Sjogren's syndrome: Clinical aspects.

Sjogren's syndrome (SS) is the 2nd most common chronic autoimmune rheumatic disease and associated with a high burden of illness. Morbidity arises not only from untreated xerostomia and keratoconjunctivitis sicca but also from extra-glandular manifestations including the development of non-Hodgkin's B cell lymphomas. Proper diagnosis of SS requires objective evidence of dry eyes and/or objective evidence of dry mouth as well as proof of autoimmunity. The recent development of new international classification criteria and clinical practice guidelines for SS should not only enhance the existing standards of care but also facilitate further studies to improve future diagnosis and outcomes.

[Combined pegylated liposomal doxorubicin and carboplatin in the treatment of recurrent epithelial ovarian cancer].

OBJECTIVE: To evaluate the efficacy and toxicity of combined pegylated liposomal doxorubicin (PLD) and carboplatin in the treatment of patients with recurrent epithelial ovarian cancer. METHODS: We retrospectively reviewed 67 patients with recurrent epithelial ovarian cancer or primary peritoneal adenocarcinoma (8 cases) who were treated with combined PLD and carboplatin. The response rate, survival and toxicity were evaluated. The mean age for 67 patients was 52.1 (39 - 76) years. All of them received cytoreductive surgery followed by platinum-based chemotherapy either with paclitaxel or cyclophosphamide and doxorubicin after diagnosis. Combined PLD and carboplatin was used as first or second-line treatment or even after multiple lines of treatment after disease recurred. Patients were treated with PLD at 35 - 40 mg/m(2) combined with carboplatin at an area under curve (AUC) of 5 once every 4 weeks. RESULTS: Forty-nine patients were evaluable for response. Twenty-three (47%) patients had a complete response, 13 (27%) had a partial response, 3 (6%) had stable disease and 10 (20%) had progressive disease. The estimated median progression-free survival (PFS) was 8 months. The 1-year and 2-year survival rates were 73% and 55%, respectively. All of the 67 patients were evaluated for toxicity. The treatment was terminated in 2 patients due to allergic-like infusion reaction. Four patients who had acute infusion reaction with shortness of breath and tightness of chest did not terminate the treatment because no such reaction occurred when restarted the infusion. There were 2 patients with G(2) and 3 patients with G(3) hand-foot syndrome, 2 patients had G(4) stomatitis, and 8 patients had G(3) leukopenia. No G(4) leukopenia or cardiotoxicity occurred. CONCLUSION: The combination of PLD and carboplatin is an active and well-tolerated regimen in the treatment of patients with recurrent epithelial ovarian cancer.

Hemodialysis leukopenia. Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes.

Acute leukopenia occurs in all patients during the first hour of hemodialysis with cellophanemembrane equipment. This transient cytopenia specifically involves granulocytes and monocytes, cells which share plasma membrane reactivity towards activated complement components. The present studies document that complement is activated during exposure of plasma to dialyzer cellophane, and that upon reinfusion of this plasma into the venous circulation, granulocyte and monocyte entrapment in the pulmonary vasculature is induced. During early dialysis, conversion of both C3 and factor B can be demonstrated in plasma as it leaves the dialyzer. Moreover, simple incubation of human plasma with dialyzer cellophane causes conversion of C3 and factor B, accompanied by depletion of total hemolytic complement and C3 but sparing of hemolytic C1. Reinfusion of autologous, cellophane-incubated plasma into rabbits produces selective granulocytopenia and monocytopenia identical to that seen in dialyzed patients. Lungs from such animals reveal striking pulmonary vessel engorgement with granulocytes. The activated complement component(s) responsible for leukostasis has an approximate molecular weight of 7,000-20,000 daltons. Since it is generated in C2-deficient plasma and is associated with factor B conversion, it is suggested that activation of complement by dialysis is predominantly through the altermative pathway.

A Case of Argyria and Acute Leukopenia Associated with the Use of an Antimicrobial Soft Silicone Foam Dressing.

