Plasma coagulation profiles in patients with severe primary pulmonary hypertension

Patients with primary pulmonary hypertension (PPH) benefit from treatment with anticoagulants, and histological findings suggest that in situ thrombosis of pulmonary vessels contributes to the pathogenesis of this disease. The mechanisms that cause a hypercoagulable state in the pulmonary vascular bed have not been fully investigated. This study compared plasminogen plasma activity, protein C and protein S plasma activities, fibrinogen and fibrin degradation products (FGDP and FBDP, respectively), von Willebrand factor antigen (vWF-Ag), prothrombin fragment F1.2, thrombin-antithrombin complexes (TAT), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) in 16 patients with PPH and in 16 healthy volunteers. In a subset of the PPH patients, these variables were also compared in simultaneously-obtained mixed-venous and arterial blood samples. Proteins C and S, FGDP, FBDP, and plasminogen levels as well as plasma concentrations of prothrombin fragment F1.2 and TAT were normal in the 16 patients with PPH. In contrast, the plasma activity of PAI was significantly elevated (p<0.0001). Arterial PAI levels were considerably higher than mixed venous PAI levels (p=0.0018), which may reflect intrapulmonary production. Furthermore, vWF-Ag levels were significantly elevated (p<0.0001), but there was no significant difference between mixed-venous and arterial blood. These data, on the whole, do not suggest increased thrombin activity in patients with primary pulmonary hypertension. However, the markedly elevated levels of plasminogen activator inhibitor as well as its transpulmonary gradient may provide a clue to locally impaired fibrinolysis in the pulmonary vascular bed.     

In situ expression of cytokines in IgA nephritis

We studied mRNA and protein expression of interleukins (IL) and tumor necrosis factor (TNF) in renal tissues biopsied from 40 patients with IgA nephritis. Immunofluorescent staining with antibodies to IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF-alpha, and TNF-beta was intense in the cytoplasm of cells in glomeruli, which were dual-stained with an anti-monocyte-macrophage antibody. In addition, moderate immunofluorescence for TNF-alpha, and weak staining for IL-1 alpha and IL-6 were occasionally found in resident glomerular cells. Immunoperoxidase-in situ hybridization dual-labeling revealed that IL-1 alpha, IL-6, and TNF-alpha mRNA signals were present in intraglomerular cells reactive with anti-monocyte-macrophage antibody, which further supported the immunofluorescent findings. Cells expressing IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF-alpha, and TNF-beta were also observed in the interstitium. Most of these cells were also labeled with the anti-monocyte-macrophage antibody. The number of IL-1 alpha, IL-6, and TNF-alpha-positive cells infiltrating the glomerulus significantly correlated with mesangial hypercellularity. IL-8 and TNF-alpha-positive intraglomerular cells were correlated with the magnitude of proteinuria. The population of interstitial cells positive for IL-1 alpha, IL-6, IL-8, and TNF-alpha was associated with the grade of tubulointerstitial changes and proteinuria. There was no correlation between local IL-1 alpha, IL-6, and TNF-alpha expression in glomeruli or interstitium and serum or urinary levels of the respective cytokines.(ABSTRACT TRUNCATED AT 250 WORDS)     

Appendectomies in patients with nephritis

Threshold temperatures for shivering in acute and chronic hypercapnia were determined in guinea pigs by measuring the time course of cervical cord temperature, skin temperature, oxygen consumption (Vo2), and electrical muscle activity during cold exposure (15 degrees C). Prior to acute exposure to CO2, the shivering threshold was determined in each animal during control conditions breathing air. With increasing CO2 concentrations (5,7.5, and 15% CO2) the shivering thresholds fell to lower temperatures, decreasing by approximately 40 degrees C at 15% CO2. The shift of the shivering threshold to lower values found during acute exposure to 15% CO2 was reversed after chronic exposure to 15% CO2 for 3 days, which marks the time of metabolic adaptation to CO2.     

Whole blood platelet aggregation and coagulation factors in patients with systemic sclerosis

It is unclear whether the changes in platelet function which are observed in systemic sclerosis are a primary characteristic of this disease or whether they occur secondary to vascular changes. Whole blood platelet aggregation was studied in 26 patients with systemic sclerosis, normal subjects matched for age, sex and secondary characteristics, 19 patients with Raynaud's disease and 19 patients with systemic lupus erythematosus. Plasma levels of fibrinogen, von Willebrand factor antigen and factor VIII:C were also measured. Systemic sclerosis was associated with a significant (P > 0.001) enhancement of the sensitivity of platelets to collagen. In contrast, significant enhancement of the response to either ADP or adrenaline was not observed. Enhanced sensitivity to collagen was not associated with the presence of either Raynaud's disease or systemic lupus erythematosus. Systemic sclerosis was associated with significantly raised levels of von Willebrand factor antigen and fibrinogen. On an individual patient basis, von Willebrand factor antigen was related to the severity of the disease whereas platelet sensitivity to collagen was not. In conclusion, this study suggests that the enhanced sensitivity to collagen which occurs in systemic sclerosis is due to a primary change in the platelet and that this change can combine with elevated levels of adhesive proteins.     

