bluuebunny/crossref_metadata_2025 huggingface dataset:
GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system
Authors: Fritschy Jean‐Marc , Panzanelli Patrizia
Published: March 2014

GABAA receptors (GABAARs) are ligand‐gated Cl− channels that mediate most of the fast inhibitory neurotransmission in the central nervous system (CNS). Multiple GABAAR subtypes are assembled from a family of 19 subunit genes, raising the question of the significance of this heterogeneity. In this review, we discuss the evidence that GABAAR subtypes represent distinct receptor populations with a specific spatio‐temporal expression pattern in the developing and adult CNS, being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post‐transcriptional and translational levels. GABAAR subtypes are targeted to specific subcellular domains to mediate either synaptic or extrasynaptic transmission, and their action is dynamically regulated by a vast array of molecular mechanisms to adjust the strength of inhibition to the changing needs of neuronal networks. These adaptations involve not only changing the gating or kinetic properties of GABAARs, but also modifying the postsynaptic scaffold organised by gephyrin to anchor specific receptor subtypes at postsynaptic sites. The significance of GABAAR heterogeneity is particularly evident during CNS development and adult neurogenesis, with different receptor subtypes fulfilling distinct steps of neuronal differentiation and maturation. Finally, analysis of the specific roles of GABAAR subtypes reveals their involvement in the pathophysiology of major CNS disorders, and opens novel perspectives for therapeutic intervention. In conclusion, GABAAR subtypes represent the substrate of a multifaceted inhibitory neurotransmission system that is dynamically regulated and performs multiple operations, contributing globally to the proper development, function and plasticity of the CNS.
SynCAMs extend their functions beyond the synapse
Authors: Frei Jeannine A. , Stoeckli Esther T.
Published: March 2014

Synaptic cell adhesion molecules are characterized by their potential to trigger synaptogenesis in vitro, even when expressed in non‐neuronal cell lines. In addition to the prototypic synaptic cell adhesion molecules (SynCAMs), other structurally unrelated families of synaptic cell adhesion molecules have been identified: neurexins and neuroligins, as well as the leucine‐rich repeat transmembrane neuronal protein family. Although in vivo the absence of individual synaptic cell adhesion molecules does not necessarily reduce the number of synapses, it does affect the function of synapses. Not surprisingly, mutations in synaptic cell adhesion molecules have been identified in patients suffering from neurodevelopmental disorders, such as autism spectrum disorders, intellectual disability or schizophrenia. In line with the major function of these genes at the synapse, their role in the pathogenesis of neurodevelopmental diseases has been attributed to synaptogenesis, synapse maintenance and synaptic plasticity. However, one family of synaptic cell adhesion molecules, the SynCAMs, have also been implicated in axon guidance, that is, an earlier step in neural circuit formation. These findings suggest that SynCAMs, and maybe other families of synaptic cell adhesion molecules as well, could contribute to the pathogenesis of neurodevelopmental disorders at multiple steps of neural circuit formation and, thus, shape the distinct symptoms associated with different disease variants or distinct neurodevelopmental disorders in addition to their effect on synaptic function. In this review, we summarize the roles of one family of synaptic cell adhesion molecules, the SynCAMs, at the synapse and beyond in axon guidance and myelination.
Microbial community dynamics alleviate stoichiometric constraints during litter decay
Authors: Kaiser Christina , Franklin Oskar , Dieckmann Ulf , Richter Andreas
Published: March 2014

Under the current paradigm, organic matter decomposition and nutrient cycling rates are a function of the imbalance between substrate and microbial biomass stoichiometry. Challenging this view, we demonstrate that in an individual‐based model, microbial community dynamics alter relative C and N limitation during litter decomposition, leading to a system behaviour not predictable from stoichiometric theory alone. Rather, the dynamics of interacting functional groups lead to an adaptation at the community level, which accelerates nitrogen recycling in litter with high initial C : N ratios and thus alleviates microbial N limitation. This mechanism allows microbial decomposers to overcome large imbalances between resource and biomass stoichiometry without the need to decrease carbon use efficiency (CUE), which is in contrast to predictions of traditional stoichiometric mass balance equations. We conclude that identifying and implementing microbial community‐driven mechanisms in biogeochemical models are necessary for accurately predicting terrestrial C fluxes in response to changing environmental conditions.
Pooled analysis of the safety and tolerability of onabotulinumtoxinA in the treatment of chronic migraine
Authors: Diener H.‐C. , Dodick D. W. , Turkel C. C. , Demos G. , DeGryse R. E. , Earl N. L. , Brin M. F.
Published: March 2014

Background and purpose

OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double‐blind, placebo‐controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double‐blind, placebo‐controlled trials were analyzed.

Methods

The pooled analysis included two phase 2 and two phase 3 double‐blind, placebo‐controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests.

Results

OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxinA injections, 1455 patients (72.9%) reported at least one AE. Neck pain (12.6%) was the most common onabotulinumtoxinA‐associated AE, followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AEs were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment and 3.0% of patients receiving placebo. AEs were consistent with the known tolerability profile of onabotulinumtoxinA.