Silver has had an important role in preventing burn-related infections for decades. Relatively few side effects is one factor that has led to its wide spread use. Here, the authors present the first case of argyria, acute leukopenia, and possibly acute kidney injury associated with the use of a silver-containing soft silicone foam dressing. A 56-year-old female was transferred to the burn center with an exfoliating skin condition involving 70% TBSA diagnosed as toxic epidermal necrolysis associated with trimethoprim/sulfamethoxazole. On presentation she appeared to have clinical sepsis and was started on vancomycin and piperacillin/tazobactam. Clinical sepsis resolved within several days. Initial wound care consisted of daily topical double antibiotic and 3% bismuth tribromophenate petroleum gauze. After several days, the wounds were covered with a silver-containing soft silicone foam dressing. After 7 days, the leukocyte count declined from 18,000 to 600/cm. Silver toxicity was suspected and the dressings removed. Initial serum silver level was 190 and 249 µg/L 1 week later. The leukocyte level normalized within 7 days. Over the following days and weeks, the patient's skin began to show blue-gray coloration consistent with argyria. The patient subsequently developed acute kidney injury requiring hemodialysis and multiple organ failure. Although controversy exists about the causal relationship between silver-containing dressings and leukopenia, the authors believe that this case represents a case of acute leukopenia and argyria from the use of a silver-containing soft silicone foam dressing. It may have been a contributing factor to the development of acute kidney injury as well.

Leukopenia and hypoxemia. Unrelated effects of hemodialysis.

Hemodialysis-induced hypoxemia has been attributed to membrane-related complement activation leading to pulmonary leukostasis and to hypoventilation secondary to carbon dioxide losses via the dialyzer. We have separately assessed the role of membrane- and dialysis-related factors by using different dialyzers and sequential ultrafiltration and hemodialysis with first-use cellulose dialyzers produced both leukopenia and hypoxemia. With reused cellulose and polyacrylonitrile dialyzers, hypoxemia still occurred, but without leukopenia. Ultrafiltration produced leukopenia and no changes in Pao2; during the subsequent hemodialysis, hypoxemia developed as the leukocyte count increased by 50%. Our data indicate that leukopenia and hypoxemia are unrelated effects of hemodialysis, and favor hypoventilation as the major determinant of hypoxemia during hemodialysis.

Granulocyte macrophage-colony stimulating factor (GM-CSF) and sucralfate in prevention of radiation-induced mucositis: a prospective randomized study.

PURPOSE: To compare subcutaneously given molgramostim (GM-CSF) and sucralfate mouth washings to sucralfate mouth washings in prevention of radiation-induced mucositis. METHODS AND MATERIALS: Forty head and neck cancer patients were randomly assigned to use either GM-CSF and sucralfate (n = 20) or sucralfate alone (n = 20) during radiotherapy. Sucralfate was used as 1.0 g mouth washing 6 times daily after the first 10 Gy of radiotherapy, and 150-300 microg GM-CSF was given subcutaneously. The grade of radiation mucositis and blood cell counts were monitored weekly. Salivary lactoferrin was measured as a surrogate marker for oral mucositis. RESULTS: We found no significant difference between the molgramostim and the control groups in the oral mucositis grade, oral pain, use of analgesic drugs, weight loss, or survival. The median maximum neutrophil counts (median, 9.2 x 10(9)/L vs. 5.9 x 10(9)/L, p = 0.0005), eosinophil counts (median, 1.3 x 10(9)/L vs. 0.2 x 10(9)/L, p = 0.0004), and salivary lactoferrin concentrations were higher in patients who received GM-CSF. The most common toxicities in the GM-CSF plus sucralfate group were skin reactions at the GM-CSF injection site (65%), fever (30%), bone pain (25%), and nausea (15%), whereas the toxicity of sucralfate given alone was minimal. CONCLUSION: We found no evidence indicating that subcutaneously given GM-CSF reduces the severity of radiation-induced mucositis.

