Systematic review of hearing loss in dental professionals.

BACKGROUND: Hearing loss leads to increased irritability and disengagement in social activities and conversations, which may impact quality of life. Dental professionals are at risk of developing hearing loss through daily exposure to noise from a wide range of equipment that produces significantly high decibels and noise frequencies. AIMS: The aim of this systematic review was to investigate the risk of hearing loss in dental professionals, including dentists, dental specialists, dental hygienists and dental assistants. METHODS: This review was conducted following the Cochrane Handbook for Systematic Reviews. PubMed, Scopus, Embase, Cochrane, Science Direct, Google Scholar and ProQuest were searched up to March 2023. Seventeen of 416 studies met the inclusion criteria. Quality assessment was performed according to the Newcastle-Ottawa Scale for cohort and case-control studies, and a modified version of this tool for cross-sectional studies. RESULTS: The majority of included studies (82%) found a positive association with hearing loss for dentists and dental specialists, with years of clinical experience identified as a prominent risk factor. Dental hygienists and dental assistants were less commonly reported in the literature. Difference between the left and right ears was found in 71% of studies, with the left ear more affected in both dentists and dental assistants due to proximity to the noise-inducing equipment. CONCLUSIONS: Dental professionals are at risk of hearing loss in their workplace, especially linked to years of clinical experience, which highlights the need for prevention and appropriate ear-protective devices.

Results of the German ESPED-recording of new patients with juvenile dermatomyositis (JDM).

In a nation-wide registration project 38 incident cases of juvenile dermatomyositis were collected in Germany over a 2-year-period. Diagnostic methods as well as the primary treatment for these patients were recorded. Detailed information was available for 25 of these patients. Diagnostic as well as therapeutic decisions varied widely. Steroids were used in almost all of the 25 patients either as oral or as parenteral pulse therapy, additional immunosuppressive drugs were used in 52%. We plan to establish national consensus recommendations for diagnostic and therapeutic standards in JDM. Due to the rarity of JDM clinical trials will have to be performed on an international basis.

Differences in saccade-evoked brain activation patterns with eyes open or eyes closed in complete darkness.

In this study we attempted to differentiate distinct components of the saccade network, namely cortical ocular motor centers and parieto-occipital brain regions, by means of a "minimal design" approach. Using a blocked design fMRI paradigm we evaluated the BOLD changes in a 2 x 2 factorial design experiment which was performed in complete darkness: while looking straight ahead with eyes open (OPEN) or closed (CLOSED) as well as during the execution of self-initiated horizontal to-and-fro saccades with the eyes open (SACCopen) or closed (SACCclosed). Eye movements were monitored outside the scanner via electro-oculography and during scanning using video-oculography. Unintentional eye-drifts did not differ during OPEN and CLOSED and saccade frequencies, and amplitudes did not vary significantly between the two saccade conditions. The main findings of the functional imaging study were as follows: (1) Saccades with eyes open or closed in complete darkness lead to distinct differences in brain activation patterns. (2) A parieto-occipital brain region including the precuneus, superior parietal lobule, posterior part of the intraparietal sulcus (IPS), and cuneus was relatively deactivated during saccades performed with eyes closed but not during saccades with eyes open or when looking straight ahead. This could indicate a preparatory state for updating spatial information, which is active during saccades with eyes open even without actual visual input. The preparatory state is suppressed when the eyes are closed during the saccades. (3) Selected ocular motor areas, not including the parietal eye field (PEF), show a stronger activation during SACCclosed than during SACCopen. The increased effort involved in performing saccades with eyes closed, perhaps due to the unusualness of the task, may be the cause of this increased activation.

Impact of QuickFISH in addition to antimicrobial stewardship on vancomycin use and resource utilization in cancer patients with coagulase-negative staphylococcal blood cultures.

