Suicide risk in epilepsy: Clinical variables, psychiatric disorders, and social support.

OBJECTIVE: To explore the relationship between suicide risk, the perception of social support and quality of life (QoL), and with the clinical variables of adult people with epilepsy (PWEs). METHODOLOGY: A total of 98 consecutive PWEs cared for in the outpatient setting, with a mean age of 48.1±15.9 years, having had epilepsy for 26.4±16.4 years and 48 (48.9%) female cases participated in this study. The MINI suicide module, the Social support satisfaction scale (SSSS), the Quality of life in epilepsy inventory (QOLIE-31), and the Hospital anxiety and depression scale (HADS) were used. A logistic regression was conducted to assess the factors associated with the suicide risk. RESULTS: Suicide risk was present in 33 cases. Younger age, earlier age at epilepsy onset, depression and anxiety in the HADS scale, and lower MMSE, QOLIE-31, and SSSS scores were significantly associated with suicide risk in the univariate analysis. The logistic regression analysis identified that lower scores in the MMSE (OR 0.826, 95%CI 0.705-0.969), presence of anxiety (OR 0.197, CI 0.073-0.530), and a low perception regarding satisfaction with family (OR 0.953, CI 0.920-0.988) are the factors associated with the highest risk of suicide. CONCLUSION: Suicide risk and recurrence of a suicide attempt was high in the PWEs. Suicide risk was associated with clinical variables, the presence of anxiety and the perception of less social support from the family.

Vitamin D status and non-alcoholic fatty liver disease in patients with type 1 diabetes.

PURPOSE: In patients with type 1 diabetes (T1D), the prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 10 to 53% and contrasting evidence suggests that vitamin D deficiency may favor liver fat accumulation. Here, we investigated the association between vitamin D status and NAFLD in adults with T1D. METHODS: 220 consecutive adult T1D patients on multiple daily injections or continuous subcutaneous insulin infusion and not taking calcium or vitamin D supplements were included. Patient characteristics, 25(OH)D serum levels, and metabolic parameters were analyzed. Vitamin D status was defined as sufficiency ( ≥ 75 nmol/L; 30 ng/ml), insufficiency (50-75 nmol/L; 20-30 ng/ml), or deficiency ( < 50 nmol/L; 20 ng/ml). NAFLD was diagnosed at ultrasound examination and graded 0-3. RESULTS: NAFLD was present in 57 patients (29.5%): 51 grade 1, 5 grade 2, and 1 grade 3. Median 25(OH)D levels were 53 nmol/L (IQR 38-70) in patients with NAFLD and 50 nmol/L (34-69) in patients without (p = 0.46). At multivariable analysis, NAFLD was not associated with 25(OH)D levels (p = 0.42) or vitamin D deficiency (p = 0.55), while BMI (OR 1.16, 95% CI 1.07-1.27) and serum triglycerides (OR 1.02, 95% CI 1.01-1.03) were independently associated with NAFLD. CONCLUSIONS: Vitamin D status appears to have no link with low-grade NAFLD in patients with type 1 diabetes.

Coronary Microvascular Dysfunction Predicts Long-Term Outcome in Simultaneous Pancreas-Kidney Transplantation.

BACKGROUND: Patients with diabetes are at increased cardiovascular risk. Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice in patients with type 1 diabetes mellitus and diabetic nephropathy. We assessed coronary flow reserve (CFR) by transthoracic echocardiography as a marker of major adverse cardiac events (MACE) in SPKT patients. METHODS: We studied 48 consecutive SPKT patients (28 male, age at SPKT 54 ± 8 years). Time from transplantation was 8.5 ± 3 years. Follow-up was 4.6 ± 1.8 years. Coronary flow velocity in the left anterior descending coronary artery was detected by Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperemic diastolic flow velocity (DFV) to resting DFV. A CFR ≤ 2 was considered abnormal and a sign of coronary microvascular dysfunction. MACE were cardiac death, myocardial infarction, and heart failure. RESULTS: CFR was 2.55 ± 0.8. CFR was ≤2 in 13 (27%) patients. CFR was lower in SPKT patients with MACE (2.1 ± 0.7 vs 2.7 ± 0.8, P = .03) and patients with MACE had a higher incidence of CFR ≤ 2 (P = .03). Time from transplantation was shorter in patients with MACE (P < .0001). Patients with CFR ≤ 2 had a lower MACE-free survival (P = .03). CFR ≤ 2 predicted the risk of MACE (P = .007) independently from coronary artery disease and metabolic control. However, this predicted role is lost when adjusted for the time from transplantation, which plays a protective role (P = .001). CONCLUSIONS: In SPKT, CFR ≤ 2 may be a reliable marker for MACE, independent of coronary artery disease diagnosis. However, this role seems to be reduced over time. This finding suggests a gradual reduction of cardiovascular risk in SPKT patients.

