Myelostimulatory activity of recombinant human interleukin-2 in mice

In a series of studies designed to extend our understanding of interleukin-2 (IL-2) and to study the effect of biologic response modifiers on bone marrow, we observed that administering recombinant human (rH) IL-2 to normal mice resulted in an increase in the frequency of colony-forming units-culture (CFU-C) in bone marrow. In addition, rH IL-2 was able to accelerate host recovery from cyclophosphamide (CTX)- or radiation-induced bone marrow depression and peripheral blood leukopenia. Not only can rH IL-2 accelerate, in a dose-dependent manner, the return of bone marrow, peripheral blood cellularity, and CFU-C frequency to normal levels following cytoreduction by CTX or irradiation, but it also significantly increases CFU-C frequency to greater than normal levels. Furthermore, rH IL-2 can significantly prolong survival of animals receiving a lethal dose of irradiation or CTX. Thus, multiple mechanisms are responsible for the synergistic therapeutic activity associated with rH IL-2 and CTX. rH IL-2 does not act only as an immunomodulatory agent in the presence or absence of suppressor T cells, but also accelerates host recovery from cytoreductive agents, resulting in decreased leukopenia and perhaps resistances to secondary infection. Thus, rH IL-2 plus chemotherapy may increase therapeutic activity against neoplastic disease, not only by adding immune stimulation to the direct antitumor effect of the drug but also by allowing delivery of higher, more effective doses of chemotherapy.     

Comparison of sotalol versus amiodarone in maintaining stability of sinus rhythm in patients with atrial fibrillation (Sotalol-Amiodarone Fibrillation Efficacy Trial [Safe-T])

The Sotalol-Amiodarone Fibrillation Efficacy Trial (SAFE-T) is a randomized, double-blind, multicenter, placebo-controlled trial in which the effects of sotalol and amiodarone in maintaining stability of sinus rhythm are being examined in patients with persistent atrial fibrillation at 20 Veterans Affairs medical centers. The time to the occurrence of atrial fibrillation or flutter in patients with atrial fibrillation converted to sinus rhythm is the primary outcome measure, with a number of parameters as secondary end points. SAFE-T had randomized 665 patients when enrollment terminated on October 31, 2001. Follow-up of patients continued until October 31, 2002, for a maximum period of 54 months and a minimum period of 12 months for all patients.     

Specific hormonal and neurochemical responses to different stressors

The neuroendocrine and neurochemical responses of rats to 5 min of cold exposure versus 5 min of forced immobilization were determined and compared. We found that plasma hormones and brain neurochemical systems responded differently to the two different stressors. Plasma prolactin levels were elevated over 10-fold in the immolilized group, while rising only 2-fold in the cold stress group. Levels of corticosterone were significantly increased and growth hormone levels were decreased in both stressed groups as compared to controls. Levels of cyclic GMP were markedly elevated in 11 brain regions following cold exposure. Surprisingly, no elevation of cyclic GMP was found after forced immobilization. Cyclic AMP, norepinephrine, and dopamine levels throughout the 17 regions of brain examined showed no significant response to 5 min of either stressor. Lesions of the ventral medial tegmental area did not affect the cyclic GMP or neuroendocrine responses to cold stress. Lesion of the nucleus locus ceruleus did not affect the cyclic GMP response but significantly reduced growth hormone levels in the cold-stressed rats.     

A Basomedial Amygdala to Intercalated Cells Microcircuit Expressing PACAP and Its Receptor PAC1 Regulates Contextual Fear

