Retina-arrestin specific CD8+ T cells are not implicated in HLA-A29-positive birdshot chorioretinitis.

BACKGROUND: HLA-A29-positive birdshot chorioretinitis (BCR) is an inflammatory eye disorder that is generally assumed to be caused by an autoimmune response to HLA-A29-presented peptides from retinal arrestin (SAG), yet the epitopes recognized by CD8+ T cells from patients remain to be identified. OBJECTIVES: The identification of natural ligands of SAG presented by HLA-A29. To quantify CD8+ T cells reactive to antigenic SAG peptides presented by HLA-A29 in patients and controls. METHODS: We performed mass-spectrometry based immunopeptidomics of HLA-A29 of antigen-presenting cell lines from patients engineered to express SAG. MHC-I Dextramer technology was utilised to determine expansion of antigen-specific CD8+ T cells reactive to SAG peptides in complex with HLA-A29 in a cohort of BCR patients, HLA-A29-positive controls, and HLA-A29-negative controls. RESULTS: We report on the naturally presented antigenic SAG peptides identified by sequencing the HLA-A29 immunopeptidome of antigen-presenting cells of patients. We show that the N-terminally extended SAG peptide precursors can be trimmed in vitro by the antigen-processing aminopeptidases ERAP1 and ERAP2. Unexpectedly, no enhanced antigen engagement by CD8+ T cells upon stimulation with SAG peptides was observed in patients or HLA-A29-positive controls. Multiplexed HLA-A29-peptide dextramer profiling of a case-control cohort revealed that CD8+ T cells specific for these SAG peptides were neither detectable in peripheral blood nor in eye biopsies of patients. CONCLUSIONS: Collectively, these findings demonstrate that SAG is not a CD8+ T cell autoantigen and sharply contrast the paradigm in the pathogenesis of BCR. Therefore, the mechanism by which HLA-A29 is associated with BCR does not involve SAG.

An Ocular Protein Triad Can Classify Four Complex Retinal Diseases.

Retinal diseases generally are vision-threatening conditions that warrant appropriate clinical decision-making which currently solely dependents upon extensive clinical screening by specialized ophthalmologists. In the era where molecular assessment has improved dramatically, we aimed at the identification of biomarkers in 175 ocular fluids to classify four archetypical ocular conditions affecting the retina (age-related macular degeneration, idiopathic non-infectious uveitis, primary vitreoretinal lymphoma, and rhegmatogenous retinal detachment) with one single test. Unsupervised clustering of ocular proteins revealed a classification strikingly similar to the clinical phenotypes of each disease group studied. We developed and independently validated a parsimonious model based merely on three proteins; interleukin (IL)-10, IL-21, and angiotensin converting enzyme (ACE) that could correctly classify patients with an overall accuracy, sensitivity and specificity of respectively, 86.7%, 79.4% and 92.5%. Here, we provide proof-of-concept for molecular profiling as a diagnostic aid for ophthalmologists in the care for patients with retinal conditions.

Reagent strips are efficient to rule out spontaneous bacterial peritonitis in cirrhotics.

BACKGROUND: The gold standard to diagnose spontaneous bacterial peritonitis (SBP) is a polymorphonuclear neutrophil count ≥ 250 cells/µl in ascitic fluid. This test is laborious and expensive. Urine reagent strips measuring leukocyte esterase activity have been proposed as a rapid and inexpensive alternative. The aim of this study was to assess the diagnostic accuracy of the Combur reagent strip for diagnosing SBP. Furthermore the possible advantage of a photospectrometer reading over visual reading of the strip was investigated. METHODS: This prospective study includes all ascitic fluid samples of cirrhotic patients undergoing diagnostic or therapeutic paracentesis over a 12-month period. The samples were collected for the standard diagnostic work-up and in addition tested with a bedside Combur reagent strip. The strip was read visually and with an automated spectrometer. RESULTS: A total of 157 samples were obtained from 53 patients, and spontaneous bacterial peritonitis was diagnosed in 12 patients based on the ascitic polymorphonuclear neutrophil count. The sensitivity, specificity, positive predictive value and negative predictive value of the reagent strip according to the photospectrometer were 100%, 93%, 55% and 100% respectively, and 75%, 99%, 82% and 98%, respectively, for visual interpretation. The diagnostic accuracy of the photospectrometer was found to be higher than visual interpretation (p = 0.007). CONCLUSION: The diagnostic accuracy of leucocyte esterase reagent strips read out by a photospectrometer was comparable with the gold standard test and was excellent for excluding SBP. Our results support implementation of reagent strips in the diagnostic work-up of ascitic fluid.

Components of the renin-angiotensin-aldosterone system in plasma and ascites in hepatic cirrhosis.