Vitamin E-bonded cellulose membrane and hemodialysis bioincompatibility: absence of an acute benefit on expression of leukocyte surface molecules.

Dialysis with unmodified cellulose membranes is associated with such bioincompatibility phenomena as leukopenia, increased expression of adhesion molecules on leukocytes, and release of reactive oxygen species. Dialysis biocompatibility can be improved by modifications in the structure of the cellulose membrane to diminish leukocyte activation and/or protect against the released free oxygen radicals. Excebrane (Terumo Corp, Tokyo, Japan) is a vitamin E-modified cellulose membrane. In the present study, the effect of dialysis with Excebrane membranes on granulocyte and monocyte counts; CD11b, CD11c, and CD45 expression on the surface of granulocytes; and CD14 expression on monocytes was evaluated and compared with low-flux polysulfone membranes. Fifteen minutes after the start of dialysis, granulocytopenia and monocytopenia were more pronounced with the Excebrane membrane compared with polysulfone. The increase in basal expression of CD11b and CD45 on circulating granulocytes was more pronounced during dialysis with Excebrane than polysulfone membranes. Regarding the increased expression on in vitro stimulation with phorbol myristate acetate, blunted upregulation was obtained during dialysis using Excebrane membranes for CD11c and CD45 expression on granulocytes and CD14 expression on monocytes. In conclusion, such indices of membrane bioincompatibility as leukocyte counts and expression of leukocyte surface molecules show more profound alterations with Excebrane than the standard low-flux polysulfone membrane in both basal and in vitro activated states.

Blood-membrane interactions during haemodialysis with cellulose and synthetic membranes.

Haemodialysis is associated with transient leucopenia, hypoxia and activation of the patient's complement system, mediated by blood-membrane contact. Changes in white blood cell counts, blood gases (PaO2 and PaCO2), carbon monoxide diffusing capacity (DLCO) and complement activation (C3d and C3a) were measured pre-treatment and during dialysis. The degree of complement activation, leucopenia and changes in DLCO were influenced by membrane type; these changes were most marked for cellulosic membranes and were much reduced for synthetic membranes. A significant relationship between the degree of leucopenia and the magnitude of change in DLCO during dialysis was demonstrated.

Platelet-activating factor production during hemodialysis: effect of BN 52021.

Platelet activating factor (PAF) production and platelet-lipoxygenase activity were studied during hemodialysis (HD) with cuprophane membranes. Six patients were treated with first-use dialyzers (FU), and 6 patients with reused dialyzers (RU). In a random and double-blind design, 2 HD were performed for each patient, with or without BN 52021 pretreatment, a selective PAF antagonist. Platelet and leukocyte counts were performed before pretreatment and 30 min before HD starting (T-30), at the beginning of HD (T0) and after 15 and 30 min of HD (T15, T30). PAF production was analyzed by direct phase HPLC. To determine platelet-lipoxygenase activity, 12-HETE was detected by reverse phase high performance liquid chromatography (HPLC) after blood stimulation by the ionophore A23187. In the FU group, PAF and 12-HETE were produced during the first 30 min of HD. After BN 52021 pretreatment, PAF production was suppressed and platelet-lipoxygenase activity reduced. In the RU group, neither PAF nor 12-HETE production occurred, and BN 52021 had no effect. We conclude that PAF, which was involved in both platelet and leukocyte activation that occurred during hemodialysis, can be considered as a bio-incompatibility marker.

Manometric assessment of impaired esophageal motor function in primary Sjögren's syndrome.