Trauma can cause dysfunctional fear regulation leading some people to develop disorders, such as post-traumatic stress disorder (PTSD). The amygdala regulates fear, whereas PACAP (pituitary adenylate activating peptide) and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs) in adult mice. In vivo optogenetic stimulation of this pathway increased CFOS expression in mICCs, decreased fear recall, and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICC PACAPergic pathway produced EPSCs in mICC neurons, which were enhanced by the PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via a microcircuit containing the BMA and mICCs, and in a manner that was dependent on behavioral state.SIGNIFICANCE STATEMENT Traumatic stress can affect different aspects of fear behaviors, including fear learning, generalization of learned fear to novel contexts, how the fear of the original context is recalled, and how fear is reduced over time. While the amygdala has been studied for its role in regulation of different aspects of fear, the molecular circuitry of this structure is quite complex. In addition, aspects of fear can be modulated differently in males and females. Our findings show that a specific circuitry containing the neuropeptide PACAP and its receptor, PAC1, regulates various aspects of fear, including acquisition, generalization, recall, and extinction in a sexually dimorphic manner, characterizing a novel pathway that modulates traumatic fear.     

Childhood Apraxia of Speech (CAS) in two patients with 16p11.2 microdeletion syndrome

We report clinical findings that extend the phenotype of the ∼550 kb 16p11.2 microdeletion syndrome to include a rare, severe, and persistent pediatric speech sound disorder termed Childhood Apraxia of Speech (CAS). CAS is the speech disorder identified in a multigenerational pedigree (‘KE'') in which half of the members have a mutation in FOXP2 that co-segregates with CAS, oromotor apraxia, and low scores on a nonword repetition task. Each of the two patients in the current report completed a 2-h assessment protocol that provided information on their cognitive, language, speech, oral mechanism, motor, and developmental histories and performance. Their histories and standard scores on perceptual and acoustic speech tasks met clinical and research criteria for CAS. Array comparative genomic hybridization analyses identified deletions at chromosome 16p11.2 in each patient. These are the first reported cases with well-characterized CAS in the 16p11.2 syndrome literature and the first report of this microdeletion in CAS genetics research. We discuss implications of findings for issues in both literatures.     

Human mesenchymal stromal cells modulate T‐cell responses through TNF‐α‐mediated activation of NF‐κB

Although mesenchymal stromal cells (MSCs) possess the capacity to modulate immune responses, little is known about the mechanisms that underpin these processes. In this study, we show that immunosupression is mediated by activation of nuclear factor kappa B (NF‐κB) in human MSCs. This pathway is activated by TNF‐α that is generated following TCR stimulation of T cells. Inhibition of NF‐κB through silencing of IκB kinase β or the TNF‐α receptor abolishes the immunosuppressive capacity of MSCs. Our data also indicate that MSC‐associated NF‐κB activation primarily leads to inhibition of T‐cell proliferation with little effect on expression of the activation markers CD69 and CD25. Thus, our data support the hypothesis that the TNF‐α/NF‐κB signalling pathway is required for the initial priming of immunosuppressive function in human MSCs. Interestingly, drugs that interfere with NF‐κB activation significantly antagonise the immunoregulatory effect of MSCs, which could have important implications for immunosuppression regimens in the clinic.     

Nutritional Status of Young Children with Inherited Blood Disorders in Western Kenya

To determine the association between a range of inherited blood disorders and indicators of poor nutrition, we analyzed data from a population-based, cross-sectional survey of 882 children 6–35 months of age in western Kenya. Of children with valid measurements, 71.7% were anemic (hemoglobin < 11 g/dL), 19.1% had ferritin levels < 12 μg/L, and 30.9% had retinol binding protein (RBP) levels < 0.7 μmol/L. Unadjusted analyses showed that compared with normal children, homozygous α⁺-thalassemia individuals had a higher prevalence of anemia (82.3% versus 66.8%, P = 0.001), but a lower prevalence of low RBP (20.5% versus 31.4%, P = 0.024). In multivariable analysis, homozygous α⁺-thalassemia remained associated with anemia (adjusted odds ratio [aOR] = 1.8, P = 0.004) but not with low RBP (aOR = 0.6, P = 0.065). Among young Kenyan children, α⁺-thalassemia is associated with anemia, whereas G6PD deficiency, haptoglobin 2-2, and HbS are not; none of these blood disorders are associated with iron deficiency, vitamin A deficiency, or poor growth.