Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1ß During Dectin-1 Signaling.

Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1ß production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1ß expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP.

Adverse allergic reactions to linear ionic gadolinium-based contrast agents: experience with 194, 400 injections.

AIM: To report the authors' experience with the administration of four gadolinium-based contrast agents (GBCA; gadopentetate dimeglumine, gadofosveset trisodium, gadoxetate disodium and gadobenate dimeglumine) in a large study population at a single, large academic medical centre. MATERIALS AND METHODS: The institutional review board approved this retrospective study in which data in the electronic incident reporting system were searched. A total of 194, 400 intravenous administrations of linear ionic GBCAs were assessed for the incidence of adverse reactions and risk factors from 1 January 2007 to 14 January 2014. The severity of reactions (mild, moderate, and severe), patient type (outpatients, inpatients, and emergency), examination type, and treatment options were also investigated. RESULTS: In total, 204/194400 (0.1%) patients (mean age 45.7 ± 14.9) showed adverse reactions, consisting of 6/746 (0.80%), 10/3200 (0.31%), 14/6236 (0.22%) and 174/184218 (0.09%), for gadofosveset trisodium, gadoxetate disodium, gadobenate dimeglumine, and gadopentetate dimeglumine, respectively. An overall significant difference was found between different GBCAs regarding the total number of reactions (p < 0.0001). When comparing the GBCAs together, significant differences were found between gadofosveset trisodium versus gadopentetate dimeglumine (p < 0.0001), gadofosveset trisodium versus gadobenate dimeglumine (p = 0.0051), gadoxetate disodium versus gadopentetate dimeglumine (p < 0.0001) and gadopentetate dimeglumine versus gadobenate dimeglumine (p = 0.0013). Rate of reaction was higher in females (F: 146/113187, 0.13%/M: 58/81213, 0.07%; p < 0.0001). Rate of reactions was higher in outpatient (180/158885, 0.11%), emergency (10/10413, 0.10%), and inpatients (14/25102, 0.05%), respectively (p < 0.0001). Most of the patients had mild symptoms 171/204 (83.8%). Abdomen-pelvis, liver, and thoracic examinations had highest rates of reactions (0.17 versus 0.16 versus 0.15). CONCLUSION: The overall rate of adverse reaction to GBCAs was 0.1%. The rates of reactions were highest in gadofosveset trisodium with (0.80%), followed by gadoxetate disodium (0.31%), gadobenate dimeglumine (0.22%) and gadopentetate dimeglumine (0.09%).

Incidence of contrast medium extravasation for CT and MRI in a large academic medical centre: a report on 502,391 injections.

AIM: To present the authors' experience of contrast medium extravasation (CME) during both CT and MRI examinations in a large academic medical centre. MATERIALS AND METHODS: The present retrospective investigation was conducted between June 2008 and June 2013. The radiology data and medical records of patients in whom CME had occurred were reviewed. RESULTS: The extravasation rate for CT and MRI was 0.11% (541/502 391); the % was 0.13% during CT and 0.06% during MRI. There was a statistically significant difference between females and males in the overall % (p = 0.0062), and the number of extravasations between CT and MRI (p < 0.0001). At MRI, the incidence of CME in patients >60 years was statistically significant when compared to the 18-60 year age group (p = 0.0072). Of 90 MRI patients with extravasation, CME occurred in 51 (0.048%, 51/105,578) patients from manual injections, and 39 (0.087%, 39/44,688) patients from automated injection with statistical significance (p = 0.0048). A statistical significance was found between females receiving automatic injections and males receiving manual injections (p = 0.0161). The majority of CME during CT and MRI occurred in the outpatient department [64.5% (291/451) and 64.4% (58/90), respectively], but the overall incidence of CME was highest in inpatients [0.29%, (160/54,664) in CT and 0.16% (32/20,048) in MRI]. CONCLUSION: Patients undergoing CT are at higher risk of developing CME than MRI patients. Females and inpatients were also were more likely to develop CME at both CT and MRI. At MRI CME is more likely in patients above the age of 60 years and for those receiving automated power injections.

Current status of nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis (NSF) occurs in patients with advanced chronic kidney disease (CKD) or acute renal failure, most commonly following exposure to gadolinium-based contrast agents (GBCAs). NSF can be debilitating and associated with increased mortality. The putative association of NSF with GBCAs prompted the development of guidelines to limit the use of these contrast agents in at-risk patients. Indeed, the incidence of NSF has decreased dramatically following application of these guidelines, which appears to be the only effective means of decreasing NSF incidence. Thus, increasing clinician awareness of these updated guidelines is important. The present review introduces and compares updated guidelines for GBCA use and discusses the latest advances in the understanding of the pathogenic mechanisms and treatment of NSF.

