Effects of reserpine treatment on dietary adaptation of the rat exocrine pancreas

Chronic reserpine treatment (500 micrograms/kg) of the rat results in generalized exocrinopathy, impaired pancreatic secretion, and decreased pancreatic amylase. These characteristics are similar to those in cystic fibrosis and are the basis for use of this experimental model for cystic fibrosis. Pancreatic enzymes adapt to diet, but it is not known whether chronic reserpine treatment affects this response. Due to the malnutrition induced by this treatment, another dose of reserpine was required that would alter pancreatic function but not induce malnutrition in order to evaluate dietary adaptation. Male rats (100-120 g) were injected subcutaneously daily for 7 days with 1) no injection (control); 2) 1.0 ml/kg vehicle or sham (pair fed-sham); or 3) reserpine: 500, 50, or 5 micrograms/kg. Food consumption was comparable among control and reserpine-treated (50 and 5 micrograms/kg) rats and significantly greater (200%) than pair fed-sham and 500 micrograms/kg reserpine-treated rats. Pancreatic amylase, however, was significantly lower in all reserpine-treated rats (500 micrograms/kg, 74%; 50 micrograms/kg, 56%; 5 micrograms/kg, 52%) than in control rats. To evaluate dietary adaptation, control and reserpine-treated (5 micrograms/kg) rats were fed high carbohydrate, high fat or high protein diets. Both groups adapted to these diets with the greatest amylase, lipase, and trypsin activities in high carbohydrate-, high fat-, and high protein-fed rats, respectively. Reserpine-treated rats fed high carbohydrate, however, had significantly lower (64%) amylase activity than high carbohydrate-fed control rats. Although reserpine-treated rats can adapt pancreatic enzymes to diet, the adaptation of amylase to carbohydrate is impaired.     

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

The interleukin (IL)-17/IL-23 axis is an important pro-inflammatory pathway in rheumatoid arthritis (RA). IL-23 maintains CD4(+) T-helper 17 (Th(17)) cells, whereas IL-12 negates IL-17A production by promoting Th(1)-cell differentiation. We sought evidence for any effect of polymorphisms within the interleukin-23 receptor (IL-23R), IL-12 or IL-21 genes on serum cytokine concentrations in 81 patients with RA. Serum cytokines were measured using bead-based multiplex assays. Targeted cytokines were detected in up to 66% of samples. A subgroup of 48 patients had detectable serum IL-17A. Within this subgroup, patients, homozygous for the IL-23R rs11209026 major allele had significantly higher serum IL-17A concentrations compared with patients with the minor allele (394.51 ± 529.72 pg ml(-1) vs 176.11 ± 277.32 pg ml(-1); P = 0.017). There was no significant difference in any of the cytokine concentrations examined in patients positive for the minor allele vs homozygosity for the major allele of IL-12B rs3213337, IL-12Bpro rs17860508 and IL-21 rs6822844. Our results suggest the IL-23R Arg381Gln substitution may influence serum IL-17A concentrations. In patients with the 381Gln allele higher IL-23 concentrations may be needed to produce similar IL-17A concentrations to those in patients with the 381Arg allele. This suggests altered IL-23R function in patients with the minor allele and warrants further functional studies.     

Quantile regression for the statistical analysis of immunological data with many non-detects

Background

Hemolytic uremic syndrome (HUS) leading to acute kidney failure, is a condition linked to the production of primarily Shiga toxin 2 (Stx2) by some E. coli serotypes. We have previously shown that Stx2 A subunit-specific human monoclonal antibody (HuMAb) 5C12, and B subunit-specific HuMAb 5H8 inhibit cultured cell death, and protect mice and piglets from fatal Stx2-intoxication. We have also shown that 5H8 blocks binding of Stx2 to its cell-surface receptor globotriaosyl ceramide (Gb₃), whereas Stx2 when complexed with 5C12 binds Gb₃ with higher affinity than Stx2. The mechanism by which 5C12 neutralizes Stx2 in vitro involves trapping of Stx2 in the recycling endosomes and releasing it into the extracellular environment. Because of the clinical implications associated with the formation of Stx2/antibody complexes and the potential for trapping and clearance through a severely damaged kidney associated with HUS, we investigated the likely site(s) of Stx2/antibody localization and clearance in intoxicated mice treated with antibody or placebo.

