N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin

Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both.     

Skin-to-skin contact (Kangaroo Care) analgesia for preterm infant heel stick

The purpose of the study was to compare a heel stick conducted during Kangaroo Care (skin-to-skin contact) with the mother to a heel stick in a warmer in reducing premature infant physiologic and behavioral pain responses. Twenty-four premature infants in a university-based neonatal intensive care unit were recruited and randomized to 2 sequences: sequence A group received 3 hours of Kangaroo Care (with a heel stick in Kangaroo Care) followed by 3 hours in a warmer (with a heel stick in the warmer). Sequence B group had warmer care and a heel stick (in the warmer) before Kangaroo Care and a heel stick (in Kangaroo Care). Heart rate, respiratory rate, oxygen saturation, crying time, and behavioral state were measured before, during, and after heel stick. Repeated measures ANOVA and Mann Whitney U statistics were performed. Heart rate and length of crying in response to pain were significantly reduced during Kangaroo Care and the Kangaroo Care heel stick as compared to when infants were in the warmer and had a heel stick in the warmer. Three infants did not cry at all during the Kangaroo Care heel stick; infants slept more during Kangaroo Care than in the warmer. Kangaroo Care positioning before and during heel stick is a simple and inexpensive analgesic intervention to ameliorate pain in stable premature infants.     

A randomized,double‐blind,placebo‐controlled,dose‐finding trial with Lolium perenne peptide immunotherapy

Background

A novel subcutaneous allergen immunotherapy formulation (gpASIT+?) containing Lolium perenne peptides (LPP) and having a short up‐dosing phase has been developed to treat grass pollen–induced seasonal allergic rhinoconjunctivitis. We investigated peptide immunotherapy containing the hydrolysate from perennial ryegrass allergens for the optimum dose in terms of clinical efficacy, immunogenicity and safety.

Methods

This prospective, double‐blind, placebo‐controlled, phase IIb, parallel, four‐arm, dose‐finding study randomized 198 grass pollen–allergic adults to receive placebo or cumulative doses of 70, 170 or 370 μg LPP. All patients received weekly subcutaneous injections, with the active treatment groups reaching assigned doses within 2, 3 and 4 weeks, respectively. Efficacy was assessed by comparing conjunctival provocation test (CPT) reactions at baseline, after 4 weeks and after completion. Grass pollen–specific immunoglobulins were analysed before and after treatment.

Results

Conjunctival provocation test (CPT) response thresholds improved from baseline to V7 by at least one concentration step in 51.2% (170 μg; P = .023), 46.3% (370 μg), and 38.6% (70 μg) of patients receiving LPP vs 25.6% of patients receiving placebo (modified per‐protocol set). Also, 39% of patients in the 170‐μg group became nonreactive to CPT vs 18% in the placebo group. Facilitated allergen‐binding assays revealed a highly significant (P < .001) dose‐dependent reduction in IgE allergen binding across all treatment groups (70 μg: 17.1%; 170 μg: 18.8%; 370 μg: 26.4%). Specific IgG₄ levels increased to 1.6‐fold (70 μg), 3.1‐fold (170 μg) and 3.9‐fold (370 μg) (mPP).

Conclusion

Three‐week immunotherapy with 170 μg LPP reduced CPT reactivity significantly and increased protective specific antibodies.

     

Lolium perenne peptide immunotherapy is well tolerated and elicits a protective B‐cell response in seasonal allergic rhinitis patients

Background

Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short‐course treatment with adjuvant‐free Lolium perenne peptides (LPP) following a 6‐week dose‐escalation protocol.

Methods

In a prospective, dose‐escalation study, 61 grass pollen–allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG₄ and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8).

Results

No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became nonreactive to CPT. sIgG₄ levels were higher at V6 (8.1‐fold, P < .001) and V8 (12.2‐fold, P < .001) than at V1. The sIgE:sIgG₄ ratio decreased at V6 (?54.6%, P < .001) and V8 (?71.6%, P < .001) compared to V1. The absolute decrease in IgE‐facilitated allergen binding was 18% (P < .001) at V6 and 25% (P < .001) at V8.

Conclusion

Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies.

     

Long-Term Safety of Short-Term Administration of Filgrastim (rhG-CSF) and Leukophresis Procedure in Healthy Children: Application of Peripheral Blood Stem Cell Collection in Pediatric Donors

Administration of filgrastim (recombinant human granulocyte colony-stimulating factor [rhG-CSF]) (Neupogen) in healthy donors to mobilize hematopoietic stem cells (HSCs) is a widespread practice in adults. Application of peripheral blood stem cell (PBSC) collection in normal pediatric donors is scarce due to ethical issues. Hence, there are insufficient data on the long-term impact of PBSC procedure in healthy children. This retrospective study aimed to evaluate the early and late adverse effects of PBSC donation in pediatric donors. Bone marrow and PBSC procedures and known adverse events of each technique were completely explained to parents and when applicable to children and written informed consent was obtained. rhG-CSF was administered for 4 days. HSCs were collected on the fifth day through continuous-flow apheresis and donors were followed for 30 days. Manual chart review was performed to collect short-term complications. Donors' health status was assessed via a questionnaire. A total of 145 healthy pediatric donors with a median age of 10 years at the time of donation (2 to 15 years) were followed for a median of 4.8 years (range, 1.2 to 14.2 years). The most frequent symptoms of rhG-CSF administration were fatigue (5%) and headache (3%). Thirty-five (24%) donors experienced hypocalcaemia during apheresis procedure that quickly responded to treatment. Two pregnancies occurred after rhG-CSF administration that resulted in normal births. We did not encounter any serious adverse events, including neoplastic disorders and death in this study. rhG-CSF and leukophresis procedure were well-tolerated in this study and all children completed the donation process without interruption or reduction of rhG-CSF dosage. Our results suggest that rhG-CSF is a safe drug in healthy children for the purpose of HSC mobilization.     

Altered Integration of Structural Covariance Networks in Young Children With Type 1 Diabetes

Type 1 diabetes mellitus (T1D), one of the most frequent chronic diseases in children, is associated with glucose dysregulation that contributes to an increased risk for neurocognitive deficits. While there is a bulk of evidence regarding neurocognitive deficits in adults with T1D, little is known about how early‐onset T1D affects neural networks in young children. Recent data demonstrated widespread alterations in regional gray matter and white matter associated with T1D in young children. These widespread neuroanatomical changes might impact the organization of large‐scale brain networks. In the present study, we applied graph‐theoretical analysis to test whether the organization of structural covariance networks in the brain for a cohort of young children with T1D (N = 141) is altered compared to healthy controls (HC; N = 69). While the networks in both groups followed a small world organization—an architecture that is simultaneously highly segregated and integrated—the T1D network showed significantly longer path length compared with HC, suggesting reduced global integration of brain networks in young children with T1D. In addition, network robustness analysis revealed that the T1D network model showed more vulnerability to neural insult compared with HC. These results suggest that early‐onset T1D negatively impacts the global organization of structural covariance networks and influences the trajectory of brain development in childhood. This is the first study to examine structural covariance networks in young children with T1D. Improving glycemic control for young children with T1D might help prevent alterations in brain networks in this population. Hum Brain Mapp 37:4034–4046, 2016. © 2016 Wiley Periodicals, Inc .