalized Estimating Equations (GEEs) were used to estimate unadjusted and adjusted odds ratios (ORs) for the factors associated with analgesic use over a five year follow-up. The proportion of persons with AD using any analgesic was low (13.6%) at baseline and remained relatively constant during the follow-up (15.3% at Year 5). Over time, the most prevalent analgesic changed from non-steroidal anti-inflammatories (8.1% of persons with AD at Year 1) to acetaminophen (11.1% at Year 5). Depressive symptoms (measured by the Beck Depression Inventory, BDI) were independently associated with analgesic use, after effects of age, gender, education, AD severity, comorbidities and somatic symptoms were taken into account. For every one unit increase in BDI, the odds of analgesic use increased by 4% (OR = 1.04, 95% confidence interval CI = 1.02-1.07). Caregiver depressive symptoms were not statistically significantly associated with analgesic use of the person with AD. Depressive symptoms were significantly associated with analgesic use during the five year follow-up period. Possible explanations warranting investigation are that persons with AD may express depressive symptoms as painful somatic complaints, or untreated pain may cause depressive symptoms. Greater awareness of the association between depressive symptoms and analgesic use may lead to safer and more effective prescribing for these conditions.


Ionic Polymer-Metal Composites: From Material Engineering to Flexible Applications.
ConspectusIonic polymer-metal composites (IPMCs) are one kind of artificial muscles that can realize energy conversions in response to external stimulus with merits of lightweight, scalability, quick response, and flexibility and have been treated as an important platform in artificial intelligence, such as bionic robotics, smart sensors, and micro-electromechanical systems. It is well-known that IPMC devices are mainly composed of one electrolyte layer laminated with symmetric electrode layers and realize energy conversion based on ion migration and redistribution inside the devices. However, several critical issues have greatly impeded the practical applications of IPMC devices, including metal electrode cracks, metal-polymer interface detachment, and water loss in the electrolyte. In the past decade, our group and collaborators have made attempts to address the mentioned critical issues with the purpose of accelerating practical applications of IPMC devices. First, in order to address the metal electrode cracks, we have developed various electrode materials to replace the metal electrode material, such as black phosphorus and graphdiyne. These materials display superior electrical and mechanical properties with enhanced material stability without cracking. Second, to address metal-polymer interface detachment, we have designed robust interfaces for IMPC devices with vertical array structures. The as-prepared interfaces present high ionic conductivity with excellent mechanical stability under bending states. As a result, the IPMC devices deliver high working stability exceeding a million cycles under air conditions. Third, in order to avoid water loss in the electrolyte, especially at ambient conditions, we have developed ionogel electrolytes containing highly stable ionic liquids as active ion sources. The ionogel electrolytes effectively prevent water loss in conventional water-containing electrolytes, just like Nafion electrolytes and greatly improve the working stability of IPMC devices. After addressing the key issues of IPMC devices, we finally obtained many high-performing IPMC devices and explored various intelligent applications of them. For instance, we have demonstrated the smart functions of IPMC devices as sensitive strain sensors, such as sign language recognition, handwriting detection, and human muscle monitoring. In addition, we have developed bionic flying robots with a vibration frequency as high as 30 Hz with the aid of high-performance IPMC actuators. A medical catheter based on IPMC actuators has been put forward by our group and can realize multiple degrees of freedom deformation under a low driving voltage of 2.5 V, which presents great potential for application in medical instruments. Lastly, a perspective on critical challenges and future research directions on IPMC materials and devices is highlighted for accelerating practical application.


[Sexual life in elderly patients with cardiovascular disease].
Sexual activity is an important component of patient and partner quality of life for men and women with cardiovascular disease, including many elderly patients. Older adults desire sexual intimacy when there is a partner and a health status that allows sexual relationships. Older individuals desire to love and enjoy sexual activity in relation to personal circumstances, and when health status allows them to experience close relations, most often within marriage especially in our country. Normal changes occur in the phases of sexual cycle with aging, male erectile dysfunction and female sexual dysfunction increase with age. Elderly patients are often affected by multiple organic diseases which can interfere with sexual function especially cardiovascular disease. Treating those disorders or modifying lifestyle-related risk factors may help prevent sexual dysfunction in the elderly. Sexuality is important for older adults and physicians should give their patient's opportunity to voice their concerns with sexual function and offer them alternatives for evaluation and treatment. Asking about sexual health remains difficult or embarrassing for many physicians; in addition, many patients find it difficult to raise sexual issues with their doctor.


Mutant Enpp1asj mice as a model for generalized arterial calcification of infancy.
Generalized arterial calcification of infancy (GACI), an autosomal recessive disorder, is characterized by early mineralization of blood vessels, often diagnosed by prenatal ultrasound and usually resulting in demise during the first year of life. It is caused in most cases by mutations in the ENPP1 gene, encoding an enzyme that hydrolyzes ATP to AMP and inorganic pyrophosphate, the latter being a powerful anti-mineralization factor. Recently, a novel mouse phenotype was recognized as a result of ENU mutagenesis - those mice developed stiffening of the joints, hence the mutant mouse was named 'ages with stiffened joints' (asj). These mice harbor a missense mutation, p.V246D, in the Enpp1 gene. Here we demonstrate that the mutant ENPP1 protein is largely absent in the liver of asj mice, and the lack of enzymatic activity results in reduced inorganic pyrophosphate (PPi) levels in the plasma, accompanied by extensive mineralization of a number of tissues, including arterial blood vessels. The progress of mineralization is highly dependent on the mineral composition of the diet, with significant shortening of the lifespan on a diet enriched in phosphorus and low in magnesium. These results suggest that the asj mouse can serve as an animal model for GACI.