Results

Mice were injected with radiolabeled Stx2 (¹²⁵I-Stx2) 4 hours after administration of 5C12, 5H8, or phosphate buffered saline (PBS) and the sites of localization of labeled Stx2, were investigated 3, 24 and 48 hours later. The liver recorded statistically much higher concentrations of labeled Stx2 for groups receiving 5C12 and 5H8 antibodies after 3, 24 and 48?hours, as compared with the PBS group. In contrast, highest levels of labeled Stx2 were detected in the kidneys of the PBS group at all 3 sampling times. Mice receiving either of the two HuMAbs were fully protected against the lethal effect of Stx2, as compared with the fatal outcome of the control group.

Conclusions

The results suggest that HuMAbs 5C12 and 5H8 promoted hepatic accumulation and presumably clearance of toxin/antibody complexes, significantly diverting Stx2 localization in the kidneys, the target of Stx2 and the cause of HUS. This is in contrast to the fatal outcome of the control group receiving PBS. The results also confirm earlier observations that both HuMAbs are highly and equally protective against Stx2 intoxication in mice.     

Anterior cingulate volume reduction in adolescents with borderline personality disorder and co-morbid major depression

Borderline Personality Disorder (BPD) is a serious illness characterized by emotional dysregulation, impulsivity, and impaired interpersonal relationships. Prior work shows the anterior cingulate gyrus (ACG)—a region primarily involved in assessing the salience of emotional information and regulating emotional responses--is smaller in adults with BPD. We tested the hypothesis that, similar to adults, adolescents with BPD would have reduced Brodmann area (BA)-24 volume. Thirteen adolescent inpatients with co-morbid BPD and Major Depressive Disorder (MDD) and 13 matched healthy controls received 3T-MRI scans. Using a cytoarchitecturally-derived approach measuring gray and white matter volume, we observed a Group × Cingulate BA (25,24,31,23,29) × Matter (gray, white) type interaction indicating the BPD/MDD adolescents had smaller BA24 volume in gray but not white matter. Greater number of suicide attempts and BPD symptom severity measured by the Diagnostic Interview for BPD-revised (DIB-R) total score but not depressive symptoms measured by the Beck Depression Inventory (BDI) was associated with smaller BA24 volume. Our preliminary findings suggest that BPD-related abnormalities in BA24 volume may occur early in the developmental course of BPD with MDD. Future studies examining samples of MDD patients with and without BPD co-morbidity will be needed to clarify whether BA24 volume reductions are specific to BPD.     

Reduced relationship to cortical white matter volume revealed by tractography-based segmentation of the corpus callosum in young children with developmental delay

OBJECTIVE: The corpus callosum is the primary anatomical substrate for interhemispheric communication, which is important for a range of adaptive and cognitive behaviors in early development. Previous studies that have measured the corpus callosum in developmental populations have been limited by the use of rather arbitrary methods of subdividing the corpus callosum. The purpose of this study was to measure the corpus callosum in a clinical group of developmentally delayed children using a subdivision that more accurately reflected the anatomical properties of the corpus callosum. METHOD: The authors applied tractography to subdivide the corpus callosum into regions corresponding to the cortical regions to and from which its fibers travel in a clinical group of very young children with developmental delay, a precursor to general mental retardation, in comparison with typically developing children. RESULTS: The data demonstrate that the midsagittal area of the entire corpus callosum is reduced in children presenting with developmental delay, reflected in the smaller area of each of the fiber-based callosal subdivisions. In addition, while the area of each subdivision was strongly and significantly correlated with the corresponding cortical white matter volume in comparison subjects, this correlation was prominently absent in the developmentally delayed group. CONCLUSIONS: A fiber-based subdivision successfully separates lobar regions of the corpus callosum, and the areas of these regions distinguish a developmentally delayed clinical group from the comparison group. This distinction was evident both in the area measurements themselves and in their correlation to the white matter volumes of the corresponding cortical lobes.     

