Glaucoma is an autoimmune disease.

Glaucoma is characterized by retinal ganglion cell (RGC) neurodegeneration. Elevated intraocular pressure (IOP) is a major risk factor however, mechanisms independent of IOP play a role in RGC pathology. Both antibodies and CD4 T-cells as well as microbiota take part in the pathogenesis of both glaucoma and rheumatoid arteritis (RA).Heat shock proteins (HSPs) which originate in bacteria cross-react with RCG epitopes and were involved in rat model of retinal injury. Enhanced expression of HSPs in the retina was associated with glaucoma-like neuropathology and previous studies have also suggested a pathogenic role for HSPs in RA. In view of these data we suggest that glaucoma should be included in the spectrum of autoimmune diseases and that proven medications for RA should be adopted as an innovative IOP -independent therapeutic strategy for glaucoma.

"General deterioration": a diagnosis that is a marker for risk of mortality upon re-admission.

BACKGROUND: Predicting mortality is important in treatment planning and professional duty towards patients and their families. OBJECTIVES: To evaluate the predictive value regarding patients' survival once the diagnosis of "general deterioration" replaces an ICD-9 diagnosis upon re-admission. METHODS: In this retrospective cohort case-control study, we screened the records of patients re-admitted at least three times during the past 2 years. For each patient's death during the third hospitalization, we matched (for age and gender) a patient who survived the third hospitalization. We evaluated 14 parameters potentially accountable for increased risk of mortality, e.g., length of stay at each admission, interval to re-admission, etc. We applied a multifactorial analysis using logistic regression to predict the risk of mortality during the third hospitalization as potentially affected by the aforementioned parameters. RESULTS: The study included 81 study patients and 81 controls. Of the 14 parameters potentially explaining an increased risk of mortality during the third hospitalization, several were found to be statistically significant. The most significant was the diagnostic switch from a specific ICD-9 diagnosis on first admission to the non-specific diagnosis of "general deterioration" at the second hospitalization. In such cases, the risk of death during the third hospitalization was increased by 5300% (odds ratio = 54, P = 0.008). The increased risk of mortality was not restricted to patients with malignancy as their background diagnosis. CONCLUSIONS: At re-admission a switch from disease-specific diagnosis to the obscure diagnosis "general deterioration" increases the subsequent risk of mortality.

Rosiglitazone improves aortic arginine transport, through inhibition of PKCalpha, in uremic rats.

Peroxisome proliferator-activated receptor (PPAR) agonists were shown to inhibit atherosclerosis through augmentation of endothelial nitric oxide synthase (eNOS) activity. In addition, rosiglitazone exerts a beneficial effect in chronic renal failure (CRF). Since l-arginine transport by CAT-1 (the specific arginine transporter for eNOS) is inhibited in uremia, we aimed to explore the effect of rosiglitazone on arginine transport in CRF. Arginine uptake by aortic rings was studied in control animals, rats, 6 wk following 5/6 nephrectomy (CRF) and rats with CRF treated with rosiglitazone. The decrease of arginine transport in CRF was prevented by rosiglitazone. Immunobloting revealed that CAT-1 protein was decreased in CRF but remained unchanged following rosiglitazone administration. Protein content of the membrane fraction of PKCalpha and phosphorylated CAT-1 increased significantly in CRF, effects that were prevented by rosiglitazone. PKCalpha phosphorylation was unchanged but significantly attenuated by rosiglitazone in CRF. Ex vivo administration of phorbol-12-myristate-13-acetate to rosiglitazone-treated CRF rats significantly attenuated the effect of rosiglitazone on arginine uptake. The decrease in cGMP response to carbamyl-choline (eNOS agonist) was significantly attenuated by rosiglitazone in CRF. Western blotting and immunohistochemistry analysis revealed that protein nitration was intensified in the endothelium of CRF rats and this was attenuated by rosiglitazone. In conclusion, rosiglitazone prevents the decrease in arginine uptake in CRF through both depletion and inactivation of PKCalpha. These findings are associated with restoration of eNO generation and attenuation of protein nitration and therefore may serve as a novel mechanism to explain the beneficial effects of rosiglitazone on endothelial function in uremia.