BACKGROUND: Decompensated liver cirrhosis is characterized by activation of the renin-angiotensin-aldosterone system (RAAS). We investigated whether compartmentalization of these components occurs in ascitic fluid. METHODS: In 26 patients with cirrhosis RAAS components and albumin were quantified in simultaneously obtained plasma and ascitic fluid samples. Renin degradation was determined in vitro in plasma and ascites. RESULTS: Plasma angiotensinogen was below normal reference values in all but two patients and correlated inversely with plasma renin (r = -0.73, P < 0.001). Plasma renin activity was elevated in most subjects. The plasma and ascites concentrations of renin, prorenin, angiotensinogen and aldosterone were closely (P < 0.001) correlated. Expressed as a percentage of plasma levels, the angiotensinogen level (18 +/- 11%) was slightly lower than the albumin level (23 +/- 8%), whereas the aldosterone level (43 +/- 18%) was considerably higher (P < 0.0001). For renin and prorenin these percentages were much lower (P < 0.0001), despite the fact that their molecular weight is lower than that of albumin and angiotensinogen. This was not due to a more rapid degradation of renin in ascites fluid, since the in-vitro degradation rates of renin in plasma and ascitic fluid were identical. CONCLUSION: In hepatic cirrhosis ascites can be regarded as an ultrafiltrate of plasma RAAS components. Since differences in molecular weight or metabolic rate cannot explain the low ascites-to-plasma ratio of renin and prorenin, either their transcapillary transport is impaired and/or they selectively bind to (pro)renin binding sites.

Ascites in cirrhosis: a review of management and complications.

Ascites is the most common manifestation in cirrhotic patients, and is associated with a reduced survival rate. Management of ascites is primarily focused on sodium restriction and diuretic treatment to which most patients respond appropriately. For the small group of patients who do not respond sufficiently, interventions such as large volume paracentesis and transjugular intrahepatic portosystemic shunt placement should be considered. Most important in the management of cirrhotic patients with ascites is prevention of complications. Spontaneous bacterial peritonitis and hepatorenal syndrome are severe complications with a poor prognosis when not detected and treated in an early stage. In all hospitalised patients with ascites, an infection of the ascitic fluid should be ruled out. For those patients at risk of developing spontaneous bacterial peritonitis, in particular patients after a first episode and patients with gastrointestinal bleeding, antibiotic prophylaxis should be given. To prevent the hepatorenal syndrome, substitution with albumin is essential, both in patients who experience an episode of spontaneous bacterial peritonitis and in patients treated with large volume paracentesis. For those patients unresponsive to standard treatment regimens, liver transplantation may be the only suitable treatment option.

[Spontaneous bacterial peritonitis, a severe complication in patients with liver cirrhosis]. / Spontane bacteriële peritonitis, een ernstige complicatie van levercirrose.

Three patients with hepatic cirrhosis and ascites, a 65-year-old man, a 17-year-old woman and a 49-year-old man, were admitted to hospital for progressive drowsiness, increased ascites, and melaena, respectively. An elevated number of polymorphonuclear leukocytes was found in the ascites. The three patients became more and more seriously ill. On the basis of the laboratory findings, a diagnosis of 'spontaneous bacterial peritonitis' was made. The patients recovered after administration of antibiotics. The signs and symptoms of spontaneous bacterial peritonitis can range from subtle, renal dysfunction or an altered mental state to the signs ofan acute abdomen. The common signs of infection such as fever and an elevated leukocyte count are present in only 50% of the patients. Gram-negative bacteria are most frequently isolated from cultures of the ascites fluid. The 1-year mortality is still 50-70% and is partly a result of the underlying liver disease. Prophylactic oral administration of a quinolone decreases the risk of spontaneous bacterial peritonitis in patients with gastrointestinal haemorrhage and in patients with a prior episode of spontaneous bacterial peritonitis. Long-term prophylaxis has been associated with the development of infections with quinolone-resistant microorganisms.

Review article: Management of ascites and associated complications in patients with cirrhosis.

BACKGROUND: Ascites is the most common complication of cirrhosis, associated with an expected survival below 50% after 5 years. Prognosis is particularly poor for patients with refractory ascites and for those developing complications, including spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS). AIM: To provide an evidence-based overview of the pathophysiology, diagnosis and clinical management of ascites secondary to liver cirrhosis. METHODS: Review based on relevant medical literature. RESULTS: Portal hypertension, splanchnic vasodilatation and renal sodium retention are fundamental in the pathophysiology of ascites formation. The SAAG (serum-ascites albumin gradient) allows reliable assessment of the cause of ascites. The majority of cirrhotic patients with ascites can be managed with dietary sodium restriction in combination with diuretic agents. Large volume paracentesis with albumin suppletion and TIPS are therapeutic options in patients with refractory ascites. Prophylactic antibiotics for SBP should be given in certain patient populations. CONCLUSIONS: Recent advances in the diagnosis and treatment of ascites and associated complications have improved the medical management and poor prognosis of patients with these manifestations of advanced liver disease. Early diagnosis, adequate treatment and focus on prevention of complications remain essential as well as timely referral for liver transplantation.