OBJECTIVE: To evaluate the impact of rapidly identifying coagulase-negative staphylococci (CoNS) from positive blood cultures combined with an established antimicrobial stewardship (AS) programme at a tertiary cancer centre. METHODS: We compared cancer patients ≥18 years old who between 01/1/13 and 12/31/13 had one or more positive CoNS blood culture(s) identified by Staphylococcus QuickFISH® (a peptide nucleic acid fluorescence in situ hybridization assay) with cancer patients ≥18 years old who had CoNS identified by standard microbiological techniques between 01/01/11 and 12/31/11 (baseline). Positive blood culture results were reported to the clinician by microbiology staff; restricted antibiotics (e.g., vancomycin) required approval by the AS team. RESULTS: There were 196 baseline and 103 QuickFISH patients. Faster median time to organism identification (33 (IQR 27-46) versus 49 (IQR 39-63) hours, p < 0.001), more vancomycin avoidance (51/103 (50%) versus 60/196 (31%), p 0.002), shorter median antibiotic duration (1 (IQR 0-3) versus 2 (IQR 0-6) days, p 0.019), fewer central venous catheter (CVC) removals (14/78 (18%) versus 57/160 (36%), p 0.004), and reduced vancomycin level monitoring (16/52 (31%) versus 71/136 (52%), p 0.009) were observed in the QuickFISH group. QuickFISH implementation was predictive of a lower likelihood of antibiotic therapy prescription (OR 0.35, 95%CI 0.20-0.62, p < 0.001). Prior transplant (RR 1.47, 95%CI 1.13-1.92, p 0.004), neutropenia (RR 1.47, 95%CI 1.09-1.99, p 0.012), multiple positive blood cultures (RR 4.23, 95%CI 3.23-5.54, p < 0.001), and CVC (RR 1.60, 95%CI 1.02-2.53, p 0.043) were independent factors for antibiotic duration. CONCLUSIONS: QuickFISH implementation plus AS support leads to greater avoidance of vancomycin therapy and improved resource utilization in cancer patients with CoNS blood cultures.

IL-6 blockade in systemic juvenile idiopathic arthritis - achievement of inactive disease and remission (data from the German AID-registry).

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. METHODS: In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) ( https://aid-register.de ). Data for this retrospective TCZ study were documented by 13 centers. RESULTS: From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1-18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. CONCLUSION: Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. TRIAL REGISTRATION: The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

Selective endocytosis of fluorothymidine and azidothymidine coupled to LDL into HIV infected mononuclear cells.

Drug targeting via lipoproteins may be of benefit for use of cytotoxic drugs like fluorothymidine (FLT) or azidothymidine (AZT). Both drugs are potent inhibitors of the human immunodeficiency virus (HIV) reverse transcriptase and are used in the therapy of HIV infection. With regard to this project, the selective endocytosis in HIV infected human macrophages was studied after covalent coupling of AZT and LDL to low density lipoproteins (LDL). Cultured human macrophages and the lymphocytic Molt 4/8 cell line were infected with HIV-1 in vitro and subsequently treated with FLT-LDL or AZT-LDL. Viral replication was followed by determination of cell-released capsid antigen p24. Internalisation into HIV-1 infected human macrophages by the scavenger receptor pathway leads to a dose dependent inhibition of HIV replication. Otherwise, in HIV infected, but scavenger receptor missing lymphocytes (Molt 4/8 cells), neither endocytosis nor inhibition of HIV replication results. Thus, covalent coupling of drugs to LDL leads to a macrophage specific transport. This strategy could possibly avoid toxic side effects in the therapeutic use of antiretroviral drugs and thus may open a way for an earlier chemotherapy in HIV infection.

Sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide for resectable high-risk breast cancer: feasibility and efficacy.

