Growth in juvenile idiopathic arthritis: the role of inflammation

Growth disorders are common among patients with juvenile idiopathic arthritis (JIA). These disorders range from general growth retardation to local acceleration of growth in the affected limb, and are associated with an increased production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Pro-inflammatory cytokines may act individually or in combination to impair child growth through systemic mechanisms and/or a local action. Whereas IL-6 affects growth mainly via systemic mechanisms altering growth hormone secretion, IL-1β and TNF-α can directly affect growth plate chondrocyte dynamics as well as longitudinal bone growth. There are emerging data suggesting that interleukin-15 and interleukin-5 may be new cytokines implicated in inflammatory diseases, but further well-designed longitudinal studies in larger groups of children are required to establish a causal relationship. Other factors, which might contribute to growth suppression associated with childhood arthritis, include the degree, extent, and duration of disease activity, age at onset, immobility, sub-optimal nutrition and corticosteroid therapy.     

Microbiology at first visit of moderate-to-severe diabetic foot infection with antimicrobial activity and a survey of quinolone monotherapy

Samples from 1295 patients with diabetic foot infection were evaluated; 4332 samples were collected with an average of 3.3 samples per patient. Fifty-seven percent of patients had a 2B ulcer and 23% had a 3B ulcer according to Texas University Classification. In 64.2% of samples collected at first visit an etiologic agent was identified. About 40% of the positive samples were polymicrobial. Gram positive bacteria were more frequently isolated (52.6%), Staphylococcus aureus was the most frequently isolated single agent (29.9%) and MRSA was 22% of S. aureus. Enterococcus spp., mainly Enterococcus faecalis, were 9.9%, all vancomycin susceptible except 2 isolates. Streptococci were 4.6%, more than 60% Streptococcus agalactiae. Gram negative rods were 40.6%, with enterobacteria 23.5% and Pseudomonas aeruginosa 10.3%. Anaerobes were only 0.3%, probably due to culture methods applied in our laboratory. Cotrimoxazole, rifampin and doxycycline were still active against S. aureus. ESBL producers, among enterobacteria, were 10%, mainly Escherichia coli and Proteus spp. Only colistin had a rate of susceptibility against P. aeruginosa above 90%. Levofloxacin had the best clinical activity with respect to the other quinolones, but when it failed, selected more resistant strains with respect to moxifloxacin among S. aureus and with respect to ciprofloxacin among P. aeruginosa.     

Reduced production of anti-inflammatory soluble HLA-G molecules in styrene exposed workers

HLA-G antigens are non-classical HLA-class I anti-inflammatory molecules. Since styrene exposure has been suggested to induce immune alteration, we analyzed plasma levels and "in vitro" peripheral blood mononuclear cell (PBMC) production of soluble HLA-G (sHLA-G) and interleukin-10 (IL-10) molecules after lipopolysaccharide (LPS) stimulation, in styrene exposed workers and healthy subjects. Exposed workers showed reduced plasma levels of sHLA-G and IL-10 in comparison to healthy controls. Similarly, lower levels of sHLA-G and IL-10 molecules were observed in PBMC culture supernatants after LPS activation. These data propose styrene exposure as a mediator of impaired sHLA-G production.     

Higher expression of BDNF receptor gp145trkB is associated with lower apoptosis intensity in T cell lines in multiple sclerosis

Conflicting data exist on expression of gp145trkB, the high affinity receptor for brain-derived neurotrophic factor (BDNF), on peripheral blood immunocompetent cells in multiple sclerosis (MS). We analyzed expression of gp145trkB by western blotting and flow cytometry in myelin basic protein (MBP)- and ovalbumin (OVA)-T cell lines prepared from 12 patients with relapsing-remitting MS and 12 normal healthy subjects (NHS) and correlated it with activation-induced apoptosis. We found a higher percentage of gp145trkB-expressing MBP-T cells in MS patients than in NHS (p=0.011). gp145trkB was mainly expressed by CD8(+) T cells to a higher extent in MS patients than in NHS (p=0.04). MBP-T cell lines from MS patients showed significantly lower apoptosis intensity than those from NHS (p=0.011). We found also a significant negative correlation between gp145trkB expression and apoptosis intensity in MS patients only (p=0.02). OVA-T cell lines showed a gp145trkB expression similar to that of MBP-T cell lines, with a higher expression in MS patients than NHS, and similar correlations with apoptosis intensity in MS. These findings suggest that gp145trkB is mainly expressed on T cell lines from MS patients and that the BDNF/gp145trkB axis is involved in the regulation of peripheral T cell apoptosis in MS.     

Role of Beta-Adrenergic Receptor Gene Polymorphisms in the Long-Term Effects of Beta-Blockade with Carvedilol in Patients with Chronic Heart Failure

Background

Beta-blockers are mainstay of current treatment of heart failure (HF). Beta-adrenergic receptors (AR) single nucleotide gene polymorphisms (SNPs) may influence the sensitivity and density of beta-AR. We assessed the relation between three common beta-AR SNPs and the response to carvedilol administration.