Negative and positive ion matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and positive ion nano-electrospray ionization quadrupole ion trap mass spectrometry of peptidoglycan fragments isolated from various Bacillus species.
A general approach for the detailed characterization of sodium borohydride-reduced peptidoglycan fragments (syn. muropeptides), produced by muramidase digestion of the purified sacculus isolated from Bacillus subtilis (vegetative cell form of the wild type and a dacA mutant) and Bacillus megaterium (endospore form), is outlined based on UV matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and nano-electrospray ionization (nESI) quadrupole ion trap (QIT) mass spectrometry (MS). After enzymatic digestion and reduction of the resulting muropeptides, the complex glycopeptide mixture was separated and fractionated by reversed-phase high-performance liquid chromatography. Prior to mass spectrometric analysis, the muropeptide samples were subjected to a desalting step and an aliquot was taken for amino acid analysis. Initial molecular mass determination of these peptidoglycan fragments (ranging from monomeric to tetrameric muropeptides) was performed by positive and negative ion MALDI-MS using the thin-layer technique with the matrix alpha-cyano-4-hydroxycinnamic acid. The results demonstrated that for the fast molecular mass determination of large sample numbers in the 0.8-10 pmol range and with a mass accuracy of +/-0.07%, negative ion MALDI-MS in the linear TOF mode is the method of choice. After this kind of muropeptide screening often a detailed primary structural analysis is required owing to ambiguous data. Structural data could be obtained from peptidoglycan monomers by post-source decay (PSD) fragment ion analysis, but not from dimers or higher oligomers and not with the necessary sensitivity. Multistage collision-induced dissociation (CID) experiments performed on an nESI-QIT instrument were found to be the superior method for structural characterization of not only monomeric but also of dimeric and trimeric muropeptides. Up to MS4 experiments were sometimes necessary to obtain unambiguous structural information. Three examples are presented: (a) CID MSn (n = 2-4) of a peptidoglycan monomer (disaccharide-tripeptide) isolated from B. subtilis (wild type, vegetative cell form), (b) CID MSn (n = 2-4) of a peptidoglycan dimer (bis-disaccharide-tetrapentapeptide) obtained from a B. subtilis mutant (vegetative cell form) and (c) CID MS2 of a peptidoglycan trimer (a linear hexasaccharide with two peptide side chains) isolated from the spore cortex of B. megaterium. All MS(n) experiments were performed on singly charged precursor ions and the MS2 spectra were dominated by fragments derived from interglycosidic bond cleavages. MS3 and MS4 spectra exhibited mainly peptide moiety fragment ions. In case of the bis-disaccharide-tetrapentapeptide, the peptide branching point could be determined based on MS3 and MS4 spectra. The results demonstrate the utility of nESI-QIT-MS towards the facile determination of the glycan sequence, the peptide linkage and the peptide sequence and branching of purified muropeptides (monomeric up to trimeric forms). The wealth of structural information generated by nESI-QIT-MSn is unsurpassed by any other individual technique.


Co-functionalization with phosphate and carboxylate on polydiacetylene for colorimetric detection of calcium ions in serum.
In this study, co-functionalization with phosphate and carboxylate on polydiacetylene (PDA) was proposed to detect calcium ions in serum, inspired by biologically abundant phosphate-calcium ion and carboxylate-calcium ion binding. The cooperative interaction of calcium ions with phosphate and carboxylate in PDA induced the change of electronic properties in the backbone without aggregation of liposomes, accompanied by blue-to-purple color transition. The cooperative effect through the introduction of mixed ligands facilitated the selective detection of calcium ions over magnesium ions, which was a source of major interference in many calcium ion probes, and in the presence of major serum metal ions. The sensor system exhibited highly sensitive detection of calcium ions with an estimated limit of detection of 0.97 μM. In addition, the detection method was employed to determine the concentration of calcium ions in various serums.


Expression of Porphyromonas gingivalis small RNA in response to hemin availability identified using microarray and RNA-seq analysis.
There is a significant body of work suggesting that sRNA-mediated post-transcriptional regulation is a conserved mechanism among pathogenic bacteria to modulate bacterial virulence and survival. Porphyromonas gingivalis is recognized as an etiological agent of periodontitis and implicated in contributing to the development of multiple inflammatory diseases including cardiovascular disease. Using NimbleGen microarray analysis and a strand-specific method to sequence cDNA libraries of small RNA-enriched P. gingivalis transcripts using Illumina's high-throughput sequencing technology, we identified putative sRNA and generated sRNA expression profiles in response to growth phase, hemin availability after hemin starvation, or both. We identified transcripts that mapped to intergenic sequences as well as antisense transcripts that mapped to open reading frames of the annotated genome. Overall, this approach provided a comprehensive way to survey transcriptional activity to discover functionally linked RNA transcripts, responding to specific environmental cues, that merit further investigation.


Optoelectronic Properties of Carbon-Bound Boron Difluoride Hydrazone Dimers.
The creation of dimeric boron difluoride complexes of chelating N-donor ligands is a proven strategy for the enhancement of the optoelectronic properties of fluorescent dyes. We report dimers based on the boron difluoride hydrazone (BODIHY) framework, which offer unique and sometimes unexpected substituent-dependent absorption, emission, and electrochemical properties. BODIHY dimers have low-energy absorption bands (λmax =421 to 479 nm, ϵ=17 200 to 39 900 m-1 cm-1 ) that are red-shifted relative to monomeric analogues. THF solutions of these dimers exhibit aggregation-induced emission upon addition of water, with emission enhancement factors ranging from 5 to 18. Thin films of BODIHY dimers are weakly emissive as a result of the inner-filter effect, attributed to intermolecular π-type interactions. BODIHY dimers are redox-active and display two one-electron oxidation and two one-electron reduction waves that strongly depend on the N-aryl substituents. These properties are rationalized using density-functional theory calculations and X-ray crystallography experiments.


Psychological status of nursing survivors in China and its associated factors: 6 years after the 2008 Sichuan earthquake.
Nursing survivors are often not only the victims but also the rescuers in a disaster. Severe natural disasters can cause them long-term psychological impact. This study aimed to investigate the psychological status of nursing survivors and its associated factors 6 years after the severe earthquake that occurred in Wenchuan, Sichuan, on May 12, 2008. The study used a cross-sectional design. A total of 597 nurses who survived the earthquake and took care of victims were recruited about 6 years after the disaster. They completed a self-report questionnaire assessing information about demographics, earthquake-related characteristics, psychological status, posttraumatic stress disorder, and posttraumatic growth and resilience. The mean score on the Symptom Checklist-90-Revised (SCL-90-R) was (123.56±41.26). Of symptoms indicated by the SCL-90-R, obsessive-compulsive dimension had the highest score (1.62±0.62). The psychological status of nursing survivors differed with the title, monthly per capita household income, financial loss, health status, residential satisfaction, and satisfaction with leaders and colleagues. Severe financial loss and poor health status were significant factors of psychological distress. In addition, psychological status was negatively related to posttraumatic stress disorder and posttraumatic growth, and positively related to resilience. Nursing survivors had a relatively normal level of psychological status 6 years after the 2008 Sichuan earthquake. However, psychological symptoms such as obsessive-compulsive patterns still remained. Interventions focusing on the improvement of financial subsidies and physical health may be particularly useful in reducing psychological problems after the disaster.


Service engagement with high-risk men who have sex with men: challenges and implications for social work practice.
This article reviews social work challenges in treatment engagement of men who have sex with men (MSM) and details issues co-morbidity creates for reaching HIV-positive MSM engaged in substance abuse. The literature reviewed within the article identifies HIV and substance use risk factors influencing out of care dynamics and examines relevant research identifying contextual and cultural factors central to achieving cultural competence. The article examines aspects of cultural sensitivity and competence in service development and engagement and identifies service qualities and characteristics social workers can incorporate into practice and programs to increase the likelihood of successful engagement and treatment adherence.