PURPOSE: Dose-dense chemotherapy is predicted to be a superior treatment plan. Therefore, we studied dose-dense doxorubicin, paclitaxel, and cyclophosphamide (A-->T-->C) as adjuvant therapy. METHODS: Patients with resected breast cancer involving four or more ipsilateral axillary lymph nodes were treated with nine cycles of chemotherapy, using 14-day intertreatment intervals. Doses were as follows: doxorubicin 90 mg/m2 x 3, then paclitaxel 250 mg/m2/24 hours x 3, and then cyclophosphamide 3.0 g/m2 x 3; all doses were given with subcutaneous injections of 5 microg/kg granulocyte colony-stimulating factor on days 3 through 10. Amenorrheic patients with hormone receptor-positive tumors received tamoxifen 20 mg/day for 5 years. Patients treated with breast conservation, those with 10 or more positive nodes, and those with tumors larger than 5 cm received radiotherapy. RESULTS: Between March 1993 and June 1994, we enrolled 42 patients. The median age was 46 years (range, 29 to 63 years), the median number of positive lymph nodes was eight (range, four to 25), and the median tumor size was 3.0 cm (range, 0 to 11.0 cm). The median intertreatment interval was 14 days (range, 13 to 36 days), and the median delivered dose-intensity exceeded 92% of the planned dose-intensity for all three drugs. Hospital admission was required for 29 patients (69%), and 28 patients (67%) required blood product transfusion. No treatment-related deaths or cardiac toxicities occurred. Doxorubicin was dose-reduced in four patients (10%) and paclitaxel was reduced in eight (20%). At a median follow-up from surgery of 48 months (range, 3 to 57 months), nine patients (19%) had relapsed, the actuarial disease-free survival rate was 78% (95% confidence interval, 66% to 92%), and four patients (10%) had died of metastatic disease. CONCLUSION: Dose-dense sequential adjuvant chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide (A-->T-->C) is feasible and promising. Several ongoing phase III trials are evaluating this approach.

Long-term outcome of low-grade oligodendroglioma and mixed glioma.

BACKGROUND: Low-grade oligodendrogliomas and mixed gliomas can be indolent and remain unchanged for years. Optimal timing and effectiveness of initial treatment is uncertain and therapy can be associated with toxicity. METHODS: Retrospective review of patients diagnosed between 1979 and 1997 with low-grade oligodendroglioma or mixed glioma. Time to progression, survival, prognostic factors, and treatment toxicities were evaluated. RESULTS: A total of 106 patients (77 oligodendroglioma, 29 mixed glioma) were identified; median age was 36.7 years. Initial presenting symptoms were seizures in 76 (72%) and headache in 11 (10%); tumor was diagnosed as an incidental finding in five patients. Tumor progression was diagnosed in 72 patients (68%). Overall median time to progression (MTTP) was 5.0 years (range 0.5 to 14.2). Median overall survival (OS) was 16.7 years. No prognostic factors reached statistical significance. MTTP and OS were not significantly affected by treatment. Of 62 patients who received radiation therapy, 9 (15%) developed radiation necrosis and 13 developed radiation therapy-related cognitive changes, requiring ventriculoperitoneal shunting in six. Significant myelosuppression was seen in 35 of 76 (46%) patients treated with chemotherapy. CONCLUSIONS: Low-grade oligodendroglioma and mixed glioma have a long median overall survival. There were no apparent differences in either immediate versus deferred treatment or choice of initial therapy on disease-free or overall survival. Chemotherapy was associated with significant acute toxicity in almost one half of patients; radiation therapy produced late neurotoxicity in one third, justifying deferred treatment until clinically necessary.

Is a clinical application of hybrid liver support systems limited by an initial disorder in cellular amino acid and alpha-keto acid metabolism, rather than by later gradual loss of primary hepatocyte function?

The in-vitro amino acid (AA) and alpha-keto acid (KA) metabolism of bioreactors initially seeded with 2.5 x 10(9) pig hepatocytes was investigated with a perfusion technique. Considerable changes in the culture medium concentrations of AA and KA were measured during the first days in culture. This is indicative of dynamic cellular metabolism in the initial phase. While the concentration of pyruvate decreased starting on the first day, alpha-ketoglutarate, alpha-ketoisocaproate, alpha-ketoisovalerate, and alpha-keto-beta-methyl-n-valerate were synthesized. The long term use of hepatocyte cultures in bioreactors and thus a desirable clinical hybrid liver support therapy appears to be possible since the hepatocytes switched, after 15 days in culture, to steady-state conditions with a stable amino acid turnover featuring general AA uptake accompanied by KA release. The release of branched chain KA, in particular that of alpha-ketoisocaproate, reflects an effective transamination activity in the bioreactor system. Primary pig hepatocytes cultivated in hybrid liver support systems for therapy of acute liver failure or as devices for bridging to liver transplantation can sustain amino acid metabolism for at least 30 days in vitro. However, an initial disorder following the cell isolation that is demonstrated may limit immediate utilization of the systems prior to the reorganisation of the cells to tissue-like structures in bioreactors.