Integration of blood volume, blood pressure, heart rate and bioimpedance monitoring for the achievement of optimal dry body weight during chronic hemodialysis.

BACKGROUND: Achieving optimal dry body weight in hemodialysis is challenging. Clinical assessment alone is inadequate, and methods such as bioimpedance monitoring may be impractical for every patient treatment. Continuous blood volume monitoring, blood pressure and heart rate variability inform clinical decision-making, but integrated use of multiple methodologies to achieve dry weight and understand patient factors has not yet been described. METHODS: Nineteen chronic hemodialysis patients underwent thrice-weekly treatments for two weeks. Baseline hydration status and target weight were determined by bioimpedance. During subsequent treatments, ultrafiltration was adjusted and relative blood volume, blood pressure and pulse were recorded non-invasively. Bioimpedance was repeated to assess hydration. Response of variables to progressive change in weight was assessed and selected patients underwent additional autonomic function testing. RESULTS: Four distinct hemodynamic patterns emerged. Profile A: 4 patients demonstrated overhydration at baseline. With decreasing target, pulse and blood pressure remained stable while blood volume and bioimpedance demonstrated achievement of dry weight. Profile B: 8 patients demonstrated overhydration at baseline. With decreasing target, blood pressure remained stable while pulse increased. Profile C: 5 patients were overhydrated, but as weight decreased, blood pressure became unstable and heart rate failed to compensate. Further testing confirmed autonomic dysfunction. Profile D: 2 patients were dehydrated, and with increasing target demonstrated stable pulse and pressure, while blood volume and bioimpedance revealed achievement of dry weight. CONCLUSIONS: Integrating existing non-invasive, continuous monitoring during hemodialysis enabled achievement of dry weight and identified distinct profiles of the patients, some with autonomic dysfunction. This strategy may contribute to achieving optimum dry weight while improving cardiovascular tolerability of hemodialysis.

Dialytic performance evaluation of Rexeed: a new polysulfone-based dialyzer with improved flow distributions.

New dialyzers are designed to optimize the convective and diffusive components of solute transport. Asahi Kasei Medical Co.,Ltd.has developed a new high flux dialyzer series called Rexeed with improved flow distributions. We evaluated the in vivo dialytic performance of two dialyzers of the Rexeed series: Rexeed-18A and Rexeed-25A (1.8 m2 and 2.5 m2 ). We calculated the clearance for urea,creatinine,phosphate and b2-microglobulin both in high flux dialysis (HFD)and in 15 liter postidiluitional on-line hemodiafiltration (HDF)mode. With n = 3 patients in high flux HD at blood flow 450, 400, 350 and 250 ml/min we found remarkably high clearance for urea (347 +/- 4%, 305 +/- 0%, 288 +/- 5%, 230 +/- 3%, for Rexeed-18A and 361 +/- 3%, 329 +/- 0%, 313 +/- 1%, 234 +/- 3%for Rexeed-25A),creatinine (282 +/- 10%, 234 +/- 0%, 221 +/- 8%, 174 +/- 8%, for Rexeed-18A and 276 +/- 6%, 245 +/- 0%, 226 +/- 9%, 172 +/- 13% for Rexeed-25A),phosphate (347 +/- 0%, 316 +/- 0%, 275 +/- 4%, 202 +/- 16%, for Rexeed-18A and 364 +/- 3%, 365 +/- 0%,286 +/- 3%, 224 +/- 2% for Rexeed-25A)and b2-microglobulin (133 +/- 21%, 124 +/- 0%,118 +/- 12%, 98 +/- 11%, for Rexeed-18A and 159 +/- 8%, 169 +/- 0%,157 +/- 8%, 129 +/- 7% for Rexeed-25A) With n = 2 patients in HDF at blood flow 300 ml/min we found remarkably high clearance for urea (268 +/- 2%, for Rexeed-18A and 283 +/- 2% for Rexeed-25A),creatinine (183 +/- 6%for Rexeed-18A and 205 +/- 9% for Rexeed-25A),phosphate (245 +/- 3%, for Rexeed-18A and 270 +/- 2% for Rexeed-25A)and b2-microglobulin (166 +/- 12%, for Rexeed-18A and 192 +/- 4% for Rexeed-25A). Our preliminary evaluation describes the characteristics and the performances of a new polysulfone-based hemodialyzer series called Rexeed. Several innovative features have been implemented by the manufacturer. These constructive approaches seem to have produced a positive effect on the dialyzer performance at the bedside.