Manganese doping mechanism in a CsPbI2Br photovoltaic material: a first-principles study.
As a light absorbing material of perovskite solar cells, Mn-doped CsPbI2Br has a better phase stability than the undoped one. In order to deeply understand the doping mechanism of Mn, the effect of substitutional and interstitial Mn doping on the structural, electronic and optical properties of CsPbI2Br has been investigated by first-principles calculations based on density functional theory. It is found that the binding energy of both the substitutional and the interstitial Mn-doped CsPbI2Br is negative and the binding energy difference between them is only 2.8 meV, which indicates that both the substitutional and the interstitial doping structures should be stable for Mn-doped CsPbI2Br and the latter is slightly preferred over the former due to the lower binding energy. The lattice parameters of CsPbI2Br change oppositely for two Mn-doping cases. Based on the comparative analysis of the electronic structures for CsPbI2Br and Mn-doped CsPbI2Br, we found that the substitutional doping of Mn introduces intermediate bands near the Fermi level, making CsPbI2Br an intermediate band semiconductor; for the interstitial Mn-doped CsPbI2Br the Fermi level enters conduction bands, making it an n-type semiconductor material with enhanced conductivity. The complex dielectric function and the absorption spectrum of Mn-doped and undoped CsPbI2Br were calculated and are basically consistent with the experimental results.


Mapping the primate lateral geniculate nucleus: a review of experiments and methods.
Mapping neuronal responses in the lateral geniculate nucleus (LGN) is key to understanding how visual information is processed in the brain. This paper focuses on our current knowledge of the dynamics the receptive field (RF) as broken down into the classical receptive field (CRF) and the extra-classical receptive field (ECRF) in primate LGN. CRFs in the LGN are known to be similar to those in the retinal ganglion cell layer in terms of both spatial and temporal characteristics, leading to the standard interpretation of the LGN as a relay center from retina to primary visual cortex. ECRFs have generally been found to be large and inhibitory, with some differences in magnitude between the magno-, parvo-, and koniocellular pathways. The specific contributions of the retina, thalamus, and visual cortex to LGN ECRF properties are presently unknown. Some reports suggest a retinal origin for extra-classical suppression based on latency arguments and other reports have suggested a thalamic origin for extra-classical suppression. This issue is complicated by the use of anesthetized animals, where cortical activity is likely to be altered. Thus further study of LGN ECRFs is warranted to reconcile these discrepancies. Producing descriptions of RF properties of LGN neurons could be enhanced by employing preferred naturalistic stimuli. Although there has been significant work in cats with natural scene stimuli and noise that statistically imitates natural scenes, we highlight a need for similar data from primates. Obtaining these data may be aided by recent advancements in experimental and analytical techniques that permit the efficient study of nonlinear RF characteristics in addition to traditional linear factors. In light of the reviewed topics, we conclude by suggesting experiments to more clearly elucidate the spatial and temporal structure of ECRFs of primate LGN neurons.


Serum uric acid is independently associated with metabolic syndrome in subjects with and without a low estimated glomerular filtration rate.
The relationship among serum uric acid (SUA), metabolic syndrome, and chronic kidney disease (CKD) is unclear. We examined whether SUA level is an independent risk factor for chronic kidney disease and whether the association between SUA and metabolic syndrome is affected by kidney function. We analyzed 28,745 subjects (17,478 men, 11,267 women, age 20-49 yrs) who underwent health examinations at this hospital between 2000 and 2007. Hyperuricemia was defined as SUA level > 7.7 mg/dl in men or > 6.6 mg/dl in women. Kidney function was assessed by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study equation modified for Chinese subjects. Impaired renal function with low GFR was defined as eGFR < 90 ml/min/1.73 m(2). The UA-low GFR groups were defined according to the observed combination of hyperuricemia and low GFR: Group A (absence of both hyperuricemia and low GFR); Group B (presence of low GFR but no hyperuricemia); Group C (presence of hyperuricemia but not low GFR); and Group D (presence of both hyperuricemia and low GFR). The prevalence of hyperuricemia, metabolic syndrome, and impaired kidney function with low GFR was 20.3% (27.6% in men, 8.9% in women), 7.6% (10.6% in men, 3.0% in women), and 9.9% (11.6% in men, 7.1% in women), respectively. The Pearson correlation between SUA and eGFR was only -0.26 (-0.21 in men, -0.22 in women; p < 0.001). In men, the age-adjusted odds ratio (OR) of metabolic syndrome was 1.41 (Group B), 2.45 (Group C), and 2.58 (Group D) in comparison with Group A. In women, the age-adjusted OR of metabolic syndrome was 0.83 (Group B), 5.47 (Group C), and 3.31 (Group D) in comparison with Group A. Hyperuricemia is prevalent in the Taiwan population. Hyperuricemia is only weakly associated with renal function, but is strongly associated with metabolic syndrome with or without a low eGFR.


Zebrafish thrombocytes: functions and origins.
Platelets play an important role in mammalian hemostasis. Thrombocytes of early vertebrates are functionally equivalent to mammalian platelets. A substantial amount of research has been done to study platelet function in humans as well as in animal models. However, to date only limited functional genomic studies of platelets have been performed but are low throughput and are not cost-effective. Keeping this in mind we introduced zebrafish, a vertebrate genetic model to study platelet function. We characterized zebrafish thrombocytes and established functional assays study not only their hemostatic function but to also their production. We identified a few genes which play a role in their function and production. Since we introduced the zebrafish model for the study of hemostasis and thrombosis, other groups have adapted this model to study genes that are associated with thrombocyte function and a few novel genes have also been identified. Furthermore, transgenic zebrafish with GFP-tagged thrombocytes have been developed which helped to study the production of thrombocytes and their precursors as well as their functional roles not only in hemostasis but also hematopoiesis. This paper integrates the information available on zebrafish thrombocyte function and its formation.


A histopathologic and immunohistochemical review of archived UK caprine scrapie cases.
In 2005, a prion disease identified in a goat from France was reported to be consistent with disease from the bovine spongiform encephalopathy (BSE) agent. Subsequent retrospective examination of UK goat scrapie cases led to the identification of one potentially similar, but as yet unconfirmed, case from Scotland. These findings strengthened concerns that small ruminant populations exposed to the BSE agent have become infected. The lack of data relating specifically to scrapie in goats has been contributory to past assumptions that, in general, sheep and goats respond similarly to prion infections. In this study, brain material from 22 archived caprine scrapie cases from the UK was reviewed by histopathology and by immunohistochemical examination for accumulations of disease-specific prion protein (PrP(Sc)) to provide additional data on the lesions of caprine scrapie and to identify any BSE-like features. The vacuolar change observed in the goats was characteristic of transmissible spongiform encephalopathies in general. PrP(Sc) immunohistochemical morphologic forms described in scrapie and experimental BSE infections of sheep were demonstrable in the goats, but these were generally more extensive and variable in PrP(Sc) accumulation. None of the cases examined showed a PrP(Sc) immunohistochemical pattern indicative of BSE.