Arginine transport is augmented, through modulation of cationic amino acid transporter-1, in obstructive uropathy in rats.

BACKGROUND: The decrease in glomerular filtration rate (GFR), which is characteristic of obstructive uropathy, was suggested to be associated with attenuated nitric oxide (NO) generation. Since availability of L-arginine, the sole precursor for NO, governs NO synthesis, we aimed to determine the role of glomerular arginine transport in rats subjected to 24 h of bilateral ureteral ligation (BUO). METHODS: Glomerular arginine transport was measured by uptake of radiolabeled arginine ([(3)H]-L-arginine), cationic amino acid transporters (CAT)-1 and -2 and arginases I and II mRNA expression were determined using reverse transcription-polymerase chain reaction. CAT-1, arginase I, and arginase II protein contents were evaluated by Western blotting. RESULTS: L-Arginine transport by freshly harvested glomeruli from BUO rats was significantly augmented than in controls. The aforementioned findings were associated with a significant increase in glomerular CAT-1 mRNA expression, while CAT-2 mRNA was unchanged. Western blotting demonstrated a significant increase in CAT-1 abundance in BUO. Expression of both glomerular arginase I and II mRNA and protein content were significantly elevated in BUO. CONCLUSIONS: BUO induces an increase in glomerular arginine transport via upregulation of CAT-1, probably due to increase in arginine utilization by a non-NO pathway.

A profound decrease in maternal arginine uptake provokes endothelial nitration in the pregnant rat.

While a specific role for nitric oxide (NO) in inducing the hemodynamic alterations of pregnancy is somewhat controversial, it is widely accepted that excess NO is generated during pregnancy. L-Arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate L-arginine uptake, cationic amino acid transporter-1 (CAT-1) acts as the specific arginine transporter for endothelial NO synthase. The present study was designed to test the hypothesis that, during pregnancy, when arginine consumption by the fetus is significantly increased, compensatory changes in maternal arginine uptake affect the endothelium. Uptake of radiolabeled arginine (L-[3H]arginine) by freshly harvested maternal aortic rings from pregnant rats decreased by 65 and 30% in mid- and late pregnancy, respectively, compared with those obtained from virgin animals. This decrease was associated with a significant increase in endothelial protein nitration (the footprint of peroxynitrite generation), as shown by both Western blotting and immunohistochemistry utilizing anti-nitrotyrosine antibodies, reflecting endothelial damage. Northern blot analysis revealed that steady-state aortic CAT-1 mRNA levels did not change throughout pregnancy, whereas CAT-1 protein abundance was significantly increased, peaking at mid-pregnancy. Protein content of protein kinase C (PKC)-alpha, which was previously shown to decrease CAT-1 activity, increased significantly in the pregnant animals and was associated with a significant increase in CAT-1 phosphorylation. Intraperitoneal injection of alpha-tocopherol, a PKC-alpha inhibitor, prevented the decrease in arginine transport and attenuated protein nitration. In conclusion, aortic arginine uptake is reduced during pregnancy, through posttranslational modulation of CAT-1 protein, presumably via upregulation of PKC-alpha. The aforementioned findings are associated with an increase in protein nitration and, therefore, in selected individuals, may lead to the development of certain forms of endothelial dysfunction, like preeclampsia.

[Asthma and scuba diving: can asthmatic patients dive?].

Self-contained underwater breathing apparatus (scuba) diving has grown in popularity, with millions of divers enjoying the sport worldwide. This activity presents unique physical and physiological challenges to the respiratory system, raising numerous concerns about individuals with asthma who choose to dive. Asthma had traditionally been a contraindication to recreational diving, although this caveat has been ignored by large numbers of such patients. Herein we review the currently available literature to provide evidence-based evaluation of the risks associated with diving that are posed to asthmatics. Although there is some indication that asthmatics may be at an increased risk of pulmonary barotrauma, the risk seems to be small. Thus, under the right circumstances, patients with asthma can safely participate in recreational diving without any apparent increased risk of an asthma-related event. Decisions on whether or not diving is hazardous must be made on an individual basis and be founded upon an informed decision shared by both patient and physician.