Conclusions

Multiple treatments with onabotulinumtoxinA at doses of 75–260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM.
Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke. Final results from the SURPRISE study
Authors: Christensen L. M. , Krieger D. W. , Højberg S. , Pedersen O. D. , Karlsen F. M. , Jacobsen M. D. , Worck R. , Nielsen H. , Ægidius K. , Jeppesen L. L. , Rosenbaum S. , Marstrand J. , Christensen H.
Published: March 2014

Background and purpose

Atrial fibrillation (AF) increases the risk of stroke fourfold and is associated with a poor clinical outcome. Despite work‐up in compliance with guidelines, up to one‐third of patients have cryptogenic stroke (CS). The prevalence of asymptomatic paroxysmal atrial fibrillation (PAF) in CS remains unknown. The SURPRISE project aimed at determining this rate using long‐term cardiac monitoring.

Methods

Patients with CS after protocolled work‐up including electrocardiography (ECG) and telemetry were included after informed consent. An implantable loop recorder (ILR) was implanted subcutaneously. PAF was defined by events of atrial arrhythmia >2 min with a correlating one‐lead ECG confirming the diagnosis.

Results

Eighty‐five patients were monitored for a mean of 569 days (SD ±310). PAF was documented in 18 patients (20.7%) during the study period and detected by ILR in 14 patients (16.1%). In three patients PAF was detected by other methods before or after monitoring and was undiscovered due to device sensitivity in one case. The first event of PAF was documented at a mean of 109 days (SD ±48) after stroke onset. PAF was asymptomatic in all cases and occurred in episodes lasting predominantly between 1 and 4 h. Four recurrent strokes were observed, three in patients with PAF; all three patients were on oral anticoagulation (OAC).

Conclusions

One in five patients with CS had PAF, which occurred at low burden and long after stroke. Future studies should determine the role of implantable cardiac monitors after stroke and determine the potential therapeutic benefit of OAC treatment of patients with PAF.
Anosognosia, neglect and quality of life of right hemisphere stroke survivors
Authors: Dai C.‐Y. , Liu W.‐M. , Chen S.‐W. , Yang C.‐A. , Tung Y.‐C. , Chou L.‐W. , Lin L.‐C.
Published: March 2014

Background and purpose

Anosognosia and neglect may coexist in stroke patients. Neglect patients often report poor quality of life (QOL), whereas patients suffering from other cognition disorders with poor insight report better QOL. This study investigates the relationship between anosognosia, neglect and QOL amongst stroke survivors.

Methods

Stroke survivors who met the criteria were used as a sampling pool. Sixty stroke patients were observed in this study, amongst whom 20 patients with anosognosia and neglect (A+N+), 20 patients with neglect but not anosognosia (A−N+) and 20 patients with neither anosognosia nor neglect (A−N−) were selected from the sampling pool based on demographic characteristics matched with the A+N+ group. A questionnaire (SS‐QOL) was used to collect the QOL perceived by the stroke survivors.

Results

The perceived QOL of the A+N+ group was significantly better than those of the other groups, including the subscales of self‐care, mobility, work/productivity, upper extremity, mood, family role and social role. However, the A+N+ group had poor balance level and more fall incidents were reported.

Conclusion

The A+N+ group perceived better QOL but had more falls and poorer balance than the other groups. Health providers should work with caregivers aggressively in preventing accidents.
Risk factors in patients with perimesencephalic hemorrhage
Authors: Mensing L. A. , Ruigrok Y. M. , Greebe P. , Vlak M. H. M. , Algra A. , Rinkel G. J. E.
Published: March 2014

Background and purpose

Smoking and hypertension are risk factors for aneurysmal subarachnoid hemorrhage (aSAH), whilst excessive alcohol consumption is less consistently linked with aSAH. Perimesencephalic hemorrhage (PMH) is a benign subset of non‐aneurysmal subarachnoid hemorrhage. The exact cause of PMH is unknown, and its risk factor profile may help to elucidate the pathogenesis. The influence of smoking, hypertension and excessive alcohol consumption on the occurrence of PMH was studied.

Methods

Seventy‐nine patients admitted with a PMH to the University Medical Center Utrecht were studied. As controls 574 persons were selected from five different general practices in the referral region of the University Medical Center Utrecht. All participants filled in a questionnaire about smoking habits, the presence of hypertension and alcohol consumption before their hemorrhage. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess the association of risk factors and PMH, and multivariable logistic regression was used to adjust for possible confounding by age and sex.

Results

Adjusted ORs for the occurrence of PMH were 1.7 (95% CI 1.0–2.8) for smoking cigarettes, cigars, pipes or any combination of these, 1.1 (95% CI 0.6–2.0) for hypertension and 1.1 (95% CI 0.5–2.1) for excessive alcohol consumption.