Linear IgA bullous dermatosis after contact with sodium hypochlorite

The onset of linear IgA bullous dermatosis (LABD) is generally spontaneous, but a number of cases of LABD have been reported either following drug exposure or in association with malignancies. We describe a patient who developed a vesicular eruption shortly after an irritant dermatitis caused by the contact with a detergent containing sodium hypochlorite. Direct immunofluorescence revealed linear deposits of IgA and C3 in the epidermal basement membrane. The patient's serum contained IgA that immunoblotted a 180-kD polypeptide in extracts of human keratinocytes. The patient responded promptly to therapy with dapsone. We suggest a possible pathogenetic relationship between the chemical dermatitis and LABD in this patient.     

Plasma renin activity in patients with coronary arteriosclerosis with different types of hyperlipoproteinemia

The examination was conducted in 142 patients with coronary atherosclerosis, aged 33 to 74 years, and in 40 normal persons, aged 25 to 48 years. The pain form of the disease was observed in 96 patients, the arrhythmic one--in 38, the painless one--in 8 patients. The arterial pressure was within the normal limits in the examined patients. In 67.6% of the patients hypercholesterolemia was diagnosed, in 47.3%--hypertriglyceridemia. Type II hyperlipoproteinemia was found in 67.6% of the cases, types III and IV--in 5.3 and 9.1%, respectively, type V--in 0.5% of the patients; the type of hyperlipoproteinemia could not be identified in 10.6%, and in 6.9% of the cases the blood level of lipoproteins did not differ from the normal. The plasma renin activity examined by the radioimmunoassay in normals comprised 1.26 +/- 0.21 ng/ml/hour; in patients with the pain form of coronary atherosclerosis--6.67 +/- 0.72 ng/ml/hour; in those with arrhythmias--6.89 +/- 1.20 ng/ml/hour; in those with the painless form--2.39 +/- 1.02 ng/ml/hour. The highest renin activity was revealed in types IIa, IIb and III hyperlipoproteinemia, as well as in paroxysmal arrhythmia and cardiac fibrillation.     

Dinitrochlorobenzene test in patients with chronic nephritis

The effect of passive immunization with hetero and isoimmune antiovary antiserum on the fertilization of mouse, rat, and hamster eggs was determined. Fertilization of the eggs could be inhibited by a single ip injection of respective antiovary antiserum obtained from rabbits. The antiovary antisera absorbed with the ovary did not prevent fertilization but antisera absorbed with the liver and kidney inhibited fertilization was not inhibited by a single ip injection of antiovary antiserum obtained from rats and mice, respectively. Fertilization in vitro of mouse eggs was low in the presence of control serum but was significantly reduced in the presence of antiserum (p less than .001).     

Cationic dextran induces mesangioproliferative nephritis in rats independent of glomerular IgA deposition

BACKGROUND: Dextran-induced mesangioproliferative glomerulonephritis in mice and, as recently reported, in rats is used as a model of IgA nephropathy. The pathogenetic role of the glomerular IgA deposits in this model, however, is unclear since IgG is often deposited in parallel. METHODS: Lewis rats were immunized with cationic DEAE-dextran. Following this, rats received 5 x/week i.v. injections of 3 mg DEAE-dextran each, from days 20 to 80 and were then followed until day 120. RESULTS: Rats developed transient proteinuria (range 63-152 mg/24 h) and haematuria on day 80. Renal biopsies obtained at days 60, 80, 100 and 120 showed mild to severe mesangioproliferative changes at days 80 and 100 which did not persist at day 120. Electron-microscopy revealed mesangial immune deposits, signs of endothelial activation and vacuoles in mesangial cells and podocytes. Compared to normal, age-matched controls, in the nephritic rats significant (P < 0.05) increases were noted for glomerular total cellularity, alpha-smooth-muscle actin expression (a marker of activated mesangial cells), monocyte/macrophage counts, and matrix proteins. Using three different antibodies, no evidence of glomerular IgA deposition was detected at any time point. In contrast, glomerular IgG, IgM, C3, and occasional small C5b-9 deposits were present in nephritic rats. Circulating IgG but not IgA anti-dextran antibodies could be demonstrated in nephritic rats. CONCLUSIONS: The data confirm that mesangioproliferative glomerulonephritis can be induced in rats by immunization and chronic challenge with cationic dextran. Our data also show that in rats glomerular IgG deposition rather than IgA, appears to play an important pathogenetic role in this mesangioproliferative glomerulonephritis model.     