Sequential convective therapies (SCT): a prospective study on feasibility, safety, adequacy and tolerance of on-line hemofiltration and hemodiafiltration in sequence.

Sequential dialysis techniques (i.e pure ultrafiltration followed by dialysis) have been used in the past, due to their capability to remove large volumes of fluids without inducing hemodynamic instability. The disadvantages of inadequate efficiency and lack of technology lead to the decline of such methods. Hemofiltration (HF) and hemodiafiltration (HDF) are recently being utilized in a greater proportion thanks to on-line fluid preparation systems. Each process (HF and HDF) has its own benefits in the removal of small, medium and high-molecular weight substances and in hemodynamic stability. Sequential convective therapies (SCT) such as hemofiltration-hemodiafiltration in sequence (HF-HDF) may combine the benefits and eliminate the disadvantages of each method and should be studied in order to explore their potential application in modern dialysis. Furthermore they can be easily applied nowadays, due to the development of new sophisticated dialysis machines. In order to evaluate the feasibility, safety, efficiency and tolerance of different SCT methods we studied 3 schedules: SCT1: 1h pre-dilution HF followed by 3h of post-dilution HDF (in the HF mode we lost 25% of the total fluid that had to be removed). SCT2: 1h pre-dilution HF followed by 3h of post-dilution HDF (in the HF mode we lost 50% of the total fluid that had to be removed). SCT3: 2h pre-dilution HF followed by 2h of post-dilution HDF (in the HF mode we lost 50% of the total fluid that had to be removed). We studied 6 chronic hemodialysis patients using the same machine (AK200 ULTRA), with on-line fluid preparation system and the same type of dialyzer (Polyflux 210). SCT schedules were compared to on-line HF, on-line HDF and high flux dialysis performed with the same dialyzers. The treatments resulted safe, easy, feasible and well tolerated with an improved hemodynamic response to high volume convective therapies. Adequacy of treatment was satisfactory in all SCT schedules while middle molecular weight solute clearance and removal resulted higher in treatments with higher convective component. SCT might represent an interesting option for the future especially in patients with hemodynamic instability and requirements for interventions during treatment.

Sequential hemofiltration-hemodiafiltration technique: all in one?

Sequential dialysis techniques (i.e. pure ultrafiltration followed by dialysis) have been used in the past, due to their capability to remove large volumes of fluids without inducing hemodynamic instability. The disadvantages of the inadequate dialysis and the lack of technology lead to the decline such methods. Hemofiltration (HF) and hemodiafiltration (HDF) are recently being utilized in a greater proportion thanks to the on line fluid preparation systems. Each process (HF and HDF) has its own benefits in the removal of small, medium and high-molecular weight substances and in the hemodynamic stability. Sequential hemofiltration/ hemodiafiltration (SHF/HDF), may combine the benefits and eliminate the disadvantages of each method. Furthermore they can be easily applied nowadays, due to the development of new high technological hemodialysis machines. In order to evaluate the feasibility and the effects of SHF/HDF we studied 7 chronic hemodialysis patients (6 months of treatment with SHF/HDF switched to 6 months of SHDF/HF), using the same machine (AK200 ULTRA), with on line fluid preparation system and the same type of dialyzer (Polyflux 210). The feasibility of such techniques (SHF/HDF or vice versa) resulted excellent. All sessions left the patients in a condition of well-being making fulltime work. No difference was observed between the different period of treatment, but a reduction in pre value was observed in calcium-phosphorous product, C-reactive protein and beta2-microglobulin, at the end of the sequential techniques. SHF/HDF therapy is a very promising technique. Further studies are needed to better explore the potential of such a therapeutic approach in the quality of life, the hemodialysis adequacy and the hemodynamic stability of our patients.

