Divergent trends in maternal cigarette smoking during pregnancy: United States 1990-99

While examination of causes for trends in smoking have largely focused on how changes have occurred with maternal age and, less commonly, time period, little is known as to how age, period and birth cohort interact on trends in the prevalence of smoking during pregnancy. We performed a population-based, retrospective cohort study based on the vital statistics records comprised of White (n=24,499,629) and Black (n = 5,096,625) women delivering in the United States in 1990-99. Smoking prevalence rates were derived by seven 5-year maternal age groups (15-19 to 45-49 years), two time periods (1990-94 and 1995-99), and eight 5-year maternal birth cohorts (1945-49 to 1980-84) after adjusting for the confounding effects of gravidity, education, marital status, and lack of prenatal care through multivariable logistic regression models. The prevalence of smoking was 17.3% among Whites, and 13.5% among Blacks, with substantial variations by age, time period, and birth cohort. The rate declined with increasing age among Whites during the 1990-94 and 1995-99 periods. Among Blacks, the rates increased steeply with advancing age up to 25-29 years and began to decline thereafter. Smoking rates declined among both Whites and Blacks with increasing birth cohort within each age strata. These rates were highest among multigravid women (gravida > or = 2), and lowest among primigravid women. The rates among Whites declined with increasing maternal age for each gravida. Among Blacks, smoking rates for each gravida increased with advancing age up to 25-29 years, and plateaued among older women. Variation in smoking prevalence by age, time period, and birth cohort provides impetus for designing interventions to reduce smoking. Such studies should not only consider cross-sectional trends, but also the divergent patterns by age and cohort among women of different race/ethnic groups and gravidity.     

Selective Inhibition of Cell Proliferation by Lycopene in MCF‐7 Breast Cancer Cells In vitro: A Proteomic Analysis

Lycopene, a red pigmented carotenoid present in many fruits and vegetables such as tomatoes, has been associated with the reduced risk of breast cancer. This study sought to identify proteins modulated by lycopene during cell proliferation of the breast cancer cell line MCF‐7 to gain an understanding into its mechanism of action. MCF‐7 breast cancer cells and MCF‐10 normal breast cells were treated with 0, 2, 4, 6, 8, and 10 μM of lycopene for 72 h. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) tetrazolium reduction assay was used to measure cell proliferation and two‐dimensional fluorescence difference gel electrophoresis to assess the changes in protein expression, which were identified using MALDI‐ToF/ToF (matrix‐assisted laser desorption ionization tandem time‐of‐flight) and Mascot database search. MTT and cell proliferation assays showed that lycopene selectively inhibited the growth of MCF‐7 but not MCF‐10 cells. Difference gel electrophoresis analysis revealed that proteins in the MCF‐7 cells respond differently to lycopene compared with the MCF‐10 cells. Lycopene altered the expression levels of proteins such as Cytokeratin 8/18 (CK8/18), CK19 and their post translational status. We have shown that lycopene inhibits cell proliferation in MCF‐7 human breast cancer cells but not in the MCF‐10 mammary epithelial cells. Lycopene was shown to modulate cell cycle proteins such as beta tubulin, CK8/18, CK19 and heat shock proteins. Copyright © 2012 John Wiley & Sons, Ltd.     

Upper gastrointestinal evaluation of Chinese patients with non-cardiac chest pain

AIMS: To test the usefulness of upper gastrointestinal investigations and quality of life assessment in Chinese patients with non-cardiac chest pain. METHODS: Seventy-eight consecutive patients with non-cardiac chest pain underwent upper endoscopy. Eight patients had upper gastrointestinal pathology (10%). The remaining 70 patients received acid perfusion test, oesophageal manometry and 24-h ambulatory oesophageal pH (n=65)/manometry (n=61), and the results were compared with those of healthy controls (n=20). Symptoms and quality of life (SF-36) were assessed by standard validated questionnaire. RESULTS: Significant acid reflux symptoms were present in five (5/70, 7%) patients. Abnormal 24-h oesophageal pH, indicating gastro-oesophageal reflux, was found in 19 (19/65, 29%) patients. The percentage of simultaneous contractions was higher and the percentage peristalsis was lower in patients with non-cardiac chest pain when compared with normal subjects by 24-h ambulatory manometry. Patients with non-cardiac chest pain had a lower SF-36 score when compared to controls. CONCLUSIONS: Typical acid reflux symptoms are uncommon in Chinese patients with non-cardiac chest pain, but abnormal 24-h pH results, indicating gastro-oesophageal reflux, were found in 29% of patients. Ineffective contractions were more frequently found in patients with non-cardiac chest pain by 24-h ambulatory manometry, which may have a bearing on the impaired quality of life in such patients. Upper gastrointestinal investigations are useful for the evaluation of Chinese patients with non-cardiac chest pain.     