A double-blind randomized controlled trial appraising the symptom-modifying effects of colchicine on osteoarthritis of the knee.

OBJECTIVES: Osteoarthritis (OA) is the most common articular disease. Common OA treatments are either not effective or associated with side effects. Calcium-containing crystals are quite common in primary OA and they worsen or may cause OA through induction of inflammation by neutrophils. Colchicine inhibits urate-crystal and calcium-pyrophosphate (CPP) crystal induced inflammation and elastase, a matrix-metalloproteinase (MMP) that play a pivotal role in degenerative joint processes. Hence, it was hypothesized that it may have symptom-modifying effects on OA. METHODS: Sixty-one postmenopausal patients with primary knee OA were enrolled. None of them had joint involvement atypical for OA or evidences of chondrocalcinosis in radiographic studies suggesting the presence of calcium-pyrophosphatedeposition-disease (CPPD). Participants were allocated to two groups receiving 0.5mg colchicines BID or placebo. Both groups received common OA treatments. Acetaminophen less than 2gr/day was used as rescue-analgesic. The efficacy end points were: patients' global assessment and physician's global assessment, recorded on a VAS (visual analogue scale). Statistical analysis was performed 3 months later. RESULTS: Thirty-one patients were assigned to the colchicine group. Fifty-eight patients were present for the last survey. Only 1 patient in colchicine group encountered adverse effect of colchicine without significant difference between the two groups. Acetaminophen consumption was significantly less in the colchicine (879.3±369.7) compared to placebo group (1620.7±393.1, p=0.000). Improvement rate at the end of 3 months was significantly higher in the colchicine group for both patients' global assessment and physician's global assessment measures compared to placebo group, (11.14±4.06 vs. 3.14±2.18, p=0.000) and (9.83±3.799 vs. 3.72±3.35, p=0.000), respectively. CONCLUSIONS: The efficacy and safety of colchicine for pain reduction in OA was affirmed by our double-blind randomised controlled trial.

Diagnostic Accuracy of Sixty Four Multi-Slice CT Angiography in Assessment of Arterial Cut-Off and Run-Off in Comparison with Surgical Findings.

BACKGROUND/OBJECTIVE: The accurate anatomic mapping and determination of the severity of arterial disease, an important health problem of the elderly, is of great significance. We aimed to determine the diagnostic value of 64-multislice CT angiography (MSCTA) in run-off and cut-off sites of arterial disease. PATIENTS AND METHODS: Throughout the study, MSCTA followed by an operative intervention was carried out on a total of 38 patients with clinical signs and symptoms suggestive of arterial disease (AD) all of whom had the indication for vascular surgery. The mean age of patients was 34±15.86 (range, 23 to 93) years. MSCTA was executed using a 64-slice CT scanner, during the arterial phase of injecting the nonionic, contrast medium with a power injector at the rate of 5 ml/sec into the antecubital vein and exploration and revascularization of peripheral arterial disease was performed intraoperatively. RESULTS: Atherosclerosis and arterial disease, the most common causes of vascular occlusion, were more common in the lower extremities. According to MSCTA findings, the most frequent site of stenosis was the superficial femoral artery. Spearman's correlation coefficient showed a high degree of agreement amongst the raters. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the accuracy of MSCTA compared to surgery were 83.8%, 96%, 96.8%, 81.3% and 89%, respectively. MSCTA findings were compared with surgery as a standard of reference, which showed concordance in the majority of cases (81.6%). Cut-off sites were correctly identified by MSCTA in 97.3% of the patients and the most common sites of discordance were the run-off sites (18.2%). CONCLUSION: MSCTA angiography as a novel diagnostic modality may be a suitable alternative and a viable choice for routine clinical diagnosis.

Africans and the myth of rural retirement in South Africa, ca 1900-1950.