Analysis of outcome of pregnancy in type 1 diabetics treated with insulin pump or conventional insulin therapy.

We evaluated the outcome of pregnancies followed between 1990 and 2000 in 93 women with type 1 diabetes, treated with conventional intensive insulin therapy (n=68) or continuous subcutaneous insulin infusion (n=25). We evaluated metabolic control (fasting and 1-hour post-prandial plasma glucose and HbA1c levels), spontaneous or induced abortions, time and mode of delivery, maternal outcome (pregnancy-induced hypertension, preeclampsia, placental insufficiency, hydramnios, hypoglycemic coma, ketoacidosis) and fetal outcome (weight, hypoglycemia, hypocalcemia, hyperbilirubinemia, fetal distress, asphyxia, hyaline membrane disease, polycythemia, shoulder dystocia, malformations). Patients treated with insulin pump more frequently had background retinopathy and clinical neuropathy. No significant differences were observed between the two groups in metabolic control and maternal outcome. Glycemic control, non-optimal in the prepregnancy state, improved significantly during pregnancy, as shown by the progressive reduction in HbA1c levels. As regards fetal outcome, no differences were observed between the two groups in morbidity and especially in malformation rate. Patients with malformed babies did not have optimal metabolic control at conception. Thus, maternal and perinatal outcomes were comparable in patients treated with insulin pump and continuous subcutaneous insulin therapy, and depended on metabolic control. In patients in higher White's class and with more unstable glycemia, we achieved metabolic control and outcomes comparable with those of women of lower White's class and more stable glycemic values using the insulin pump. Our data suggest that insulin pump therapy is useful in problematic, complicated cases of women who want a baby.

Caspase-3 and -8 activation and cytokine removal with a novel cellulose triacetate super-permeable membrane in an in vitro sepsis model.

Pro-apoptotic molecules are generated during sepsis which may be responsible for alteration of organ function in sepsis. Removal of systemic apoptotic activity may affect recovery from sepsis. Current high flux membranes might not be sufficiently permeable to eliminate pro-apoptotic factors. We evaluated the elimination of pro-apoptotic factors induced by LPS in human whole blood by a super-permeable cellulose triacetate membrane (SUREFLUX FH 150, Nipro, Osaka, Japan) in comparison to a standard high flux cellulose triacetate membrane (UT 700, Nipro, Osaka, Japan) and a polyethersulfone plasmafilter (Bellco, Mirandola Italy) in an in vitro blood circulation. We spiked human whole blood with lipopolysaccharide from Escherichia coli (Serotype 026-86, 10 mg/ml), incubated it for 3 hours to allow cytokine generation and recirculated it at 300 ml/min for 3 hours. The UF line was first returned to the blood module at 10 min. After this, the UF was drained from 10 to 60 min at a rate of 1000 ml/h. Zero balance was obtained by re-infusion of bicarbonate buffered hemofiltration fluid. Apoptosis was assessed on U937 monocytes (incubated with plasma or ultrafiltrate) by fluorescence microscopy dyes (Hoechst 33342, propidium iodide) and annexin V flow cytometry. Caspase-3 and Caspase-8 activity was assessed on the recirculated blood monocytes by spectrophotometric methods. IL-2, IL-10 and TNFalpha were determined by commercially available ELISAs. Sieving coefficients and clearances were determined for the different cytokines. Caspase-3 and Caspase-8 were activated by LPS and remained either stable or increased during in vitro circulation. Apoptosis activity of U937 cells, when incubated with the ultrafiltrate, increased in parallel with arterial plasma values (for Uf: UT700 = 23.1%; Sureflux FH150 = 42.5%). However, by 60 min the apoptotic activity recorded with the ultrafiltrate was reduced to the levels of arterial plasma (for Uf: UT700 = 19.8%; Sureflux FH150 = 11.2%). Sieving coefficients in the super-permeable membrane were significantly higher for all measured cytokines in comparison to the standard high flux membrane (e.g. TNFalpha 0.72 vs 0.03 p < 0.001) and close to the values observed for the plasmafiltration membrane. Nevertheless protein losses measured by albumin leakage were much lower with the Sureflux filter in comparison to the plasmafilter. In conclusion, pro-apoptotic factors can be eliminated by dialytic membranes with the removal rate maximized by using super high flux dialysers which may represent a compromise between hemofiltration and plasmafiltration membranes.

