bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of TBT on the vitellogenesis and sex hormones in freshwater prawn Macrobrachium rosenbergii (De Man, 1879)
Authors: Revathi Peranandam , Iyapparaj Palanisamy , Vasanthi Lourduraj Arockia , Munuswamy Natesan , Krishnan Muthukalingan
Published: May 2013

Background

Tributyltin (TBT) is a ubiquitous persistent xenobiotic that can be found in freshwater, estuarine and marine ecosystem. TBT is a strong endocrine disrupting compound (EDC) that can cause toxic threat to aquatic organisms. Imposex, sexual deformities and endocrine dysfunctions are the causes of TBT to most of the aquatic organisms. Effect of TBT on the vitellogenesis and sex hormonal changes in Macrobrachium rosenbergii has never been reported. Hence, the present investigation was undertaken to find out the impact of TBT on histological changes in the different reproductive tissues, sex hormonal alterations and level of biomarkers like vitellogenin and vitellin in M. rosenbergii.

Results

The present investigation documents the possible impact of tributyltin (TBT) on the vitellogenesis in freshwater female prawn M. rosenbergii. TBT at 10 ng/l, 100 ng/l and 1000 ng/l concentrations were exposed individually to prawns for a period of three months. At higher concentration of 1000 ng/l, the ovarian development was arrested and ovary remained at spent stage. At lower concentration of TBT (10 ng/l), the development proceeded up to early vitellogenic stage. At intermediate concentration of 100 ng/l TBT, the ovary remained at pre vitellogenic stage and thereafter no development was noticed. Histological results indicated the normal ovarian development with vitellogenic oocytes, filled with yolk globules in control prawn. On the other hand, the TBT treated groups showed reduction in yolk globules, fusion of developing oocytes and abundance of immature oocytes. Immunofluorescence staining denoted the remarkable reduction in vitellin content in ovary of TBT treated prawn. Hence, TBT had conspicuously inhibited the vitellogenesis by causing hormonal imbalance in M. rosenbergii.

Conclusion

TBT had notably inhibited the vitellogenesis due to hormonal imbalance. This endocrine dysfunction ultimately impaired the oogenesis in the freshwater female prawn M. rosenbergii.
Attempted suicide v. non-suicidal self-injury:
behaviour, syndrome or diagnosis?
Authors: Butler Aine M. , Malone Kevin
Published: May 2013

Nomenclature used to describe acts of self-harm without fatal consequences
varies considerably. The term ‘non-suicidal self-injury’ (NSSI) offers an
opportunity to clarify study in this field, dichotomising the presence or
absence of suicidal intent. This may improve consistency in reporting
suicide and self-injurious behaviour with implications for management and
prognosis.
Fetal antipsychotic exposure in a changing landscape: seeing the
future
Authors: Abel Kathryn M.
Published: May 2013

Pregnant women and their fetuses are increasingly likely to be exposed to
antipsychotics. However, safety data remain limited. This editorial suggests
that, in future, well-designed observational pharmaco-epidemiology is our
best chance of illuminating risk for exposed populations and of informing
decision-making for women and clinicians.
Joint crisis plans for people with borderline personality
disorder: feasibility and outcomes in a randomised controlled
trial
Authors: Borschmann Rohan , Barrett Barbara , Hellier Jennifer M. , Byford Sarah , Henderson Claire , Rose Diana , Slade Mike , Sutherby Kim , Szmukler George , Thornicroft Graham , Hogg Joanna , Moran Paul
Published: May 2013

Background

People with borderline personality disorder frequently experience crises.
To date, no randomised controlled trials (RCTs) of crisis interventions
for this population have been published.

Aims

To examine the feasibility of recruiting and retaining adults with
borderline personality disorder to a pilot RCT investigating the
potential efficacy and cost-effectiveness of using a joint crisis
plan.

Method

An RCT of joint crisis plans for community-dwelling adults with
borderline personality disorder (trial registration: ISRCTN12440268). The
primary outcome measure was the occurrence of self-harming behaviour over
the 6-month period following randomisation. Secondary outcomes included
depression, anxiety, engagement and satisfaction with services, quality
of life, well-being and cost-effectiveness.

Results

In total, 88 adults out of the 133 referred were eligible and were
randomised to receive a joint crisis plan in addition to treatment as
usual (TAU; n=46) or TAU alone (n=42).
This represented approximately 75% of our target sample size and
follow-up data were collected on 73 (83.0%) participants.
Intention-to-treat analysis revealed no significant differences in the
proportion of participants who reported self-harming (odds ratio (OR)
=1.9, 95% CI 0.53-6.5,P = 0.33) or the frequency of
self-harming behaviour (rate ratio (RR)=0.74, 95% CI 0.34-1.63,
P=0.46) between the two groups at follow-up. No
significant differences were observed between the two groups on any of
the secondary outcome measures or costs.

Conclusions

It is feasible to recruit and retain people with borderline personality
disorder to a trial of joint crisis plans and the intervention appears to
have high face validity with this population. However, we found no
evidence of clinical efficacy in this feasibility study.
Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies
Authors: Diniz Breno S. , Butters Meryl A. , Albert Steven M. , Dew Mary Amanda , Reynolds Charles F.
Published: May 2013

Background

Late-life depression may increase the risk of incident dementia, in particular of Alzheimer's disease and vascular dementia.

Aims

To conduct a systematic review and meta-analysis to evaluate the risk of incident all-cause dementia, Alzheimer's disease and vascular dementia in individuals with late-life depression in population-based prospective studies.