Centrosome replication, genomic instability and cancer.
Karyotypic alterations, including whole chromosome loss or gain, ploidy changes, and a variety of chromosome aberrations are common in cancer cells. If proliferating cells fail to coordinate centrosome duplication with DNA replication, this will inevitably lead to a change in ploidy, and the formation of monopolar or multipolar spindles will generally provoke abnormal segregation of chromosomes. Indeed, it has long been recognized that errors in the centrosome duplication cycle may be an important cause of aneuploidy and thus contribute to cancer formation. This view has recently received fresh impetus with the description of supernumerary centrosomes in almost all solid human tumors. As the primary microtubule organizing center of most eukaryotic cells, the centrosome assures symmetry and bipolarity of the cell division process, a function that is essential for accurate chromosome segregation. In addition, a growing body of evidence indicates that centrosomes might be important for initiating S phase and completing cytokinesis. Centrosomes undergo duplication precisely once before cell division. Recent reports have revealed that this process is linked to the cell division cycle via cyclin-dependent kinase (cdk) 2 activity that couples centriole duplication to the onset of DNA replication at the G(1)/S phase transition. Alterations in G(1)/S phase regulating proteins like the retinoblastoma protein, cyclins D and E, cdk4 and 6, cdk inhibitors p16(INK4A) and p15(INK4B), and p53 are among the most frequent aberrations observed in human malignancies. These alterations might not only lead to unrestrained proliferation, but also cause karyotypic instability by uncontrolled centrosome replication. Since several excellent reports on cell cycle regulation and cancer have been published, this review will focus on the role of centrosomes in cell cycle progression, as well as causes and consequences of aberrant centrosome replication in human neoplasias.


Use of 'natural' products as alternatives to antibiotic feed additives in ruminant production.
The banning in 2006 of the use of antibiotics as animal growth promoters in the European Union has increased demand from producers for alternative feed additives that can be used to improve animal production. This review gives an overview of the most common non-antibiotic feed additives already being used or that could potentially be used in ruminant nutrition. Probiotics, dicarboxylic acids, enzymes and plant-derived products including saponins, tannins and essential oils are presented. The known modes of action and effects of these additives on feed digestion and more especially on rumen fermentations are described. Their utility and limitations in field conditions for modern ruminant production systems and their compliance with the current legislation are also discussed.


Coadministration of Liposomal Amphotericin B and Contrast Medium Does Not Increase Risk of Kidney Injury.
Intravenous radiographic contrast medium and amphotericin B are commonly required in the care of patients with fungal infections. Both interventions have proposed nephrotoxicity through similar mechanisms. We systematically examined patients who received coadministration of liposomal amphotericin B (AmBisome; GE Healthcare) and intravenous contrast medium within a 24-h period and compared the results for those patients with the results for patients who underwent non-contrast medium studies. We found 114 cases and 85 controls during our study period. Overall, no increased risk of renal injury was seen with coadministration of these 2 agents. Adjustment for age, baseline kidney function, and other clinical factors through propensity score adjustment did not change this result. Our observations suggest that, when clinically indicated, coadministration of contrast medium and liposomal amphotericin B does not present excess risk compared with that from the administration of liposomal amphotericin B alone.


[Staphylococcus aureus enterotoxin A detection using the polymerase chain reaction (PCR) and its correlation with coagulase and thermonuclease tests].
Staphylococcus aureus is a pathogenic bacterium, widely distributed on nature and associated to general infection and food borne outbreaks. The relationship between this bacterium and food borne outbreaks has been done, historically, using several tests, including coagulase, thermonuclease and actually, PCR for the genes codifying for the enterotoxin responsible of clinical symptoms. The objective of this work is to detect enterotoxin A codifying gene through PCR in a group of S. aureus strains isolated from food samples, and also to correlate the presence of this gene with the production of coagulase and thermonuclease enzymes. A total of 69 staphylococcal strains were analyzed, 58 obtained from non pasteurized milk samples from the Estación Experimental Alfredo Volio Mata and 11 from the Food and Water Microbiology Laboratory collection, Universidad de Costa Rica. Coagulase, thermonuclease and enterotoxin A were analyzed in all the strains, and a statistical correlation was performed in order to verify possible associations. Results show that there is no correlation between the three variables, nevertheless, all coagulase positive strains were thermonuclease positive, and all enterotoxin positive strains were coagulase and thermonuclease positive, but not inversely. These results show that the use of presumptive or indirect tests for establishing entorotoxigenity of S. aureus strains is not truthful, more sensible and specific analysis, as PCR, shall be performed.


Comparison of Computational Strategies for the Calculation of the Electronic Coupling in Intermolecular Energy and Electron Transport Processes.
Electronic couplings in intermolecular electron and energy transfer processes calculated by six different existing computational techniques are compared to nonorthogonal configuration interaction for fragments (NOCI-F) results. The paper addresses the calculation of the electronic coupling in diketopyrrolopyrol, tetracene, 5,5'-difluoroindigo, and benzene-Cl for hole and electron transport, as well as the local exciton and singlet fission coupling. NOCI-F provides a rigorous computational scheme to calculate these couplings, but its computational cost is rather elevated. The here-considered ab initio Frenkel-Davydov (AIFD), Dimer projection (DIPRO), transition dipole moment coupling, Michl-Smith, effective Hamiltonian, and Mulliken-Hush approaches are computationally less demanding, and the comparison with the NOCI-F results shows that the NOCI-F results in the couplings for hole and electron transport are rather accurately predicted by the more approximate schemes but that the NOCI-F exciton transfer and singlet fission couplings are more difficult to reproduce.


Preparation of microbiological specimens for scanning electron microscopy.
This tutorial paper describes techniques for processing microorganisms for scanning electron microscopy (SEM). For ease of discussion, the subject is divided into two sections: A. General Processing Requirements, and B. Specific Processing Techniques. The objective of the first section is to outline processing requirements, explain their purpose, and point out where variations are possible. The following basic steps are discussed: (1) specimen selection, (2) prefixation treatment, (3) chemical fixation, (4) dehydration, (5) critical-point drying and freeze-drying, (6) coating, and (7) viewing. The second section describes methods of manipulating microorganisms through the processing steps. Instructions will cover microorganisms processed for SEM (1) in suspension, (2) in tissues. (3) in tissue culture, and (4) on agar. We are relying heavily on our own experiences in the laboratory and the results are illustrated by use of bacteria, mycoplasmas, rickettsiae, fungi, free-living protozoa, and parasitic protozoa. This tutorial is intended to be a general reference for processing microorganisms for study with the scanning electron microscope. Although we have described basic requirements and several specific techniques, it must be emphasized that there is a wide range of preparation flexibility permissible, depending upon the objectives of the study.


Implications of Rho GTPase Signaling in Glioma Cell Invasion and Tumor Progression.
Glioblastoma (GB) is the most malignant of primary adult brain tumors, characterized by a highly locally invasive cell population, as well as abundant proliferative cells, neoangiogenesis, and necrosis. Clinical intervention with chemotherapy or radiation may either promote or establish an environment for manifestation of invasive behavior. Understanding the molecular drivers of invasion in the context of glioma progression may be insightful in directing new treatments for patients with GB. Here, we review current knowledge on Rho family GTPases, their aberrant regulation in GB, and their effect on GB cell invasion and tumor progression. Rho GTPases are modulators of cell migration through effects on actin cytoskeleton rearrangement; in non-neoplastic tissue, expression and activation of Rho GTPases are normally under tight regulation. In GB, Rho GTPases are deregulated, often via hyperactivity or overexpression of their activators, Rho GEFs. Downstream effectors of Rho GTPases have been shown to promote invasiveness and, importantly, glioma cell survival. The study of aberrant Rho GTPase signaling in GB is thus an important investigation of cell invasion as well as treatment resistance and disease progression.