Conclusions

Similar to aSAH, smoking is a risk factor for PMH and excessive alcohol consumption is not. In contrast to aSAH, hypertension is not a risk factor for PMH. This implies that the pathophysiological mechanisms causing PMH might be slightly different from those causing aSAH.
Stepparents and Parenting Stress: The Roles of Gender, Marital Quality, and Views about Gender Roles
Authors: Shapiro Danielle
Published: March 2014

Previous research suggests that stepparenting can be stressful, although the mechanisms that contribute to the experience of parenting stress in stepfamilies are less clear. This study examines gender, marital quality, and views about gendered family roles as correlates of parenting stress among 310 stepmothers, stepfathers, and biological mothers and fathers. Findings suggest that stepparents, and especially stepmothers, experience higher levels of parenting stress than biological parents. Findings also suggest that less traditional views about gendered family roles and higher dyadic adjustment are associated with lower parenting stress for stepparents, particularly in combination. Stepparents reporting both of these protective factors were indistinguishable in terms of parenting stress from biological parents. These findings indicate potential pathways to mitigate the stress associated with stepparenting.
A knot in the protein structure – probing the near‐infrared fluorescent protein iRFP designed from a bacterial phytochrome
Authors: Stepanenko Olesya V. , Bublikov Grigory S. , Stepanenko Olga V. , Shcherbakova Daria M. , Verkhusha Vladislav V. , Turoverov Konstantin K. , Kuznetsova Irina M.
Published: March 2014

The possibility of engineering near‐infrared fluorescent proteins and biosensors from bacterial phytochrome photoreceptors (BphPs) has led to substantial interest in this family of proteins. The near‐infrared fluorescent proteins have allowed non‐invasive bio‐imaging of deep tissues and whole organs in living animals. BphPs and derived near‐infrared fluorescent proteins contain a structural element, called a knot, in their polypeptide chains. The formation of knot structures in proteins was refuted for a long time. Here, we studied the denaturation and renaturation processes of the near‐infrared fluorescent probe iRFP, engineered from RpBphP2, which utilizes a heme‐derived tetrapyrrole compound biliverdin as a chromophore. iRFP contains a unique figure‐of‐eight knot. The denaturation and renaturation curves of the iRFP apoform coincided well, suggesting efficient refolding. However, the iRFP holoform exhibited irreversible unfolding and aggregation associated with the bound chromophore. The knot structure in the apoform did not prevent subsequent binding of biliverdin, resulting in the functional iRFP holoform. We suggest that the irreversibility of protein unfolding is caused by post‐translational protein modifications, such as chromophore binding, rather than the presence of the knot. These results are essential for future design of BphP‐based near‐infrared probes, and add important features to our knowledge of protein folding.
A novel cryptochrome in the diatom Phaeodactylum tricornutum influences the regulation of light‐harvesting protein levels
Authors: Juhas Matthias , von Zadow Andrea , Spexard Meike , Schmidt Matthias , Kottke Tilman , Büchel Claudia
Published: March 2014

Diatoms possess several genes for proteins of the cryptochrome/photolyase family. A typical sequence for a plant cryptochrome was not found in our analysis of the Phaeodactylum tricornutum genome, but one protein grouped with higher plant and green algal cryptochromes. This protein, CryP, binds FAD and 5,10‐methenyltetrahydrofolate, according to our spectroscopic studies on heterologously expressed protein. 5,10‐Methenyltetrahydrofolate binding is a feature common to both cyclobutane pyrimidine dimer photolyases and DASH cryptochromes. In recombinant CryP, however, the FAD chromophore was present in its neutral radical state and had a red‐shifted absorption maximum at 637 nm, which is more characteristic for a DASH cryptochrome than a cyclobutane pyrimidine dimer photolyase. Upon illumination with blue light, the fully reduced state of FAD was formed in the presence of reductant. Expression of CryP was silenced by antisense approaches, and the resulting cell lines showed increased levels of proteins of light‐harvesting complexes, the Lhcf proteins, in vivo. In contrast, the levels of proteins active in light protection, the Lhcx proteins, were reduced. Thus, CryP cannot be directly grouped with known members of the cryptochrome/photolyase family. Of all P. tricornutum proteins, it is the most similar in sequence to a plant cryptochrome, and is involved in the regulation of light‐harvesting protein expression, but shows spectroscopic features and a chromophore composition that are most typical of a DASH cryptochrome.
Diphtheria toxin conformational switching at acidic pH
Authors: Leka Oneda , Vallese Francesca , Pirazzini Marco , Berto Paola , Montecucco Cesare , Zanotti Giuseppe
Published: March 2014

Diphtheria toxin (DT), the etiological agent of the homonymous disease, like other bacterial toxins, has to undergo a dramatic structural change in order to be internalized into the cytosol, where it finally performs its function. The molecular mechanism of toxin transit across the membrane is not well known, but the available experimental evidence indicates that one of the three domains of the toxin, called the central α‐helical domain, inserts into the lipid bilayer, so favoring the translocation of the catalytic domain. This process is driven by the acidic pH of the endosomal lumen. Here, we describe the crystal structure of DT grown at acidic pH in the presence of bicelles. We were unable to freeze the moment of DT insertion into the lipid bilayer, but our crystal structure indicates that the low pH causes the unfolding of the TH2, TH3 and TH4 α‐helices. This event gives rise to the exposure of a hydrophobic surface that includes the TH5 and TH8 α‐helices, and the loop region connecting the TH8 and TH9 α‐helices. Their exposure is probably favored by the presence of lipid bilayers in the crystallization solution, and they appear to be ready to insert into the membrane.