Method

A total of 23 studies were included in the meta-analysis. We used the generic inverse variance method with a random-effects model to calculate the pooled risk of dementia, Alzheimer's disease and vascular dementia in older adults with late-life depression.

Results

Late-life depression was associated with a significant risk of all-cause dementia (1.85, 95% CI 1.67-2.04, P< 0.001), Alzheimer's disease (1.65, 95% CI 1.42-1.92, P<0.001) and vascular dementia (2.52, 95% CI 1.77-3.59, P<0.001). Subgroup analysis, based on five studies, showed that the risk of vascular dementia was significantly higher than for Alzheimer's disease (P=0.03).

Conclusions

Late-life depression is associated with an increased risk for all-cause dementia, vascular dementia and Alzheimer's disease. The present results suggest that it will be valuable to design clinical trials to investigate the effect of late-life depression prevention on risk of dementia, in particular vascular dementia and Alzheimer's disease.
Cyberbullying and its impact on young people's emotional health and well-being
Authors: Cowie Helen
Published: May 2013

Aims and method

The upsurge of cyberbullying is a frequent cause of emotional disturbance in children and young people. The situation is complicated by the fact that these interpersonal safety issues are actually generated by the peer group and in contexts that are difficult for adults to control. This article examines the effectiveness of common responses to cyberbullying.

Results

Whatever the value of technological tools for tackling cyberbullying, we cannot avoid the fact that this is an interpersonal problem grounded in a social context.

Clinical implications

Practitioners should build on existing knowledge about preventing and reducing face-to-face bullying while taking account of the distinctive nature of cyberbullying. Furthermore, it is essential to take account of the values that young people are learning in society and at school.
Previous History of Chronic Stress Changes the Transcriptional Response to Glucocorticoid Challenge in the Dentate Gyrus Region of the Male Rat Hippocampus
Authors: Datson Nicole A. , van den Oever Jessica M.E. , Korobko Oksana B. , Magarinos Ana Maria , de Kloet E. Ronald , McEwen Bruce S.
Published: May 2013

Chronic stress is a risk factor for several neuropsychiatric diseases, such as depression and psychosis. In response to stress glucocorticoids (GCs) are secreted that bind to mineralocorticoid and glucocorticoid receptors, ligand-activated transcription factors that regulate the transcription of gene networks in the brain necessary for coping with stress, recovery, and adaptation. Chronic stress particularly affects the dentate gyrus (DG) subregion of the hippocampus, causing several functional and morphological changes with consequences for learning and memory, which are likely adaptive but at the same time make DG neurons more vulnerable to subsequent challenges. The aim of this study was to investigate the transcriptional response of DG neurons to a GC challenge in male rats previously exposed to chronic restraint stress (CRS). An intriguing finding of the current study was that having a history of CRS had profound consequences for the subsequent response to acute GC challenge, differentially affecting the expression of several hundreds of genes in the DG compared with challenged nonstressed control animals. This enduring effect of previous stress exposure suggests that epigenetic processes may be involved. In line with this, CRS indeed affected the expression of several genes involved in chromatin structure and epigenetic processes, including Asf1, Ash1l, Hist1h3f, and Tp63. The data presented here indicate that CRS alters the transcriptional response to a subsequent GC injection. We propose that this altered transcriptional potential forms part of the molecular mechanism underlying the enhanced vulnerability for stress-related disorders like depression caused by chronic stress.
Effects of Ingestion Routes on Hormonal and Metabolic Profiles in Gastric-Bypassed Humans
Authors: Lindqvist Andreas , Spégel Peter , Ekelund Mikael , Mulder Hindrik , Groop Leif , Hedenbro Jan , Wierup Nils
Published: May 2013

Context:

Gastric bypass surgery (GBP) results in the rapid resolution of type 2 diabetes. Most studies aiming to explain the underlying mechanisms are limited to data obtained after a postsurgical recovery period, making assessment of confounding influences from, for example, weight loss and altered nutrient intake difficult.

Objective:

To examine the impact of GBP on hormonal and metabolite profiles under conditions of identical nutrient intake independent of weight loss, we studied GBP patients fitted with a gastrostomy tube to enable the administration of nutrients to bypassed segments of the gut. Thus, this model allowed us to simulate partially the preoperative condition and compare this with the postoperative situation in the same patient.

Design:

Patients (n = 4) were first given a mixed meal test (MMT) orally and then via the gastrostomy tube, preceded by overnight and 2-hour fasting, respectively. Blood samples were assessed for hormones and metabolites.

Results:

The oral MMT yielded 4.6-fold increase in plasma insulin (P < .05), 2-fold in glucagon-like peptide-1 (P < .05), and 2.5-fold in glucose-dependent insulinotropic peptide (P < .05) plasma levels, compared with the gastrostomy MMT. The changes in hormone levels were accompanied by elevated branched-chain amino acid levels (1.4–2-fold, P < .05) and suppressed fatty acid levels (∼50%, P < .05).