Molecular basis of resistance to proteasome inhibitors in hematological malignancies.
Over the past decade, the proteasome inhibitor bortezomib (Velcade) has not only gained a cornerstone position in the treatment of hematological malignancies, particularly multiple myeloma and mantle cell lymphoma, but also in experimental therapeutics of acute leukemia. However, the therapeutic efficacy of bortezomib is hampered by the emergence of acquired resistance, for which multifactorial mechanisms have been identified. This review summarizes the current status of the molecular mechanisms underlying resistance to proteasome inhibitors that emerged in preclinical therapeutic studies, and discusses these findings in the clinical perspective of novel therapeutic modalities of hematological malignancies. The specific topics that will be addressed in the current review include the recently established mechanisms of resistance to proteasome inhibitors: the role of constitutive and immunoproteasomes, mutations in proteasome subunits, unfolded protein response, XBP1 and MARCKS proteins, multidrug efflux transporters, aggresomes and autophagy, as well as the impact of pro-survival signaling pathways and bone marrow microenvironment. The growing knowledge of the determinants that confer bortezomib resistance and/or toxicity has provided the basis for the rational development of second generation proteasome inhibitors, some of which were recently approved or that are undergoing clinical evaluation as novel strategies to overcome bortezomib resistance as well as to enhance clinical therapeutic efficacy along with minimal side effects. Collectively, these combined approaches should enhance therapeutic efficacy and outcome in patients with hematological malignancies.


Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy.
Chemoradiotherapy (CRT) remains one of the most common cancer treatment modalities, and recent data suggest that CRT is maximally effective when there is generation of an anti-tumoral immune response. However, CRT has also been shown to promote immunosuppressive mechanisms which must be blocked or reversed to maximize its immune stimulating effects. Therefore, using a preclinical model of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), we developed a clinically relevant therapy combining CRT and two existing immunomodulatory drugs: cyclophosphamide (CTX) and the small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL). In this model, we treated the syngeneic HPV-HNSCC mEER tumor-bearing mice with fractionated (10 fractions of 3 Gy) tumor-directed radiation and weekly cisplatin administration. We compared the immune responses induced by CRT and those induced by combinatory treatment (CRT + CTX/L-NIL) with flow cytometry, quantitative multiplex immunofluorescence and by profiling immune-related gene expression changes. We show that combination treatment favorably remodels the tumor myeloid immune microenvironment including an increase in anti-tumor immune cell types (inflammatory monocytes and M1-like macrophages) and a decrease in immunosuppressive granulocytic myeloid-derived suppressor cells (MDSCs). Intratumoral T cell infiltration and tumor antigen specificity of T cells were also improved, including a 31.8-fold increase in the CD8+ T cell/ regulatory T cell ratio and a significant increase in tumor antigen-specific CD8+ T cells compared to CRT alone. CTX/LNIL immunomodulation was also shown to significantly improve CRT efficacy, leading to rejection of 21% established tumors in a CD8-dependent manner. Overall, these data show that modulation of the tumor immune microenvironment with CTX/L-NIL enhances susceptibility of treatment-refractory tumors to CRT. The combination of tumor immune microenvironment modulation with CRT constitutes a translationally relevant approach to enhance CRT efficacy through enhanced immune activation.


Genetic mapping of the amino-terminal domain of bacteriophage T4 DNA polymerase.
The DNA polymerase of bacteriophage T4 is a multifunctional enzyme that harbors DNA-binding, DNA-synthesizing and exonucleolytic activities. We have cloned in bacterial plasmids about 99% of the structural gene for this enzyme (T4 gene 43). The gene was cloned in six contiguous 5'-terminal DNA fragments that defined seven intragenic mapping regions. Escherichia coli hosts harboring recombinant plasmids carrying the gene 43 subsegments were used in marker-rescue experiments that assigned a large number of ts and nonsense polymerase mutations to different physical domains of the structural gene. Conspicuously, only one missense mutation in a large collection of mutants mapped in the 5'-terminal 450 base-pair segment of the approximately 2700 base-pair gene. To test if this indicated a DNA polymerase domain that is relatively noncritical for biological activity, we mutagenized a recombinant plasmid carrying this 5'-terminal region and generated new conditional-lethal mutations that mapped therein. We identified five new ts sites, some having mutated at high frequency (nitrosoguanidine hot spots). New ts mutations were also isolated in phage genes 62 and 44, which map upstream of gene 43 on the T4 chromosome. A preliminary examination of physiological consequences of the ts gene 43 mutations showed that they exhibit effects similar to those of ts lesions that map in other gene 43 segments: some were mutators, some derepressed gene 43 protein synthesis and they varied in the severity of their effects on T4-induced DNA synthesis at nonpermissive temperatures. The availability of the gene 43 clones should make it possible to isolate a variety of lesions that affect different activities of the T4 DNA polymerase and help to define the different domains of this multifunctional protein.


Seasonal Changes in Photoperiod: Effects on Growth and Redox Signaling Patterns in Atlantic Salmon Postsmolts.
Farmed Atlantic salmon reared under natural seasonal changes in sea-cages had an elevated consumption of antioxidants during spring. It is, however, unclear if this response was caused by the increase in day length, temperature, or both. The present study examined redox processes in Atlantic salmon that were reared in indoor tanks at constant temperature (9 °C) under a simulated natural photoperiod. The experiment lasted for 6 months, from vernal to autumnal equinoxes, with the associated increase and subsequent decrease in day length. We found that intracellular antioxidants were depleted, and there was an increase in malondialdehyde (MDA) levels in the liver and muscle of Atlantic salmon with increasing day length. Antioxidant enzyme activity in liver and muscle and their related gene profiles was also affected, with a distinct upregulation of genes involved in maintaining redox homeostasis, such as peroxiredoxins in the brain in April. This study also revealed a nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress response in muscle and liver, suggesting that fish integrate environmental signals through redox signaling pathways. Furthermore, growth and expression profiles implicated in growth hormone (GH) signaling and cell cycle regulation coincided with stress patterns. The results demonstrate that a change in photoperiod without the concomitant increase in temperature is sufficient to stimulate growth and change the tissue oxidative state in Atlantic salmon during spring and early summer. These findings provide new insights into redox regulation mechanisms underlying the response to the changing photoperiod, and highlight a link between oxidative status and physiological function.


Determinants of the number of antenatal visits in a metropolitan region.
Antenatal care has a positive effect on pregnancy, both clinically and psychologically, but consensus about the optimal number of antenatal visits is lacking. This study aims to provide insight into the dynamics of the number of antenatal visits a woman receives. Independent effects of predisposing, enabling and pregnancy-related determinants are examined. Women were recruited in nine clinical centres in the Brussels Metropolitan region. Antenatal care use was measured prospectively. A Poisson regression model was applied to measure the independent effect of individual determinants on the number of antenatal visits. Data on antenatal care trajectories in 333 women were collected. The multivariate analyses showed that women with a Maghreb or Turkish origin had 14% fewer visits compared with European (EU15) women. More highly educated women had 22% more visits compared with those with a low education. Women with a high income had 14% more antenatal visits compared with those with a low income. Fewer antenatal visits were observed in multiparae (15%), women initiating care after 14 weeks of gestation (31%), women without medical risks during the pregnancy (12%) and in women with a continuity of care index of 50% or more (12%). More visits were observed in delivering after week 37 (22% increase). Predisposing and enabling factors have to be considered when antenatal care programmes are evaluated in a metropolitan area. Variations in the number of antenatal visits show that socially vulnerable women are more at risk of having fewer visits.