Database

Coordinates and structure factors have been deposited in the Protein Data Bank under accession number 4OW6.
Patterns of dental services and factors that influence dental services among 64–65‐year‐old regular users of dental care in Denmark
Authors: Christensen Lisa B. , Rosing Kasper , Lempert Susanne M. , Hede Børge
Published: March 2014

Objectives

To describe the pattern of dental services provided to 64–65‐year‐old Danes who are regular users of dental care over a 5‐year period, to analyse whether this pattern is associated with socio‐demographic and/or socioeconomic factors, and if different uses of dental services are related to dental status and caries experience. Finally, to discuss the future planning of dental services aimed at the increasing population of elderly citizens. [Correction made on 21 March 2014, after first online publication: The sentence ‘Data on elderly's dental service are scarce, although increased use is seen and more teeth are present in this age group.’ was removed.]

Methods

A cross‐sectional study of all aged 64–65 (n = 37 234) who received a dental examination in 2009 was conducted. Clinical data comprised dental services received under the National Health Insurance reimbursement scheme, dental status and DMFT. Geographical, socio‐demographic and socioeconomic data derived from public registers.

Results

Almost all received restorations, while periodontal treatment was received by <50% during 5 years. Heavy use of dental services was dominated by periodontal services. Periodontal services were most prevalent in the capital and the most affluent areas. Relatively more extractions were related to low income and persons in least affluent areas. Total number of services was highest among women, persons with ≥20 teeth, persons living in the capital, and where the ratio user per dentist was low.

Conclusion

For future planning of dental care for elderly, dental status, geographical and social area‐based factors and to some degree gender, income, and education must be taken into consideration as all these factors seem to influence the future demand for dental services.
Variability in germination behaviour ofPaspalum dilatatumPoir. seeds is genotype dependent
Authors: Glison N. , Viega L. , Cornaglia P. , Gutiérrez L. , Speranza P.
Published: March 2014

Dallisgrass (Paspalum dilatatumPoir.) is a warm‐season grass, native to South America. Its adoption as a pasture crop has been hindered by low seed germination and slow establishment. However, variability in germination behaviour for this species has never been systematically analysed. ForPaspalumspp., dry‐storage and moist cold or warm pre‐conditioning treatments have been reported as effective for the relief or breaking of seed dormancy. In the present work, seed germination responses at 32°C were assayed for sixteenP. dilatatumgenotypes, representing its known natural genetic variability, to two moist pre‐conditioning treatments (at 5 and 20°C) and without pre‐conditioning, and three seed storage periods (0, 3 and 6 months). Pre‐conditioning at 20°C showed high germination percentages (>80%), with ratios equal to or higher than pre‐conditioning at 5°C, suggesting that cold is not required to break dormancy. Longer storage times resulted in increases in germination responses for most of the genotypes, while other biotypes showed no effect. BiotypesVirasoro andChirú showed a remarkably different behaviour with higher germination percentages of untreated freshly harvested seeds. Our results show that diversity for traits involved in seed germination exists among naturally occurringP. dilatatumgenotypes and the characterization of these traits should be addressed during ecotype characterization and evaluation of potential domesticates of this species.
Effect of applications of organic solid cattle manure on Hungarian vetch and barley intercropping mixtures grown on soils of different depths
Authors: Yolcu H.
Published: March 2014

Sloping fields on soils of shallow depth to tillage are commonly left uncultivated in many parts of the world. This study was conducted to compare the effects on morphological traits, dry‐matter (DM) yield, legume ratio (LR), crude protein content (CP), crude protein yield (CPyield) and mineral concentrations (N, P, K, S, Ca, Cu, Fe, Mg, Mn, Na, B and Zn) of Hungarian vetch (Vicia pannonicaCrantz.) and barley (Hordeum vulgareL.) grown in intercropping mixtures in response to three rates of organic solid cattle manure application (M0: 0, M1: 10, M2: 20 t ha−1). Experimentation was conducted on soils of two different soil depths [shallow (8–12 cm; low‐medium erosion risk) and normal soil depth (18–22 cm; no erosion risk)] on a sloping field in the 2006–2007 and 2007–2008 growing seasons at Gumushane, Turkey. Herbage harvested on the shallow depth area had 22–73% lessDMyield, 14–72% lessCPyield, 6–9% greaterCPcontent and generally higher minerals contents than herbage from the normal soil depth area. Cattle manure applications increasedDMyield by about 23%, increasedCPcontent andCPyield, and also increased the contents of most minerals in herbage of the intercropping mixtures, relative to the control, averaged over the two soil depths. It is suggested that, for areas with shallow soil depths that are prone to erosion, plant cover should be used for forage production, and that fertilization with solid cattle manure at 20 t ha−1can support production of quality forage of acceptableDMyield.
Phenotypic and allelic distribution of the ABO and Rhesus (D) blood groups in the Cameroonian population
Authors: Ndoula S. T. , Noubiap J. J. N. , Nansseu J. R. N. , Wonkam A.
Published: March 2014

