Increased levels of soluble ST2 in patients with active newly diagnosed ANCA-associated vasculitis.

OBJECTIVE: ST2, a member of the interleukin-1 receptor family, is selectively expressed on Th2 cells and mediates important Th2 functions. IL-33 is a specific ligand of ST2. The aim of the study was to determine whether serum levels of soluble ST2 (sST2) or IL-33 predict activity of the disease in patients with ANCA-associated vasculitides (AAV). METHODS: 139 AAV patients and 62 controls were studied. IL-33 and sST2 in the blood were measured with a commercially available ELISA. RESULTS: Newly diagnosed AAV patients had higher sST2 levels than controls (P < 0.01). Levels of sST2 were significantly higher in active newly diagnosed AAV patients than in patients with remission (P < 0.001). IL-33 levels were higher in AAV patients than in the control groups (P = 0.002). However, serum IL-33 levels were not increased in patients with active AAV compared to patients in remission. IL-33 levels were higher in patients with granulomatosis with polyangiitis than in patients with microscopic polyangiitis (P = 0.012). CONCLUSIONS: Serum sST2, but not serum IL-33, may be a marker of activity in AAV patients.

Cytokines in acute kidney injury (AKI).

In acute kidney injury (AKI), many cytokines are released by leukocytes and renal tubular cells in the injured kidney and are important components of both the initiation and extension of inflammation. Cytokines are 1) produced by the kidney and mediate AKI, 2) produced by the kidney, released into the blood or urine and serve as biomarkers of AKI, and 3) produced by the kidney or other organs in AKI and mediate or protect against distant organ injury. Further understanding of the role of cytokines in AKI may result in therapeutic approaches like cytokine inhibition that may reduce the degree of kidney injury itself, as well as deleterious effects of kidney injury on other organs.

Chronic migraine and medication overuse headache: clarifying the current International Headache Society classification criteria.

Despite the recent advances in the understanding and classification of the chronic daily headaches, considerable controversy still exists regarding the classification of individual headaches, including chronic migraine (CM) and medication overuse headache (MOH). The original criteria, published in 2004, were difficult to apply to most patients with these disorders and were subsequently revised, resulting in broader clinical applicability. Nonetheless, they remain a topic of debate, and the revisions to the criteria have further added to the confusion. Even some prominent headache specialists are unsure which criteria to use. We aimed to explain the nature of the controversies surrounding the entities of CM and MOH. A clinical case will be used to illustrate some of the problems faced by clinicians in diagnosing patients with chronic daily headache.

Therapeutic and predictive targets of AKI.

Acute kidney injury (AKI) is a very common condition encountered in a hospital setting. AKI is an independent risk factor for in-hospital mortality. In this review, we discuss in detail about the tubular, inflammatory and vascular molecular targets of AKI which may result in therapies to improve mortality and biomarkers for earlier diagnosis of AKI.

HIV-associated nephropathy in Caucasians: case report and review of literature.

HIV-associated nephropathy (HIVAN) is almost exclusively seen in African-Americans (AA) and is rare in Caucasians. The mechanisms responsible for the predilection of HIVAN in AA are not well understood. In transgenic mouse studies, genetic background plays a vital role in the development of the HIVAN phenotype. Larger studies in humans have been initiated to study genetic polymorphisms responsible for HIVAN. As our case illustrates, HIVAN should be considered in Caucasian patients with HIV infection complicated by nephrotic syndrome and renal failure.

Effect of Sirolimus on Native Total Kidney Volume After Transplantation in Patients with Autosomal Dominant Polycystic Kidney Disease: A Randomized Controlled Pilot Study.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway has been shown to be central to cyst formation and growth in patients with autosomal dominant polycystic kidney disease (ADPKD). Drugs that suppress mTOR signaling are frequently used as antiproliferative agents for maintenance immunosuppression in patients who have undergone kidney transplantation. The aim of this study was to determine the effect of sirolimus, an mTOR inhibitor, on cyst volume regression in patients with ADPKD who have undergone renal transplantation. METHODS: In this single-center, prospective, open-label, parallel-group, randomized trial, 23 adult patients with ADPKD who successfully underwent renal transplantation from 2008 to 2012 were subsequently randomized (on a 1:1 basis) to a maintenance immunosuppression regimen with either sirolimus (sirolimus, tacrolimus, prednisone) or mycophenolate (mycophenolate, tacrolimus, prednisone). Total kidney volumes were measured by means of high-resolution magnetic resonance imaging within 2 weeks after transplantation and at 1 year. The primary end point was change in total kidney volume at 1 year. RESULTS: Sixteen patients completed the 1-year study (8 patients in each group). There was a decrease in kidney volume in both the sirolimus group (percentage change from baseline, 20.5%; P < .001) and mycophenolate group (percentage change from baseline, 17%; P = .048), but there was no significant difference in percentage change of total kidney volume between the groups (P = .665). CONCLUSIONS: In ADPKD patients at 1 year after kidney transplantation, there was a similar decrease in polycystic kidney volume in patients receiving an immunosuppression regimen containing sirolimus compared with patients receiving mycophenolate.