OBJECTIVE: To evaluate by manometry the esophageal motility changes in patients with primary Sjögren's syndrome (SS). METHODS: Esophageal manometry was carried out in 25 (F/M: 22/3) primary SS patients with systemic manifestations and in 42 control subjects. The primary SS patients also completed a dysphagia scoring questionnaire and underwent whole salivary flow measurements. RESULTS: As compared with the controls the primary SS patients exhibited a decreased lower esophageal sphincter (LES) pressure (P < 0.01) and a prolongation of LES relaxations (P < 0.02). In the esophageal body (EB) a decreased peristaltic velocity (p < 0.01), an increased duration of contractions (p < 0.01) and a higher occurrence of simultaneous waves (p < 0.01) were detected. Since decreased peristaltic velocity was the most frequent motor abnormality (11/25 cases), two groups of patients were formed for further analysis: patients with a decreased (group I, n = 11) and patients with a normal (group II, n = 14) peristaltic velocity. The SS patients with a decreased EB propagation velocity (< or = 2.7 cm/s, group I) displayed more significantly decreased pressures (p < 0.01) and more prolonged relaxation times (p < 0.05) in the LES, with higher rates of simultaneous contractions on dry swallows (p = 0.05) in the EB, as compared with those who had a normal peristaltic velocity (group II). Of the clinical parameters, the decreased EB peristaltic velocity was associated with a smaller whole saliva production both in the basal state and after stimulation. Furthermore, this group of patients had a significantly higher liquid requirement for swallowing than those who had normal peristaltic velocities (p = 0.05). CONCLUSIONS: Primary SS patients with systemic manifestations exhibit several esophageal motility abnormalities. In this study, a decreased EB peristaltic velocity was the most common manometric change, and showed an association with impaired saliva production and higher liquid requirement for swallowing, but not with the laboratory parameters or with the systemic manifestations of the disease.

Hematologic abnormalities among HIV-infected patients: associations of significance for dentistry.

OBJECTIVE: The purpose of this study was to determine the prevalence and severity of and the factors associated with peripheral blood cytopenias among HIV-infected patients. STUDY DESIGN: The investigation involved 516 HIV-infected adults in a longitudinal study of oral disease. Prevalence of hemoglobin, hematocrit, white blood cell, neutrophil, lymphocyte, and platelet values below the lower limit of normal and certain hematologic "critical values" were determined. Demographic, clinical/immunologic/viral stage, medications, and oral lesions were assessed for association with cytopenias by chi(2) and bivariate analyses. RESULTS: Findings with respect to prevalence were as follows: anemia, 51%; leukopenia, 43. 4%; neutropenia, 27.5%; lymphopenia, 20.7%; thrombocytopenia, 15.5%. Severe cytopenias were detected in fewer than 1% of the patients. Severity of HIV clinical disease and CD4 cell count depletion were significantly associated with all cytopenias. High viral load was associated only with the leukopenias. Black race, antiparasitic therapy, and some oral lesions were associated with certain cytopenias. CONCLUSIONS: In HIV-infected patients, mild cytopenias are common; however, severe anemia, neutropenia, and thrombocytopenia that may predispose to certain oral manifestations and dental surgical complications are rare.

Complement activation in haemodialysis: a comparison of new and re-used dialysers.

The magnitude of leucopenia and complement activation when reusing cellulose based (Cuprophan) and synthetic (polyacrylonitrile AN-69S) haemodialysis membranes as well as their modifications by the priming of the dialysers with fresh frozen plasma and by the introduction of a period of stagnation during haemodialysis were studied using radioimmunoassay (C3a), centrifugal analysis (C3d), immunochemical (C3, Factor B) and functional (CH50 and alternate pathway) assays. Our findings demonstrate that complement activation and leucopenia induced by Cuprophan are linked and are modified when the membrane is reused, or primed with plasma protein. However, chemical exposure during reuse to sodium hypochlorite modifies these observations. Reuse of the AN-69S membrane resulted in no modification of either leucopenia or complement activity, but this membrane consistently demonstrated lower levels of C3a than observed with either first use or reused Cuprophan membranes.

Adult respiratory distress-like syndrome during hemodialysis: relationship between activation of complement, leukopenia, and release of granulocyte elastase.

