Alcohol expectancies, conduct disorder and early-onset alcoholism: negative alcohol expectancies are associated with less drinking in non-impulsive versus impulsive subjects

AIMS: Research suggests that positive alcohol expectancies promote excessive alcohol use while negative alcohol expectancies discourage excessive alcohol use. Evidence suggests that disinhibitory characteristics, such as conduct disorder and impulsivity, are associated with a general neglect of long-term negative outcomes. This study assessed whether negative expectancies would be associated more strongly with lower levels of alcohol use for low- compared with high-impulsive individuals. DESIGN: Positive and negative alcohol expectancies, alcohol use and impulsivity were assessed in a sample of 99 young adults with alcohol dependence (AD) and conduct disorder (CD), 77 with AD and no CD and 124 controls. FINDINGS: AD/CD subjects had higher proximal (same day) and distal (next day) negative alcohol expectancies, even though they drank more alcohol, compared with AD-alone and control subjects. Distal negative expectancies were associated more strongly with lower levels of drinking for low-impulsive compared with high-impulsive subjects. Proximal negative expectancies were associated more strongly with higher alcohol consumption for high- versus low-impulsive subjects. CONCLUSIONS: Impulsivity and conduct disorder may be important factors in determining how much distal negative alcohol expectancies may discourage excessive alcohol consumption.     

DNA sequencing and melting curve.

The dependence of DNA absorbance (for light at about 260 nm) on temperature is related to a specific DNA sequence structure in the vicinity of DNA thermal denaturation (the so-called DNA melting or coiling). A straightforward analysis of the experimental DNA melting curve allows us to determine the lengths, the A+T content, and the location in DNA of certain domains. In the case of a specific DNA fragmentation, the order of fragments in DNA can be learned from this analysis, nondestructively and quickly, without fractionating the fragments and other methods of fragmentation. If the DNA nucleotide sequence is known except for some sites and uncertain portions, the analysis determines these sites and the accuracy of the sequence at the portions. This information may complement exact methods of DNA sequencing. The proposed analysis is applied to bacteriophage phiX174, whose melting curve is known. The results are compared to and found to be in an excellent agreement with the known phiX174 nucleotide sequence.     

Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells.

Interactions between the kinase inhibitor STI571 and pharmacological antagonists of the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) cascade have been examined in human myeloid leukemia cells (K562 and LAMA 84) that express the Bcr-Abl kinase. Exposure of K562 cells to concentrations of STI571 that minimally induced apoptosis (e.g., approximately 200 nM) resulted in early suppression (i.e., at 6 h) of p42/44 MAPK phosphorylation followed at later intervals (i.e., > or =24 h) by a marked increase in p42/44 MAPK phosphorylation/activation. Coadministration of a nontoxic concentration of the MEK1/2 inhibitor PD184352 (5 microM) prevented STI571-mediated activation of p42/44 MAPK. Cells exposed to STI571 in combination with PD184352 for 48 h demonstrated a very dramatic increase in mitochondrial dysfunction (e.g., loss of DeltaPsim and cytosolic cytochrome c release) associated with procaspase-3 activation, poly(ADP-ribose) polymerase cleavage, and the appearance of the characteristic morphological features of apoptosis. Similar results were obtained using other pharmacological MEK1/2 inhibitors (e.g., PD 98059 and U0126) as well as another leukemic cell line that expresses Bcr-Abl (e.g., LAMA 84). However, synergistic induction of apoptosis by STI571 and PD184352 was not observed in human myeloid leukemia cells that do not express the Bcr-Abl kinase (e.g., HL-60 and U937) nor in normal human peripheral blood mononuclear cells. Synergistic potentiation of STI571-mediated lethality by PD184352 was associated with multiple perturbations in signaling and apoptotic regulatory pathways, including caspase-dependent down-regulation of Bcr-Abl and Bcl-2; caspase-independent down-regulation of Bcl-x(L) and Mcl-1; activation of JNK, p38 MAPK, and p34(cdc2); and diminished phosphorylation of Stat5 and CREB. Significantly, coexposure to PD184352 strikingly increased the lethality of a pharmacologically achievable concentration of STI571 (i.e., 1-2 microM) in resistant K562 cells expressing marked increases in Bcr-Abl protein levels. Together, these findings raise the possibility that treatment of Bcr-Abl-expressing cells with STI571 elicits a cytoprotective MAPK activation response and that interruption of the latter pathway (e.g., by pharmacological MEK1/2 inhibitors) is associated with a highly synergistic induction of mitochondrial damage and apoptosis. They also indicate that in the case of Bcr-Abl-positive cells, simultaneous interruption of two signal transduction pathways may represent an effective antileukemic strategy.     