Eosinophilia: A study of 100 hospitalized patients.

BACKGROUND: Eosinophilia accompanies a large number of diseases and conditions, but information is lacking about the clinical characteristics of patients who are hospitalized due to this abnormality. Our aim was to determine the clinical profile and most informative diagnostic tests in patients hospitalized in a tertiary hospital because of hypereosinophilia. METHODS: A retrospective review was done of the medical records of all patients hospitalized in a large urban medical center due to hypereosinophilia. All relevant clinical, laboratory, and imaging data were analyzed. RESULTS: A total of 100 patients were included in the study (58 males and 42 females, mean age 55.2+/-29 years). The blood eosinophil blood count was 4107+/-7254/mul (mean+/-SD) and this usually persisted for a few months. The cause of the eosinophilia was asthma or other atopic disease in 13% of the cases, allergic drug reaction in 6%, eosinophilic pneumonia in 10%, neoplastic diseases in 10%, idiopathic hypereosinophilic syndrome in 8%, Churg-Strauss Syndrome in 4%, infections in 10%, allergic fungal disease in 2%, and skin diseases in 3%; the cause remained unknown in 34% of cases. CONCLUSION: Guidelines are suggested for the investigation of patients with eosinophilia, including the level of the eosinophilia associated with specific diseases and the most informative diagnostic tests.

Arginine uptake is attenuated, through post-translational regulation of cationic amino acid transporter-1, in hyperlipidemic rats.

Endothelial cell dysfunction (ECD) is a common feature of hypercholesterolemia. Defective nitric oxide (NO) generation due to decreased endothelial nitric oxide synthase (eNOS) activity is a crucial parameter characterizing ECD. L-arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate L-arginine uptake, cationic amino acid transporter-1 (CAT-1) acts as a specific arginine transporter for eNOS. Our hypothesis implies that CAT-1 is a major determinant of eNOS activity in hypercholesterolemia. We studied aortic arginine uptake, CAT-1 and CAT-2 mRNA expression, and CAT-1, and PKC alpha protein in: (a) control, untreated animals (CTL), (b) rats fed with 4% cholesterol+1% cholate and 2% corn oil for 6 weeks (CHOL) and (c) rats with hypercholesterolemia treated orally with either atorvastatin (CHOL+ATORVA, 20mg/kg BW/day) or arginine 1% (CHOL+ARG) in the drinking water (modalities which have been shown to enhance CAT-1 activity and improve endothelial function). Serum cholesterol levels significantly increased in cholesterol fed animals, an increase which was blocked by atorvastatin (CTL: 66.8+/-15, CHOL: 133.9+/-22, CHOL+ARG: 128.2+/-20, CHOL+ATORVA: 77+/-15 mg/dl). Arginine transport was significantly decreased in CHOL. Treatment with neither arginine nor atorvastatin had an effect. Using RT-PCR, we found no change in aortic CAT-1 and CAT-2 mRNA expression in CHOL as well as following arginine or atorvastatin administration. The abundance of CAT-1 protein was significantly augmented in cholesterol fed rats and was not affected by arginine or atorvastatin. PKC alpha protein content, which was previously shown to regulate CAT-1 activity, increased significantly in CHOL and was neither affected by atorvastatin nor arginine. In conclusion, aortic arginine uptake is attenuated in hypercholesterolemia, through post-translational modulation of CAT-1 protein, possibly via upregulation of PKC alpha.

Differential regulation of L-arginine transporters (cationic amino acid transporter-1 and -2) by peroxynitrite in rat mesangial cells.

BACKGROUND: It has become evident that increased nitric oxide (NO) generation may be associated with production of reactive oxygen species, such as peroxynitrite (ONOO-). Peroxynitrite has been postulated to be responsible for several of the cytotoxic effects previously ascribed to NO. Since cellular arginine uptake has been shown to modulate nitric oxide synthase activity, we were intrigued to study the effect of ONOO- on arginine traffic in renal mesangial cells. METHODS: Arginine uptake, CAT-1 and CAT-2 mRNA expression by northern blotting analysis, and CAT-1 protein content using western blotting were determined in mesangial cells pre-treated with peroxynitrite (0.1 and 0.5 mM) for 2 h. RESULTS: Peroxynitrite induced a significant increase in arginine uptake and CAT-2 mRNA expression compared with untreated cells. In contrast, CAT-1 mRNA expression and protein abundance were diminished. CONCLUSIONS: In rat mesangial cells, peroxynitrite augments arginine uptake via augmentation of CAT-2 while decreasing CAT-1 expression.