Data on blood group phenotypes are important for blood transfusion programs, for disease association and population genetics studies. This study aimed at reporting the phenotypic and allelic distribution of ABO and Rhesus (Rh) groups in various ethnolinguistic groups in the Cameroonians. We obtained ABO and Rhesus blood groups and self‐identified ethnicity from 14 546 Cameroonian students. Ethnicity was classified in seven major ethnolinguistic groups: Afro‐Asiatic, Nilo‐Saharan, Niger‐Kordofanian/West Atlantic, Niger‐Kordofanian/Adamawa‐Ubangui, Niger‐Kordofanian/Benue‐Congo/Bantu/Grassfield, Niger‐Kordofanian/Benue‐Congo/Bantu/Mbam and Niger‐Kordofanian/Benue‐Congo/Bantu/Equatorial. ABO allelic frequencies were determined using the Bernstein method. Differences in phenotypic distribution of blood groups were assessed using the chi‐square test; a P value <0.05 being considered as statistically significant. The frequencies of the antigens of blood groups O, A, B and AB were 48.62%, 25.07%, 21.86% and 4.45%, respectively. Rhesus‐positive was 96.32%. The allelic frequencies of O, A and B genes were 0.6978, 0.1605 and 0.1416, respectively. Phenotypic frequencies of the blood groups in the general study population and in the different ethnolinguistic groups were in agreement with Hardy–Weinberg equilibrium expectations (P > 0.05). The frequencies of O, A, and B blood phenotypes were significantly lower, respectively, in the Nilo‐Saharan group (P = 0.009), the Niger‐Kordofanian/Benue‐Congo/Bantu groups (P = 0.021) and the Niger‐Kordofanian/West‐Atlantic group. AB blood group was most frequent in the Niger‐Kordofanian/Adamawa‐Ubangui group (P = 0.024). Our study provides the first data on ethnic distribution of ABO and Rhesus blood groups in the Cameroonian population and suggests that its general profile is similar to those of several sub‐Saharan African populations. We found some significant differences in phenotypic distribution amongst major ethnolinguistic groups. These data may be important for blood donor recruitment policy and blood transfusion service in Cameroon.
Disruption of HLA class II antigen presentation in Burkitt lymphoma: implication of a 47 000 MW acid labile protein in CD4+ T‐cell recognition
Authors: God Jason M. , Zhao Dan , Cameron Christine A. , Amria Shereen , Bethard Jennifer R. , Haque Azizul
Published: March 2014

While Burkitt lymphoma (BL) has a well‐known defect in HLA class I‐mediated antigen presentation, the exact role of BL‐associated HLA class II in generating a poor CD4+ T‐cell response remains unresolved. Here, we found that BL cells are deficient in their ability to optimally stimulate CD4+ T cells via the HLA class II pathway. This defect in CD4+ T‐cell recognition was not associated with low levels of co‐stimulatory molecules on BL cells, as addition of external co‐stimulation failed to elicit CD4+ T‐cell activation by BL. Further, the defect was not caused by faulty antigen/class II interaction, because antigenic peptides bound with measurable affinity to BL‐associated class II molecules. Interestingly, functional class II–peptide complexes were formed at acidic pH 5·5, which restored immune recognition. Acidic buffer (pH 5·5) eluate from BL cells contained molecules that impaired class II‐mediated antigen presentation and CD4+ T‐cell recognition. Biochemical analysis showed that these molecules were greater than 30 000 molecular weight in size, and proteinaceous in nature. In addition, BL was found to have decreased expression of a 47 000 molecular weight enolase‐like molecule that enhances class II‐mediated antigen presentation in B cells, macrophages and dendritic cells, but not in BL cells. These findings demonstrate that BL likely has multiple defects in HLA class II‐mediated antigen presentation and immune recognition, which may be exploited for future immunotherapies.
Lack of transglutaminase 2 diminished T‐cell responses in mice
Authors: Kim Jin‐Hee , Hong Jun Man , Jeong Eui Man , Lee Wang Jae , Kim Hang‐Rae , Kang Jae Seung , Kim In‐Gyu , Hwang Young‐il
Published: March 2014

Transglutaminase 2 (TG2) has been reported to play a role in dendritic cell activation and B‐cell differentiation after immunization. Its presence and role in T cells, however, has not been explored. In the present study, we determined the expression of TG2 on mouse T cells, and evaluated its role by comparing the behaviours of wild‐type and TG2−/− T cells after activation. In our results, naive T cells minimally expressed TG2, expression of which was increased after activation. T‐cell proliferation, expression of activation markers such as CD69 and CD25, and secretions of interleukin‐2 and interferon‐γ were suppressed in the absence of TG2, presumably due, in part, to diminished nuclear factor‐κB activation. These effects on T cells seemed to be reflected in the in vivo immune response, the contact hypersensitivity reaction elicited by 2,4‐dinitro‐1‐fluorobenzene, with lowered peak responses in the TG2−/− mice. When splenic T cells from mice immunized with tumour lysate‐loaded wild‐type dendritic cells were re‐challenged ex vivo with the same antigen, the profile of surface markers including CD44, CD62L, and CD127 strongly indicated lesser generation of memory CD8+ T cells in TG2−/− mice. In the TG2−/− CD8+ T cells, moreover, Eomes expression was markedly decreased. These results indicate possible roles of TG2 in CD8+ T‐cell activation and CD8+ memory T‐cell generation.
Platelet‐activating factor enhances tumour metastasis via the reactive oxygen species‐dependent protein kinase casein kinase 2‐mediated nuclear factor‐κB activation
Authors: Kim Kyoung‐Jin , Cho Kyung‐Deuk , Jang Kyu Yun , Kim Han‐A , Kim Hae‐Kyoung , Lee Hern‐Ku , Im Suhn‐Young
Published: March 2014