Conclusions:

These data, comparing identical nutrient delivery, demonstrate markedly higher incretin and insulin responses after oral MMT than after gastric MMT, thereby providing a potential explanation for the rapid remission of type 2 diabetes observed after GBP. The simultaneous increase in branched-chain amino acid questions its role as a marker for insulin resistance.
Sewerage's Reproduction of Caste
Authors: Tam Stephanie
Published: May 2013

The development of Ahmedabad's sewerage system both impinged upon and was itself modified to accommodate India's caste structure. Sewers became markers of legitimacy, sophistication, and moral citizenship through the notion of the “civic sense,” having corporeal, political, and economic repercussions upon the untouchable Bhangi caste, whose livelihood changed from sweeping gutters to clearing choked sewer pipes. Sanitation technology's humane intents were subverted over time by how the sewers were used and maintained, as caste discrimination was perpetuated under the aegis of public well-being and urban necessity.
Water, North African Immigrants, and the Parisian Bidonvilles, 1950s – 1960s
Authors: McDonnell Hugh
Published: May 2013

Water was a fundamental issue in the life of North African residents of the shantytowns, or bidonvilles, that proliferated around Paris in the postwar period. In this regard, this essay examines these immigrants' experience of inadequate shelter in the face of the wet Parisian climate, the supply and use of water in the shantytown home, and the ordeal of being gazed at by French neighbors of the bidonvilles because of their muddy appearance or while undergoing the arduous task of fetching water from communal water points. In large part, the article draws from the archives, diaries, and interviews of Monique Hervo, who lived and worked in the shantytowns of Nanterre in northwestern Paris. Furthermore, it engages with her explicit commitment to justice to examine how the daily experience of water for the North African residents connected to questions of justice, in terms of both material distribution and recognition.
Watershed
Authors: Lampert Nicolas , Deal Raoul
Published: May 2013

Watershed: Art, Activism, and Community Engagement uses art as a form of activism to comment on water issues in Milwaukee and the Great Lakes basin and their impact on the world at large. This project, organized by Raoul Deal and Nicolas Lampert and initiated in 2009, tackles issues such as water shortages, notions of abundance, water privatization, invasive species, industrial pollution, and water as a human right.
Social Capital and Political Accountability
Authors: Nannicini Tommaso , Stella Andrea , Tabellini Guido , Troiano Ugo
Published: May 2013

We investigate a channel through which social capital may improve economic well-being and the functioning of institutions: political accountability. The main idea is that voters who share values and beliefs that foster cooperation are more likely to vote based on criteria of social welfare rather than narrow personal interest. We frame this intuition into a simple model of political agency and take it to the data using information on the criminal prosecutions and absenteeism rates of Italian members of Parliament. Empirical evidence shows that the electoral punishment of these misbehaviors is considerably larger in districts with higher social capital. (JEL D72, I31, Z13)
Feeling the Florida Heat? How Low-Performing Schools Respond to Voucher and Accountability Pressure
Authors: Rouse Cecilia Elena , Hannaway Jane , Goldhaber Dan , Figlio David
Published: May 2013

While numerous studies have found that school accountability boosts test scores, it is uncertain whether estimated test score gains reflect genuine improvements or merely “gaming” behaviors. This paper brings to bear new evidence from a unique five-year, three-round survey conducted of a census of public elementary schools in Florida that is linked with detailed administrative data on student performance. We show that schools facing accountability pressure changed their instructional practices in meaningful ways, and that these responses can explain a portion of the test score gains associated with the Florida school accountability system. (JEL H75, I21, I28)
Avaliação das Contribuições do Programa de Fortalecimento da Agricultura Familiar – PRONAF e a Melhoria da Renda Familiar dos Piscicultores de Blumenau, Santa Catarina
Authors: Gomes Giancarlo , Kaleski Deise Weber , Cunha Paulo Roberto da , Toledo Filho Jorge Ribeiro
Published: May 2013

A produção de peixes de água doce em viveiros naturais ou artificiais oferece oportunidades para o desenvolvimento de atividades com fins de recreação, alimentação ou mesmo ecológicas. Blumenau - Santa Catarina comporta atualmente 1,2 mil propriedades rurais sendo que 80% delas têm lagoas que produzem entre aproximadamente 8 toneladas de peixes por hectare. O estudo aqui relatado objetivou avaliar a participação e influência do Programa de Fortalecimento da Agricultura Familiar – PRONAF na renda oriunda da piscicultura familiar no município de Blumenau. A pesquisa foi quantitativa quanto à abordagem. Foram enviados questionários a 47 piscicultores inscritos no PRONAF. Os produtores revelam dificuldades relacionadas ao valor do produto e a problemas ocasionados pelo clima. Os resultados do estudo demonstraram que o PRONAF tem alcançado seus objetivos ao proporcionar, na visão dos agricultores que aderiram ao programa, melhoria na qualidade de vida em virtude do aumento da renda familiar.
Cultura Organizacional e Mito Fundador: Um Estudo de Caso em uma Empresa Familiar
Authors: Lourenço Cléria Donizete da Silva , Ferreira Patricia Aparecida
Published: May 2013

Nos últimos anos, o tema simbolismo organizacional assumiu importância crescente na administração. Dentro desta abordagem, encontram-se conceitos relacionados ao mito fundador e à cultura organizacional. O fundador assume um papel fundamental no processo de moldar os padrões culturais de uma organização e após sua morte o mesmo pode ser transformado em um mito. Neste trabalho, procurou-se identificar o sentido da morte do fundador para os atores organizacionais bem como compreender as mudanças ocorridas nas relações de trabalho após a sua morte. Para tanto, utilizou-se da pesquisa qualitativa, do método do estudo de caso, de entrevistas em profundidade e da análise de conteúdo. Observou-se que a história de uma organização carrega muito da história do seu fundador. Constatou-se também que o sentido da morte do fundador para os atores organizacionais envolveu uma série de mudanças que acarretaram em um rompimento com os valores e princípios preconizados por ele.
Resultados da Terceirização da Tecnologia da Informação em Organizações Brasileiras
Authors: Prado Edmir Parada Vasques , Cristofoli Fulvio
Published: May 2013