Social hierarchy reveals thermoregulatory trade-offs in response to repeated stressors.
Coping with stressors can require substantial energetic investment, and when resources are limited, such investment can preclude simultaneous expenditure on other biological processes. Among endotherms, energetic demands of thermoregulation can also be immense, yet our understanding of whether a stress response is sufficient to induce changes in thermoregulatory investment is limited. Using the black-capped chickadee as a model species, we tested a hypothesis that stress-induced changes in surface temperature (Ts), a well-documented phenomenon across vertebrates, stem from trade-offs between thermoregulation and stress responsiveness. Because social subordination is known to constrain access to resources in this species, we predicted that Ts and dry heat loss of social subordinates, but not social dominants, would fall under stress exposure at low ambient temperatures (Ta), and rise under stress exposure at high Ta, thus permitting a reduction in total energetic expenditure toward thermoregulation. To test our predictions, we exposed four social groups of chickadees to repeated stressors and control conditions across a Ta gradient (n=30 days/treatment/group), whilst remotely monitoring social interactions and Ts Supporting our hypothesis, we show that: (1) social subordinates (n=12), who fed less than social dominants and alone experienced stress-induced mass-loss, displayed significantly larger changes in Ts following stress exposure than social dominants (n=8), and (2) stress-induced changes in Ts significantly increased heat conservation at low Ta and heat dissipation at high Ta among social subordinates alone. These results suggest that chickadees adjust their thermoregulatory strategies during stress exposure when resources are limited by ecologically relevant processes.


Separation, Characterization, and Handling of Microalgae by Dielectrophoresis.
Microalgae biotechnology has a high potential for sustainable bioproduction of diverse high-value biomolecules. Some of the main bottlenecks in cell-based bioproduction, and more specifically in microalgae-based bioproduction, are due to insufficient methods for rapid and efficient cell characterization, which contributes to having only a few industrially established microalgal species in commercial use. Dielectrophoresis-based microfluidic devices have been long established as promising tools for label-free handling, characterization, and separation of broad ranges of cells. The technique is based on differences in dielectric properties and sizes, which results in different degrees of cell movement under an applied inhomogeneous electrical field. The method has also earned interest for separating microalgae based on their intrinsic properties, since their dielectric properties may significantly change during bioproduction, in particular for lipid-producing species. Here, we provide a comprehensive review of dielectrophoresis-based microfluidic devices that are used for handling, characterization, and separation of microalgae. Additionally, we provide a perspective on related areas of research in cell-based bioproduction that can benefit from dielectrophoresis-based microdevices. This work provides key information that will be useful for microalgae researchers to decide whether dielectrophoresis and which method is most suitable for their particular application.


Immunofluorescent localization of renin in mouse submaxillary gland and kidney.
An antibody prepared against purified submaxillary renin was used to determine the site of renin concentration in male mice using immunofluorescent localization. The results provide direct evidence that the granular tubules of the submaxillary glands are the source of submaxillary renin. The antibody against submaxillary renin cross-reacts with kidney renin as evidenced by immunofluorescent localization in the juxtaglomerular apparatus of mouse kidney.


Judges in judo conform to the referee because of the reactive feedback system.
This experiment tested whether the conformism observed among panels of judges in aesthetic sports also occurs among judges in judo. Similar to aesthetic sports, judo judging relies upon a form of open feedback. However, in judo, this system is reactive (i.e. two judges have to publicly 'correct' the score given by the higher-status referee), whereas it is active in aesthetic sports (i.e. judges with equal status report their score simultaneously and can use the feedback about the scores of their colleagues for evaluating later performances). In order to test whether such reactive open-feedback system leads to conformism among judges in judo, we designed an experiment in which this feedback was manipulated. Participants were 20 certified Flemish judges, who had to score two sets of 11 ambiguous video sequences that are used during formation and training of judo judges: one set with feedback about the referee's score and one set without feedback. The results revealed that when participants knew the referee's score, their scores were significantly more in line with this score than when they did not know this score. More specifically, for both sets of sequences at least 10% less deviations from the referee were observed when participants were given feedback about the score of the referee. These results suggest that preventable conformism can occur in typical judo judging, that is with reactive open feedback.


The Synbiotic Combination of probiotics and inulin Improves NAFLD though Modulating Gut Microbiota.
Prebiotics can promote the growth of probiotics, co-combine of these is called synbiotics, and synbiotics is powerful regulators of gut microbiota. Intestinal microbiota plays an important role in non-alcoholic fatty liver disease (NAFLD), so synbiotics could be a therapeutic alternative. This study aims to investigate the effect of synbiotics combination of probiotics (Streptococcus Bifidobacterium and Streptococcus thermophilus) and prebiotics (Inulin) in vivo model of early NAFLD using yogurt as carrier. The results demonstrate that the yogurt with synbiotics combination group (HS) improves the biochemical indicators related to total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and insulin resistance (IR) in mice (P < 0.01). HS improves the development of lipid metabolism and inflammation by activating the AMPK and NFκB signaling pathway. In addition, HS restores the intestinal barrier dysfunction and inflammation caused by a high-fat diet. The 16S rRNA demonstrates that the gut microbiota composition of mice treated with HS is significantly altered specifically, the Firmicutes/Bacteroidetes ratio is significantly lower than in HFD-fed mice (P < 0.01). Our findings suggest the applicability of HS in preventing obesity-related NAFLD via its antioxidant, anti-inflammatory, and improved lipid metabolism by the gut-liver axis and provide a solid theoretical foundation for developing prebiotics for the prevention of NAFLD.


Mitochondrial genome evidence reveals successful Late Paleolithic settlement on the Tibetan Plateau.
Due to its numerous environmental extremes, the Tibetan Plateau--the world's highest plateau--is one of the most challenging areas of modern human settlement. Archaeological evidence dates the earliest settlement on the plateau to the Late Paleolithic, while previous genetic studies have traced the colonization event(s) to no earlier than the Neolithic. To explore whether the genetic continuity on the plateau has an exclusively Neolithic time depth, we studied mitochondrial DNA (mtDNA) genome variation within 6 regional Tibetan populations sampled from Tibet and neighboring areas. Our results confirm that the vast majority of Tibetan matrilineal components can trace their ancestry to Epipaleolithic and Neolithic immigrants from northern China during the mid-Holocene. Significantly, we also identified an infrequent novel haplogroup, M16, that branched off directly from the Eurasian M founder type. Its nearly exclusive distribution in Tibetan populations and ancient age (>21 kya) suggest that M16 may represent the genetic relics of the Late Paleolithic inhabitants on the plateau. This partial genetic continuity between the Paleolithic inhabitants and the contemporary Tibetan populations bridges the results and inferences from archaeology, history, and genetics.