Methods and Results

We studied 183 consecutive patients with chronic HF due to ischemic or nonischemic cardiomyopathy, a LV ejection fraction (LVEF)?≤?0.35, not previously treated with beta-blockers. Each patient underwent gated-SPECT radionuclide ventriculography, cardiopulmonary exercise testing and invasive hemodynamic monitoring at baseline and after 12 months of carvedilol administration at maintenance dosages. The beta1-AR gene Arg389Gly and the beta2-AR gene Arg16Gly SNPs were not related to the response to carvedilol administration. Homozygotes for the Glu27Glu allele showed a greater increase in the LVEF, compared to the other patients (+13.0?±?12.2% versus +7.1?±?8.1% in the Gln27Gln homozygotes, and 8.3?±?11.4% units in the Gln27Glu heterozygotes; p?=?0.022 by ANOVA). Glu27Glu homozygotes also showed a greater decline in the pulmonary wedge pressure both at rest and at peak exercise. Gln27Glu SNP was selected amongst the determinants of the LVEF response to carvedilol at multivariable analysis, in addition to the cause of cardiomyopathy, baseline systolic blood pressure and the dose of carvedilol administered.

Conclusion

Beta1-AR Arg389Gly and beta2-AR Arg16Gly SNPs are not related to the response to carvedilol therapy. In contrast, the Gln27Glu SNP is a determinant of the LVEF response to this agent in patients with chronic HF.     

Lack of Association between Dialysis Modality and Outcomes in Atheroembolic Renal Disease

Background and objectives: Atheroembolic renal disease (AERD) can require dialytic support. Because anticoagulation may trigger atheroembolization, peritoneal dialysis may be preferred to hemodialysis. However, the effect of dialysis modality on renal and patient outcomes in AERD is unknown.Design, settings, participants, & measurements: A subcohort of 111 subjects who developed acute/subacute renal failure requiring dialysis was identified from a larger longitudinal study of AERD. The main exposure of interest was dialysis modality (peritoneal versus extracorporeal therapies). Logistic regression was used to study the probability of renal function recovery. Times from dialysis initiation to death were studied using Cox''s regression.Results: Eighty-six patients received hemodialysis and 25 received peritoneal dialysis. The probability of renal function recovery was similar by dialysis modality (25% among hemodialysis patients and 24% among peritoneal dialysis patients; P = 0.873). During follow-up, 58 patients died, 14 among peritoneal patients and 44 among hemodialysis patients (P = 0.705). In multivariable analysis, gastrointestinal tract involvement and use of statins maintained an independent effect on the risk of patient death.Conclusions: This study does not support the notion that one dialysis modality is superior to the other. However, the observational nature of the data precludes any firm conclusions.Atheroembolic renal disease (AERD) is due to the occlusion of small renal arteries and glomerular capillaries by cholesterol crystals derived from atherosclerotic aortic plaques (1). The severity of renal dysfunction depends on the amount and frequency of embolic showers and inflammatory reactions. Although chronic “spontaneous” AERD may represent an underdiagnosed, slowly progressive cause of ESRD mimicking nephrosclerosis, in patients developing acute or subacute renal failure AERD is usually “iatrogenic” and dialysis may be required in 25% to 60% of the patients. In one third of these patients renal function may recover. Recovery may be related to reversal of inflammation, resolution of acute tubular necrosis in ischemic areas, hypertrophy in surviving nephrons, and reduction in intensity of embolic showers (2–6).Invasive aortic manipulation, including angiography and vascular surgery, is the leading cause of AERD. However, the disease may be rarely precipitated by anticoagulation; by preventing the formation of a protective thrombus overlying the ulcerated plaques; or even disrupting the fibrin cap of atherosclerotic plaques and exposing their soft, cholesterol-laden core to the arterial circulation (1–3,7–12). The requirement for systemic anticoagulation makes extracorporeal dialysis treatments less attractive for patients with AERD who need dialysis. Although systemic anticoagulation can be avoided or at least minimized initially, this can be more difficult in the long run. On the other hand, peritoneal dialysis may not be available in all facilities to treat acute kidney injury and can be contraindicated in patients with AERD for gut ischemia or protein losses.Current data on benefits and harms of extracorporeal and peritoneal dialysis therapies are scant and come from small cohorts or case series (2,3,13–16). Although evidence from clinical trials of interventions is ideally necessary to inform practice, for rare disorders cohort studies may provide relevant information. In this study, we sought to determine whether peritoneal dialysis is superior to extracorporeal therapies in terms of renal and patient outcomes of acute/subacute AERD using data from a large longitudinal study (12).     