Esta pesquisa tem como objetivo analisar os resultados obtidos com a terceirização da TI em organizações brasileiras. A pesquisa caracteriza-se por ser um estudo empírico e exploratório realizado a partir de uma amostra não probabilística de 299 organizações brasileiras de grande e médio porte, obtidas por um processo de amostragem por conveniência. A coleta de dados foi feita através de questionário e realizada no segundo semestre de 2010. Aplicou-se a técnica estatística de Análise Fatorial e foram identificados dois resultados principais obtidos com a terceirização da TI em organizações brasileiras. A partir desses resultados principais e usando a técnica estatística de Análise de Grupos foi possível classificar as organizações em quatro grupos, associando o perfil da organização aos resultados obtidos por elas.
As Parcerias Público-Privada - PPP’s no Estado de São Paulo: A Contribuição ao Processo de Descentralização da Administração Pública
Authors: Moreira Leandro Capergiani , Bresciani Luis Paulo , Vieira Sirlei Tereza Pitteri , Queiroz Geison Cantarelli Muniz de
Published: May 2013

Este estudo objetiva verificar como as Parcerias Público-Privadas – PPP’s podem contribuir no processo de descentralização administrativa do Estado em complemento aos modelos tradicionais de concessões e privatizações e apresentar uma análise empírica sobre a experiência da concessão patrocinada da Linha 4 – do Metrô de São Paulo. Para tanto foram realizadas, além do resgate do processo de descentralização da administração pública no Brasil, a análise de documentos oficiais referentes a PPP da Linha 4 – do Metrô de São Paulo e entrevistas com gestores públicos envolvidos com as PPP’s no Estado de São Paulo. O resultado dos estudos demonstrou que as PPP’s proporcionam novas possibilidades de parcerias entre o público e o privado e é um importante instrumento de política pública para viabilizar investimentos em infraestrutura e aumentar a eficiência do Estado brasileiro.
Proton Pump Inhibitor–Associated Hypomagnesemia: What Do FDA Data Tell Us?
Authors: Luk Chee Phun , Parsons Richard , Lee Ya Ping , Hughes Jeffery David
Published: May 2013

BACKGROUND:

Proton pump inhibitors (PPIs) are a class of medications indicated for the treatment of gastric acid–related diseases. Hypomagnesemia is a rare but serious adverse effect of PPIs.

OBJECTIVE:

To address the association between the use of different PPIs and hypomagnesemia by examining the frequency of occurrence of hypomagnesemia among the reported adverse drug reactions from the Food and Drug Administration (FDA) Adverse Event Reporting System database.

METHODS:

We conducted a cross-sectional study of PPI-associated adverse effect cases reported to the FDA between November 1, 1997, and April 1, 2012. Logistic regression was used to examine the association of sex, age, and different PPIs with hypomagnesemia. χ2 Analysis was conducted to investigate the association of PPI-associated hypomagnesemia with hypocalcemia and hypokalemia.

RESULTS:

Among 66,102 subjects identified as experiencing 1 or more adverse effects while taking a PPI, 1.0% (n = 693) were reported to have hypomagnesemia. The mean (SD) age of PPI users presenting with hypomagnesemia was 64.4 (12.9) years. Results from logistic regression indicated that, compared with esomeprazole, all other PPIs had a higher rate of hypomagnesemia, with pantoprazole having the highest rate (OR 4.3; 95% CI 3.3–5.7; p < 0.001). The risk of female subjects having hypomagnesemia (OR 0.83; 95% CI 0.71–0.97; p = 0.016) was significantly lower than that of males. Elderly subjects (age >65 years) were at increased risk of PPI-associated hypomagnesemia (OR 1.5; 95% CI 1.2–1.7; p < 0.001). χ2 Analysis showed strong association between hypomagnesemia and both hypocalcemia (p < 0.001) and hypokalemia (p < 0.001).

CONCLUSIONS:

All PPIs were associated with hypomagnesemia, with esomeprazole having the lowest risk and pantoprazole having the highest risk. The risk of PPI-associated hypomagnesemia was higher in males and the elderly population. Hypocalcemia and hypokalemia commonly coexisted with PPI-associated hypomagnesemia.
Rivoglitazone: A New Thiazolidinedione for the Treatment of Type 2 Diabetes Mellitus
Authors: Koffarnus Robin L , Wargo Kurt A , Phillippe Haley M
Published: May 2013

OBJECTIVE:

To review the pharmacology, pharmacokinetics, efficacy, and safety of the thiazolidinedione rivoglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, to determine its potential role in the treatment of type 2 diabetes mellitus.

DATA SOURCES:

A MEDLINE search (1966-February 2013) was conducted for English-language studies in humans, using the terms rivoglitazone and CS011. Abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes annual meetings from 2007 to 2012 were also evaluated for relevant data.

STUDY SELECTION AND DATA EXTRACTION:

Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of rivoglitazone were reviewed.

DATA SYNTHESIS:

Rivoglitazone has been shown, through small clinical studies, to decrease hemoglobin A1c (A1C) by 0.11-1.1% when compared with placebo and may provide greater A1C reduction than pioglitazone. Rivoglitazone reduces hyperglycemia, hyperinsulinemia, and hypertriglyceridemia by acting as an agonist of PPAR-γ. Rivoglitazone is the most potent PPAR-γ agonist; the initial recommended dose is 1 mg daily, with adjustment as needed to a maximum dose of 2 mg daily. Additionally, rivoglitazone has a longer half-life than other PPAR-γ agonists. Similar to those of the other PPAR-γ agonists, rivoglitazone's adverse effects include peripheral edema and weight gain.