The effectiveness of intradermal pre-exposure rabies vaccination in an Australian travel medicine clinic

BACKGROUND: The objective of the study was to assess the effectiveness of intradermal (ID) rabies vaccination and to determine whether any difference in response with age or gender exists. No published Australian data on the subject is available and controversy continues to surround the use of ID rabies vaccination for pre-exposure prophylaxis. Vaccinated travelers requiring postexposure treatment are sometimes considered unvaccinated. By confirming their immunity prior to travel, this problem may be avoided. METHODS: The data was collected by retrospective analysis over 2 years at a specialized travel medicine clinic in Perth, Western Australia. The standard protocol is three ID injections of 0.1 mL, given on days 0, 7, and 28 with a booster after 12 months. The vaccine used was the Pasteur Merieux human diploid cell vaccine. Serology was performed 3 weeks after completion of the primary course or after a booster. Antibody levels were measured using the rapid fluorescent focus inhibition test, and levels of >0.5 IU/mL were considered protective. RESULTS: A total of 164 travelers were included in the study, of which 144 had completed the three primary ID doses, and 20 had received an ID booster after a previous primary ID course. The mean age was 34.75 years, and gender distribution was equal. The median time between vaccination and serology was 23 days. The antibody levels ranged from 0 to 50 IU/mL with a mean of 8.42 IU/mL. Three travelers had no detectable antibodies giving a seroconversion rate of 98.2%. No statistically significant correlation between age or gender and antibody levels was present. CONCLUSION: We have found that ID rabies vaccination is effective in a travel clinic with nurses experienced in the technique. The lower cost of ID rabies vaccination makes it accessible to a larger number of travelers. Further studies will be required to determine the duration of protection after ID vaccination and antibody response after postexposure boosters. We will continue to recommend ID rabies vaccination if there is sufficient time for serology to be performed and for results to be available prior to departure.     

Mitogen-activated protein kinases contribute to reactive oxygen species-induced cell death in renal proximal tubule epithelial cells

Extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK/SAPK), and p38 mitogen-activated protein kinase (MAPK) were all rapidly activated in a ROS-dependent manner during 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ)-mediated oxidative stress and oncotic cell death in renal proximal tubule epithelial cells (LLC-PK1). TGHQ-induced phosphorylation of ERK1/2 and JNK MAPKs required epidermal growth factor receptor (EGFR) activation, whereas p38 MAPK activation was EGFR independent. In contrast to their established roles in cell survival, TGHQ-activated ERK1/2 and p38 MAPK (but not JNK) appear to contribute to cell death, since inhibition of ERK1/2 or p38 MAPKs with PD098059 or SB202190 respectively, attenuated TGHQ-mediated cell death. TGHQ increased AP-1 and NFkappaB DNA-binding activity, but whereas pharmacological inhibition of ERK1/2 or p38 MAPKs attenuated AP-1 DNA binding activity, it potentiated TGHQ-mediated NFkappaB activation. Consistent with a role for NFkappaB activation in the cytoprotective response to ROS in renal epithelial cells, an anti-NFkappaB peptide SN50 suppressed the protective effects of ERK inhibition (PD098059 treatment). The data provide evidence that the activation of MAPKs by ROS in renal epithelial cells plays an important role in oncotic cell death, and NF-kB is involved in the cytoprotective effects of PD098059.     

