Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent ...features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.
Primary Open-Angle Glaucoma Kwon, Young H; Fingert, John H; Kuehn, Markus H ...
New England journal of medicine/The New England journal of medicine,
03/2009, Letnik:
360, Številka:
11
Journal Article
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Glaucoma is one of the leading causes of blindness worldwide. This review discusses the clinical features, genetics, molecular biology, and cell biology of glaucoma. The authors present a typical ...case of glaucoma, together with the ocular findings.
This review discusses the clinical features, genetics, molecular biology, and cell biology of glaucoma. The authors present a typical case of glaucoma, together with the ocular findings.
Glaucoma is a chronic, degenerative optic neuropathy that can be distinguished from most other forms of acquired optic neuropathy by the characteristic appearance of the optic nerve. In glaucoma, the neuroretinal rim of the optic nerve becomes progressively thinner, thereby enlarging the optic-nerve cup. This phenomenon is referred to as optic-nerve cupping. Its cause is the loss of retinal ganglion cell axons, along with supporting glia and vasculature. The remaining neuroretinal rim retains its normal pink color. In other optic neuropathies, the optic-nerve tissue loses its pink color and cupping does not develop. A rare exception is arteritic anterior ischemic . . .
Recent studies suggest that betaKlotho (KLB) and endocrine FGF19 and FGF21 redirect FGFR signaling to regulation of metabolic homeostasis and suppression of obesity and diabetes. However, the ...identity of the predominant metabolic tissue in which a major FGFR-KLB resides that critically mediates the differential actions and metabolism effects of FGF19 and FGF21 remain unclear.
We determined the receptor and tissue specificity of FGF21 in comparison to FGF19 by using direct, sensitive and quantitative binding kinetics, and downstream signal transduction and expression of early response gene upon administration of FGF19 and FGF21 in mice. We found that FGF21 binds FGFR1 with much higher affinity than FGFR4 in presence of KLB; while FGF19 binds both FGFR1 and FGFR4 in presence of KLB with comparable affinity. The interaction of FGF21 with FGFR4-KLB is very weak even at high concentration and could be negligible at physiological concentration. Both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB. The binding of FGF1 is dependent on where FGFRs are present. Both FGF19 and FGF21 are unable to displace the FGF1 binding, and conversely FGF1 cannot displace FGF19 and FGF21 binding. These results indicate that KLB is an indispensable mediator for the binding of FGF19 and FGF21 to FGFRs that is not required for FGF1. Although FGF19 can predominantly activate the responses of the liver and to a less extent the adipose tissue, FGF21 can do so significantly only in the adipose tissue and adipocytes. Among several metabolic and endocrine tissues, the response of adipose tissue to FGF21 is predominant, and can be blunted by the ablation of KLB or FGFR1.
Our results indicate that unlike FGF19, FGF21 is unable to bind FGFR4-KLB complex with affinity comparable to FGFR1-KLB, and therefore, at physiological concentration less likely to directly and significantly target the liver where FGFR4-KLB predominantly resides. However, both FGF21 and FGF19 have the potential to activate responses of primarily the adipose tissue where FGFR1-KLB resides.
The thermal state of the intergalactic medium (IGM) provides an indirect probe of both the H i and He ii reionization epochs. Current constraints on the IGM temperature from the Lyα forest are ...restricted to the redshift range 2 ≤z≤ 4.5, limiting the ability to probe the thermal memory of H i reionization towards higher redshift. In this work, we present the first direct measurement of the IGM temperature around a z= 6 quasar by analyzing the Doppler widths of Lyα absorption lines in the proximity zone of SDSS J0818+1722. We use a high-resolution (R= 40 000) Keck/HIRES spectrum in combination with detailed numerical modelling to obtain the temperature at mean density, T0= 23 600 ±50006900 K (±92009300 K) at 68 (95) per cent confidence assuming a prior probability following H i and He ii reionization. This enables us to place an upper limit on the redshift of H i reionization, zH, within 33 comoving Mpc of SDSS J0818+1722. If the quasar reionizes the He ii in its vicinity, then in the limit of instantaneous reionization we infer zH < 9.0(11.0) at 68 (95) per cent confidence assuming photoheating is the dominant heat source and that H i reionization is driven by ionizing sources with soft spectra, typical of Population II stars. If the H i and He ii in the IGM around SDSS J0818+1722 are instead reionized simultaneously by a population of massive metal-free stars, characterized by very hard ionizing spectra, we obtain a tighter upper limit of zH < 8.4(9.4). Initiating reionization at higher redshifts produces temperatures which are too low with respect to our constraint unless the H i ionizing sources or the quasar itself has spectra significantly harder than typically assumed.