Morphologic high-risk factors in IgA nephropathy

The 2-benzoylthiophene chromophore of the photosensitizing drug tiaprofenic acid and of its decarboxylated derivative is characterized by a unusually high energy gap between the T1 (pi, pi*) and T2 (n, pi*) excited states, which makes this a unique system to study the intrinsic photoreactivity of the two states. Weak fluorescence and phosporescence emission were detected at room temperature. Tiaprofenic acid undergoes photodecarboxylation from the triplet manifold as the main reaction. The photoprocess is temperature dependent with activation energy of 7-10 kcal/mol, close to the energy gap between T1 and T2. The decarboxylated product abstracts hydrogen in type I reactions. The involvement of T2 in the above processes is proposed. Moreover the decarboxylated derivative exhibits reactivity toward phenols, consistent with a participation of the T1 state as electron acceptor. The observed photoprocesses can account for biological photosensitization reactions, like membrane damage and protein modification.     

Physical activity status and adverse age-related differences in coagulation and fibrinolytic factors in women

BACKGROUND/AIMS: Current criteria to predict sustained response for a patient with chronic hepatitis C virus during interferon treatment are not consistent. The aim of this study was to determine a reliable point in time to predict non-response to therapy, as a theoretical basis for early cessation of treatment. METHODS: Sera (-70 degrees C) from 66 patients treated with interferon (3 million units three times a week for 6 months) were assayed with a quantitative polymerase chain reaction (sensitivity < or =100 copies per milliliter). Evaluations were made at baseline, during treatment at weeks 1, 2, 4, 12, and 24, and at follow-up week 48. Biochemical response was defined using standard alanine aminotransferase criteria. Virologic response was defined as: sustained if loss of HCV RNA persisted through therapy and follow-up; relapse if HCV RNA became undetectable but reappeared during treatment or follow-up; and non-response if HCV RNA remained detectable during the study period. Alanine aminotransferase and HCV RNA results were analyzed at defined time intervals to determine a predictive value for non-response and sustained response. RESULTS: HCV RNA results are a more accurate predictor than alanine aminotransferase for both non-response and sustained response. Serum HCV RNA predicted non-response better than sustained response. The optimal time to predict non-response with serum HCV RNA was treatment week 12. CONCLUSIONS: Treatment week 12 results indicate that HCV RNA was a more accurate predictor for non-response than serum alanine aminotransferase. This prediction would have theoretically permitted stopping treatment for 75% of the patients in this study at treatment week 12 allowing an overall cost savings of 28%.     

Neonatal cytokines and coagulation factors in children with cerebral palsy

We explored the association of inflammatory mediators and markers of autoimmune and coagulation disorders with cerebral palsy (CP), examining 53 analytes in dried neonatal blood of 31 children with spastic CP, most born at term, and 65 control children. Ultramicroanalysis was performed by recycling immunoaffinity chromatography coupled with laser-enhanced fluorescence and chemiluminescence detection. Reactive antibodies to lupus anticoagulant, anticardiolipin, antithrombin III, and the translational product of the factor V Leiden mutation were isolated by recycling immunoaffinity chromatography and measured by capillary electrophoresis with chemiluminescence-enhanced immunoassay. Higher concentrations of interleukins (ILs) 1, 8, 9, tumor necrosis factor-alpha, and RANTES were observed in these children with CP than in any control child. There were also substantial elevations of IL-6, 11, 13, and other chemokines and colony-stimulating factors in children with CP. Antiphospholipid antibody was present in a titer of 1:100 or greater in 4 children with CP and no control child. Using cuts empirically chosen by recursive partitioning, we found higher concentrations of antibody to antithrombin III, to a translational product of factor V Leiden mutation, and to proteins C and S in children with CP than in controls. We conclude that inflammation and these coagulation abnormalities, which have interacting pathways, are important in the etiology of CP.     