Evidence that the fibrinogen binding domain of Apo(a) is outside the lysine binding site of kringle IV-10: a study involving naturally occurring lysine binding defective lipoprotein(a) phenotypes.

It is now established that the lysine binding site (LBS) of apo(a) kringle IV-10, and particularly Trp72, plays a dominant role in the binding of lipoprotein(a) [Lp(a)] to lysine. To determine the role of the LBS in the binding of Lp(a) to fibrinogen, we examined the binding to plasmin-modified (PM) fibrinogen of human and rhesus monkey Lp(a) species classified as either Lys' or Lys- based on their capacity to bind lysine Sepharose and to have Trp or Arg, respectively, in position 72 of the LBS of kringle IV-10. We also examined the free apo(a)s obtained by subjecting their corresponding parent Lp(a)s to a mild reductive procedure developed in our laboratory. Our results show that both Lyst and Lys- Lp(a)s and their derived apo(a)s, bound to PM-fibrinogen with similar affinities (Kds: 33-100 nM), whereas the B(max) values were threefold higher for apo(a)s. Both the lysine analog epsilon-aminocaproic acid and L-proline inhibited the binding of Lp(a) and apo(a) to PM fibrinogen. We conclude that the LBS of kringle IV-10 is not involved in this process and that apo(a) binds to PM-fibrinogen via a lysine-proline-sensitive domain located outside the LBS and largely masked by the interaction of apo(a) with apoB100. The significant difference in the PM fibrinogen binding capacity also suggests that apo(a) may have a comparatively higher athero-thrombogenic potential than parent Lp(a).

Comparative in vitro study of the pro-apolipoprotein A-I to apolipoprotein A-I converting activity between normal and Tangier plasma.

We examined the ability of the plasma of a 52-yr-old male Tangier patient to effect the conversion of radiolabeled pro-apolipoprotein A-I (apo A-I), isolated from hepatoma cell culture media, into mature apo A-I. The conversion was assessed by amino-terminal sequence analysis, isoform patterns with two-dimensional gel electrophoresis, and a rapid assay based on the different solubilities of intact pro-apo A-I and its hexapeptide prosegment in 10% trichloroacetic acid. We found that the converting activity of Tangier plasma was comparable to that exhibited by control normolipidemic plasma and that in both cases pro-apo A-I was correctly processed at the Gln-Asp bond. After ultracentrifugal fractionation of Tangier plasma at d = 1.21 g/ml, the pro-apo A-I-to-mature apo A-I converting activity was mainly recovered in the middle fraction of d = 1.225 g/ml and was at least 10-fold more effective than the top and bottom fractions. In contrast, in normal plasma the activity was only present in the top and bottom fractions. It has been previously established that in Tangier plasma the pro-apo A-I/apo A-I ratio is significantly higher than normal (1 vs. 0.02). Our studies suggest that this abnormal ratio is not the result of a reduced converting enzyme activity and may relate to differences in turnover rates between Tangier and normal plasma apolipoproteins.

Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure.

We sought to determine whether mice deficient in the proinflammatory caspase-1, which cleaves precursors of IL-1 beta and IL-18, were protected against ischemic acute renal failure (ARF). Caspase-1(-/-) mice developed less ischemic ARF as judged by renal function and renal histology. These animals had significantly reduced blood urea nitrogen and serum creatinine levels and a lower morphological tubular necrosis score than did wild-type mice with ischemic ARF. Since caspase-1 activates IL-18, lack of mature IL-18 might protect these caspase-1(-/-) mice from ARF. In wild-type animals, we found that ARF causes kidney IL-18 levels to more than double and induces the conversion of the IL-18 precursor to the mature form. This conversion is not observed in caspase-1(-/-) ARF mice or sham-operated controls. We then injected wild-type mice with IL-18-neutralizing antiserum before the ischemic insult and found a similar degree of protection from ARF as seen in caspase-1(-/-) mice. In addition, we observed a fivefold increase in myeloperoxidase activity in control mice with ARF, but no such increase in caspase-1(-/-) or IL-18 antiserum-treated mice. Finally, we confirmed histologically that caspase-1(-/-) mice show decreased neutrophil infiltration, indicating that the deleterious role of IL-18 in ischemic ARF may be due to increased neutrophil infiltration.