Hydrogen sulfide is an endogenous gaseous mediator that plays important roles in many physiological processes in microbes, plants, and animals. This chapter focuses on the important roles of hydrogen ...sulfide in protecting tissues against injury, promoting the repair of damage, and downregulating the inflammatory responses. The chapter focuses largely, but not exclusively, on these roles of hydrogen sulfide in the gastrointestinal tract. Hydrogen sulfide is produced throughout the gastrointestinal tract, and it contributes to maintenance of mucosal integrity. Suppression of hydrogen sulfide synthesis renders the tissue more susceptible to injury and it impairs repair. In contrast, administration of hydrogen sulfide donors can increase resistance to injury and accelerate repair. Hydrogen sulfide synthesis is rapidly and dramatically enhanced in the gastrointestinal tract after injury is induced. These increases occur specifically at the site of tissue injury. Hydrogen sulfide also plays an important role in promoting resolution of inflammation, and restoration of normal tissue function. In recent years, these beneficial actions of hydrogen sulfide have provided the basis for development of novel hydrogen sulfide-releasing drugs. Nonsteroidal anti-inflammatory drugs that release small amounts of hydrogen sulfide are among the most advanced of the hydrogen sulfide-based drugs. Unlike the parent drugs, these modified drugs do not cause injury in the gastrointestinal tract, and do not interfere with healing of preexisting damage. Because of the increased safety profile of these drugs, they can be used in circumstances in which the toxicity of the parent drug would normally limit their use, such as in chemoprevention of cancer.
Mobile phone technologies for health promotion and disease prevention have evolved rapidly, but few studies have tested the efficacy of mobile health in full-fledged programs. Text4baby is an example ...of mobile health based on behavioral theory, and it delivers text messages to traditionally underserved pregnant women and new mothers to change their health, health care beliefs, practices, and behaviors in order to improve clinical outcomes. The purpose of this pilot evaluation study is to assess the efficacy of this text messaging campaign.
We conducted a randomized pilot evaluation study. All participants were pregnant women first presenting for care at the Fairfax County, Virginia Health Department. We randomized participants to enroll in text4baby and receive usual health care (intervention), or continue simply to receive usual care (control). We then conducted a 24-item survey by telephone of attitudes and behaviors related to text4baby. We surveyed participants at baseline, before text4baby was delivered to the intervention group, and at follow-up at approximately 28 weeks of baby's gestational age.
We completed 123 baseline interviews in English and in Spanish. Overall, the sample was predominantly of Hispanic origin (79.7%) with an average age of 27.6 years. We completed 90 follow-up interviews, and achieved a 73% retention rate. We used a logistic generalized estimating equation model to evaluate intervention effects on measured outcomes. We found a significant effect of text4baby intervention exposure on increased agreement with the attitude statement "I am prepared to be a new mother" (OR = 2.73, CI = 1.04, 7.18, p = 0.042) between baseline and follow-up. For those who had attained a high school education or greater, we observed a significantly higher overall agreement to attitudes against alcohol consumption during pregnancy (OR = 2.80, CI = 1.13, 6.90, p = 0.026). We also observed a significant improvement of attitudes toward alcohol consumption from baseline to follow-up (OR = 3.57, CI = 1.13 - 11.24, p = 0.029).
This pilot study is the first randomized evaluation of text4baby. It is a promising program in that exposure to the text messages was associated with changes in specific beliefs targeted by the messages.
IMPORTANCE Identifying treatment moderators may help mental health practitioners arrive at more precise treatment selection for individual patients and can focus clinical research on subpopulations ...that differ in treatment response. OBJECTIVE To demonstrate a novel exploratory approach to moderation analysis in randomized clinical trials. DESIGN, SETTING, AND PARTICIPANTS A total of 291 adults from a randomized clinical trial that compared an empirically supported psychotherapy with selective serotonin reuptake inhibitor (SSRI) pharmacotherapy as treatments for depression. MAIN OUTCOMES AND MEASURES We selected 8 relatively independent individual moderators out of 32 possible variables. A combined moderator, M*, was developed as a weighted combination of the 8 selected individual moderators. M* was then used to identify individuals for whom psychotherapy may be preferred to SSRI pharmacotherapy or vice versa. RESULTS Among individual moderators, psychomotor activation had the largest moderator effect size (0.12; 95% CI, <.01 to 0.24). The combined moderator, M*, had a larger moderator effect size than any individual moderator (0.31; 95% CI, 0.15 to 0.46). Although the original analyses demonstrated no overall difference in treatment response, M* divided the study population into 2 subpopulations, with each showing a clinically significant difference in response to psychotherapy vs SSRI pharmacotherapy. CONCLUSIONS AND RELEVANCE Our results suggest that the strongest determinations for personalized treatment selection will likely require simultaneous consideration of multiple moderators, emphasizing the value of the methods presented here. After validation in a randomized clinical trial, a mental health practitioner could input a patient’s relevant baseline values into a handheld computer programmed with the weights needed to calculate M*. The device could then output the patient’s M* value and suggested treatment, thereby allowing the mental health practitioner to select the treatment that would offer the greatest likelihood of success for each patient.