Platelet‐activating factor (PAF) promotes tumour metastasis via activation of the transcription factor nuclear factor‐κB (NF‐κB). We here investigated the role of the protein kinase CK2 (formerly Casein Kinase 2 or II) in PAF‐induced NF‐κB activation and tumour metastasis, given that PAF has been reported to increase CK2 activity, and that CK2 plays a key role in NF‐κB activation. PAF increased CK2 activity, phosphorylation and protein expression in vivo as well as in vitro. CK2 inhibitors inhibited the PAF‐mediated NF‐κB activation and expression of NF‐κB‐dependent pro‐inflammatory cytokines and anti‐apoptotic factors. Pre‐treatment with the antioxidant N‐Acetyl‐L‐Cysteine (NAC) resulted in a significant inhibition in PAF‐induced enhancement of CK2 activity, phosphorylation and protein expression in vivo as well as in vitro. H2O2 and known reactive oxygen species inducers, lipopolysaccharide (LPS) and tumour necrosis factor‐α (TNF‐α) enhanced CK2 activity, phosphorylation and protein expression, which was again inhibited by antioxidant. PAF, LPS and TNF‐α induced increased CK2 activity, phosphorylationand protein expression, which were inhibited by p38 inhibitor. PAF, LPS or TNF‐α increased pulmonary metastasis of B16F10, which was inhibited by antioxidants, CK2 inhibitor and p38 inhibitor. Our data suggest that (i) reactive oxygen species activate CK2 via p38, which, in turn, induces NF‐κB activation, and (ii) PAF, LPS and TNF‐α increase pulmonary tumour metastasis via the induction of the reactive oxygen species (ROS)/p38/CK2/NF‐κB pathway.
Cognitive performance profiles by latent classes of drug use
Authors: Harrell P. Truman , Mancha Brent Edward E. , Martins Silvia S. , Mauro Pia M. , Kuo Julie H. , Scherer Michael , Bolla Karen I. , Latimer William W.
Published: March 2014

Background and Objectives

The relationship between substance use and cognitive deficits is complex and requires innovative methods to enhance understanding. The present study is the first to use LCA to examine associations of drug use patterns with cognitive performance.

Methods

Cocaine/heroin users (N = 552) completed questionnaires, and cognitive measures. LCA identified classes based on past‐month drug use and adjusted for probabilities of group membership when examining cognitive performance. Latent indicators were: alcohol (ALC), cigarettes (CIG), marijuana (MJ), crack smoking (CS), nasal heroin (NH), injection cocaine (IC), injection heroin (IH), and injection speedball (IS). Age and education were included as covariates in model creation.

Results

Bootstrap likelihood ratio test (BLRT) supported a 5‐class model. Prevalent indicators (estimated probability of over 50%) for each class are as follows: “Older Nasal Heroin/Crack Smokers” (ONH/CS, n = 166.9): ALC, CIG, NH, CS; “Older, Less Educated Polysubstance” (OLEP, n = 54.8): ALC, CIG, CS, IH, IC, and IS; “Younger Multi‐Injectors” (MI, n = 128.7): ALC, CIG, MJ, IH, IC, and IS; “Less Educated Heroin Injectors” (LEHI, n = 87.4): CIG, IH; and “More Educated Nasal Heroin” users (MENH, n = ALC, CIG, NH. In general, all classes performed worse than established norms and older, less educated classes performed worse, with the exception that MENH demonstrated worse cognitive flexibility than YMI.

Discussion and Conclusions

This study demonstrated novel applications of a methodology for examining complicated relationships between polysubstance use and cognitive performance.

Scientific Significance

Education and/or nasal heroin use are associated with reduced cognitive flexibility in this sample of inner city drug users. (Am J Addict 2014;23:431–439)
Parental history of substance use disorders (SUD) and SUD in offspring: A controlled family study of bipolar disorder
Authors: Wilens Timothy E. , Yule Amy , Martelon MaryKate , Zulauf Courtney , Faraone Stephen V.
Published: March 2014

Background and Objectives

Adolescents with bipolar disorder (BPD) have been previously shown to be at very high risk for substance use disorders (SUD). We now examine the influence of a parental history of substance use disorders on SUD risk in offspring with and without BPD.

Methods

We studied 190 parents ascertained through 104 adolescent BPD probands and 189 parents ascertained through 98 control probands using structured interviews. We compared the prevalence of SUD using logistic regression.

Results

While adjusting for BPD in our combined sample, probands with a parental history of SUD were more likely to have an alcohol use disorder compared to probands without a parental history. Probands with a parental history of SUD were not more likely to have a drug use disorder or overall SUD compared to probands without a parental history. BPD in the offspring did not pose any additional risk between parental history of SUD and offspring SUD.

Conclusion

Alcohol use disorders were more common in the offspring of parents with a SUD history compared to parents without SUD and the risk was not influenced by offspring BPD.

Scientific Significance

Clarifying the mechanisms linking parental SUD to offspring SUD, particularly in children and adolescents with BPD, would help clinicians to educate and monitor high‐risk families, which would facilitate strategies to mitigate risks associated with parental substance abuse. (Am J Addict 2014;23:440–446)
Ziprasidone versus clozapine in the treatment of dually diagnosed (DD) patients with schizophrenia and cannabis use disorders: A randomized study
Authors: Schnell Thomas , Koethe Dagmar , Krasnianski Anna , Gairing Stefanie , Schnell Knut , Daumann Jörg , Gouzoulis‐Mayfrank Euphrosyne
Published: March 2014

Background and Objectives

Clozapine is considered to be particularly effective in the treatment of dually diagnosed (DD) patients with psychosis and substance use disorders. However, its use is restricted by potentially severe side effects. The aim of the present pilot study was to compare the effects of clozapine with the newer second generation antipsychotic (SGA) ziprasidone in DD‐patients.