Effects of novel manufacturing technology on blood and dialysate flow distribution in a new low flux "alpha Polysulfone" hemodialyzer.

The main target for low flux hemodialyzers is an efficient low molecular weight solutes clearance. Such efficiency is largely dependent on the optimization of diffusion between blood and dialysis solution. The diffusion process can be impaired if there is a mismatch between blood and dialysate flow distribution in the dialyzer. Thus optimized flow distribution both in the blood and dialysate compartment becomes quintessential for the maximal efficiency of the diffusion process within the hemodialyzer. The present paper describes the distribution of the blood and dialysate flows in a new low flux polysulfone hollow fiber hemodialyzer characterized by a specific undulation of the fibers and a new cutting technology of the fibers for an improved micro-flow condition in the blood compartment headers. Twelve Diacap alpha Polysulfone LO PS 15 (1.5 sqm) (B. Braun Medizintechnologie, Melsungen Germany) were employed for the study. Six were analyzed in vitro and six were studied in vivo. Blood flow distribution was studied in vitro by dye injection in the blood compartment during experimental extracorporeal circulation utilizing human blood with hematocrit adjusted at 33%. Sequential images were obtained with a helical scanner in a fixed longitudinal section of the dialyzer 1 cm thick. Average and regional blood flow velocities were measured utilizing the reconstructed imaging sequence. The method allowed the calculation of single fiber blood flow (SF Qb) and the mass transfer zone (MTR) definition in digitally subtracted images. The patterns 20-10 and 40-30 were utilized. The same technology was used to evaluate flow distribution in the dialysate compartment after dye injection in the Hansen's connector. Regional dialysate flow was calculated in central and peripheral sample areas of 1 cm2. Six in vivo hemodialysis treatments on patients with end stage renal disease were performed at three different blood flow rates (250-350 and 450 ml/min) in order to measure urea, creatinine and phosphate clearance. Macroscopic and densitometrical analysis revealed that flow distribution was homogeneous in the blood compartment while in the dialysate compartment a slight difference between the peripheral and central regions in terms of flow velocity was observed. This however was not generating channeling phenomena. Urea creatinine and phosphate clearances were remarkably high and so were the Kt/V observed in all sessions, especially in relation to the studied blood flows. In conclusion, a significant blood to dialysate flow match with optimized countercurrent flow condition was observed in the studied hollow fiber hemodialyzers. Such optimization might be due both to the improved dialyzer design at the level of the blood header and to the specific fiber undulation that prevents dialysate channeling.

Iron management in hemodialysis patients: optimizing outcomes in Vicenza, Italy.

The management of anemia in uremic patients undergoing hemodialysis requires the appropriate combination of erythropoietin treatment, iron supplementation, and on occasion androgen therapy. Identifying and correcting functional iron deficiency is crucial to optimizing erythropoietin efficiency. Recently, however, the trend to administer maintenance iron with resultant high serum ferritin and high transferrin saturation has led to an increase in reports of iron overload. Oral iron supplementation is inexpensive and safe, but poor patient compliance and reduced intestinal absorption may limit its efficacy. Intravenous iron, on the other hand, is effective, and its safety is related to the iron salt used. Currently available data suggest that iron saccharate may be the safest iron salt available for intravenous administration, although iron gluconate is safer than the dextran forms of intravenous iron. It should be kept in mind, however, that all forms of intravenous iron may have the potential of inducing iron overload. At this time, the levels of ferritin that define iron overload are not clearly established. The side effects of iron overload are well recognized (infections, malignancies, vascular diseases); however, no guidelines exist for safe practice. There are many markers of iron deficiency, with serum ferritin and hypochromic red cell percentage currently the best markers available in clinical practice.

Effects of interleukin-2 therapy on the proliferation and differentiation of CD4/CD25 positive and CD4/CD25 negative cells in HIV+ patients.