Effect of high-density lipoproteins with varying ratios of apolipoprotein A-I to apolipoprotein A-II on steroidogenesis by cultured rat ovary granulosa cells.

Plasma high-density lipoproteins (HDL) can provide rat ovary steroidogenic tissue with cholesterol for steroid hormone production, but the mechanism of cholesterol transfer is unknown. To test the importance of apolipoprotein A-I (the major HDL apolipoprotein) in HDL-cell interactions, we examined the ability of canine-human HDL hybrids containing various proportions of canine apolipoprotein A-I and human apolipoprotein A-II to stimulate steroidogenesis by cultured rat ovary granulosa cells. We observed that as the apolipoprotein A-II to apolipoprotein A-II ratio decreased, the ability of the hybrid particles to stimulate granulosa cell progestin (progesterone and 20 alpha-dihydroprogesterone) production diminished. However, granulosa cell progestin (progesterone and 20 alpha-dihydroprogesterone) production diminished. However, apolipoprotein A-I was not necessary for cholesterol transfer, since hybrids with less than 5% of their total apolipoprotein mass as apolipoprotein A-I stimulated progestin production 30% as effectively as canine HDL, which contained essentially only apolipoprotein A-I. These data indicate that the delivery of cholesterol from HDL into the rat ovary cell for steroidogenesis is not strictly dependent on the presence of a specific HDL apolipoprotein.

Caspases as drug targets in ischemic organ injury.

Caspases are intracellular cysteine proteases that mediate cell death and inflammation. Caspase-3 is a major mediator of both apoptotic and necrotic cell death. Caspase-1 mediates inflammation though the activation of the cytokines interleukin-1beta (IL-1beta) and interleukin-18 (IL-18). Increases in both caspase-1 and -3 have been described in ischemic injury to various organs including brain, heart and kidney. Both pharmacological inhibitors and genetic approaches have been used to inhibit caspases in vivo. Pancaspase inhibitors protect against ischemic injury in brain, heart and kidney. Pancaspase inhibition also reduces cold preservation injury due to apoptosis in liver endothelial cells and prolongs animal survival after orthotopic liver transplantation. Caspase-1 inhibition or caspase-1 deficiency protects against ischemic injury in brain, heart and kidney models of ischemia. Specifically, impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. This review focuses on studies of caspase-1 and pancaspase inhibition in ischemic injury to brain, heart and kidney. In addition, the studies of pancaspase inhibition in cold ischemic injury and organ preservation will be reviewed. The therapeutic potential of caspase inhibition in ischemic injury will be discussed.

Changes in plasma triglyceride levels shift lipoprotein(a) density in parallel with that of LDL independently of apolipoprotein(a) size.

Lipoprotein(a) [Lp(a)] represents a class of low density lipoprotein (LDL) particles that have as a protein moiety apolipoprotein B-100-linked covalently to a single molecule of apolipoprotein(a) [apo(a)], a specific multikringle protein of the plasminogen family. Lp(a) is polymorphic in density because of either the density heterogeneity of constitutive LDL, apo(a) size, or both. Authentic LDL also represents a set of heterogeneous particles whose density is affected by metabolic events. Whether in vivo these events may also affect Lp(a) density is not clearly established. To this effect, we studied 75 subjects with plasma Lp(a) protein levels between 7 and 50 mg/dL and containing a single apo(a) size isoform. We used density gradient ultracentrifugation to simultaneously monitor the changes in the peak density of LDL and Lp(a) at entry and during the course of treatments directed at reducing plasma triglyceride levels. In each case, we found that at entry, Lp(a) peak density was correlated with LDL peak density (r=0.71, P<0.0001) and that during treatment, changes in plasma triglycerides were associated with shifts of Lp(a) peak density that paralleled those of LDL peak density. A high correlation (r=0.94, P<0.0001) was particularly evident in subjects with initial plasma triglycerides in the 300-mg/dL range. In vitro assembly studies showed that an apo(a) isoform containing 14 kringle IV type 2 repeats, exhibited, on incubation with LDL, a comparable degree of incorporation into LDL species varying in density between 1.035 and 1.057 g/mL Taken together, our results indicate that metabolically dependent changes in the peak density of Lp(a) can occur independently of apo(a) size. These changes may have to be taken into account in assessing the cardiovascular pathogenicity of this lipoprotein particle in hypertriglyceridemic subjects.