High interleukin 12 and low interleukin 10 production after in vitro stimulation detected in sepsis survivors

Objective To evaluate viability of isolated peripheral blood mononuclear cells (PBMC) and production of cytokines in vitro after stimulation as prognostic factors for survival in sepsis patients.Design Prospective study of the biological response of PBMC in the onset of severe sepsis.Setting Research laboratory of molecular biology and immunology and university hospital ICU, Faculty of Medicine, Trakia University.Patients Twenty-three patients meeting the criteria for severe sepsis, and 14 control subjects.Interventions Isolated PBMC were stimulated in vitro with: C3-binding glycoprotein (C3bgp; 30 µg), lipopolysaccharide (30 µg), phytohemagglutinin (20 µg), pokeweed mitogen (30 µg), and dexamethasone (500 µg).Measurements and results We measured the levels of interleukins (IL) 6, 10, and 12 in culture supernatants. Stimulation with C3bgp and phytohemagglutinin led to significantly lower PBMC secretion of IL-6 in nonsurvivors than in survivors and healthy donors. Stimulation with C3bgp, lipopolysaccharide, and pokeweed mitogen considerably reduced IL-12 production in nonsurvivors. Stimulation with lipopolysaccharide and pokeweed mitogen caused immune cells in nonsurvivors to produce higher levels of IL-10 than in survivors. Survival of PBMC reduced viability for nonsurvivors PBMC, both spontaneously and as induced by lipopolysaccharide or pokeweed mitogen.Conclusions The viability of PBMC at the onset of sepsis and enhanced production of IL-12 and diminished production of IL-10 after stimulation with all stimuli used may be a favorable prognostic factor in sepsis.     

Perceptions of Health-Related Community Reentry Challenges among Incarcerated Drug Users in Azerbaijan,Kyrgyzstan, and Ukraine

Facing competing demands with limited resources following release from prison, people who inject drugs (PWID) may neglect health needs, with grave implications including relapse, overdose, and non-continuous care. We examined the relative importance of health-related tasks after release compared to tasks of everyday life among a total sample of 577 drug users incarcerated in Ukraine, Azerbaijan, and Kyrgyzstan. A proxy measure of whether participants identified a task as applicable (easy or hard) versus not applicable was used to determine the importance of each task. Correlates of the importance of health-related reentry tasks were analyzed using logistic regression, with a parsimonious model being derived using Bayesian lasso method. Despite all participants having substance use disorders and high prevalence of comorbidities, participants in all three countries prioritized finding a source of income, reconnecting with family, and staying out of prison over receiving treatment for substance use disorders, general health conditions, and initiating methadone treatment. Participants with poorer general health were more likely to prioritize treatment for substance use disorders. While prior drug injection and opioid agonist treatment (OAT) correlated with any interest in methadone in all countries, only in Ukraine did a small number of participants prioritize getting methadone as the most important post-release task. While community-based OAT is available in all three countries and prison-based OAT only in Kyrgyzstan, Kyrgyz prisoners were less likely to choose help staying off drugs and getting methadone. Overall, prisoners consider methadone treatment inapplicable to their pre-release planning. Future studies that involve patient decision-making and scale-up of OAT within prison settings are needed to better improve individual and public health.     

Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics

Introduction

Whether cancer stem cells occur in BRCA1-associated breast cancer and contribute to therapeutic response is not known.

Methods

We generated and characterized 16 cell lines from five distinct Brca1deficient mouse mammary tumors with respect to their cancer stem cell characteristics.

Results

All cell lines derived from one tumor included increased numbers of CD44⁺/CD24^- cells, which were previously identified as human breast cancer stem cells. All cell lines derived from another mammary tumor exhibited low levels of CD44⁺/CD24^- cells, but they harbored 2% to 5.9% CD133⁺ cells, which were previously associated with cancer stem cells in other human and murine tumors. When plated in the absence of attachment without presorting, only those cell lines that were enriched in either stem cell marker formed spheroids, which were further enriched in cells expressing the respective cancer stem cell marker. In contrast, cells sorted for CD44⁺/CD24^- or CD133⁺ markers lost their stem cell phenotype when cultured in monolayers. As few as 50 to 100 CD44⁺/CD24^- or CD133⁺ sorted cells rapidly formed tumors in nonobese diabetic/severe combined immunodeficient mice, whereas 50-fold to 100-fold higher numbers of parental or stem cell depleted cells were required to form few, slow-growing tumors. Expression of stem cell associated genes, including Oct4, Notch1, Aldh1, Fgfr1, and Sox1, was increased in CD44⁺/CD24^- and CD133⁺ cells. In addition, cells sorted for cancer stem cell markers and spheroid-forming cells were significantly more resistant to DNA-damaging drugs than were parental or stem cell depleted populations, and they were sensitized to the drugs by the heat shock protein-90 inhibitor 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride).