The role of apolipoprotein AI domains in lipid binding

Apolipoprotein AI (apoAI) is the principal protein constituent of high density lipoproteins and it plays a key role in human cholesterol homeostasis; however, the structure of apoAI is not clearly understood. To test the hypothesis that apoAI is organized into domains, three deletion mutants of human apoAI expressed in Escherichia coli were studied in solution and in reconstituted high density lipoprotein particles. Each mutant lacked one of three specific regions that together encompass almost the entire 243 aa sequence of native apoAI (apoAI Δ44-126, apoAI Δ139-170, and apoAI Δ190-243). Circular dichroism spectroscopy showed that the α-helical content of lipid-free apoAI Δ44-126 was 27% while the other mutants and native apoAI averaged 55 ± 2%, suggesting that the missing N-terminal portion contains most of the α-helical structure of lipid-free apoAI. ApoAI Δ44-126 exhibited the largest increase in α-helix upon lipid binding (125% increase versus an average of 25% for the others), confirming the importance of the C-terminal half of apoAI in lipid binding. Denaturation studies showed that the N-terminal half of apoAI is primarily responsible for α-helix stability in the lipid-free state, whereas the C terminus is required for α-helix stability when lipid-bound. We conclude that the N-terminal half (aa 44–126) of apoAI is responsible for most of the α-helical structure and the marginal stability of lipid-free apoAI while the C terminus (aa 139–243) is less organized. The increase in α-helical content observed when native apoAI binds lipid results from the formation of α-helix primarily in the C-terminal half of the molecule.     

Low-dose ibuprofen in self-medication of mild to moderate headache: a comparison with acetylsalicylic acid and placebo

A double-blind, threefold crossover, double-dummy trial was performed, investigating the efficacy of 200 mg ibuprofen compared with 500 mg acetylsalicylic acid and placebo in patients who usually treated their headaches with over-the-counter drugs. Ninety-five patients suffering from mild to moderate migraine or episodic tension-type headache were included. Seventy-seven patients entered the intention-to-treat analysis and 65 completed all three treatments. For the main response criterion, a minimum 50% decrease of headache intensity on a visual analogue scale at I h after treatment, ibuprofen was significantly superior to acetylsalicylic acid and placebo. This was true for migraine attacks and tension-type headache episodes. Towards the end of the observation period (150 min), the differences between ibuprofen and acetylsalicylic acid were no longer significant. In conclusion, ibuprofen was at least equivalent to acetylsalicylic acid and superior to placebo.     

Clonal dysregulation of the antibody response to tetanus-toxoid after bone marrow transplantation

After bone marrow transplantation (BMT), a prolonged dysregulation of humoral immunity can be observed. In the present study, we investigated whether this is reflected in an abnormal production of specific antibodies (Ab) to the T-cell-dependent recall antigen tetanus-toxoid (TT). The study group consisted of children receiving transplants of an unmodified allogeneic graft and of adults receiving either a T-cell- depleted allogeneic or an unmodified autologous BM graft. Findings were compared with those in healthy controls. In pediatric graft recipients, who were routinely revaccinated early after BMT, the Ab response was quantitatively superior to that in adult graft recipients who did not receive early revaccination. In the majority of graft recipients, the time period after vaccination required to reach the peak level of antibodies was prolonged and the number of responding TT-specific B- cell clones was markedly decreased in comparison with controls. In controls, a low frequency of dominant B-cell clones may produce low quantities of homogeneous Ab components (H-Ab) against a heterogeneous background. However, in BM graft recipients, "overshooting" of Ab production by separate B-cell clones was observed, resulting in the development of H-Ab at a relatively high concentration. These abnormalities were present up to 10 years after BMT, irrespective of either the age of the recipient, the modulation of the graft, or the vaccination schedule used. It is hypothesized that the dysregulated Ab production is the consequence of activation of a restricted number of resting memory B cells, present in germinal centers, repopulating gradually after BMT. Our data show that routine revaccination early after BMT improves the humoral immune response. However, because of a clonally dysregulated Ab production, long-lasting qualitative defects may be present even after normalization of Ab titers.