Twelve patients with terminal uremia (8 females and 4 males) treated with chronic maintenance hemodialysis, were extensively studied during two successive dialyses with alternate use of either a Cuprophan (CP) based membrane, or a Polycarbonate (PC) membrane. Arterial plasma levels of total hemolytic complement, complement factors C3d and C5a, and granulocyte derived elastase were determined immediately before dialysis and sequentially during the entire procedure. Effluent line from the hemodialyzer was similarly sampled. Collected samples were centrifuged immediately at the bedside and instantly frozen in liquid nitrogen in order to preserve labile plasma components of complement. Analysis of the overall results shows that initial arterial leukopenia and generation of C5a in the hemodialyzer, as well as maximal values of hemodialysis-induced free plasma C3d and granulocyte elastase are related. Reflecting differences in biocompatibility, CP membranes were shown to induce significantly more leukopenia, increase in plasma free C3d, generation of C5a, and release of granulocyte-derived elastase. These results indicate that activation of complement, leukopenia, and release of granulocyte derived elastase are interlinked pathophysiological mechanisms of importance for acute deterioration of pulmonary function during hemodialysis, and that this condition is closely related to adult respiratory distress syndrome (ARDS).

Biocompatibility of different hemodialysis membranes: activation of complement and leukopenia.

The ability of three hollow-fiber dialyzers (Cuprophane [CU], polymethylmethacrylate [PMMA], and polyacrylonitrile [PAN]) to activate complement and to induce leukopenia was studied prospectively in six patients on long-term hemodialysis. CU membranes caused the most intense complement activation with C3a, C3d, and C5a levels peaking 15 min after beginning dialysis. Total white blood cell (WBC) counts dropped simultaneously by 76%, and the decrease in leukocytes was inversely correlated with the levels of C3a and C5a. In contrast, PMMA membranes led only to slight complement activation with an associated fall in WBC counts of 29%, and PAN membranes induced very little complement activation without leukopenia. In vitro studies involving incubation of normal human plasma with each of the three membranes corroborated these findings. The results suggest that the biocompatibility of PMMA and PAN dialyzers is superior to CU.

In vitro and in vivo biocompatibility of substituted cellulose and synthetic membranes.

Regenerated cellulosic membranes are held as bioincompatible due to their high complement - and leukopenia - inducing properties. Adherence of polymorphonuclear neutrophils and monocyte purified from normal human blood to the three membranes were evaluated in an in vitro recirculation circuit in the presence or absence of fresh, autologous plasma after recirculation in an in vitro circuit using minimodules with each of the three membranes. In in vivo studies, 9 patients were treated with conventional haemodialysis for 2 weeks with each membrane and 1 week for wash-out using haemodialysers with the following surface: 1.95 m2 for benzyl-cellulose, 1.8 m2 for acetate-cellulose and low-flux polysulfone. Measurement of leukopenia, plasma C3a des Arg and elastase-alpha1 proteinase inhibitor complex levels as well as urea, creatinine, phosphate and uric acid clearances was performed. Plasma-free neutrophils adhered maximally to acetate-cellulose (65% remaining in the circulation), while there was no significant difference between low-flux polysulfone and benzyl-cellulose (80% circulating neutrophils, at 15 min, p<0.001 vs acetate cellulose). In the presence of fresh plasma, as source of complement, the differences between acetate cellulose vs polysulfone and benzyl-cellulose were even more evident, suggesting the role of complement-activated products in neutrophil adherence. A similar trend was observed for monocyte adherence with the three membranes in the absence or presence of plasma. In vivo studies showed that the nadir of leukopenia was at 15 and 30 min with acetate-cellulose (79%) and benzyl-cellulose (50%) (p<0.05 acetate- vs benzyl-cellulose) and at 15 min with polysulfone (24%) (p<0.01 vs acetate- and benzyl-cellulose). Plasma C3a des Arg levels arose to 2037 +/- 120 ng/ml, 1216 + 434 ng/ml and 46 +/- 55 ng/ml with acetate-, benzyl-cellulose and polysulfone, respectively. No pre- vs post-dialysis increase in the intracellular content of TNF-alpha was detected with any of three membranes. Clearance values of urea, creatinine and uric acid were superimposable for all the three membranes. However, benzyl cellulose had a significantly higher clearance for phosphorus (normalized for surface area) (p<0.01 vs acetate-cellulose, 0.001 vs polysulfone). These results implicate that synthetic modification of the cellulose polymer as for the benzyl-cellulose significantly reduces the in vitro adherence, delays the in vivo activation of "classic" biocompatibility parameters and notably improves the removal of inorganic phosphorus.