Autism spectrum disorder (ASD) has been linked with eating- and feeding-related atypicalities, including food neophobia (FN) (refusal to try unfamiliar foods), since its earliest description. ...Nevertheless, whether associations between ASD traits and FN extend subclinically into the broader population of children and their potential additive health impacts remains unexplored.
We examined ASD-control group differences in FN and ASD trait-FN trait associations, as well as the ability of FN and autistic traits to predict one index of later health-related outcomes body mass index (BMI).
Participants in the present study were a large community-based sample of 8- to 11-y-olds (n = 4564), including a relatively small group of children diagnosed with ASD (n = 37). Parents of these 8- to 11-y-old children completed assessments of FN and autistic traits and provided height and weight metrics at 12 y of age.
Children with ASD were rated as more food neophobic than their same-age non-ASD peers (2.67 ± 0.83 compared with 2.22 ± 0.73; P < 0.001), and there were subclinical associations between FN and ASD traits (social, communication, and restricted/repetitive behavior) in this community-based sample of children (P < 0.05). Moreover, whereas FN alone predicted lower BMI, the interaction of FN and ASD traits predicted higher BMI (P ≤ 0.01), suggesting that elevated ASD traits in combination with FN exert opposing influences on weight compared with FN alone.
These findings implicate clinical and subclinical connections between ASD traits and feeding behaviors that could affect health outcomes and therefore should be further explored in future studies of shared etiology and intervention strategy.
How does your cortex grow? Raznahan, Armin; Shaw, Phillip; Lalonde, Francois ...
The Journal of neuroscience,
2011-May-11, 2011-05-11, 20110511, Letnik:
31, Številka:
19
Journal Article
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Understanding human cortical maturation is a central goal for developmental neuroscience. Significant advances toward this goal have come from two recent strands of in vivo structural magnetic ...resonance imaging research: (1) longitudinal study designs have revealed that factors such as sex, cognitive ability, and disease are often better related to variations in the tempo of anatomical change than to variations in anatomy at any one time point; (2) largely cross-sectional applications of new surface-based morphometry (SBM) methods have shown how the traditional focus on cortical volume (CV) can obscure information about the two evolutionarily and genetically distinct determinants of CV: cortical thickness (CT) and surface area (SA). Here, by combining these two strategies for the first time and applying SBM in >1250 longitudinally acquired brain scans from 647 healthy individuals aged 3-30 years, we deconstruct cortical development to reveal that distinct trajectories of anatomical change are hidden within, and give rise to, a curvilinear pattern of CV maturation. Developmental changes in CV emerge through the sexually dimorphic and age-dependent interaction of changes in CT and SA. Moreover, SA change itself actually reflects complex interactions between brain size-related changes in exposed cortical convex hull area, and changes in the degree of cortical gyrification, which again vary by age and sex. Knowing of these developmental dissociations, and further specifying their timing and sex-biases, provides potent new research targets for basic and clinical neuroscience.
The hemispheric lateralization of certain faculties in the human brain has long been held to be beneficial for functioning. However, quantitative relationships between the degree of lateralization in ...particular brain regions and the level of functioning have yet to be established. Here we demonstrate that two distinct forms of functional lateralization are present in the left vs. the right cerebral hemisphere, with the left hemisphere showing a preference to interact more exclusively with itself, particularly for cortical regions involved in language and fine motor coordination. In contrast, right-hemisphere cortical regions involved in visuospatial and attentional processing interact in a more integrative fashion with both hemispheres. The degree of lateralization present in these distinct systems selectively predicted behavioral measures of verbal and visuospatial ability, providing direct evidence that lateralization is associated with enhanced cognitive ability.
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