The South African mining industry relied upon a massive African migrant workforce from the rural areas. Rural transformations in this migrant labor system form an important part of the story of developing capitalism in industrializing South Africa. Yet, recent historical studies on southern African migrant and rural wage labor have paid little attention to life adjustments made by the elderly and those 'burned out' by the mines and forced to leave formal wage employment in the urban areas. The South African segregationist state's rhetoric implied that 'retired' Africans could find economic security in their designated rural reserves. Indeed, legislation sought to prohibit Africans who were not employed from remaining in the 'white' urban areas. By the 1930s, however, the reserves were rapidly deteriorating. Many elderly Africans could not retire and were forced to seek wage labor. This raises significant questions about how retirement came to be defined and experienced by Africans in South Africa during a critical period of dramatic economic decline in the 1930s and 40s, and what the underlying material circumstances of African South Africans were with regard to adaptations to employment and ageing-related life changes. In many cases, elderly Africans were forced to forgo retirement, and find wage labor, usually in the most poorly paid, least sought-after or dangerous fields of employment. This article thus seeks to illuminate critical generational dimensions of the impact of segregation and racism in South Africa prior to the formal articulation of Apartheid.

The antihypertensive effects of doxazosin on the arterial system: changes in peripheral vascular resistance and wall tension.

Background: Hypertension is characterized by structural and functional abnormalities that affect the entire cardiovascular system, including the large arteries. The antihypertensive efficacy of doxazosin, a selective alpha(1) antagonist, and its effects on the arterial system were investigated. Method: In our double-blind, randomized, placebo-controlled study including 30 hypertensive patients (doxazosin group: nine males, 11 females; mean age 45+/-12 years; placebo group: four males, six females; mean age 47+/-9 years), the systolic, diastolic and mean blood pressure (BP), heart rate, diameter and area of the brachial artery, peak systolic velocity, end-diastolic velocity, pulsatility index (PI), resistance index (RI), S/D (systolic velocity/diastolic velocity), flow volume, local resistance, and wall tension were recorded before and 4 h after the administration of 2 mg doxazosin or placebo. The two groups were statistically compared. Results: In the doxazosin group, systolic, diastolic and mean pressures decreased significantly (P<0.001), while heart rate remained unchanged. Local resistance (P<0.001), RI (P<0.05), PI (P<0.05), and wall tension (P<0.001) all decreased significantly, while flow volume increased significantly (P<0.05). However, no significant changes were observed in arterial diameter, surface area, peak systolic velocity, end-diastolic velocity or S/D ratio. The placebo group did not show a significant difference in any of the parameters listed above. Conclusion: The antihypertensive effect of doxazosin is accompanied by a reduction in brachial arterial wall tension that occurs without any change in arterial diameter. The lack of change in the diameter of the artery leads us to suggest different effects on other vasomotor determinants.

Effect of diltiazem on renal function in patients with liver cirrhosis.

Calcium channel blockers have strong vasodilator, natriuretic and diuretic actions in normal and hypertensive subjects. The aim of this study was to evaluate the effect of diltiazem on renal function, renin-angiotensin-aldosterone axis (RAA) and atrial natriuretic factor (ANF) in patients with liver cirrhosis. Seven patients (3 females and 4 males) with a mean age of 56.3 +/- 11.1 years (36-68) entered the trial. All of the patients had HBV (6 cases) or HCV (1 case) related Child A (3 cases) or Child B (4 cases) liver cirrhosis proven by liver biopsy. Patients were given placebo for 15 days followed by p.o. diltiazem 30 mg t.i.d. for 15 days. Urinary volume, natriuresis, creatinine clearance, plasma renin activity (PRA), ANF and aldosterone (ALD) levels were determined after the washout period and during the first and second weeks of drug treatment. Urinary volume increased by 25-170% in 5 cases but this difference did not reach statistical significance. Slight increases in natriuresis occurred in some cases on the 3rd day of the trial but the overall results were not statistically significant (191.50 +/- 26.85 vs 204.07 +/- 39.83 mmol/l). Diltiazem induced no significant changes in PRA, ALD and ANF levels or creatinine clearance during the first or second weeks of the trial. There was a significant drop in the pulse rate on the first or second weeks of the treatment (p less than 0.01 and p less than 0.05, respectively). No significant changes were noted on mean arterial pressure (MAP).(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of baclofen-induced antinociception by intrathecal administration of phaclofen or 2-hydroxy-saclofen, but not delta-aminovaleric acid in the rat.