Expression of the chemokine receptor CCR2 on immature B cells negatively regulates their cytoskeletal rearrangement and migration.

Immature B cells are targeted to specific areas in the spleen, where a fraction of these cells receive signals that induce them to mature and participate in the immune response. In this study, we show that the C-C chemokine receptor 2 (CCR2) is transcribed in immature B cells, while its message is dramatically down-regulated at the mature stage. CCR2-deficient cells exhibit up-regulation of chemokine-induced actin polymerization, migration, and homing to the lymph nodes of immature B cells. In addition, we demonstrate that control of homing by CCR2 is mediated by its ligand, CCL2/JE, which is secreted by B cells and down-regulates the stromal derived factor-1 (SDF-1) signaling cascade. Thus, this study describes an additional, previously uncharacterized, role for CCR2 and its ligand as negative regulators of the homing of immature B cells.

Augmented arginine uptake, through modulation of cationic amino acid transporter-1, increases GFR in diabetic rats.

BACKGROUND: It is suggested that either arginine or its metabolites, nitric oxide and polyamines play a role in the renal hemodynamic alterations observed in the early stages of diabetes. Yet, the regulation of arginine transport in diabetic kidneys has never been studied. METHODS: Arginine uptake was determined in glomeruli harvested from control rats; diabetic rats (2 weeks following an intraperitoneal injection of streptozotocin, 60 mg/kg body weight); rats, 4 days following left nephrectomy (a nondiabetic model of hyperfiltration); diabetes + lysine (0.5% in the drinking water to attenuate arginine uptake); and control + lysine. RESULTS: Glomerular arginine transport was significantly increased in diabetic rats, but remained unchanged following uninephrectomy. Lysine abolished the increase in arginine uptake in diabetic rats but had no effect in controls. The increase in creatinine clearance observed in diabetes was completely abolished by lysine. Using reverse transcription-polymerase chain reaction (RT-PCR), Northern blotting, and immunohistochemistry, we found a significant increase in glomerular cationic amino acid transporter-1 (CAT-1) expression in diabetic animals, which was unaffected by lysine. When human endothelial cells were incubated with arginine end products no effect on arginine transport was observed. However, only in the presence of 0.5 mM/L sodium nitroprusside (SNP) an augmented steady-state CAT-1 mRNA was demonstrated by RT-PCR. CONCLUSION: In a rat model of early diabetes, glomerular arginine uptake is elevated through modulation of CAT-1 expression, thus, contributing to the pathogenesis of hyperfiltration. Increased nitric oxide formation may play a role in this process.

The anti-inflammatory effects of 1,25-dihydroxyvitamin D3 on Th2 cells in vivo are due in part to the control of integrin-mediated T lymphocyte homing.

The fat soluble vitamin D3 metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D(3)], and its nuclear receptor play an important role in regulating immune responses. While 1,25(OH)(2)D(3 )is known to inhibit transcription of cytokine genes that are required for Th1 differentiation or are products of differentiated Th1 cells, its role in regulating differentiation of Th2 cells is less clear. In this study, we show that 1,25(OH)(2)D(3) has anti-inflammatory effects in an in vivo Th2-dependent asthma model. In addition, we demonstrate that 1,25(OH)(2)D(3 )down-regulates the cytoskeleton rearrangement required for promoting integrin-mediated adhesion of naive and effector CD4(+) T cells. Finally, 1,25(OH)(2)D(3 )inhibits chemokine-induced migration of naive cells and their homing to the lymph nodes. Thus, in addition to its regulation of cytokine transcription, 1,25(OH)(2)D(3 )regulates migration of cells and thus controls the skewing of various Th subsets in the secondary lymphoid organs and inhibits Th function at sites of inflammation.