Interleukin-2 has been widely used in HIV-1+ subjects as an immunoactivating agent. In this study, we investigated cytokine production, Ki67 antigen expression and the modulation of the surface phenotype of the CD4/CD25+ subset as compared to the reciprocal CD4/CD25- subset in IL-2-treated HIV+ patients. Our findings suggest that CD4 T cells are heterogeneous in responding to IL-2, because CD4/CD25+ cells sharply increased their "memory" phenotype, their Ki67 antigen expression and were the main in vivo targets for IL-2-dependent proliferation during therapy, while the percentages of IFN-gamma+ (terminally differentiated) cells remained unchanged at the end of therapy. Conversely, the CD4+/CD25- subpopulation showed an expansion of differentiated cells and a slight increase in the proliferation rate. The use of anti-retroviral therapy alone (HAART) reduced the proliferation and increased the differentiation of both CD4 subsets. Our data suggest that IL-2 has a moderate capacity to activate resting T cells in vivo and is probably unable to boost HIV-1 from latency to the replicative state.

Different rates of CD4+ and CD8+ T-cell proliferation in interleukin-2-treated human immunodeficiency virus-positive subjects.

BACKGROUND: Interleukin-2 (IL-2) has been used successfully to increase CD4 cell counts in patients who are human immunodeficiency virus (HIV) positive. The mechanisms involved in this phenomenon are unknown. We hypothesized that a differential proliferation rate of CD4+ compared with CD8+ lymphocytes could be related to the increase of CD4 counts and of CD4/CD8 ratios that occur in HIV+ patients during IL-2 treatment. METHODS: We enrolled in our study 14 HIV+ patients treated with IL-2 or with highly active antiretroviral therapy (HAART) during a 96-week observation period. Using flow cytometry, we measured longitudinally the expression of the Ki67 antigen in peripheral blood CD4+ and CD8+ lymphocyte subsets. RESULTS: Compared with HAART alone, IL-2 produced a rapid increase of Ki67+ proliferating CD4 cells and a concomitant increase of the CD4/CD8 ratios, whereas the corresponding CD8 proliferation increased slightly. On the contrary, HAART alone was effective in suppressing equally both CD4 and CD8 proliferation. CONCLUSIONS: Our results suggest a selective activity of IL-2 on CD4 T-cell proliferation; on the contrary, CD8-specific proliferation is affected minimally during treatment. This information may offer the potential to plan correctly immune activating regimens.

Practice pattern and treatment options for kidney patients in a single North Italian nephrology center.

The experience and the current practice of a single center located in northern Italy is reported. The center of Vicenza is a self-standing nephrologic unit serving a population of about 300,000 individuals. The overall province counts approximately 800,000 individuals and some of them are referred to our center from peripheral hospitals for renal transplantation and/or particular pathologic conditions. The center offers an integrated approach to the treatment of uremia including hemodialysis (HD), peritoneal dialysis (PD), and renal transplantation. In HD and PD, the most peculiar aspect is the treatment personalization that leads to numerous types of applied therapies and technologies. The policy of the center is based on the belief that the nephrology team has a substantial influence on the outcomes of dialysis patients. A large number of treatment options are available. Special care is placed on the delivery of an adequate amount of dialysis, but the fractional clearance of urea in relation to volume (Kt/V) is seen as a prerequisite and other factors are considered important. Reduction in mortality and morbidity is largely dependent on beginning therapy early in the course of renal treatment. The attainment of appropriate hemoglobin concentrations, good nutrition, good control of calcium and phosphorus metabolism, lipids, and blood pressure, is considered of great importance. Beyond all these factors the time spent by the physician with the patient is considered one of the major factors influencing quality of care. The particularly low mortality of the center (6%/yr) may also be ascribed to a lower incidence of diabetes and other comorbidities.

Lymphocyte subsets and viral load in patients with HIV-associated non-Hodgkin's lymphoma treated with anti-CD20 monoclonal antibody and chemotherapy.