Selected parameters affecting characterization of nebulized aqueous solutions by inertial impaction and comparison with phase-Doppler analysis.
The objective of this study was to evaluate selected parameters affecting the characterization of air-jet nebulized aqueous solutions by inertial impaction. Parameters affecting characterization of the droplet size distribution by inertial impaction were considered to be nebulizer T-piece connecting tube length, solute concentration, droplet charge accumulation, sample time and marker concentration. Parametric effects on nebulizer output characteristics were evaluated using a fractional factorial design. Response factors were defined as mass median aerodynamic diameter (MMAD), relative span factor (Delta), fine particle mass and delivery rate of solute. Connecting tube length, grounding the impaction stages and marker concentration did not significantly affect the response factors (0.05). Mass median aerodynamic diameter (MMAD) and delivery rate of solute were significantly affected by solute concentration (p<0.05). Fine particle mass was significantly affected by the interaction between solute concentration and sampling time. Droplets attained an equilibrium size with an MMAD=1.0 microm, Delta=2.12 (0.9% solute) and MMAD=1.7 microm, Delta=2.00 (9. 0% solute) before the exit of the nebulizer T-piece. The droplet size distributions obtained by inertial impaction were compared with data obtained by phase-Doppler analysis.


Problems in the diagnosis of foodborne infection in general practice.
The incidence of acute gastroenteritis and self suspected food poisoning in general practice populations was compared with consultation rates in four group practices during a 3-month winter period and a 2-month autumn period. The average monthly consultation rate for acute gastroenteritis and self suspected food poisoning was 0.3% and 0.06% respectively. However, over the same period, on average, an estimated 7% of the practice population per month reported an acute gastroenteritis illness, and 0.7% suspected a food poisoning illness. Only about one in 26 people who suffer an acute episode of gastroenteritis consult their general practitioner (GP). In two practices, faecal samples were sought from all patient cases; the isolation rate for salmonellas was 2% (3/191) and for campylobacters it was 12% (23/191). In the other two practices following routine management, the isolation rate for salmonellas was 9% (6/64) and for campylobacters it was 2% (1/64). Isolation of faecal pathogens was not associated with patients' suspicion of food poisoning. A history of eating out in the week before onset was associated with a significantly increased yield of salmonellas and campylobacters.


Inhibition of glucose-induced insulin secretion by indomethacin and sodium salicylate in the fetal lamb.
The modulation of fetal insulin secretion by prostaglandins was studied with the aid of the prostaglandin synthesis inhibitors indomethacin and sodium salicylate in 10 chronically catheterized fetal lambs. Glucose-induced fetal insulin secretion was inhibited within 60 minutes by preinjection of either indomethacin or sodium salicylate in the fetal lambs. In the sodium salicylate experiments a significant (p less than 0.01) dose-related response (degree of insulin suppression) was noted between doses of 100 to 350 mg/kg of fetal weight. In a selected group of sodium salicylate injections prostaglandin levels were found to fall to 58% of control by 2 hours after injection. Five neonatal lambs exposed to a similar regimen were noted to have an exaggerated insulin response to glucose infusion when compared to fetal lambs. However, indomethacin or sodium salicylate pretreatment resulted in no suppression of glucose-induced insulin release. This finding may be of importance in explaining the observation of an increased incidence of fetal growth retardation after long-term exposure to salicylates in humans and in animal models.


Efficacy of pancrease: crossover comparative study versus eurobiol in cystic fibrosis.
An open crossover study in patients with documented cystic fibrosis (CF) compared the efficacy and acceptability of Pancrease (Cilag, PC), consisting of pH-sensitive, enteric-coated microspheres, with those of Eurobiol, consisting of lyophilized total pancreas. Eleven patients, age 6-17 years, were hospitalized for study. A hypercaloric, normal fat diet as well as previous antibiotic, vitamin, and other CF therapy were maintained during the 2-week study period. During the first study week, eight patients were given four divided doses of either Pancrease, 8 capsules daily, and two patients were given Eurobiol, 2 bottles daily. One patient received six Pancrease capsules or 1.5 bottles of Eurobiol daily. Patients were switched to the alternate drug for the second study week. Stools were collected for analysis over the final 3 days of each week. Steatorrhea (mean +/- 1 SD) with Pancrease was 11.8 +/- 6.6 g/24 h and with Eurobiol was 17.9 +/- 11.7 g/24 h. The coefficient of lipid absorption was 74.1 +/- 13.3% for Pancrease and 58.6 +/- 22.5% for Eurobiol (p less than 0.02). The decrease in steatorrhea and increase in lipid absorption with Pancrease compared to Eurobiol were 33.9% and 26.5%, respectively. All patients considered the acceptability of Pancrease superior to that of Eurobiol. No adverse effects were seen with either drug.


Interactive obstruction-free lensing for volumetric data visualization.
Occlusion is an issue in volumetric visualization as it prevents direct visualization of the region of interest. While many techniques such as transfer functions, volume segmentation or view distortion have been developed to address this, there is still room for improvement to better support the understanding of objects' vicinity. However, most existing Focus+Context fail to solve partial occlusion in datasets where the target and the occluder are very similar density-wise. For these reasons, we investigate a new technique which maintains the general structure of the investigated volumetric dataset while addressing occlusion issues. With our technique, the user interactively defines an area of interest where an occluded region or object is partially visible. Then our lens starts pushing at its border occluding objects, thus revealing hidden volumetric data. Next, the lens is modified with an extended field of view (fish-eye deformation) to better see the vicinity of the selected region. Finally, the user can freely explore the surroundings of the area under investigation within the lens. To provide real-time exploration, we implemented our lens using a GPU accelerated ray-casting framework to handle ray deformations, local lighting, and local viewpoint manipulation. We illustrate our technique with five application scenarios in baggage inspection, 3D fluid flow visualization, chest radiology, air traffic planning, and DTI fiber exploration.


The effect of wet cupping on serum lipid concentrations of clinically healthy young men: a randomized controlled trial.
The aim of this study was to determine if a reduction in serum lipoproteins, especially LDL cholesterol, is a preventive approach against atherosclerosis. Phlebotomy has been a recommended method to reduce serum lipoprotein levels. The present study was conducted to investigate the effects of wet cupping on serum lipoprotein concentrations. In this randomized controlled trial, 47 men (18 to 25 years old), without chronic disease or a history of hyperlipidemia and antihyperlipidemic drug consumption were randomly assigned into control (N = 24) and treated (N = 23) groups. Men in the treated group were subjected to wet cupping, whereas men in the control group remained untreated. The serum concentrations of lipids, collected from brachial veins, were determined at the time of wet cupping and then once a week for 3 weeks. Data were analyzed using a repeated measure ANOVA. A substantial decrease in LDL cholesterol (p < 0.0001) and in the LDL/HDL ratio (p < 0.0001) was found in the treated group compared to the control. There were no significant changes in serum triglyceride between groups (p > 0.05). Although there were no statistically significant variations in total cholesterol and HDL cholesterol (p > 0.05), a 7% decrease in total cholesterol and 3% increase in HDL cholesterol may be clinically important. Wet cupping may be an effective method of reducing LDL cholesterol in men and consequently may have a preventive effect against atherosclerosis.