Psychiatric Morbidity in Ketamine Users Attending Counselling and Youth Outreach Services

Background: No study has examined ketamine users’ psychiatric morbidity using structured diagnostic instruments. The aim of this study was thus to determine the psychiatric comorbidity of community-based ketamine users using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), Axis I Disorders (SCID). Methods: A convenience sample of 200 frequent ketamine users was recruited from community organizations in Hong Kong. Participants were screened with the Severity of Dependence Scale (SDS), Beck Depression Inventory (BDI), Anxiety subscale of the Hospital Anxiety Depression Scale (HADSA), and SCID psychotic symptoms. Those who scored above the threshold (cutoff point of 8/9 on the BDI and 4/5 on HADSA) or displayed evidence of psychotic symptoms were referred for a structured clinical interview conducted by a psychiatrist. Results: One hundred and seventy participants scored above the cutoff point on 1 or more of the scales, and 115 participants attended the SCID interview. Fifty-one of these 115 participants received a psychiatric diagnosis of 1 or more comorbidities for the month preceding the interview. Mood disorders accounted for 80.4% of the diagnoses, anxiety disorders for 33.3%, and psychotic disorders for 7.8%. Conclusions: Female gender and history of psychiatric/psychological clinic attendance were significantly associated with comorbid psychiatric disorders, whereas ketamine dependence had a borderline association.     

Evidence for corticotropin-releasing factor regulation of serotonin in the lateral septum during acute swim stress: adaptation produced by repeated swimming

RATIONALE: Swim stress decreases extracellular serotonin (5-HT) levels in the rat lateral septum, and adaptation to this effect occurs with repeated swimming. Corticotropin-releasing factor (CRF) administered into the dorsal raphe nucleus (DRN) also decreases 5-HT release in the lateral septum, suggesting that CRF may mediate the effects of swim stress. OBJECTIVES: The hypothesis that endogenous CRF mediates the reduction of 5-HT levels in the lateral septum evoked by swim stress and is involved in the adaptation that occurs with repeated swim stress was tested. METHODS: Extracellular 5-HT levels in rat lateral septum were quantified by means of in vivo microdialysis. Extracellular single unit activity was recorded from the DRN. RESULTS: Intracerebroventricular (i.c.v.) administration of a CRF receptor antagonist prevented the ability of swim stress to decrease 5-HT release in the lateral septum. Prior exposure to swim stress reduced the ability of both CRF (i.c.v.) and a subsequent swim stress to decrease lateral septum 5-HT release (cross adaptation). Additionally, the effects of CRF, administered into the DRN, on DR neuronal discharge were attenuated in rats with a history of swim stress. Finally, administration of a CRF receptor antagonist (i.c.v.) between two swim stress sessions restored the neurochemical response to swim stress (i.e., 5-HT levels were reduced during the second exposure to swim). CONCLUSIONS: Endogenous CRF modulates 5-HT transmission during acute environmental stress and is also integral to adaptation of the 5-HT response produced by repeated stress. Modulation of the 5-HT system by CRF during acute stress may underlie certain coping behaviors, while stress-induced adaptation of this effect may be involved in psychiatric manifestations of repeated stress.     

Specific,sensitive and accurate LC-MS/MS method for the measurement of levovirin in rat and monkey plasma

Levovirin is a guanosine nucleoside analogue and the L-enantiomer of ribavirin. Levovirin has a better safety profile than ribavirin, exerts similar immunomodulatory effects in a mouse efficacy model, and may provide a better therapeutic option than ribavirin in patients with chronic hepatitis C virus (HCV) infection. To facilitate pharmacokinetic studies, a LC-MS/MS method for the analysis of levovirin in rat and monkey plasma was developed and validated. The method involved adding ICN 10537 as an internal standard, protein precipitation with acetonitrile followed by separation on an Intersil Silica column, and quantification by a MS/MS system equipped with positive electrospray ionization (ESI) in the multiple reaction monitoring (MRM) mode. The MS/MS reaction was selected to monitor the 245-->113 and 259-->128 transitions for levovirin and internal standard, respectively. The calibration curve was linear over a concentration range of 10-5000 ng/ml. The limit of quantitation was 10 ng/ml, the coefficient of variation (CV) was 3-5%, and the bias was 3-6%. Intra- and inter-day analysis of QC samples at 30, 1500 and 3500 ng/ml indicated that the method was precise (CV<6%) and accurate (bias <9%). Levovirin in rat and monkey plasma was stable at 5 degrees C for at least 24 h, 0 degrees C for at least 4 h, and after three freeze-thaw cycles. This specific, accurate and precise assay is useful in the study the pharmacokinetic characteristics of this compound.     