First visualization of cholinergic cells and fibers by immunohistochemistry for choline acetyltransferase of the common type in the optic lobe and peduncle complex of Octopus vulgaris

This study provides the first immunohistochemical evidence visualizing cholinergic octopus neurons containing choline acetyltransferase (ChAT), the synthetic enzyme of acetylcholine. Because the antiserum applied here was raised against a recombinant protein encoded by exons 7 and 8 of the rat gene for ChAT, and initially used for studies in mammals, to validate antibody specificity for the octopus counterpart enzyme we therefore used three methods. Immunoprecipitation using Pansorbin indicated that immunoreactive octopus brain molecules were capable of synthesizing acetylcholine. Western blot analysis after denatured gel electrophoresis of octopus brain extracts revealed a single band at approximately 81 kDa. A gel slice containing the 81-kDa protein after native (nondenatured) gel electrophoresis exhibited high ChAT activity. All findings obtained with these three methods clearly indicated that the antiserum effectively recognizes octopus ChAT. The immunohistochemical use of the antiserum in the retina, optic lobe, and its neighboring peduncle complex detected enzyme-containing neuronal cell bodies in only two regions, the cell islands of the optic lobe medulla and the cortical layer of the posterior olfactory lobule. Immunoreactive fibers and probable nerve terminals were also found in the plexiform layer of the deep retina, within the stroma of the optic gland, and the neuropils of the optic lobe, peduncle lobe, and olfactory lobe. These results provide information on the morphology and distribution patterns of cholinergic neurons in the octopus visual system, a useful invertebrate model for learning and memory where the cholinergic system, as in higher vertebrates including mammals, plays an important role.     

Azithromycin in an older woman with diabetic gastroparesis

Diabetic neuropathy is a common chronic complication of diabetes and cause of significant morbidity and mortality, because it may involve the autonomous and peripheral nervous systems. Autonomic diabetic neuropathy is a challenging chronic complication of long-standing diabetes manifested with hypotension, syncope, gastroparesis, diarrhea, constipation, bladder dysfunction, sexual dysfunction, cardiac arrest, and/or sudden death. We present a case of diabetic gastroparesis in an older woman. The patient was an 83-year-old woman with a 40-year history of type 2 diabetes who was admitted with hypoglycemia, malnutrition, persistent vomiting, and obstinate constipation. After several unsuccessful attempts with different therapies, we administered intravenous azithromycin (500 mg/day). After 3 days of treatment, vomiting was resolved and the patient evacuated normal feces, with notable improvement in the general conditions and metabolic control. Because diabetic gastroparesis frequently is difficult to manage clinically and there are few beneficial therapeutic choices available at present, the macrolide antibiotic azithromycin, which has strong prokinetic properties, may be a useful option in the treatment of this complex condition.     

RAGE and modulation of ischemic injury in the diabetic myocardium

OBJECTIVE—Subjects with diabetes experience an increased risk of myocardial infarction and cardiac failure compared with nondiabetic age-matched individuals. The receptor for advanced glycation end products (RAGE) is upregulated in diabetic tissues. In this study, we tested the hypothesis that RAGE affected ischemia/reperfusion (I/R) injury in the diabetic myocardium. In diabetic rat hearts, expression of RAGE and its ligands was enhanced and localized particularly to both endothelial cells and mononuclear phagocytes.RESEARCH DESIGN AND METHODS—To specifically dissect the impact of RAGE, homozygous RAGE-null mice and transgenic (Tg) mice expressing cytoplasmic domain-deleted RAGE (DN RAGE), in which RAGE-dependent signal transduction was deficient in endothelial cells or mononuclear phagocytes, were rendered diabetic with streptozotocin. Isolated perfused hearts were subjected to I/R.RESULTS—Diabetic RAGE-null mice were significantly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH and lower glycoxidation products carboxymethyl-lysine (CML) and pentosidine, improved functional recovery, and increased ATP. In diabetic Tg mice expressing DN RAGE in endothelial cells or mononuclear phagocytes, markers of ischemic injury and CML were significantly reduced, and levels of ATP were increased in heart tissue compared with littermate diabetic controls. Furthermore, key markers of apoptosis, caspase-3 activity and cytochrome c release, were reduced in the hearts of diabetic RAGE-modified mice compared with wild-type diabetic littermates in I/R.CONCLUSIONS—These findings demonstrate novel and key roles for RAGE in I/R injury in the diabetic heart.Cardiac complications remain a leading cause of morbidity and mortality in subjects with diabetes (1–3). Although many factors contribute to depressed cardiac function in diabetes, innate disturbances within the diabetic heart contribute importantly to progressive dysfunction, which often leads to irreversible failure and death (3). Alterations in substrate metabolism and increased levels of oxygen free radicals have been observed in diabetic tissues. Inflammatory cytokines may exert direct negative inotropic effects on cardiac myocytes and contribute to aberrant remodeling in the failed heart (4–8). The pathophysiology of diabetes-associated cardiac complications is complex and involves a host of factors linked to metabolic and immune/inflammatory cell activation.The accumulation of late-stage glycoxidation adducts of proteins, termed advanced glycation end products (AGEs), occurs in diabetic tissues. AGEs modify long-lived molecules in the blood vessel wall and structural tissues of the heart considerably earlier than symptomatic cardiac dysfunction occurs (9). A major way in which AGEs exert their cellular effects is by ligation of the multiligand receptor for AGE (RAGE) (10–13).We tested the role of RAGE in rodent models of type 1 diabetes, and we show that pharmacological blockade of ligand-RAGE interaction or genetic modulation of RAGE suppresses ischemia/reperfusion (I/R) injury in the isolated perfused heart, at least in part secondary to critical contributions evoked from RAGE-expressing endothelial cells and mononuclear phagocytes in the diabetic heart.