CONCLUSIONS:

Rivoglitazone is the fourth agent in the thiazolidinedione class of antidiabetes drugs. Although rivoglitazone appears to be more potent in its ability to lower A1C levels compared with other thiazolidinediones, further studies of longer duration are needed to fully assess the risks associated with this drug. Until these can be completed, we cannot recommend rivoglitazone over currently approved drugs in this class.
The Parental Experiences of Mothers of Adolescents With Hearing Impairments
Authors: Morgan-Redshaw M. , Wilgosh L. , Bibby M. A.
Published: April 2013

Adolescence is a difficult time in the life of any youth. In the hearing-impaired child it can be an especially stressful period. The mother, who in many families is the primary care giver, has probably put more of her time and energy into helping the child than any other individual. Familiarity with the thoughts and feelings of the mothers, then, should contribute to our understanding of the hearing-impaired adolescent. Yet, few studies have examined the experiences of mothers during this stage. In this study, five hearing mothers of hearing-impaired adolescents were interviewed on their experiences in rearing a hearing-impaired child. The information culled from these interviews and the subsequent analysis should help fill the void of knowledge on this aspect of the hearing-impaired child. Using qualitative analysis of the mothers' experiences the researchers identified six major themes from the data collected in the interviews: (1) the mothers' personal growth, (2) the mother-child relationship, (3) parent-professional relationships, (4) concerns about educational programming, (5) the importance of fluent communications, and (6) support systems available to the mothers. Suggestions are made for parents and to help improve parent-professional relationships and the programs that serve the hearing impaired and their families. Areas for further research on the subject of rearing hearing-impaired adolescents are identified.
Maternal Immune Activation during Gestation Interacts withDisc1Point Mutation to Exacerbate Schizophrenia-Related Behaviors in Mice
Authors: Lipina Tatiana V. , Zai Clement , Hlousek Daniela , Roder John C. , Wong Albert H.C.
Published: May 2013

Schizophrenia is thought to result from interactions between susceptible genotypes and environmental risk factors.DISC1is an important gene for schizophrenia and mood disorders based on both human and animal studies. In the present study we sought to investigate interactions between two distinct point mutations in the mouseDisc1gene (L100P and Q31L) and maternal immune activation (MIA) during pregnancy with polyinosinic:polycytidylic acid (polyI:C). PolyI:C given at 5 mg/kg impaired cognitive and social behavior in both wild-type (WT) andDisc1-Q31L+/−offspring, and reduced prepulse inhibition at 16 but not 8 weeks of age.Disc1-L100P+/−mutants were more sensitive to MIA than WT or Disc1-Q31L+/−mice. Interleukin-6 (IL-6) is a critical cytokine for mediating the behavioral and transcriptional effects of polyI:C. We found a more pronounced increase of IL-6 in response to polyI:C in fetal brain inDisc1-L100P+/−mice compared with WT orDisc1-Q31L+/−mice. Coadministration of an anti-IL-6 antibody with polyI:C reversed schizophrenia-related behavioral phenotypes inDisc1-L100P+/−mice. In summary, we found specific interactions between discrete genetic (Disc1-L100P+/−) and environmental factors (MIA) that exacerbate schizophrenia-related phenotypes. IL-6 may be important in the pathophysiology of this interaction.
Glutamatergic Signaling from the Parabrachial Nucleus Plays a Critical Role in Hypercapnic Arousal
Authors: Kaur Satvinder , Pedersen Nigel P. , Yokota Shigefumi , Hur Elizabeth E. , Fuller Patrick M. , Lazarus Michael , Chamberlin Nancy L. , Saper Clifford B.
Published: May 2013

The mechanisms of arousal from apneas during sleep in patients suffering from obstructive sleep apnea are not well understood. However, we know that respiratory chemosensory pathways converge on the parabrachial nucleus (PB), which sends glutamatergic projections to a variety of forebrain structures critical to arousal, including the basal forebrain, lateral hypothalamus, midline thalamus, and cerebral cortex. We tested the role of glutamatergic signaling in this pathway by developing an animal model for repetitive CO2arousals (RCAs) and investigating the effect of deleting the gene for the vesicular glutamate transporter 2 (Vglut2) from neurons in the PB. We used mice with lox P sequences flanking exon2 of theVglut2gene, in which adeno-associated viral vectors containing genes encoding Cre recombinase and green fluorescent protein were microinjected into the PB to permanently and selectively disruptVglut2expression while labeling the affected neurons. We recorded sleep in these mice and then investigated the arousals during RCA.Vglut2deletions that included the external lateral and lateral crescent subdivisions of the lateral PB more than doubled the latency to arousal and resulted in failure to arouse by 30 s in >30% of trials. By contrast, deletions that involved the medial PB subdivision had minimal effects on arousal during hypercapnia but instead increased non-rapid eye movement (NREM) sleep by ∼43% during the dark period, and increased delta power in the EEG during NREM sleep by ∼50%. Our results suggest that glutamatergic neurons in the lateral PB are necessary for arousals from sleep in response to CO2, while medial PB glutamatergic neurons play an important role in promoting spontaneous waking.
Autophagy Promotes Oligodendrocyte Survival and Function following Dysmyelination in a Long-Lived Myelin Mutant
Authors: Smith Chelsey M. , Mayer Joshua A. , Duncan Ian D.
Published: May 2013