[Hepatic hydrothorax]. / Hepatische hydrothorax.

Hepatic hydrothorax was diagnosed in four patients with liver cirrhosis, three men aged 65, 41, and 48 and a woman aged 48. They presented with either right-sided or bilateral pleural-fluid accumulations in the absence of cardiopulmonary disease. In the first man with no concurrent ascites, the disorder was missed, resulting in prolonged chest tube drainage, multiple severe complications and death. In the 41-year-old man chest tube drainage was also associated with complications including renal failure and encephalopathy. Pleurodesis was effective in the woman while in the remaining man hepatic hydrothorax was only a temporary, asymptomatic finding. Pleural effusions in cirrhotic patients should be considered and managed as hepatic hydrothorax unless diagnostic studies reveal a different aetiology. Absence of ascites is not uncommon and should not delay the correct diagnosis. The gradient between pleural and serum albumin concentration is typically more than 11 g/l. Prolonged chest tube drainage is dangerous and should be avoided. In cases refractory to salt restriction and diuretic therapy, transjugular introduction of an intrahepatic portosystemic shunt is the treatment of choice. Recently, pleurodesis combined with thoracoscopic repair ofdiaphragmatic defects has been reported as a potentially effective form of therapy.

Initial manifestation of primary hyperoxaluria type I in adults-- recognition, diagnosis, and management.

Primary hyperoxaluria type I may initially manifest as urolithiasis, renal insufficiency, or symptoms of systemic oxalosis. This hereditary disorder was fatal until effective therapies evolved during the past two decades. Difficulty in recognizing and diagnosing this disorder in adults is illustrated in a report of a patient eventually restored to good health by high-flux dialysis and combined renal and hepatic transplantation. I explore the molecular processes of the genetic defect and discuss clinical indicators of primary hyperoxaluria type I, manifestations of oxalosis, the pathogenesis of chronic oxalate nephropathy, and the diagnosis and management of this disease.

Malignant ventricular arrhythmias are well tolerated in patients receiving long-term left ventricular assist devices.

OBJECTIVES: We sought to quantitate the incidence of malignant ventricular arrhythmias and to identify subsequent hemodynamic changes and untoward events in patients who have received an implantable left ventricular circulatory assist device as an extended bridge to heart transplantation. BACKGROUND: Implantable long-term mechanical circulatory assist devices have been used clinically with increasing frequency and success for the past 4 years. Previous investigators have suggested that patients with malignant ventricular arrhythmias receiving a left ventricular assist device will require both left and right ventricular assistance to maintain vital organ perfusion. METHODS: We reviewed our 4-year experience with 21 patients who underwent implantation of a left ventricular assist device. Device flows and mean arterial pressure were used to assess systemic perfusion; central venous pressure provided a gauge of right ventricular function. Charts were screened for evidence of end-organ injury resulting from malignant ventricular arrhythmias. RESULTS: Malignant ventricular arrhythmias occurred in 4 patients (19%) before device placement and in 9 patients (43%) during device support. The latter nine patients formed the final study group; their arrhythmias occurred 0 to 186 days after device implantation and had a duration of 10 min to 12 days. The patients reported weakness or palpitation; however, none reported syncope or dyspnea. Mean arterial pressure and central venous pressure were insignificantly changed by the arrhythmias. Device flow decreased by 1.4 +/- 0.6 liters/min (p < 0.05) at the onset of the arrhythmias but returned to normal after cardioversion. No thromboembolic events or significant end-organ dysfunction occurred. CONCLUSION: Absence of right ventricular contraction during malignant ventricular arrhythmias is well tolerated in recipients of a left ventricular assist device. The diagnosis of malignant arrhythmia should be suspected if an unexplained decrease in left ventricular assist device flow occurs. Early electrical cardioversion is warranted to avoid both thrombus formation in the native heart and right ventricular myocardial injury from prolonged fibrillation.

Medullary sponge kidney.

"Medullary sponge kidney" applies to pathologically dilated collecting tubules within one or more renal pyramids of one or both kidneys, almost always diagnosed radiographically, of uncertain etiology, and presenting a clinical spectrum varying from an asymptomatic, incidental finding to severely complicating calcareous-infective disease, renal insufficiency, and death. Recognition of the characteristic urographic pattern affords the patient presenting clinically with hematuria, ureteral colic, urinary tract infection, or nephrocalcinosis a prompt diagnosis with a frequently benign prognosis, and usually averts more extensive or invasive investigations.