Generalized vasculitis, thrombocytopenia, and transient lymphoproliferative disorder caused by idiopathic mixed cryoglobulinemia.

We present a 75-year-old patient with recurrent palpable purpura and multiorgan involvement by leukocytoclastic vasculitis caused by mixed-type cryoglobulinemia. The disease spanned 40 years, with many flare-ups, each associated with thrombocytopenia, and finally culminated in widespread involvement of not only the skin and the kidneys but also the lungs and spleen. Despite extensive investigation, no association with hepatitis C virus or with any malignant or connective tissue disorder was found.

Asthma in adventure travelers: a prospective study evaluating the occurrence and risk factors for acute exacerbations.

BACKGROUND: Exacerbation of asthma during travel to remote regions may lead to devastating consequences. The course of asthma in travelers and the risk factors for disease exacerbation during travel have not been studied. METHODS: We screened 5835 consecutive travelers and identified 203 patients with asthma. Before travel, all enrollees were assessed for presumed risk factors for asthma exacerbation by means of an interview and an exercise test combined with spirometry. After travel, data regarding travel characteristics and asthma severity were recorded by means of a structured telephone interview. RESULTS: The 203 enrollees visited 56 countries for a median duration of 13 weeks, 147 were engaged in high-altitude trekking, and 88 had asthma attacks. Among these, 40 reported worsening asthma during travel, 32 experienced the worst asthma attack ever, and 11 reported a life-threatening asthma attack. Two independent risk factors for attacks during travel were identified: frequent use (> or = 3 times weekly) of inhaled bronchodilators before travel (relative risk [RR], 3.35; 95% confidence interval [CI], 1.75-6.39) and participation in intensive physical exertion during treks (RR, 2.04; 95% CI, 1.04-3.98). When both risk factors were present, the RR for asthma attacks increased to 5.52 (95% CI, 2.81-10.84). CONCLUSIONS: Asthma frequently worsens during travel and should not be ignored as a potentially life-threatening condition requiring pretravel consideration. Asthmatic travelers who frequently use inhaled bronchodilators before travel or participate in intensive trekking during travel are at increased risk to develop asthma attacks. Therapy should be intensified to achieve better disease control; intensive trekking should be discouraged.

L-Arginine transport is augmented through up-regulation of tubular CAT-2 mRNA in ischemic acute renal failure in rats.

BACKGROUND: Ischemic acute renal failure (iARF) is associated with increased nitric oxide (NO) production during the reperfusion period, as endothelial nitric oxide synthase (eNOS) is maximally activated, and renal tubular inducible NOS (iNOS) is stimulated. Increased NO production leads to augmented tubular injury, probably through the formation of peroxynitrite. l-Arginine (l-Arg), the only precursor for NO, is transported into cells by cationic amino acid transporters, CAT-1 and CAT-2. We hypothesized that the increased NO production observed in iARF may result from increased l-Arg uptake, which would be reflected in the augmented expression of l-Arg transporter(s). METHODS: Ischemic acute renal failure was induced in rats by right nephrectomy + left renal artery clamping for 60 minutes. l-Arg uptake was examined in freshly harvested glomeruli and tubuli from control, sham operated, and animals subjected to 15, 30, and 60 minutes, and 24 hours of reperfusion, following 60 minutes of ischemia. Using RT-PCR, renal tissues were examined further for the expression of iNOS, CAT-1, CAT-2, arginase I and arginase II. RESULTS: Tubular expression of iNOS mRNA was initiated by ischemia, continued to increase after 60 minutes of reperfusion, and decreased after 24 hours. l-Arg transport into glomeruli was similar in all experimental groups. l-Arg uptake into tubuli was markedly augmented following the 60-minute reperfusion, while it moderately increased after 24 hours of reperfusion. This was accompanied by a parallel, preferential increase in tubular CAT-2 mRNA expression at 60 minutes of reperfusion. CAT-1 mRNA expression was unchanged, as detected by RT-PCR. In addition, the expression of arginase II and arginase I mRNA was attenuated by 30 minutes and one hour of reperfusion, and returned to baseline values after 24 hours of reperfusion. CONCLUSIONS: Ischemic ARF is associated with augmented tubular CAT-2 mRNA expression, which leads to enhanced l-Arg transport and increased NO production. This may contribute to the renal injury exhibited in iARF.