The Long–Evans shaker (les) rat has a mutation in myelin basic protein that results in severe CNS dysmyelination and subsequent demyelination during development. During this time,lesoligodendrocytes accumulate cytoplasmic vesicles, including lysosomes and membrane-bound organelles. However, the mechanism and functional relevance behind these oligodendrocyte abnormalities inleshave not been investigated. Using high-magnification electron microscopy, we identified the accumulations inlesoligodendrocytes as early and late autophagosomes. Additionally, immunohistochemistry and Western blots showed an increase in autophagy markers inles. However, autophagy did not precede the death oflesoligodendrocytes. Instead, upregulating autophagy promoted membrane extensions inlesoligodendrocytesin vitro. Furthermore, upregulating autophagy inlesrats via intermittent fasting increased the proportion of myelinated axons as well as myelin sheath thickness inlesand control rats. Overall, this study provides insight into the abnormalities described inlesas well as identifying a novel mechanism that promotes the survival and function of oligodendrocytes.
Bovine Spongiform Encephalopathy Induces Misfolding of Alleged Prion-Resistant Species Cellular Prion Protein without Altering Its Pathobiological Features
Authors: Vidal Enric , Fernández-Borges Natalia , Pintado Belén , Ordóñez Montserrat , Márquez Mercedes , Fondevila Dolors , Torres Juan María , Pumarola Martí , Castilla Joaquín
Published: May 2013

Bovine spongiform encephalopathy (BSE) prions were responsible for an unforeseen epizootic in cattle which had a vast social, economic, and public health impact. This was primarily because BSE prions were found to be transmissible to humans. Other species were also susceptible to BSE either by natural infection (e.g., felids, caprids) or in experimental settings (e.g., sheep, mice). However, certain species closely related to humans, such as canids and leporids, were apparently resistant to BSE.In vitroprion amplification techniques (saPMCA) were used to successfully misfold the cellular prion protein (PrPc) of these allegedly resistant species into a BSE-type prion protein. The biochemical and biological properties of the new prions generatedin vitroafter seeding rabbit and dog brain homogenates with classical BSE were studied. Pathobiological features of the resultant prion strains were determined after their inoculation into transgenic mice expressing bovine and human PrPC. Strain characteristics of thein vitro-adapted rabbit and dog BSE agent remained invariable with respect to the original cattle BSE prion, suggesting that the naturally low susceptibility of rabbits and dogs to prion infections should not alter their zoonotic potential if these animals became infected with BSE. This study provides a sound basis for risk assessment regarding prion diseases in purportedly resistant species.
Differential GABAB-Receptor-Mediated Effects in Perisomatic- and Dendrite-Targeting Parvalbumin Interneurons
Authors: Booker Sam A. , Gross Anna , Althof Daniel , Shigemoto Ryuichi , Bettler Bernhard , Frotscher Michael , Hearing Matthew , Wickman Kevin , Watanabe Masahiko , Kulik Ákos , Vida Imre
Published: May 2013

Inhibitory parvalbumin-containing interneurons (PVIs) control neuronal discharge and support the generation of theta- and gamma-frequency oscillations in cortical networks. Fast GABAergic input onto PVIs is crucial for their synchronization and oscillatory entrainment, but the role of metabotropic GABABreceptors (GABABRs) in mediating slow presynaptic and postsynaptic inhibition remains unknown. In this study, we have combined high-resolution immunoelectron microscopy, whole-cell patch-clamp recording, and computational modeling to investigate the subcellular distribution and effects of GABABRs and their postsynaptic effector Kir3 channels in rat hippocampal PVIs. Pre-embedding immunogold labeling revealed that the receptors and channels localize at high levels to the extrasynaptic membrane of parvalbumin-immunoreactive dendrites. Immunoreactivity for GABABRs was also present at lower levels on PVI axon terminals. Whole-cell recordings further showed that synaptically released GABA in response to extracellular stimulation evokes large GABABR-mediated slow IPSCs in perisomatic-targeting (PT) PVIs, but only small or no currents in dendrite-targeting (DT) PVIs. In contrast, paired recordings demonstrated that GABABR activation results in presynaptic inhibition at the output synapses of both PT and DT PVIs, but more strongly in the latter. Finally, computational analysis indicated that GABABIPSCs can phasically modulate the discharge of PT interneurons at theta frequencies. In summary, our results show that GABABRs differentially mediate slow presynaptic and postsynaptic inhibition in PVIs and can contribute to the dynamic modulation of their activity during oscillations. Furthermore, these data provide evidence for a compartment-specific molecular divergence of hippocampal PVI subtypes, suggesting that activation of GABABRs may shift the balance between perisomatic and dendritic inhibition.
Inactivation of mTORC1 in the Developing Brain Causes Microcephaly and Affects Gliogenesis
Authors: Cloëtta Dimitri , Thomanetz Venus , Baranek Constanze , Lustenberger Regula M. , Lin Shuo , Oliveri Filippo , Atanasoski Suzana , Rüegg Markus A.
Published: May 2013

