Distinct T-cell subtypes induced with whole cell and acellular pertussis vaccines in children.

Recent clinical trials have demonstrated that new generation acellular pertussis vaccines can confer protection against whooping cough. However, the mechanism of protective immunity against Bordetella pertussis infection induced by vaccination remains to be defined. We have examined cellular immune responses in children immunized with a range of acellular and whole cell pertussis vaccines. Immunization of children with a potent whole-cell vaccine induced B. pertussis-specific T cells that secreted interferon-gamma (IFN-gamma), but not interleukin-5 (IL-5). In contrast, T cells from children immunized with acellular pertussis vaccines secreted IFN-gamma and/or IL-5 following stimulation with B. pertussis antigens in vitro. These observations suggest that protective immunity conferred by whole-cell vaccines, like natural immunity, is mediated by type 1 T cells, whereas the mechanism of immune protection generated with acellular vaccines may be more heterogeneous, involving T cells that secreted type 1 and type 2 cytokines.     

Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction.

SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokine-dependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS-1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1(-/-) mice were born but failed to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1(-/-) mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects.     

Beta cyclodextrins bind,stabilize, and remove lipofuscin bisretinoids from retinal pigment epithelium

Accumulation of lipofuscin bisretinoids (LBs) in the retinal pigment epithelium (RPE) is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there are no approved treatments for these diseases; hence, agents that efficiently remove LBs from RPE would be valuable therapeutic candidates. Here, we show that beta cyclodextrins (β-CDs) bind LBs and protect them against oxidation. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of LBs within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from Abca4-Rdh8 double knock-out (DKO) mice, respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of DKO animals. Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs.The retinal pigment epithelium (RPE), strategically situated between the neural retina and the choroid blood vessels, is essential for photoreceptor (PR) function. It recycles vitamin A, which is required for the visual cycle and clears debris generated by the circadian shedding of PR outer segments (1, 2). Each RPE cell phagocytoses and digests the material produced by 30–50 overlying PRs, which shed 10% of their mass daily. The intense and continual phagocytic activity of RPE cells results in the progressive accumulation of indigestible products or “lipofuscin” in their lysosomal compartment (3, 4). Unlike lipofuscins found in other body tissues, which are composed mainly of protein, RPE lipofuscin consists predominantly of lipid-bisretinoids and only 2% protein (5). Lipofuscin bisretinoids (LBs) are vitamin A-derived side products of the visual cycle. Light converts 11-cis-retinal (11CR), the visual pigment chromophore, into all-trans-retinal (ATR), which is immediately flipped by the ATP-binding cassette transporter 4 (Abca4) transporter from the lumen of the outer segment discs to the cytoplasm, where it is reduced to inert all-trans-retinol by retinol dehydrogenase 8 (Rdh8), in mice (6, 7). Small fractions of 11CR and ATR are converted into N-retinylidine-N-ethanolamine (A2E) and other less abundant bisretinoids, which once accumulated in the lysosomes of RPE cells are refractory to all known lysosomal hydrolases (8, 9). The concept that LB accumulation causes retinal degeneration is supported by in vitro and in vivo data that show that excessive LBs are toxic for cultured RPE cells (10, 11), that photoreceptors overlying A2E-laden RPE are more prone to degeneration (12) and that excessive accumulation of LBs in Stargardt’s disease precedes macular degeneration (13). Mice carrying null mutations in Abca4 and Rdh8 develop blindness, basal laminar deposits, and focal accumulations of extracellular debris between the RPE and the Bruch membrane (drusen) (6).Here we report that a family of modified cyclic oligosaccharides, beta cyclodextrins (β-CDs), formed by seven d-glucose units, can encapsulate the hydrophobic arms of A2E within their nonpolar cavity, protect A2E from oxidation, and remove A2E from RPE cells. Our data demonstrate a direct correlation between the ability of β-CDs to perform these protective functions and their affinity for A2E.     