Garlic attenuates nitric oxide production in rat cardiac myocytes through inhibition of inducible nitric oxide synthase and the arginine transporter CAT-2 (cationic amino acid transporter-2).

It is now accepted that allicin, the main biologically active compound in garlic, exhibits antioxidant activity. The present study was designed to test the hypothesis that the antioxidant activity of garlic can be partially attributed to the inhibition of nitric oxide (NO) production by cytokine-induced NO synthase (iNOS). Cardiac myocytes cultured from neonatal Wistar rats were stimulated by lipopolysaccharide (LPS) and incubated for 24 h with various concentrations of allicin. This resulted in marked inhibition of nitrite production. Interestingly, a low concentration of allicin (10 microM) was significantly more potent in abrogating the effect of LPS on nitrite production than a higher concentration (40 microM). Allicin decreased steady-state iNOS mRNA levels, and this effect was maximal when a lower concentration was used (10 microM compared with 40 microM). In order to explore additional effects of allicin on NO generation that might counteract the effect on iNOS, we assessed the effects of higher allicin concentrations on arginine transport. Allicin inhibited the uptake of 1 mM extracellular arginine in a concentration-dependent manner. The expression of the two arginine transporters that are expressed in cardiac myocytes [CAT-1 (cationic amino acid transporter-1) and CAT-2] was studied using reverse transcription-PCR. A concentration of 200 microM allicin abolished the expression of CAT-2 mRNA, 100 microM significantly attenuated it, whereas 50 microM had no effect. Allicin had no effect on steady-state CAT-1 mRNA levels. Our results suggest that allicin inhibits iNOS activity through two different mechanisms: at lower concentrations it decreases iNOS mRNA levels, whereas at higher concentrations it inhibits arginine transport through down-regulation of CAT-2 mRNA.

Cutting edge: anti-inflammatory properties of low levels of IFN-gamma.

Activation of naive T and B cells occurs only within the context of organized lymphoid tissue. Thus, the continuous recirculation of mature lymphocytes is crucial for the development of primary immune response to foreign Ags. We have previously shown that low levels of IFN-gamma inhibit homing of B cells to the secondary lymphoid organs. In this study, we demonstrate that similarly low doses of IFN-gamma down-regulate integrin-mediated adhesion and migration of naive T and Th2 cells, and have a profound effect on the in vivo homing of naive T cells to the lymph nodes. Moreover, we show that these low doses of IFN-gamma have anti-inflammatory effects in an in vivo asthma model. Thus, in contrast to the proinflammatory effects of IFN-gamma at relatively high concentrations, low dose IFN-gamma appears to exert global suppressory effects on T cell trafficking and may have clinical application as an anti-inflammatory agent.

Preferential Th1 immune response in invariant chain-deficient mice.

MHC class II molecules associate with the invariant chain (Ii) molecule during biosynthesis. Ii facilitates the folding of class II molecules, interferes with their peptide association, and is involved in MHC class II transport. In this study, we have investigated the in vitro and in vivo immune response of Ii-deficient mice (Ii(-/-)). Our results have demonstrated that CD4(+) T cells from Ii(-/-) mice proliferate normally in vitro after in vivo immunization with protein Ags. However, cytokine secretion profiles of Ag-primed CD4(+) T cells from Ii(-/-) mice differ from CD4(+) T cells from wild-type mice. Whereas cells from wild-type mice secrete IFN-gamma and IL-4, cells from Ii(-/-) mice secrete mostly IFN-gamma. Moreover, Ii(-/-) mice exhibit a normal Th1 response in the delayed-type hypersensitivity and trinitrobenzene sulfonic acid colitis models; however, these mice lack an in vivo Th2 response, as demonstrated in the asthma model. Therefore, we suggest that defective Ag presentation in Ii(-/-) mice leads selectively to a Th1 effector response.