The mammalian target of rapamycin (mTOR) regulates cell growth in response to various intracellular and extracellular signals. It assembles into two multiprotein complexes: the rapamycin-sensitive mTOR complex 1 (mTORC1) and the rapamycin-insensitive mTORC2. In this study, we inactivated mTORC1 in mice by deleting the gene encoding raptor in the progenitors of the developing CNS. Mice are born but never feed and die within a few hours. The brains deficient for raptor show a microcephaly starting at E17.5 that is the consequence of a reduced cell number and cell size. Changes in cell cycle length during late cortical development and increased cell death both contribute to the reduction in cell number. Neurospheres derived from raptor-deficient brains are smaller, and differentiation of neural progenitors into glia but not into neurons is inhibited. The differentiation defect is paralleled by decreased Stat3 signaling, which is a target of mTORC1 and has been implicated in gliogenesis. Together, our results show that postnatal survival, overall brain growth, and specific aspects of brain development critically depend on mTORC1 function.
Dual Cleavage of Neuregulin 1 Type III by BACE1 and ADAM17 Liberates Its EGF-Like Domain and Allows Paracrine Signaling
Authors: Fleck Daniel , van Bebber Frauke , Colombo Alessio , Galante Chiara , Schwenk Benjamin M. , Rabe Linnea , Hampel Heike , Novak Bozidar , Kremmer Elisabeth , Tahirovic Sabina , Edbauer Dieter , Lichtenthaler Stefan F. , Schmid Bettina , Willem Michael , Haass Christian
Published: May 2013

Proteolytic shedding of cell surface proteins generates paracrine signals involved in numerous signaling pathways. Neuregulin 1 (NRG1) type III is involved in myelination of the peripheral nervous system, for which it requires proteolytic activation by proteases of the ADAM family and BACE1. These proteases are major therapeutic targets for the prevention of Alzheimer's disease because they are also involved in the proteolytic generation of the neurotoxic amyloid β-peptide. Identification and functional investigation of their physiological substrates is therefore of greatest importance in preventing unwanted side effects. Here we investigated proteolytic processing of NRG1 type III and demonstrate that the ectodomain can be cleaved by three different sheddases, namely ADAM10, ADAM17, and BACE1. Surprisingly, we not only found cleavage by ADAM10, ADAM17, and BACE1 C-terminal to the epidermal growth factor (EGF)-like domain, which is believed to play a pivotal role in signaling, but also additional cleavage sites for ADAM17 and BACE1N-terminal to that domain. Proteolytic processing at N- and C-terminal sites of the EGF-like domain results in the secretion of this domain from NRG1 type III. The soluble EGF-like domain is functionally active and stimulates ErbB3 signaling in tissue culture assays. Moreover, the soluble EGF-like domain is capable of rescuing hypomyelination in a zebrafish mutant lacking BACE1. Our data suggest that NRG1 type III-dependent myelination is not only controlled by membrane-retained NRG1 type III, but also in a paracrine manner via proteolytic liberation of the EGF-like domain.
Foxa1 and Foxa2 Are Required for the Maintenance of Dopaminergic Properties in Ventral Midbrain Neurons at Late Embryonic Stages
Authors: Stott Simon R. W. , Metzakopian Emmanouil , Lin Wei , Kaestner Klaus H. , Hen Rene , Ang Siew-Lan
Published: May 2013

The maintained expression of transcription factors throughout the development of mesodiencephalic dopaminergic (mDA) neurons suggests multiple roles at various stages in development. Two members of the forkhead/winged helix transcription factor family, Foxa1 and Foxa2, have been recently shown to have an important influence in the early development of mDA neurons. Here we present data demonstrating that these genes are also involved in the later maintenance of the mDA system. We conditionally removed both genes in postmitotic mDA neurons using the dopamine transporter-cre mouse. Deletion of both Foxa1 and Foxa2 resulted in a significant reduction in the number of tyrosine hydroxylase (TH)-positive mDA neurons. The decrease was predominantly observed in the substantia nigra region of the mDA system, which led to a loss of TH+ fibers innervating the striatum. Further analysis demonstrated that the reduction in the number of TH+ cells in the mutant mice was not due to apoptosis or cell-fate change. Using reporter mouse lines, we found that the mDA neurons were still present in the ventral midbrain, but that they had lost much of their dopaminergic phenotype. The majority of these neurons remained in the ventral mesencephalon until at least 18 months of age. Chromatin immunoprecipitation suggested that the loss of the mDA phenotype is due to a reduction in the binding of the nuclear orphan receptor, Nurr-1 to the promoter region of TH. These results extend previous findings and demonstrate a later role for Foxa genes in regulating the maintenance of dopaminergic phenotype in mDA neurons.
Physical Exercise Prevents Stress-Induced Activation of Granule Neurons and Enhances Local Inhibitory Mechanisms in the Dentate Gyrus
Authors: Schoenfeld Timothy J. , Rada Pedro , Pieruzzini Pedro R. , Hsueh Brian , Gould Elizabeth
Published: May 2013

Physical exercise is known to reduce anxiety. The ventral hippocampus has been linked to anxiety regulation but the effects of running on this subregion of the hippocampus have been incompletely explored. Here, we investigated the effects of cold water stress on the hippocampus of sedentary and runner mice and found that while stress increases expression of the protein products of the immediate early genes c-fosandarcin new and mature granule neurons in sedentary mice, it has no such effect in runners. We further showed that running enhances local inhibitory mechanisms in the hippocampus, including increases in stress-induced activation of hippocampal interneurons, expression of vesicular GABA transporter (vGAT), and extracellular GABA release during cold water swim stress. Finally, blocking GABAA receptors in the ventral hippocampus, but not the dorsal hippocampus, with the antagonist bicuculline, reverses the anxiolytic effect of running. Together, these results suggest that running improves anxiety regulation by engaging local inhibitory mechanisms in the ventral hippocampus.
Ventral Hippocampal Neurons Are Shaped by Experience to Represent Behaviorally Relevant Contexts
Authors: Komorowski Robert W. , Garcia Carolyn G. , Wilson Alix , Hattori Shoai , Howard Marc W. , Eichenbaum Howard
Published: May 2013