Pressure ulcer risk factors among hospitalized patients with activity limitation

OBJECTIVE: To identify specific demographic, medical, functional status, and nutritional characteristics that predict the development of stage 2 or greater pressure ulcers among patients whose activity is limited to bed or chair. DESIGN: Prospective inception cohort study. SETTING: Tertiary care, urban, university teaching hospital. PATIENTS: A total of 286 patients fulfilling the following criteria: admitted to the hospital within the previous 3 days, age 55 years or more, expected to be confined to bed or chair for at least 5 days or had a hip fracture, and without a stage 2 or greater pressure ulcer. MAIN OUTCOME MEASURE: Time to in-hospital development of a stage 2 or greater pressure ulcer. RESULTS: Total cumulative incidence of pressure ulcers was 12.9% (n = 37) after a median time of 9 days from admission to final skin examination. Age of 75 years or more, dry skin, nonblanchable erythema (a stage 1 pressure ulcer), previous pressure ulcer history, immobility, fecal incontinence, depleted triceps skinfold, lymphopenia (lymphocyte count < 1.50 x 10(9)/L), and decreased body weight (< 58 kg) were significantly associated with pressure ulcer development by univariate Kaplan-Meier survival analyses (P < .05 by log-rank test). Risk ratios (and 95% confidence intervals) for predictors (P < or = .05) of pressure ulcer development after multivariable Cox regression analysis included the following: nonblanchable erythema, 7.52 (1.00 to 59.12); lymphopenia, 4.86 (1.70 to 13.89); immobility, 2.36 (1.14 to 4.85); dry skin, 2.31 (1.02 to 5.21); and decreased body weight, 2.18 (1.05 to 4.52). The 3-week cumulative incidence of pressure ulcers with none, one, two, or three or more of these characteristics was 0%, 11.4%, 39.6%, and 67.9%, respectively (P < .001 by log-rank test). CONCLUSIONS: These results suggest that nonblanchable erythema, lymphopenia, immobility, dry skin, and decreased body weight are independent and significant risk factors for pressure ulcers in hospitalized patients whose activity is limited to bed or chair.     

Serum IgA1 and IgA2 subclass antibodies against collagens in patients with ankylosing spondylitis

Clear cell papulosis is a newly described skin disease characterized by multiple white papules. Histopathologically, diagnostic clear cells were seen among the basal cells of the epidermis. We report clear cell papulosis on the lumbar area and buttocks of a 1-year-old girl.     

Plasma selenium in patients with cirrhosis

S100B(betabeta) is a dimeric Ca2+-binding protein that is known to inhibit the protein kinase C (PKC)-dependent phosphorylation of several proteins. To further characterize this inhibition, we synthesized peptides based on the PKC phosphorylation domains of p53 (residues 367-388), neuromodulin (residues 37-53), and the regulatory domain of PKC (residues 19-31), and tested them as substrates for PKC. All three peptides were shown to be good substrates for the catalytic domain of PKC. As for full-length p53 (Baudier J, Delphin C, Grunwald D, Khochbin S, Lawrence JJ. 1992. Proc Natl Acad Sci USA 89:11627-11631), S100B(betabeta) binds the p53 peptide and inhibits its PKC-dependent phosphorylation (IC50 = 10 +/- 7 microM) in a Ca2+-dependent manner. Similarly, phosphorylation of the neuromodulin peptide and the PKC regulatory domain peptide were inhibited by S100B(betabeta) in the presence of Ca2+ (IC50 = 17 +/- 5 microM; IC50 = 1 +/- 0.5 microM, respectively). At a minimum, the C-terminal EF-hand Ca2+-binding domain (residues 61-72) of each S100beta subunit must be saturated to inhibit phosphorylation of the p53 peptide as determined by comparing the Ca2+ dependence of inhibition ([Ca]IC50 = 29.3 +/- 17.6 microM) to the dissociation of Ca2+ from the C-terminal EF-hand Ca2+-binding domain of S100B(betabeta).     

Activation of coagulation and fibrinolysis in patients with abdominal true aortic aneurysm associated with disseminated intravascular coagulation

Two cases of abdominal true aortic aneurysm (AAA) associated with disseminated intravascular coagulation (DIC) were reported. Case 1 was an 81-year-old male who was admitted because of hematoma on the left leg and in whom was found by MRI an aortic aneurysm of 14 cm in diameter. Coagulation studies indicated DIC by revealing thrombocytopenia, hypofibrinogenemia and increased level of FDP. DIC was well controlled by surgical repair of the aneurysm after the administration of a small dose of heparin. Case 2 was a 60-year-old male who was admitted because of lumbago and hematoemesis and in whom was found by CT and echography an aortic aneurysm of 5.5 cm in diameter. Coagulation studies indicated DIC by revealing thrombocytopenia and an increased level of FDP. On the 2nd hospital day, he suddenly died due to the rupture of the aortic aneurysm. In most of 9 cases with AAA without DIC, plasma levels of thrombin-antithrombin III complex, plasmin-alpha 2 plasmin inhibitor complex and FDP-D dimer were also elevated. These findings indicate that the coagulation and fibrinolysis systems were generally activated in patients with AAA, and that DIC tends to occur in patients with a giant aortic aneurysm or an impending ruptured aneurysm.     