Methods

Thirty (n = 30) patients with schizophrenia and cannabis abuse/dependence were randomized to ziprasidone or clozapine and were followed up for up to 12 months.

Results

Cannabis use was reduced in both groups during follow‐up. Clozapine treatment was associated with less positive symptoms of schizophrenia, more side effects and poorer compliance with treatment.

Conclusions

Results from this small pilot RCT suggest beneficial effects of both clozapine and ziprasidone in the treatment of cannabis use disorders in psychotic patients. Larger‐scale RCTs are needed in order to assess advantages and disadvantages of the different SGAs in dually diagnosed populations. (Am J Addict 2014;23:308–312)
Pilot study of Creating Change, a new past‐focused model for PTSD and substance abuse
Authors: Najavits Lisa M. , Johnson Kay M.
Published: March 2014

Background and Objectives

Creating Change (CC) is a new past‐focused behavioral therapy model developed for comorbid posttraumatic stress disorder (PTSD) and substance use disorder (SUD). It was designed to address current gaps in the field, including the need for a past‐focused PTSD/SUD model that has flexibility, can work with complex clients, responds to the staffing and resource limitations of SUD and other community‐based treatment programs, can be conducted in group or individual format, and engages clients and clinicians. It was designed to follow the style, tone, and format of Seeking Safety, a successful present‐focused PTSD/SUD model. CC can be used in conjunction with SS and/or other models if desired.

Methods

We conducted a pilot outcome trial of the model with seven men and women outpatients diagnosed with current PTSD and SUD, who were predominantly minority and low‐income, with chronic PTSD and SUD. Assessments were conducted pre‐ and post‐treatment.

Results

Significant improvements were found in multiple domains including some PTSD and trauma‐related symptoms (eg, dissociation, anxiety, depression, and sexual problems); broader psychopathology (eg, paranoia, psychotic symptoms, obsessive symptoms, and interpersonal sensitivity); daily life functioning; cognitions related to PTSD; coping strategies; and suicidal ideation (altogether 19 variables, far exceeding the rate expected by chance). Effect sizes were consistently large, including for both alcohol and drug problems. No adverse events were reported.

Discussion and Conclusions

Despite study methodology limitations, CC is promising.

Scientific Significance

Clients can benefit from past‐focused therapy that addresses PTSD and SUD in integrated fashion. (Am J Addict 2014;23:415–422)
Social network correlates of participation in telephone continuing care for alcohol dependence
Authors: Van Horn Deborah H.A. , Rennert Lior , Lynch Kevin G. , McKay James R.
Published: March 2014

Background and Objectives

Research on face‐to‐face treatment for substance misuse suggests that patients' social networks may impact treatment entry and participation, but there has been no similar research on entry and participation in telephone‐based continuing care. We examined whether alcohol‐specific social support predicted engagement and participation in telephone continuing care for alcohol dependence, and whether treatment participation resulted in beneficial changes in participants' social networks.

Methods

Participants were 252 adults (162 male) enrolled in a randomized clinical trial testing the effectiveness of telephone continuing care for alcohol dependence. Participants who completed 3 weeks of intensive outpatient treatment were randomly assigned to treatment as usual, telephone monitoring (TM; N = 83), or telephone monitoring and brief counseling (TMC; N = 83). TM and TMC included 18 months of telephone treatment. Alcohol‐specific social support was measured with the Important People Inventory at baseline and 6, 12, 18, and 24‐month follow‐up.

Results

Alcohol‐specific social support did not predict entry into TM or TMC. Among those who entered telephone treatment (N = 127), participants with higher network percentage of daily drinkers, higher percentage of network members who accept drinking, and lower percentage of network members who do not accept drinking completed more continuing care calls. There was no effect of continuing care participation on alcohol‐specific social support over 24 months of follow‐up.

Conclusion

Participants with more problematic social networks may self‐select additional support in the form of telephone continuing care. Telephone continuing care does not appear to result in social network change. (Am J Addict 2014;23:447–452)
Cue‐induced craving in dependence upon prescription opioids and heroin
Authors: McHugh R. Kathryn , Park Sara , Weiss Roger D.
Published: March 2014

Background and Objectives

Cues associated with heroin use (eg, needles, powder) elicit robust craving responses in individuals dependent upon heroin. Elevated cue‐induced craving may be a risk factor for relapse and can persist after periods of drug abstinence. Despite the growing prevalence of opioid dependence involving prescription opioids, published studies have yet to examine whether cue‐induced craving is also present in prescription opioid dependence.

Methods

A sample of 50 adults diagnosed with opioid dependence (20 prescription opioid users, 25 heroin users, and 5 mixed opioid users) completed a cue reactivity assessment. Participants were administered a series of 90 pictures, including heroin‐specific, prescription opioid‐specific, and neutral images, and were asked to rate craving and cue salience after each image.