Assessment of blood compatibility of haemodialysis membranes using a miniature flat sheet dialyser.

Available pre-clinical techniques of assessing severity of untoward reaction by blood following contact with haemodialysis membranes do not account for the effects of dialysate and flow characteristics in the observed blood changes. A miniature flat sheet dialyser that considered these effects was prepared and tested in both in-vitro and ex-vivo circuits. Changes in platelets and leucocytes in heparinised human blood in-vitro tests did not distinguish regenerated cellulose (Cuprophan 150PM) membrane from a synthetic membrane, a copolymer of acrylonitrile and sodium methyl sulphonate (AN69S). Ex-vivo tests using rats showed more marked leucocyte (41.3%) and platelet (43.1%) depletion by Cuprophan 150PM than AN69S after 90 minutes of dialysis. Leucocyte and platelet loss due to AN69S were 26.9% and 13.4% respectively. In addition, Cuprophan 150PM membranes exhibited high affinity for leucocytes and platelets in both in-vitro and ex-vivo tests compared to AN69S membranes which were primarily covered with erythrocytes. Application of simulated in-use techniques in preclinical evaluation of blood compatibility membranes that are used in extra-corporeal treatment are recommended.

Cytogenic investigations of serious overexposures to an industrial gamma radiography source.

This paper describes the sequence of events, medical aspects and dose estimations for two radiographers and their driver who were seriously exposed to an iridium-192 industrial radiography source that became detached from its wind-out cable. The men came to medical attention about 1 month later by which time all three were severely leucopenic and one had skin burns on both hands. Doses were estimated by (i) physics calculations combined with their accounts of the event. (ii) the levels of depression of their blood neutrophils, (iii) electron spin resonance on tooth enamel and (iv) blood lymphocyte chromosomal analyses by the conventional dicentric and the fluorescence in situ hybridisation methods. Intercomparison of these methods for estimating doses showed a good level of agreement. In brief, the averaged whole body dose for the most seriously exposed man was about 2.5-3.0 Gy and for the others it was 1.0-2.0 Gy.

[Activation of complement during hemodialysis].

In hemodialysis using 3 types of dialysis membrane materials [regenerated cellulose (RC), cellulose triacetate (CTA), and polysulfone (PS)], activation of the complement, reduction of white blood cells, and variation of vitronectin (VN) were observed. RC membrane caused a significant reduction of white blood cells and elevations of Bb and soluble membrane attack complex (S-MAC), indicating a strong activation of the alternative complement pathway. Especially, the increase of S-MAC persisted for a long time during hemodialysis. Because reduction of VN was transient, it was assumed that the S-MAC escaping removal by VN receptors might have persisted in the circulation. These findings suggested that S-MAC would become useful as an index for evaluating biocompatibility of various artificial organs including dialysis membranes.

[The effect of the primary and repeated use of dialyzers with different membranes on the degree of dialysis-induced leukopenia]. / Vliianie pervichogo i povtornogo ispol'zovaniia dializatorov s razlichnymi membranami na stepen' dializnoi leikopenii.

The degree of leukopenia that occurs during hemodialysis is one of the main parameters characterizing biocompatibility of the dialysis membranes. It has been demonstrated that the use of the DIP-03-02 dialyzer fitted with a membrane manufactured from Soviet polysulfone produces much less remarkable leukopenia as compared to the use of dialyzers fitted out with conventional cellulose membranes. It has also been shown that the repeated use of dialyzers brings about a decrease in leukopenia and that the method of washing off dialyzers influences the degree of leukopenia.