Influx of kininogens into nasal secretions after antigen challenge of allergic individuals.

We have recently demonstrated that kinins are generated in vivo after nasal challenge with antigen of allergic, but not nonallergic, individuals. The present study was undertaken as a first step in determining the mechanism(s) of kinin formation during the allergic reaction and was directed towards establishing the availability and origin of kininogens in nasal secretions. Allergic individuals (n = 6) and nonallergic controls (n = 5) were challenged with antigen; and by using specific radioimmunoassays, nasal washes, obtained before and after challenge, were assayed for high molecular weight kininogen (HMWK), total kininogen (TK), albumin, and kinins. Dramatic increases in HMWK (1,730 +/- 510 ng/ml), TK (3,810 +/- 1035 ng/ml), kinin (9.46 +/- 1.75 ng/ml), and albumin (0.85 +/- 0.2 mg/ml) were observed after challenge of allergic individuals which correlated (P less than 0.001) with increases in histamine and N-alpha-tosyl-L-arginine methyl esterase activity and with the onset of clinical symptoms. For nonallergic individuals, levels of kininogens, albumin, and all mediators after antigen challenge were not different from base line. Linear regression analysis revealed excellent correlations (P less than 0.001 in each case) between increases in HMWK, TK, kinin, and albumin during antigen titration experiments and between the time courses of appearance and disappearance of HMWK, TK, kinin, and albumin after antigen challenge. Gel filtration revealed no evidence of degradation products of kininogens in nasal washes. For each allergic individual the ratio of HMWK/TK in postchallenge nasal washes was similar to the ratio of these two proteins in the same individual's plasma. These data suggest that, during the allergic reaction, there is an increase in vascular permeability and a transudation of kininogens from plasma into nasal secretions, where they can provide substrate for kinin-forming enzymes.     

Deep inspiration-induced changes in lung volume decrease with severity of asthma

We have previously reported that the magnitude of deep inspiration (DI)-induced bronchodilation is only slightly reduced in mild asthmatics, compared to healthy subjects. The aim of this study was to evaluate whether increased severity of asthma is associated with impairment in the ability of DI to induce changes in lung volume. Thirty-six consecutive asthmatics recruited from the Pulmonary and the Allergy Outpatient Clinics of the Institute of Respiratory Diseases of the University of Palermo were divided into 3 groups: Intermittent (I), Mild Persistent (MP) and Moderate-Severe (MS), based on GINA guidelines. Single dose methacholine (Mch) bronchoprovocations were performed in the absence of DI, to induce at least 15% reduction in inspiratory vital capacity (IVC) from baseline. The post-Mch IVC was followed by 4 consecutive DI and by another IVC, to determine the bronchodilatory effect of DI. The bronchodilatory effect of DI was found to significantly decrease with increasing severity of asthma (I: 68+/-5.4%, MP: 45+/-7.2%, MS: 4+/-15.6%; ANOVA: P<0.0001). Bronchodilation by DI, but not FEV(1) or FEV(1)/FVC, was also inversely correlated to symptom scores (r=-0.42, P=0.01) and to weekly salbutamol usage (r=-0.47, P=0.004). These observations provide support to the hypothesis that the attenuation of the bronchodilatory effect of DI contributes to the severity of the clinical manifestations of asthma.     

Associations between osteoprotegerin and femoral neck BMD in hemodialysis patients

Numerous humoral factors are involved in the development of renal osteodystrophy, causing perturbations in bone mineral density (BMD) in patients with end-stage renal disease (ESRD). The RANKL/OPG cytokine system appears to mediate the effects of many of these factors on bone turnover, contributing to the pathogenesis of renal bone disease. The aim of this study was to evaluate the clinical and biochemical correlations of BMD measurements in patients on chronic hemodialysis. Fifty-four hemodialysis patients underwent measurement of BMD at the proximal femur and the lumbar spine (L2–L4). Intact parathyroid hormone (PTH), osteoprotegerin (OPG), sRANKL, and main bone biochemical markers were also measured in serum samples of all patients. BMD of the femoral neck was negatively correlated with OPG levels (r = 0.333, P = 0.014). OPG levels were significantly different among normal, osteopenic, and osteoporotic tertiles defined according to BMD of the femoral neck. The highest OPG levels were measured in the lowest T-score (osteoporotic) tertile and were higher than in the osteopenic and normal tertiles (P < 0.05). A threshold level for OPG at 21.5 pmol/l enabled the detection of osteoporotic patients with 76.5% sensitivity and 62.2% specificity. BMD values of trabecular bone-rich sites of the skeleton such as lumbar spine (L2–L4), trochanter, and Ward’ s triangle were inversely correlated with total ALP levels (P < 0.05). Hemodialysis patients with low BMD of the femoral neck demonstrated higher OPG levels than patients with normal BMD. Those with lumbar spine (L2–L4), trochanteric, and Ward's triangle BMDs below the normal range presented higher total ALP levels. These results suggest that OPG and total ALP may be clinically useful markers in the detection of significant femoral neck and trabecular bone mineral deficit in hemodialysis patients, warranting further investigations.     

Upper airways reactions to cold air

Cold air-induced rhinitis is a common complaint of individuals with chronic allergic or nonallergic rhinitis and those with no chronic nasal disease. It is characterized by rhinorrhea, nasal congestion, and nasal burning that appear within minutes of exposure to cold air and dissipate soon after exposure is terminated. The symptoms of cold-air rhinitis are reproduced experimentally with nasal cold-air provocation. This procedure has shown that nasal mast cell activation and sensory nerve stimulation are associated with the development of nasal symptoms. Sensory nerve activation generates a cholinergic reflex that leads to rhinorrhea; therefore, anticholinergic agents are highly effective in treating cold-air rhinitis. Experimental data suggest that individuals with nasal cold-air sensitivity may have reduced ability to compensate for the water loss that occurs during exposure to cold air. Therefore, the symptoms of cold air-induced rhinitis may reflect the activation of compensatory mechanisms to restore mucosal homeostasis.     

Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria

Background  

Familial hematuria (FH) is associated with at least two pathological entities: thin basement membrane nephropathy (TBMN), caused by heterozygous COL4A3/COL4A4 mutations, and C3 nephropathy caused by CFHR5 mutations. It is now known that TBMN patients develop proteinuria and changes of focal segmental glomerulosclerosis when biopsied. End-stage kidney disease (ESKD) is observed in 20% of carriers, at ages 50–70. A similar progression is observed in CFHR5 nephropathy. Recent evidence suggests that NPHS2-R229Q, a podocin polymorphism, may contribute to proteinuria in TBMN and to micro-albuminuria in the general population.