Alpha 2-adrenergic receptor function in depression. The cortisol response to yohimbine.
There is evidence that the abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function observed in patients with depression may be related to changes in central neurotransmitter receptor function. To evaluate this possibility further, the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride, which increases brain norepinephrine turnover, was administered to 40 patients with DSM-III major depression (18 melancholic, 22 nonmelancholic) and 16 healthy controls. Plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) level was measured as an index of noradrenergic function, and plasma cortisol level was used to assess the HPA response. Baseline cortisol levels were elevated in melancholic depressed patients, but not in nonmelancholic patients, when compared with healthy controls. The cortisol response to yohimbine was significantly greater in depressed patients than in controls, despite similar MHPG responses between groups. Since there is evidence that stimulation of postsynaptic alpha 2-adrenergic receptors inhibits HPA axis function, the abnormally increased cortisol response to the alpha 2-antagonist yohimbine suggests a relative subsensitivity of postsynaptic alpha 2-adrenergic receptors in depression.


β-Blocker treatment during pregnancy and adverse pregnancy outcomes: a nationwide population-based cohort study.
To investigate the association between exposure to β-blockers during pregnancy and the risk of being born small for gestational age (SGA), preterm birth and perinatal mortality in a nationwide cohort. A population-based retrospective cohort study, using the Danish Fertility Database. The authors identified all pregnant women redeeming a prescription for β-blockers using the National Prescription Registry. Multivariate logistic regression models were used to assess the association between exposure and our outcomes. Register-based survey. 911'685 births between 1995 and 2008 obtained from the Danish Fertility Database. Being born SGA was defined as having a birth weight below the 10th percentile for the corresponding gestational week. Preterm birth was defined as birth before the 37th gestational week. Perinatal mortality was defined as either death occurring within the first 28 days of life or stillbirth. Before 2004, fetal deaths were recorded as stillbirths if they occurred after 28 weeks of gestation, but since then stillbirth is recorded for deaths after 22 gestational weeks. The authors identified 2459 pregnancies exposed to β-blockers. β-Blocker exposure during pregnancy was found to be associated with increased risk of SGA (adjusted OR 1.97, 95% CI 1.75 to 2.23), preterm birth (adjusted OR 2.26, 95% CI 2.03 to 2.52) and perinatal mortality (adjusted OR 1.89, 95% CI 1.25 to 2.84). Analyses were adjusted for socioeconomic and maternal variables. The authors found similar risk profiles for pregnancies exposed to labetalol and for pregnancies exposed to other β-blockers. The authors found that exposure to β-blockers during pregnancy was associated with being born SGA, preterm birth and perinatal mortality. Our findings show that labetalol is not safer than other β-blockers during pregnancy.


Tissue, cell type, and breast cancer stage-specific expression of a TGF-beta inducible early transcription factor gene.
This laboratory has previously identified a novel TGF-beta inducible early gene (TIEG) in human osteoblasts [Subramaniam et al. (1995): Nucleic Acids Res 23:4907-4912]. Using TIEG specific polyclonal antibody and immunoprecipitation methods in normal human fetal osteoblast cells (hFOB cells), we have now demonstrated that TIEG encodes a 72-kDa protein whose levels are transiently increased at as early as 2 h of TGF-beta treatment. Polarized confocal microscopic analysis of hFOB cells shows a nuclear localized TIEG protein in untreated cells under the conditions described under Methods. Interestingly, the levels of TIEG protein in the nuclei increase when the cells are treated with TGF-beta 1 for 2 h. In contrast, similar analyses of untreated human keratinocytes show a cytoplasmic localized TIEG protein that appears to be translocated to the nucleus after H2O2 treatment. Additional immunohistochemical studies have demonstrated that TIEG protein is expressed in epithelial cells of the placenta, breast, and pancreas, as well as in osteoblast cells of bone and selected other cells of the bone marrow and cerebellum with some cells showing a cytoplasmic localization and others a nuclear localization. All cells of the kidney display negative staining for this protein. Interestingly, a stage specific expression of TIEG protein is found in a dozen breast cancer biopsies, using immunohistochemistry. The cells in normal breast epithelium displays a high expression of TIEG protein, those in the in situ carcinoma display less than one-half of the levels, and those in the invasive carcinoma show a complete absence of the TIEG protein. TIEG has been localized to chromosome 8q22.2 locus, the same locus as the genes involved in osteopetrosis and acute myeloid leukemia and close to the c-myc gene locus and a locus of high polymorphism in cancer biopsies. The correlation between the levels of TIEG protein and the stage of breast cancer, its prime location in human chromosome 8q22.2, and past studies with pancreatic carcinoma, suggests that TIEG may play a role in tumor suppressor gene activities, apoptosis, or some other regulatory function of cell cycle regulation.


Hepatocyte growth factor induction of collagenase 3 production in human osteoarthritic cartilage: involvement of the stress-activated protein kinase/c-Jun N-terminal kinase pathway and a sensitive p38 mitogen-activated protein kinase inhibitor cascade.
Osteoarthritis (OA) involves both a decreased reparative process and an increased degradative phenomenon. Several cytokines and growth factors are known to facilitate the repair of articular cartilage defects. The hepatocyte growth factor (HGF) present in OA cartilage is suggested to be involved in the cartilage repair process as well as in matrix remodeling and chondrocyte migration, leading to partial reconstruction of articular cartilage. Since cell migration is often correlated with metalloprotease activity, the effect of HGF on collagenase 3 production was studied because of its possible implication in OA cartilage remodeling. We examined HGF-stimulated collagenase 3 production in human OA chondrocytes by Western and Northern blotting. Furthermore, we explored the intracellular signaling pathways through which HGF induced collagenase 3 production. This study showed that HGF stimulated collagenase 3 production in human OA chondrocytes at the transcriptional level, and this induction was mediated by activation of the stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) pathway, but not the p38 mitogen-activated protein kinase (MAPK). The p44/42 MAPKs were also phosphorylated and the use of their specific inhibitor (PD 98059) did not affect HGF-induced collagenase 3 production in OA chondrocytes. Induced collagenase 3 production via the SAPK/JNK pathway was mediated, at least in part, by the TRE site in the promoter, and in the activator protein 1 complex, c-Jun, JunD, and Fra-1 were activated. Surprisingly, further experiments revealed that the specific p38 MAPK inhibitor SB 202190 also inhibited collagenase 3 production early in the HGF-induced process. The 50% inhibitory concentration was as low as 50 nM, which is unlikely to be related to p38 MAPK inhibition (which is usually in the microM range), suggesting the involvement of another kinase sensitive to SB 202190. This is the first study to show that HGF has the ability to induce both the expression and synthesis of collagenase 3 in OA chondrocytes. The effect is mediated by kinase cascades involving SAPK/JNK and another, unidentified kinase. This study provides novel information implicating a role for HGF in the pathophysiology of OA through its effect on the production of collagenase 3, which is an enzyme that is possibly involved in OA cartilage remodeling.