Dominant role of the C-terminal domain in the binding of apolipoprotein(a) to the protein core of proteoglycans and other members of the vascular matrix.

The C-terminal domain of apolipoprotein(a) binds in vitro to the protein core of proteoglycans as well as fibrinogen and fibronectin, suggesting that this domain plays a role in anchoring lipoprotein(a) or free apolipoprotein(a) to the vascular subendothelial matrix.

A 20-month follow-up study of 628 women with eating disorders, I: Course and severity.

A national sample of 628 women with eating disorders completed questionnaires in 1982 and again in 1984. According to initial simulated DSM-III diagnoses, 34 had anorexia nervosa with bulimic features, 392 had normal-weight bulimia, and 202 had a subdiagnostic eating disorder. Most respondents in the latter two groups met some criteria for alternative eating disorders. At follow-up, 29% of the anorexia nervosa group and 43% of the normal-weight bulimia group had improved enough to be classified as having a subdiagnostic disorder. Respondents who sought professional help between the initial survey and follow-up reported no more improvement than those who did not seek help.

Effects of weight loss on the dexamethasone suppression test.

The authors studied postdexamethasone cortisol secretion in 18 depression-free, healthy, obese subjects before and after weight loss. Although all subjects suppressed cortisol normally before weight loss, 5 of 18 (27.5%) failed to suppress cortisol after an average loss of 13.5 kg. This failure to suppress cortisol was not associated with any change in depression ratings.

Apolipoprotein(a): structure and biology.

Apolipoprotein(a), apo(a), the distinctive glycoprotein constituent of lipoprotein(a), Lp(a), is synthesized in the liver, links covalently to apoB100-lipoprotein, and travels so linked in the plasma to tissue sites where removal mechanisms are yet undetermined. Depending on the redox status of the surrounding milieu, apo(a) may re-acquire its unbound state shown to have structural and functional properties different from those of the bound form. Apo(a) is potentially athero-thrombogenic, a property which may be influenced by its size, sequence polymorphism, type of lipoprotein it is linked to and the inflammatory state of the vessel wall. This set of variables must be taken into account when assessing the cardiovascular pathogenicity of free and bound apo(a).

Progress in blood pressure control in autosomal dominant polycystic kidney disease.

Hypertension occurs commonly in autosomal dominant polycystic kidney disease (ADPKD) and is an important factor in the progression of the disease and cardiovascular mortality. The aim of this prospective 15-year study is to report the rate of blood pressure control and the potential effect of a 10-point education program developed by our center for ADPKD patients and their physicians. The patients' blood pressure treatment was managed by their primary care physicians. Three 5-year periods were analyzed in which similar rates of hypertension in patients with ADPKD were present (63% to 68%). In the first period (1985 to 1989), the rate of blood pressure control (<140/90 mm Hg) was 38% for 216 hypertensive patients with ADPKD. From 1990 to 1994, the percentage of blood pressure control increased to 55% in 194 hypertensive patients with ADPKD (P < 0.001 versus 1985 to 1989); and the level of blood pressure control increased to 64% in 181 hypertensive patients with ADPKD during 1995 to 1999 (P < 0.001 versus 1985 to 1989). Although this percentage of blood pressure control in patients with ADPKD remains suboptimal, it compares very favorably with the 27% estimated blood pressure control in patients with essential hypertension from 1991 to 1994 in the United States.

Effect of antihypertensive therapy on renal function and urinary albumin excretion in hypertensive patients with autosomal dominant polycystic kidney disease.