Validity of the verbal IQ as a short form of the Wechsler adult intelligence scale-revised

Assessed the validity of the Verbal IQ as a short form of the WAIS-R. Ss were 104 psychiatric patients with means for age, education, and Full Scale IQ of 36.22 (SD = 9.04), 12.46 (SD = 1.98), and 93.94 (SD = 12.19), respectively. A correlation of 0.93 (p < 0.001) between the Verbal and Full Scale IQs was found. The average Verbal IQ exceeded the average Full Scale IQ by a small (i. e., 1.65 IQ points) but statistically significant amount (p < 0.001). Thirty-three (32%) Ss showed changes in their intelligence categories when the Verbal IQ was compared to the Full Scale IQ. However, when the Verbal IQ was banded by the standard error of measurement (SE_M = ± 3) and the precision range was compared to the Full Scale IQ, results indicated 88% agreement. If clinicians must rely on the Verbal IQ as an estimate of the Full Scale, reporting the score in conjunction with a precision range will increase its accuracy.     

Involvement of CD14 and beta2-integrins in activating cells with soluble and particulate lipopolysaccharides and mannuronic acid polymers

Lipopolysaccharide (LPS) and related bacterial products can be recognized by host inflammatory cells in a particulate, bacterium-bound form, as well as in various soluble, released forms. In the present study we have compared the mechanisms used by LPS, detoxified LPS (DLPS), and mannuronic acid polymers (M-polymers), in solution or covalently linked to particles, in stimulating monocytes to tumor necrosis factor (TNF) production. The addition of recombinant LPS binding protein (LBP) and/or soluble CD14 (sCD14) enhanced the production of TNF from monocytes stimulated with soluble LPS, DLPS, or M-polymer, but did not affect the response to M-polymer or DLPS attached to particles. Treatment of monocytes with antibody to CD14, CD18, or CD11b showed that CD14, but not CR3 (CD11b/CD18), mediated monocyte TNF production in response to the soluble antigens. In contrast, anti-CD14, anti-CD11b and anti-CD18 monoclonal antibodies all inhibited the response to the particulate stimuli. On the other hand, B975, a synthetic analog of Rhodobacter capsulatus lipid A, completely abrogated the monocyte TNF response induced by LPS but did not affect the TNF induction by DLPS or M-polymer, either in soluble or particulate forms. These data demonstrate that the engagement of immune receptors by bacterial products such as LPS, DLPS, and M-polymer is dependent upon the presentation form of their constituent carbohydrates, and that factors such as aggregation state, acylation, carbohydrate chain length, and solid versus liquid phase of bacterial ligands influence the mechanisms used by cells in mediating proinflammatory responses.     

Emotion perception and executive functioning predict work status in euthymic bipolar disorder

Functional recovery, including return to work, in Bipolar Disorder (BD) lags behind clinical recovery and may be incomplete when acute mood symptoms have subsided. We examined impact of cognition on work status and underemployment in a sample of 156 Euthymic-BD and 143 controls (HC) who were divided into working/not working groups. Clinical, health, social support, and personality data were collected, and eight cognitive factors were derived from a battery of neuropsychological tests. The HC groups outperformed the BD groups on seven of eight cognitive factors. The working-BD group outperformed the not working-BD group on 4 cognitive factors composed of tasks of emotion processing and executive functioning including processing speed and set shifting. Emotion processing and executive tasks were predictive of BD unemployment, after accounting for number of mood episodes. Four cognitive factors accounted for a significant amount of the variance in work status among the BD participants. Results indicate that patients with BD who are unemployed/unable to work exhibit greater difficulties processing emotional information and on executive tasks that comprise a set shifting or interference resolution component as compared to those who are employed, independent of other factors. These cognitive and affective factors are suggested as targets for treatment and/or accommodations.     

Catecholamine regulation of neocortical spindling in DBA/2 mice

The waking EEG of DBA/2 mice is punctuated by conspicuous bursts of high-amplitude, 6-7-cps spindles. Catecholamine depletion by 2.0 mg/kg, i.p., reserpine or 120 mg/kg, i.p., alpha-methyl-p-tyrosine increased the occurrence and duration of these brief spindle episodes (BSEs). This effect may reflect noradrenergic depletion because the beta-noradrenergic antagonist propranolol (10 mg/kg, i.p.) powerfully promoted BSE occurrence and increased BSE duration in freely-moving and midpontine-transected mice, whereas the dopamine antagonist haloperidol (2.0 mg/kg, i.p.) neither increased nor decreased BSE occurrence. The alpha-noradrenergic agonist clonidine (0.05 mg/kg, i.p.), which is known to inhibit noradrenergic neuronal firing as well as act at postsynaptic alpha receptors, also promoted BSE occurrence in transected mice. In addition, the dopamine agonist apomorphine (2.0 mg/kg, i.p.) increased BSE occurrence in freely-moving mice once the behavioral activation it produced subsided. These effects were blocked by 2.0 mg/kg haloperidol, i.p. The convulsant drug pentylenetetrazol, which is known to promote BSE occurrence at subconvulsant doses in DBA/2 mice, may activate BSEs, in part, by activating dopamine neurons: 2.0 mg/kg haloperidol, i.p., partially blocked the facilitation of BSEs by 20 mg/kg pentylenetetrazol, i.p., in midpontine DBA/2 mice. Thus, noradrenergic neurons may block spindle occurrence in DBA/2 mice whereas dopamine neurons may be one of several systems that can promote spindle occurrence.     