Results

Both the prescription opioid and heroin groups experienced significantly more craving to drug than to neutral stimuli. The prescription opioid group reported significantly less craving to prescription opioid stimuli than the heroin group to heroin stimuli; however, this effect was smaller and non‐significant when controlling for group differences in cue salience.

Discussion and Conclusions

This study found evidence for cue‐induced craving in individuals dependent upon prescription opioids. Further research is needed to better understand the role of cue reactivity in the course and treatment of opioid dependence involving prescription opioid use.

Scientific Significance

As elevated craving reactivity to drug cues may reflect a risk factor for relapse, understanding the nature of cue‐induced craving in individuals with opioid dependence is important to improving treatments for this population. (Am J Addict 2014;23:453–458)
Effects of varenicline, nicotine or placebo on depressive symptoms in postmenopausal smokers
Authors: Avery Naomi , Kenny Anne M. , Kleppinger Alison , Brindisi Jennifer , Litt Mark D. , Oncken Cheryl A.
Published: March 2014

Background

Varenicline carries a black box warning for neuropsychiatric adverse events.

Objective

We examined varenicline use and past history of major depressive disorder (MDD) on depressive symptoms during smoking cessation.

Method

This is a secondary analysis of two smoking cessation studies in 152 postmenopausal women who received placebo or nicotine patch, or 78 women who received varenicline with relaxation. Lifetime history of MDD (LH‐MDD) was assessed at baseline and women with current MDD were excluded. Center for Epidemiologic Study Depression scale (CESD) measured depressive symptoms at baseline, 6 and 12 weeks.

Results

Baseline CESD scores were 5.3 + 4.4. Those with a LH‐MDD reported higher CESD scores (p > .001). Those taking varenicline reported lower scores over all time periods compared to nicotine or placebo (p < .01). The differences between varenicline and the other treatments remained when controlling for LH‐MDD, indicating an independent effect. CESD scores were associated with concurrent smoking status (p < .001), and with withdrawal symptoms (p < .001).

Conclusion

CESD score were lower in those receiving varenicline, whether this is due to an anti‐depressant effect, subject selection, use of relaxation or another cause is unknown. Varenicline does not increase depressive symptoms during smoking cessation in postmenopausal women without current MDD. Subjects with a LH‐MDD are susceptible to developing depressive symptoms during smoking cessation, regardless of pharmacologic aid.

Scientific Significance

Pharmacologic aids did not increase depression symptoms in this select population of postmenopausal women without current depression. Smoking cessation does increase depressive symptoms in those with LH‐MDD, though the degree of increase was not clinically meaningful. (Am J Addict 2014;23:459–465)
Assessment concordance and predictive validity of self‐report and biological assay of cocaine use in treatment trials
Authors: Decker Suzanne E. , Frankforter Tami , Babuscio Theresa , Nich Charla , Ball Samuel A. , Carroll Kathleen M.
Published: March 2014

Background and Objectives

Cocaine use during randomized clinical trials (RCTs) is typically assessed by participant self‐report or biological assay (eg, urinalysis). There have been few direct comparisons of these assessment methods to investigate their concordance and their predictive validity for cocaine use and psychosocial outcomes following treatment completion.

Method

In a combined sample of 380 participants from 5 cocaine RCTs, the concordance between cocaine use assessment methods was examined. Sequential multiple linear and logistic regression models evaluated the predictive validity of two assessment methods for cocaine use and psychosocial outcomes assessed at 1, 3, 6, and 12 months after treatment.

Results

Concordance for self‐report and urinalysis indicators of cocaine use was high within‐treatment (k = 0.72) and moderate during follow‐up (k = 0.51). Rates of concordance were higher in studies using test cups with immediate urinalysis results. Regression analyses indicated that self‐report data within‐treatment predicted self‐reported cocaine use at all post‐treatment points (β 0.22–0.30, p < .01), while urinalysis results within‐treatment predicted urinalysis results at 1, 3, and 6 months post‐treatment (OR 3.92–20.99, p < .05). Cocaine‐positive urinalyses within‐treatment were negatively associated with a composite “good outcome” indicator at 1 and 3 months post‐treatment (OR 0.17–0.32, p < .05).

Discussion and Conclusions

These results suggest a significant role of method variance in predicting post‐treatment outcomes from within‐treatment cocaine use indices.

Scientific Significance

Results support recommendations that cocaine treatment trials should include both biological assay and self‐report assessment. Test cups may facilitate increased self‐report accuracy. (Am J Addict 2014;23:466–474)
A successful treatment of buprenorphine withdrawal with the dopamine receptor agonist pramipexole
Authors: Makhinson Michael , Gomez‐Makhinson Juliana
Published: March 2014

Background

Buprenorphine, used for treating opioid dependence, may have a withdrawal syndrome requiring treatment. Modulation of the dopamine system, which has been implicated in opioid withdrawal, may be a target for withdrawal for opioids such as buprenorphine.

Case Report

A case is reported of a buprenorphine withdrawal syndrome with predominant symptoms of restlessness that were resistant to clonidine and benzodiazepines. It was successfully treated with the dopamine agonist pramipexole.

Scientific Significance

Dopamine receptor agonists may have a place in the treatment of restlessness associated with opioid withdrawal and may have value for the broader spectrum of opioid withdrawal symptoms. (Am J Addict 2014;23:475–477)