Memories can be recalled at different levels of resolution, from a detailed rendition of specific events within a single experience to a broad generalization across multiple related experiences. Here we provide evidence that neural representations reflecting the specificity or generality of memories are differentially represented along the dorsoventral axis of the CA3 area of the rat hippocampus. In dorsal CA3, neurons rapidly associate the identity of events with specific locations whereas, in more ventrally located CA3 regions, neurons gradually accumulate information across extended training to form representations that generalize across related events within a spatial context and distinguish events across contexts.
Critical Role of Increased PTEN Nuclear Translocation in Excitotoxic and Ischemic Neuronal Injuries
Authors: Zhang Shu , Taghibiglou Changiz , Girling Kimberly , Dong Zhifang , Lin Shinn-Zong , Lee Wei , Shyu Woei-cherng , Wang Yu Tian
Published: May 2013

Stroke is the leading cause of disability in developed countries. However, no treatment is available beyond 3 h post-ictus. Here, we report that nuclear translocation of PTEN (phosphatase and tensin homolog deleted on chromosome TEN) is a delayed step causatively leading to excitotoxic (in vitro) and ischemic (in vivo) neuronal injuries. We found that excitotoxic stimulation ofN-methyl-d-aspartate (NMDA) resulted in PTEN nuclear translocation in cultured neurons, a process requiring mono-ubiquitination at the lysine 13 residue (K13), as the translocation was prevented by mutation of K13 or a short interfering peptide (Tat-K13) that flanks the K13 residue. More importantly, using a rat model of focal ischemia, we demonstrated that systemic application of Tat-K13, even 6 h after stroke, not only reduced ischemia-induced PTEN nuclear translocation, but also strongly protected against ischemic brain damage. Our study suggests that inhibition of PTEN nuclear translocation may represent a novel after stroke therapy.
Dopamine Differentially Modulates the Excitability of Striatal Neurons of the Direct and Indirect Pathways in Lamprey
Authors: Ericsson Jesper , Stephenson-Jones Marcus , Pérez-Fernández Juan , Robertson Brita , Silberberg Gilad , Grillner Sten
Published: May 2013

The functions of the basal ganglia are critically dependent on dopamine. In mammals, dopamine differentially modulates the excitability of the direct and indirect striatal projection neurons, and these populations selectively express dopamine D1and D2receptors, respectively. Although the detailed organization of the basal ganglia is conserved throughout the vertebrate phylum, it was unknown whether the differential dopamine modulation of the direct and indirect pathways is present in non-mammalian species. We aim here to determine whether the receptor expression and opposing dopaminergic modulation of the direct and indirect pathways is present in one of the phylogenetically oldest vertebrates, the river lamprey. Usingin situhybridization and patch-clamp recordings, we show that D1receptors are almost exclusively expressed in the striatal neurons projecting directly to the homolog of the substantia nigra pars reticulata. In addition, the majority of striatal neurons projecting to the homolog of the globus pallidus interna/globus pallidus externa express D1or D2receptors. As in mammals, application of dopamine receptor agonists differentially modulates the excitability of these neurons, increasing the excitability of the D1-expressing neurons and decreasing the excitability of D2-expressing neurons. Our results suggest that the segregated expression of the D1and D2receptors in the direct and indirect striatal projection neurons has been conserved across the vertebrate phylum. Because dopamine receptor agonists differentially modulate these pathways, increasing the excitability of the direct pathway and decreasing the excitability of the indirect pathway, this organization may be conserved as a mechanism that biases the networks toward action selection.
Uterine secretome and its modulation in rat (Rattus norvegicus)
Authors: Bhutada Sumit , Katkam R R , Nandedkar Tarla , Metkari S M , Chaudhari U K , Varghese Sneha , Kholkute S D , Sachdeva Geetanjali
Published: May 2013

The present study identifies uterine fluid (UF) proteins that display differential abundance during the embryo-permissive phase in nonconception and conception cycles in rats. UF samples were collected from nonpregnant rats in the proestrous (n=17) and metestrous (n=18) phases and also from pregnant (n=17) and pseudopregnant (n=17) rats on day 4 post coitus. UF protein profile in the metestrous phase was compared with that in the proestrous phase. Similarly, UF protein profile of the pregnant rats was compared with that of the pseudopregnant rats. Two-dimensional PAGE, followed by densitometric analysis of the paired protein spots, revealed differential abundance of 44 proteins in the metestrous phase, compared with that in the proestrous phase. Of these, 29 proteins were identified by matrix-assisted laser desorption/ionization time-of-flight or liquid chromatography–tandem mass spectrometry. Functional groups such as proteases, protease inhibitors, and oxidoreductases were enriched in differentially abundant proteins. Total protease activity in UF was found to be significantly (P<0.05; t-test) higher in the proestrous phase, compared with that in the metestrous phase. Furthermore, 41 UF proteins were found to be differentially abundant in pregnant rats, compared with pseudopregnant rats. Of these, 11 proteins could be identified. Immunoblotting analysis confirmed significantly higher (P<0.05; t-test) abundance of β-actin, Rho-specific guanine nucleotide dissociation inhibitor alpha (Rho-GDIα), and peroxiredoxin-2 and -6 in the metestrous phase, compared with that in the proestrous phase. Compared with pseudopregnant rats, pregnant rats had significantly higher (P<0.05; t-test) levels of UF β-actin and Rho-GDIα. Furthermore, these proteins could be detected in the culture supernatants of endometrial epithelial cell lines, thereby providing an evidence of their secretion from endometrial epithelial cells. Data obtained from the study expand our knowledge on the uterine milieu that favours embryo implantation.