The anti-CD20 monoclonal antibody Rituximab is a novel antitumor agent used in association with chemotherapy (CT) for the treatment of high-grade/intermediate non-Hodgkin's lymphomas (NHL) in HIV-negative populations. This therapeutic combination is currently also being explored in HIV-positive patients with NHL (HIV-NHL). The objective of our study was to determine CD4 and CD8T cell counts, HIV plasma viremia and proviral load in patients with CD20-positive HIV-NHL treated with Rituximab plus CT and highly active antiretroviral therapy (HAART). We studied eight patients with HIV-NHL treated by anti-CD20 and CT before, after three, and after six cycles of therapy; CD4, CD8 and CD19 lymphocyte subsets were measured by monoclonal antibodies and flow cytometry. HIV plasma viremia was determined by the b-DNA assay, and proviral load by a quantitative competitive PCR. CD4T cell counts remained stable after three cycles of therapy, while a significant reduction of this subset was present at the end of therapy. HIV plasma viremia was significantly reduced after the third cycle, but returned to pretreatment levels at the end of therapy; we also observed individual fluctuations of proviral load during therapy, this marker being increased in two out of three patients at the end of therapy. These observations suggest that Rituximab plus CT accelerated the rate of CD4 depletion and of HIV replication in the peripheral blood of HIV-NHL patients and that HAART may be able to delay these effects.

Dialysate flow distribution in hollow fiber hemodialyzers with different dialysate pathway configurations.

UNLABELLED: The efficiency of a hemodialyzer is largely dependent on its ability to facilitate diffusion, since this is the main mechanism by which small solutes are removed. The diffusion process can be impaired if there is a mismatch between blood and dialysate flow distribution in the dialyzer. The objective of the paper was to study the impact of different dialysate compartment designs on dialysate flow distribution and urea clearances. Eighteen hollow fiber 1.3 m2 hemodialyzers were studied, 6 each of 3 designs: Type A--standard fiber bundle (PAN 65DX Asahi Medical, Tokyo, Japan); Type B--spacing filaments external to the fibers (PAN 65SF Asahi Medical, Tokyo, Japan); Type C--fibers waved to give Moiré structure (FB130 Nissho-Nipro, Osaka, Japan). IN VITRO STUDIES: 3 dialyzers of each type were studied following dye injection into the dialysate compartment. Dynamic sequential imaging of longitudinal sections of the dialyzer were undertaken, using a new generation helical CT scanner (X-Press/HS1 Toshiba Corporation, Tokyo, Japan). In vivo studies: 3 dialyzers of each type were studied, in randomized sequence, in 3 different patients under standardized dialysis conditions. Blood- and dialysate-side urea clearances were measured at 30 and 150 minutes of treatment. Macroscopic and densitometrical analysis revealed that flow distribution was most homogeneous in the dialyzer with Moiré structure (Type C) and least homogeneous in the standard dialyzer (Type A). Space yarns (Type B) gave an intermediate dialysate flow distribution. Significantly increased urea clearances (p<0.001) were seen with Types B and C, compared to the standard dialyzer. Type C (Moiré) had the highest clearances although these were not significantly greater than Type B (space yarns). In conclusion, more homogeneous dialysate flow distribution and improved small solute clearances can be achieved by use of spacing yarns or waved (Moiré structure) patterns of fiber packing in the dialyzer. These effects are achieved probably as a result of reduced dialysate channeling resulting in a lower degree of mismatch between blood and dialysate flows. The new radiological technique using the helical CT scanner allows detailed flow distribution analysis and has the potential for testing future modifications to dialyzer design.

Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and type I diabetic subjects.