Potent and long-acting corticotropin releasing factor (CRF) receptor 2 selective peptide competitive antagonists

We present evidence that members of the corticotropin releasing factor (CRF) family assume distinct structures when interacting with the CRF(1) and CRF(2) receptors. Predictive methods, physicochemical measurements, and structure-activity relationship studies have suggested that CRF, its family members, and competitive antagonists such as astressin [cyclo(30-33)[DPhe(12),Nle(21),Glu(30),Lys(33),Nle(38)]hCRF((12-41))] assume an alpha-helical conformation when interacting with their receptors. We had shown that alpha-helical CRF((9-41)) and sauvagine showed some selectivity for CRF receptors other than that responsible for ACTH secretion(1) and later for CRF2.(2) More recently, we suggested the possibility of a helix-turn-helix motif around a turn encompassing residues 30-33(3) that would confer high affinity for both CRF(1) and CRF(2)(2,4) in agonists and antagonists of all members of the CRF family.(3) On the other hand, the substitutions that conferred ca. 100-fold CRF(2) selectivity to the antagonist antisauvagine-30 [[DPhe(11),His(12)]sauvagine((11-40))] did not confer such property to the corresponding N-terminally extended agonists. We find here that a Glu(32)-Lys(35) side chain to side chain covalent lactam constraint in hCRF and the corresponding Glu(31)-Lys(34) side chain to side chain covalent lactam constraint in sauvagine yield potent ligands that are selective for CRF(2). Additionally, we introduced deletions and substitutions known to increase duration of action to yield antagonists such as cyclo(31-34)[DPhe(11),His(12),C(alpha)MeLeu(13,39),Nle(17),Glu(31),Lys(34)]Ac-sauvagine((8-40)) (astressin(2)-B) with CRF(2) selectivities greater than 100-fold. CRF receptor autoradiography was performed in rat tissue known to express CRF(2) and CRF(1) in order to confirm that astressin(2)-B could indeed bind to established CRF(2) but not CRF(1) receptor-expressing tissues. Extended duration of action of astressin(2)-B vs that of antisauvagine-30 is demonstrated in the CRF(2)-mediated animal model whereby the inhibition of gastric emptying of a solid meal in mice by urocortin administered intraperitoneally at time zero is antagonized by the administration of astressin(2)-B but not by antisauvagine-30 at times -3 and -6 h while both peptides are effective when given 10 min before urocortin.     

Tau protein phosphorylation as a therapeutic target in Alzheimer's disease

Neurofibrillary tangles (NFTs) are a distinguishing neuropathological feature found in postmortem brains of Alzheimer s disease (AD) and tauopathy patients. The density of these lesions correlates with severity of AD and their distribution follows a characteristic pattern of expansion as the disease progresses. The principle components of NFTs are highly phosphorylated forms of the microtubule-associated protein, tau. Tau phosphorylation is believed to initiate or facilitate dissociation from microtubules leading to microtubule destabilization, decay of cellular transport properties, and cell death. This review summarizes recent data and prevailing views on the roles of protein kinases and phosphatases in the regulation of tau phosphorylation in vitro and in vivo, taking into account data from human neurodegenerative diseases and from transgenic rodent models. Small molecule inhibitors of tau phosphorylation that serve as important research tools and possibly the basis of potential new therapeutics, are also described. Key challenges in developing effective therapeutic agents include identification of the relevant kinase(s) responsible for aberrant tau phosphorylation in AD, synthesis of inhibitors selectively targeting those kinases and establishment of appropriate animal models.