Regionally specific increased volume of the amygdala in Williams syndrome: Evidence from surface‐based modeling

Williams syndrome (WS) is a condition caused by a contiguous deletion of approximately 26–28 genes from chromosome 7, and is characterized by abnormal social and emotional processing and abnormal structure and function of the amygdala. Prior studies show that the amygdala is relatively enlarged in WS, but very little is known regarding the regional specificity of increased amygdalar volume in this condition. Here we investigated the regional specificity of structural alterations of the amygdala in WS, compared to a typically developing (TD) control group. We acquired high resolution brain MRI data from 79 participants (39 WS, 40 TD) and used a surface‐based analytical modeling approach. The WS group exhibited several areas of increased radial expansion of the amygdalar surface and no areas of decreased radial expansion of the amygdalar surface compared to TD controls. The areas found to exhibit particularly increased radial expansion in WS included the bilateral posterior cortical nucleus, lateral nucleus, and the central nucleus. This greater regional and anatomical specificity of altered amygdala structure in WS contributes to a model relating genetic risk in WS to the development of key brain regions for social and emotional functioning. Hum Brain Mapp 35:866–874, 2014. © 2012 Wiley Periodicals, Inc.     

Peri-sleep-onset cortisol levels in children and adolescents with affective disorders.

BACKGROUND: Changes in the hypothalamic-pituitary-adrenal (HPA) axis, as evidenced by patterns of cortisol secretion, have been of interest in understanding depression and anxiety disorders across the life span. Previous studies of pediatric depression have pointed to the period around sleep onset as a key time point for observing alterations in cortisol secretion associated with affective disorders. Evidence also indicates that pubertal development may influence the expression of HPA dysregulation. We hypothesized that adolescents with depression and youth with anxiety disorders exhibit elevated peri-sleep-onset cortisol. METHODS: Plasma cortisol was sampled every 20 min around sleep onset from children and adolescents with major depressive disorder (n = 116), anxiety disorders (n = 32), or no history of psychiatric disorder (control; n = 76). Sleep onset was determined by polysomnography. Classification of participants as children or adolescents was based on Tanner staging of pubertal maturation. RESULTS: Children with anxiety disorders had higher peri-sleep-onset cortisol than children with depression or control children. Adolescents with depression had marginally higher peri-sleep-onset cortisol than control adolescents and significantly higher peri-sleep-onset cortisol than children with depression. CONCLUSIONS: Depression and anxiety are associated with altered cortisol secretion around sleep onset, and these changes appear to be influenced by pubertal maturation.     

CRF Receptor Antagonist Attenuates Immobilization Stress-Induced Norepinephrine Release in the Prefrontal Cortex in Rats

Neuroanatomical, neurophysiological, and behavioral studies suggest that brain stem nucleus locus coeruleus (LC) plays an important role in stress response. The present study was designed to clarify, whether infusion of CRF antagonist, αhCRF, into LC could attenuate or block stress-induced changes in norepinephrine (NE) concentrations in microdialysates collected from the medial prefrontal cortex (PFM). Rats were implanted with a bilateral cannulae assembly aimed in the LC and a microdialysis probe (4 mm active membrane length) into the LC. Immobilization of animals significantly increased the concentration of NE in microdialysates from PFM to a maximum of 170.8 ± 12.8% of the baseline ten minutes after the onset of stressor. Concentration of NE in dialysates remained significantly elevated for the next 40 min. Infusion of αhCRF into the LC significantly attenuated stress-induced increase in PFM NE concentration in samples collected at 10, 20, 30, and 50 min after the onset of immobilization. Infusion of αhCRF alone (no immobilization) did not change concentrations at any time during sample collection. These results are consistent with other studies and suggest that stress can facilitate NE release in the PFM through the activation of the CRF system in the brain.