Hereditary deficiency of vitamin K-dependent coagulation factors with skeletal abnormalities

Thirteen patients with localized unresectable pancreas carcinoma were treated with a combination of accelerated radiotherapy and 5-fluorouracil. Radiotherapy consisted in 3 fractions of 1.1 Gy per day during 3 weeks up to a total dose of 45-50 Gy. 5-Fluorouracil was administered as continuous infusion in a dosis of 25 mg/kg/24 h the first and the third week concomitantly to radiotherapy. Grade 3 mucositis, diarrhoea and nausea/vomiting were observed in 15% of the patients. Eleven patients completed the treatment without modifications and in two patients the dose of 5-fluorouracil was reduced to 75% during the third week of treatment. Radiotherapy was always administered as planned. Median survival was 36 weeks.     

Correlations of C1q- and C3d-bearing circulating immune complexes with immunopathological disease activity in lupus nephritis patients

The serum levels of circulating immune complexes (CIC) measured by three different types of enzyme immunoassay (EIA) using monoclonal anti-C1q and antibodies and C1q as solid phase reagents were compared with clinical disease activity and immunohistological glomerular lesions in 29 SLE patients. Three types of CIC measured by these assays (anti-C1q CIC, anti-C3d CIC and C1q SP CIC) showed significantly higher levels in patients than in controls and were significantly associated with the clinical and serological disease activities. Anti-C1q CIC showed good correlation not only with mesangial IgG depositions (P < 0.01), but also with that of C1q (P < 0.05). C1q SP CIC also showed a weak correlation with mesangial C1q deposition (P < 0.05). Serum levels of anti-C3d CIC increased with the degree of mesangial IgG and complement depositions. Analysis of the clinical course of a patient with active SLE revealed a more rapid decrease of anti-C1q CIC and anti-C3d CIC along with the improvement of disease activity, including the mesangial lesion, than that of C1q SP CIC. According to these results, the CIC detected with assays using monoclonal antibodies against complement fragments, especially the anti-C1q assay, is likely to provide specific information regarding the clinical, serological and immunohistological disease activity in lupus nephritis.     

Long-term prognosis for tonsillectomy patients with IgA nephropathy

A retrospective study of 85 patients with IgA nephropathy was undertaken to determine the long-term effect of tonsillectomy. Forty-three patients (24 males and 19 females) had received tonsillectomies (Group A) and 42 patients (17 males and 25 females) had not (Group B). These patients had been followed up for more than 5 years after renal biopsy. The average age at the initial renal biopsy was 25.72 years in Group A, and 33.16 years old in Group B. The average period of renal biopsy to tonsillectomy in Group A was 10.47 months. The average follow-up period was 8 years and 9 months in both groups. At the beginning of treatment, the two groups were well matched in terms of creatinine clearance, urinalysis, and blood pressure. Six patients in Group A and eight patients in Group B were treated with steroids. The glomerular injury detected at the renal biopsy was more extensive in Group A than in Group B. Renal function in the two groups was compared. The clinical remission rate in Group A was significantly higher than in group B (P<0.05). The stable renal function rate in Group A was significantly higher than in Group B (P<0.05). The renal survival rate was 97.7% in Group A and 83.3% in Group B, but there was no significant difference between the two groups. Histologically, the rate of remission of the minor lesion in Group A was significantly higher than in Group B (P < 0.05). Our results showed that tonsillectomy for IgA nephropathy was clinically of great value.     

Diabetic patients with IgA nephropathy and diabetic glomerulosclerosis

Eleven diabetic patients with biopsy-proven IgA nephropathy were studied. Seven exhibited coexistence of both IgA nephropathy and diabetic glomerulosclerosis and the remaining four patients had IgA nephropathy without diabetic lesion. The clinicopathological features and follow-up of those patients with IgA nephropathy surperimposed on diabetic glomerulosclerosis were compared with a similar group of patients with diabetic glomerulosclerosis alone. Our observation suggests that the occurrence of both glomerulopathies was fortuitous with IgA nephropathy coexisting with or preceding diabetic glomerulosclerosis. There was no apparent causal relationship between the two glomerulopathies. The renal outcome is poor in both groups of patients and is possibly related to diabetic glomerulosclerosis.