This study evaluated the ability of two new, selective antagonists of the gamma-aminobutyric acidB (GABAB) receptor, phaclofen (PHAC) and 2-hydroxy-saclofen (2-OH-S), to antagonize the increase in tail-flick latency (TFL) and hot-plate latency (HPL) produced by i.t. administered baclofen (BAC) in the rat. The putative GABAB receptor antagonist delta-aminovaleric acid (DAVA) was also examined for comparative purposes. Intrathecal (i.t.) pretreatment with increasing doses of PHAC (10-100 micrograms) shifted the dose-effect relationship of i.t. administered BAC progressively to the right in a parallel manner in both the tail-flick (TF) and hot-plate (HP) test. Schild analysis of the data yielded an apparent pA2 value of 7.3 +/- 0.1 and a slope of -0.98 +/- 0.14. By comparison, PHAC did not antagonize the increase in HPL produced by i.t. injection of the serotonin1A agonist, 8-hydroxy-N,N-dipropyl-2-aminotetralin. These observations indicate that PHAC competitively and selectively antagonizes BAC and further suggest that the antinociceptive effects of i.t. administered BAC are mediated by the PHAC-sensitive subtype of the GABAB receptor. Intrathecal injection of PHAC alone did not decrease TFL or HPL, suggesting that spinal GABAB receptors involved in nociception are not tonically activated. Although i.t. pretreatment with 2-OH-S (10-30 micrograms) also antagonized the antinociceptive effects of i.t. administered BAC, increasing doses of 2-OH-S did not produce progressive, rightward shifts in the dose-effect relationship of BAC. Indeed, i.t. administration of 2-OH-S alone modestly increased TFL, but not HPL in the rat. These observations suggest that 2-OH-S may be a partial agonist at spinal GABAB receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Antinociceptive interactions between intrathecally administered alpha noradrenergic agonists and 5'-N-ethylcarboxamide adenosine.

Recently, it has been shown that intrathecal injection of norepinephrine and the mixed A1/A2 adenosine agonist 5'-N-ethylcarboxamide adenosine (NECA) interact in a supra-additive manner to produce antinociception. The present studies were designed to determine whether alpha 1 or alpha 2 noradrenergic receptors are involved in producing the antinociception induced by NECA and norepinephrine. The results indicated that intrathecal injection of NECA (0.97-4.9 nmol), the alpha 2 noradrenergic agonist clonidine (3.8-375 nmol), or the alpha 1 agonist phenylephrine (4.9-73.4 nmol) produced dose-dependent antinociception in rats. Furthermore, intrathecal injection of subeffective doses of NECA and clonidine interacted supra-additively to produce potent antinociception. In contrast, no supra-additive interaction was observed between NECA and phenylephrine. The supra-additive interaction of NECA and clonidine did not appear to result from alterations in cardiovascular tone because changes in blood pressure and nociceptive thresholds were not correlated in time. These results suggest that the noradrenergic component of the supra-additive interaction between adenosine A2 receptor agonists and noradrenergic agonists is mediated by alpha 2 noradrenergic receptors.

Antinociception produced by interactions between intrathecally administered adenosine agonists and norepinephrine.

It is well-established that intrathecal injection of noradrenergic agonists produces dose-dependent antinociception in rats. Recently, the antinociceptive actions of norepinephrine in the central nervous system have been shown to be modulated by adenosine and adenosine analogs. This study examined whether there is an interaction between norepinephrine and adenosine analogs in the regulation of nociceptive transmission in the rat spinal cord using the tail flick and hot plate tests. The results indicate that dose-dependent antinociception was produced by intrathecal injection of norepinephrine (4.8-195 nmol), the A1/A2 adenosine agonist 5'-N-ethylcarboxamide adenosine (NECA; 0.97-4.9 nmol), and the A1 adenosine agonist R-phenylisopropyladenosine (R-PIA; 0.78-26 nmol). Furthermore, subeffective doses of NECA and norepinephrine interacted synergistically to produce potent antinociception. In contrast, no synergistic interaction was observed between norepinephrine and doses of R-PIA as high as 26 nmol. The antinociception produced by coadministration of norepinephrine and NECA appears to be mediated by adenosine receptors, since it was attenuated by pretreatment with theophylline, a non-selective adenosine antagonist. The synergistic interaction between NECA and norepinephrine did not appear to result from alterations in cardiovascular tone because blood pressure values were not significantly altered by drug administration. These results suggest that purinergic and noradrenergic systems interact synergistically to modify nociceptive transmission in the spinal cord. The purinergic component of this interaction may be mediated, in part, by adenosine A2 receptors.