Hypertensive patients with autosomal dominant polycystic kidney disease (ADPKD) have a faster progression to end-stage renal disease (ESRD) than their normotensive counterparts. The aim of this prospective, randomized study is to compare the effects of the calcium channel blocker amlodipine and the angiotensin-converting enzyme inhibitor enalapril as first-line therapy on blood pressure, renal function, and urinary albumin excretion in hypertensive patients with ADPKD. Twenty-four patients with ADPKD with hypertension with creatinine clearances (Ccrs) greater than 50 mL/min/1.73 m(2) were included in the study. Twelve patients received amlodipine (mean dose, 9 mg/d), and 12 patients received enalapril (mean dose, 17 mg/d). The patients were followed up for 5 years. Baseline mean arterial pressures, which were 109 +/- 3 mm Hg in the amlodipine group and 108 +/- 3 mm Hg in the enalapril group, decreased significantly after 1 year of follow-up (amlodipine, 96 +/- 3 mm Hg; P < 0.005; enalapril, 89 +/- 2 mm Hg; P < 0.0005) and remained stable at year 5 (amlodipine, 97 +/- 3 mm Hg; P < 0.0005 versus baseline; enalapril, 94 +/- 3 mm Hg; P < 0.005 versus baseline). Ccrs, which were 83 +/- 5 mL/min/1.73 m(2) in the amlodipine group and 77 +/- 6 mL/min/1.73 m(2) in the enalapril group, remained stable after 1 year of follow-up and decreased significantly at year 3 in both groups (amlodipine, 67 +/- 5 mL/min/1.73 m(2); P < 0.01 versus year 1 and baseline; enalapril, 58 +/- 4 mL/min/1.73 m(2); P < 0.05 versus year 1 and P < 0.0005 versus baseline) with no significant change thereafter. No change was observed in urinary albumin-creatinine ratio in the amlodipine group (baseline, 68 +/- 21 mg/g; year 1, 52 +/- 21 mg/g; year 5, 148 +/- 74 mg/g), whereas it decreased significantly in the enalapril group at year 1 (baseline, 23 +/- 4 mg/g; year 1, 13 +/- 3 mg/g; P < 0.05) and remained stable until the end of the study at year 5 (14 +/- 6 mg/g). The investigators concluded that blood pressure was similar in both groups but only enalapril had a significant effect to sustain decreased urinary albumin excretion for a 5-year follow-up. Although proteinuria has been considered a surrogate of renal disease progression, further studies will be necessary to confirm this hypothesis in ADPKD, because after 5 years, no differences in renal function were observed between the enalapril and amlodipine groups. In comparison with patients with ADPKD with uncontrolled hypertension, effective control of blood pressure, as undertaken in the present study, should delay the onset of ESRD by approximately 15 years.

Presumed adenocarcinoma of the retinal pigment epithelium in a blind eye with a staphyloma.

The retinal pigment epithelium (RPE) can undergo reactive hyperplasia and metaplasia following a variety of ocular insults. However, true neoplasms of the RPE are rare. We report a case of a papillary adenocarcinoma of the RPE arising in the blind staphylomatous right eye of a 79-year-old woman with a long history of bilateral posterior staphylomas who was seen with increasing pain and exophthalmos of the right eye. Findings from ultrasonography and computed tomography demonstrated linear calcification consistent with osseous metaplasia of the RPE. Progression of the exophthalmos and worsening exposure keratitis led to enucleation of the eye. Gross pathology showed a 79-mm-long globe. Histopathologic findings revealed a largely amelanotic papillary adenocarcinoma arising from the RPE. Positive immunoreactivity for cytokeratin supported the epithelial origin of the tumor. Adenocarcinoma of the RPE is rare but may develop in a blind eye.

Postprandial lipoprotein(a) response to a single meal containing either saturated or omega-3 polyunsaturated fatty acids in subjects with hypoalphalipoproteinemia.

We have recently reported that the apolipoprotein (apo) B-100-apo(a) complex, the protein moiety of lipoprotein(a) [Lp(a)], has a high affinity for triglyceride(TG)-rich particles (TRP) and that this complex can affiliate with endogenous TG-rich lipoproteins. To shed more light on the apo B-100-apo(a) complex associated with plasma TRP during postprandial lipidemia, we fed five male subjects presenting with primary hypoalphalipoproteinemia (HP) and four male controls a single fat meal (60 g/m2) containing saturated fatty acids (SFA) and, 6 weeks later, an isocaloric meal containing omega-3 polyunsaturated fatty acids. The subjects were phenotyped for plasma Lp(a) and apo C-III levels, apo(a) and apo E isoforms, and lipoprotein lipase and hepatic lipase activities. Vitamin A was included in the meal as a marker of intestinally derived TRP. Following the SFA meal, three of the HP subjects showed a decrease in plasma levels of Lp(a) that lasted 10 to 12 hours in the presence of an increased hypertriglyceridemic response. Two HP subjects who had low preprandial lipoprotein lipase activity and elevated plasma apo C-III levels showed an increase in plasma Lp(a) levels along with the hypertriglyceridemic excursion. However, in all cases, inclusive of the controls, there was an elevation in plasma levels of TRP of Sf greater than 1,000 that contained apo B-100-apo(a) 6 to 8 hours after the meal. This TRP excursion appeared not to be related to the basal levels of plasma Lp(a), high-density lipoprotein (HDL) cholesterol, TGs, or apo(a) and apo E isoforms, and it did not coincide with the retinyl ester peak.(ABSTRACT TRUNCATED AT 250 WORDS)