We have compared analgesic requirements, perceived pain, and self-assessment of 'health locus of control' for 72 h in 88 subjects after cholecystectomy, randomized to either a standard technique of self-administration of meperidine (patient-controlled analgesia, PCA) or to intramuscular injections on demand (i.m.). Multivariate analysis revealed no statistical differences between group scores for pain (over any 24 h period) and only minor differences in total meperidine administered. However, the PCA group received significantly less analgesic in the first 24 h (P less than 0.01) and described significantly more pain over the first 4 h (P less than 0.01). Assessment of 'health locus of control' did not show any marked changes. Analysis of patient questionnaires suggests more enthusiasm for patient-controlled analgesia, but in this study, it was difficult to clearly demonstrate any significant advantage for pain management or amount of opiate administered.
Patients with sickle cell disease (SCD) may develop kidney dysfunction from childhood. The purpose of this study was to examine the value of serum cystatin C as a marker for glomerular filtration rate (GFR) in children with SCD, as compared to serum creatinine and creatinine clearance (CrCl). Twenty children (ages 9-21, ten males) with SCD with and without albuminuria were studied. The mean serum cystatin for the whole group was 0.89 mg/l (0.5-1.7 mg/l). Mean serum cystatin C was significantly different among the children with proteinuria (n=4), microalbuminuria (n=5), and without albuminuria (n=11) (1.25 mg/l, 0.84 mg/l, and 0.78 mg/l, respectively). The mean GFR derived from serum cystatin was significantly different among these subgroups, becoming abnormal in the proteinuric cohort (63 ml/min per 1.73 m2), in contrast to 94 for the microalbuminuric, and 103 for the normal subgroups. Serum creatinine (mean: 0.58 mg/dl, range: 0.3-1.1) did not change significantly with the level of albuminuria. Mean CrCl remained normal to increased within the subgroups, (133 ml/min per 1.73 m2 for those with proteinuria, 144 for those with microalbuminuria, and 163 for the normal subgroup). We conclude that serum cystatin C correlates with the level of albuminuria and may be a reliable method to measure renal function in SCD.
Repository corticotrophin injection (RCI, H.P Acthar gel) has been approved for use in the management of multiple autoimmune and inflammatory diseases for more than a half-century, but its mechanism of action is not well understood. We used RNA-Seq methods to define RCI-regulated mRNAs in cultured human B cells under conditions of activation by interleukin (IL)-4 and CD40 ligand. Following IL-4/CD40L activation and RCI treatment we found up-regulation of 115 unique mRNA transcripts and down-regulation of 80 unique mRNAs. The effect on these RNA levels was dose-dependent for RCI and was distinct from changes in mRNA expression induced by treatment with a potent synthetic glucocorticoid. RCI down-regulated mRNAs were observed to include a significant over-representation of genes critical for B cell proliferation under activating conditions. These data confirm that RCI exerts direct effects on human B cells to modulate mRNA expression in specific pathways of importance to B cell function and that, at the molecular level, the effects of RCI are distinct from those exerted by glucocorticoids.
Background:Melanocortin receptor agonists, such as αMSH have been shown to reduce inflammation in preclinical models, suppressing the production of proinflammatory cytokines. Natural and synthetic ACTH analogues remain linked to the induction of corticosteroids as their primary mechanism of action, leading to the anti-inflammatory and immunosuppressive responses. Repository Corticotropin Injection (RCI) is a complex mixture containing purified porcine pituitary ACTH-analogue, and is an FDA-approved treatment for several inflammatory diseases. RCI has been shown to be effective in steroid-refractory autoimmune disease.Objectives:We hypothesize that Acthar has an immune regulatory response distinct from synthetic ACTH and steroids. These studies sought to explore the differences between RCI and synthetic ACTH on corticosterone levels in rats and cytokine production in a murine T cell activation model.Methods:RCI (10, 40, or 400 IU/kg) or ACTH (0.6, 1.2, or 2.4 mg/kg) was administered to Sprague Dawely rats, plasma samples collected and analyzed for corticosterone. To determine the effect on T cell cytokine production, Balb/C mice were treated with RCI (10, 40, and 400 U/kg), ACTH (0.6, 1.2, or 2.4 mg/kg) or prednisolone 1 hour prior to the administration of an anti-CD3. Two hours after antibody administration, plasma cytokines were measured using Meso Scale multiplex ELISA.Results:RCI and ACTH peak corticosterone and area under the curve (AUC) were evaluated. RCI-induced corticosterone rapidly peaked between 2 -8 hrs. and was dependent on the dose. ACTH displays a delay in the peak time (8-24 hours) and was not dose dependent. When compared to the high dose ACTH, RCI reduced the AUC by 50.0 ± 2.6%, 45.5 ± 5.6% and 27.3 ± 12.5% respectively for 10, 40, and 400 IU/kg. However, there was no significant reduction between any of the ACTH doses tested.To further explore functional differences between RCI and ACTH, we examined the effects on T cell activation. In vivo T cell activation with the anti-CD3 antibody (clone, 145-2C11) increased several cytokines, including IL-2, IL-6, IL-10, and IFNγ. Treatment with RCI, ACTH, or prednisolone significantly reduced the production of IL-2, IL-4, IFNγ, and TNFα. Interestingly, RCI showed an inverse dose-response on the production of IL-6 and IL-10. RCI inhibited the production of IL-6 at 74.7 ± 4.4% and 67.9 ± 8.5% and IL-10 at 39.1 ± 7.1% and 26.7 ± 9.3% for 10 and 40 IU/kg, respectively, whereas 400 IU/kg had no effect. ACTH inhibited the production of IL-6 at a similar level for all doses tested and had no effect on IL-10 production, whereas treatment with prednisolone inhibited all cytokines.Conclusion:These data show that RCI has a reduced steroidal response compare to synthetic ACTH. RCI has a direct and distinct immunomodulatory response on T cells unique from both synthetic ACTH and steroids. These characteristic effects suggest a mechanism of action for RCI that is steroid-independent and may help explain its benefit in steroid refractory syndromes.Disclosure of Interests...
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