AIMS/HYPOTHESIS: We have previously shown that lactate protects brain function during insulin-induced hypoglycaemia. An adaptation process could, however, not be excluded because the blood lactate increase preceded hypoglycaemia. METHODS: We studied seven healthy volunteers and seven patients with Type I (insulin-dependent) diabetes mellitus with a hyperinsulinaemic (1.5 mU.kg-1.min-1) stepwise hypoglycaemic clamp (4.8 to 3.6, 3.0 and 2.8 mmol/l) with and without Na-lactate infusion (30 mumol.kg-1.min-1) given after initiation of hypoglycaemic symptoms. RESULTS: The glucose threshold for epinephrine response was similar (control subjects 3.2 +/- 0.1 vs 3.2 +/- 0.1, diabetic patients = 3.5 +/- 0.1 vs 3.5 +/- 0.1 mmol/l) in both studies. The magnitude of the response was, however, blunted by lactate infusion (AUC; control subjects 65 +/- 28 vs 314 +/- 55 nmol/l/180 min, zenith = 2.6 +/- 0.5 vs 4.8 +/- 0.7 nmol/l, p < 0.05; diabetic patients = 102 +/- 14 vs 205 +/- 40 nmol/l/180 min, zenith = 1.4 +/- 0.4 vs 3.2 +/- 0.3 nmol/l, p < 0.01). The glucose threshold for symptoms was also similar (C = autonomic 3.0 +/- 0.1 vs 3.0 +/- 0.1, neuroglycopenic = 2.8 +/- 0.1 vs 2.9 +/- 0.1 mmol/l, D = autonomic 3.2 +/- 0.1 vs 3.2 +/- 0.1, neuroglycopenic 3.1 +/- 0.1 vs 3.2 +/- 0.1 mmol/l) but peak responses were significantly attenuated by lactate (score at 160 min C = 2.6 +/- 1 vs 8.8 +/- 1, and 0.4 +/- 0.4 vs 4.8 +/- 1, respectively; p = 0.02-0.01, D = 1.3 +/- 0.5 vs 6.3 +/- 1.7, and 2.3 +/- 0.6 vs 5.7 +/- 1.1 p = 0.07-0.02). Cognitive function deteriorated in both studies at similar glucose thresholds (C = 3.1 +/- 0.1 vs 3.0 +/- 0.1, D = 3.2 +/- 0.1 vs 3.3 +/- 0.2 mmol/l). Although in normal subjects a much smaller impairment was observed with lactate infusion (delta four-choice reaction time at 160 min = 22 +/- 12 vs 77 +/- 31 ms; p = 0.02), in Type I diabetic patients lactate infusion was associated with an improvement in cognitive dysfunction (0.2 +/- 0.4 vs -38 +/- 0.2 delta ms, p = 0.0001). CONCLUSION/INTERPRETATION: A blood lactate increase after the development of hypoglycaemic symptoms reduces counterregulatory and symptomatic responses to insulin-induced hypoglycaemia and favours brain function rescue both in normal and diabetic subjects. These findings confirm that lactate is an alternative substrate to glucose for cerebral metabolism under hypoglycaemic conditions.

Plasma free fatty acids and endothelium-dependent vasodilation: effect of chain-length and cyclooxygenase inhibition.

Free fatty acids (FFA) are known to interfere with glucose metabolism. Moreover, it has been shown that they are able to impair the endothelium-dependent vasodilation. Therefore, we sought to determine whether their negative effect on endothelial function depends on their chain length or on their ability to modify PG production. Fourteen normal volunteers were studied under baseline conditions and then randomly allocated to two of the following four studies: 1) long chain triglyceride (LCT) emulsion and heparin infusion (n = 7), 2) infusion of an emulsion containing 56% medium chain triglycerides (MCT) and 44% LCT plus heparin (n = 7), 3) infusion of LCT and heparin preceded by an i.v. bolus of 900 mg lysine-salicylate (ASA; n = 7), and 4) after an i.v. bolus of ASA (n = 7). Basal forearm blood flow (FBF), endothelium-dependent vasodilation in response to intraarterial acetylcholine (Ach), and endothelium-independent vasodilation in response to intraarterial nitroprusside were assessed by venous occlusion plethysmography. Both LCT and MCT infusions significantly increased basal FBF from 1.58 +/- 0.35 to 2.60 +/- 0.76 and 2.28 +/- 0.56 mL/min 100 mL tissue, respectively (both P < 0.05). This increase was also observed for LCT plus heparin, but not after ASA alone. The percent increase in FBF during Ach was lowered during both LCT (252 +/- 34% of the ratio infused/control arm at maximal Ach dose) and MCT (255 +/- 41%) compared to the baseline conditions (436 +/- 44%; both P < 0.05). The response to Ach was also lower during LCT plus ASA, whereas it was similar to baseline with ASA alone. No differences were observed in the response to nitroprusside among the experimental conditions. In conclusion, 1) the effect of FFA on endothelium-dependent vasodilation is independent of their chain length; 2) both LCT and MCT increase baseline FBF, independently from cyclooxygenase inhibition; and 3) acute ASA administration does not affect endothelium-dependent vasodilation. The FFA effect on the endothelial response to Ach may contribute to altered endothelial function and, hence, to the development and progression of atherosclerotic cardiovascular disease.