Conclusion

Brca1-deficient mouse mammary tumors harbor heterogeneous cancer stem cell populations, and CD44⁺/CD24^- cells represent a population that correlates with human breast cancer stem cells.     

Using the California Verbal Learning Test,Second Edition as an embedded performance validity measure among individuals with TBI and individuals with psychiatric disorders

Objective: Among embedded performance validity tests (PVTs), little research addresses the use of Total Hits and Total False Positives from the California Verbal Learning Test, Second Edition (CVLT-II) in spite of low sensitivity, particularly in psychiatric samples. Method: This study examined the classification accuracy of these two measures in individuals with psychiatric disorders or mild traumatic brain injury (MTBI). These samples were separated into two groups using the criteria of passing all PVTs versus failing 2 or more PVTs. They were also compared to a criterion group of moderate to severe traumatic brain injury (M-STBI) patients who passed all PVTs. The sample included 176 individuals consecutively referred for neuropsychological testing (mean age = 46.31, SD = 15.30; mean education = 13.07, SD = 2.50, 52.3% males; 91.2% Caucasian) who met study criteria. Results: For classification accuracy, Total Hits in the psychiatric group had excellent classification accuracy (Area Under the Curve [AUC] = .82; Sensitivity = .47; Specificity = .90), whereas Total False Positives (AUC = .49) demonstrated poor classification accuracy. The MTBI group had similar results, with Total Hits having excellent classification accuracy (AUC = .88; Sensitivity = .60; Specificity = .90), whereas Total False Positive (AUC = .62) did not. Conclusions: Results provide preliminary support for using Total Hits; however, Total False Positives were ineffective in identifying non-credible patients with psychiatric disorders or MTBI. Total Hits also compared favorably to other embedded CVLT measures.     

Malaligned bioprosthetic valve causing left ventricular outflow tract obstruction

Left ventricular outflow tract obstruction resulting from strut impingement upon the interventricular septum is a rare complication of bioprosthetic mitral valve insertion. Obstruction is more likely to develop when a small, high profile prosthetic valve is inserted into a patient with a small outflow tract. The likelihood of this complication may be reduced by appropriate modification of surgical technique.     

Attitudes Toward Addiction,Methadone Treatment,and Recovery Among HIV-Infected Ukrainian Prisoners Who Inject Drugs: Incarceration Effects and Exploration of Mediators

In this study, we use data from a survey conducted in Ukraine among 196 HIV-infected people who inject drugs, to explore attitudes toward drug addiction and methadone maintenance therapy (MMT), and intentions to change drug use during incarceration and after release from prison. Two groups were recruited: Group 1 (n = 99) was currently incarcerated and Group 2 (n = 97) had been recently released from prison. This paper’s key finding is that MMT treatment and addiction recovery were predominantly viewed as mutually exclusive processes. Group comparisons showed that participants in Group 1 (pre-release) exhibited higher optimism about changing their drug use, were less likely to endorse methadone, and reported higher intention to recover from their addiction. Group 2 participants (post-release), however, reported higher rates of HIV stigma. Structural equation modeling revealed that in both groups, optimism about recovery and awareness of addiction mediated the effect of drug addiction severity on intentions to recover from their addiction.     

Alterations in serum levels of IL-17 in contrast to TNF-alpha correspond to disease-modifying treatment in relapsing-remitting multiple sclerosis

Cytokines of different types play an important role in multiple sclerosis (MS) pathogenesis as mediators and regulators of the immune processes in the central nervous system. The aim of the study was to determine the effect of interferon-beta and glatiramer acetate on serum concentrations of TNF-alpha and IL-17?A and their correlation with the degree of disability in clinically stable patients with relapsing-remitting MS. A cross-sectional, case-control study of 220 patients (68 treatment naïve; 152 treated with interferon-beta or glatiramer acetate) and 99 clinically healthy age-gender-body mass index-matched subjects were performed. Serum cytokine concentrations were measured during remission of the disease by means of ELISA. Treatment naïve patients showed significantly higher levels of IL-17?A than the treated individuals (p?=?.000109) and controls (p?=?.000044). Within the treated group, only patients with interferon-beta had significantly higher serum IL-17 than the controls (p?=?.023). TNF-alpha concentrations were significantly higher in the treated patients compared to the healthy controls (p?=?.000013), regardless of the type of the therapy. Treatment naïve individuals did not differ from the controls according to their serum TNF-alpha (p?=?.922). No correlation was found between the serum cytokine concentrations and Expanded Disability Status Scale (EDSS) score (p?>?.05). Serum concentrations of these cytokines could not be regarded as reliable predictors for the severity of the residual neurological deficit during disease-modifying treatment. Our data suggest that suppression of IL-17?A production as one of the mechanisms underlying the beneficial effect of first-line disease-modifying treatments is stronger in glatiramer acetate than in interferon-beta.