Lymphoscintigraphy and sentinel node localization in breast cancer patients: a comparison between 1-day and 2-day protocols.

UNLABELLED: The purpose of this study was to compare the results of isotope injection the morning of surgery (1-d protocol) with isotope injection the day before surgery (2-d protocol) in patients having sentinel lymph node (SLN) biopsy for breast cancer. METHODS: The 1-d (protocol 1) and 2-d (protocol 2) protocols included 514 and 152 patients, respectively, treated contemporaneously by surgeons experienced with the SLN biopsy technique. All had preoperative lymphoscintigraphy (LSG) and SLN biopsy using both blue dye and (99m)Tc-sulfur colloid. All patients had a single-site intradermal injection of unfiltered (99m)Tc-sulfur colloid in 0.05 mL normal saline: 3.7 MBq (0.1 mCi) on the morning of surgery for protocol 1 and 18.5 MBq (0.5 mCi) on the afternoon before surgery for protocol 2. RESULTS: The patients in protocols 1 and 2 were comparable in terms of age, tumor size, tumor location, histologic type, node positivity, and frequency of a previous surgical biopsy. Comparing protocols 1 and 2, early (30 min) LSG images found the SLN equally often (69% vs. 68%). Isotope identified the SLN equally often at surgery (93% vs. 97%) as did isotope plus dye (98% vs. 99%). A comparable number of SLNs was found (2.5 vs. 2.8 per axilla), and the concordance between isotope and dye in the SLN was also comparable (97% vs. 95%). Late LSG images (at 2 h, possible only for protocol 2) identified the SLN in significantly more patients compared with early images (86% vs. 68%). CONCLUSION: With unfiltered (99m)Tc-sulfur colloid injected intradermally, the results of SLN biopsy under the 1-d and 2-d protocols are virtually identical. A 2-d protocol allows increased efficiency in scheduling, both for nuclear medicine physicians and for the operating room, with no compromise in the effectiveness of SLN mapping.

Rapid and specific targeting of monoclonal antibody A33 to a colon cancer xenograft in nude mice.

Monoclonal antibody (mAb) A33 detects a glycoprotein homogeneously expressed by > 95% of human colon cancers and by normal colon cells. The A33 antigen is not secreted or shed and after mAb A33 binds to antigen on the cell membrane, a fraction of membrane-bound mAb A33 is internalized into endosomes. Phase I 131I-mAb A33 biodistribution studies have shown consistent, specific tumor-targeting, and phase I radioimmunotherapy trials with 131I- or 125I-mAb A33 have demonstrated antitumor effects. Here we describe a nude mouse model that was established using a human colon cancer cell line, SW1222, which grows as a relatively hypovascular, invasive heterotransplant when injected i.m. Peak uptake of 131I-labeled or 111In-chelated mAb A33 was observed at 48-96 h, with a mean of 34% (SE +/- 5.0) and 46.7% (SE +/- 1.7) injected dose per gram of tumor tissue, respectively. 111In-mAb A33 was retained in tumor tissue longer than halide radioimmunoconjugates. The specificity of antibody localization was assessed using a control antibody (tumor uptake and pharmacokinetics), a control tumor, corrections for vascular antibody blood-pooling in tumor tissue, and blocking of radiolabeled mAb A33 localization by pretreating mice with excess unlabeled mAb A33. These experiments demonstrate that mAb A33 localization in tumor was specific, and they emphasize the unexpected rapidity with which the antibody localizes. Our conclusions were confirmed by immunohistochemical techniques which allowed direct visualization of localization and distribution of the humanized version of mAb A33 in tumor tissue. Furthermore, antibody doses approximating tumor-saturating doses demonstrated that a homogeneous distribution of antibody in tumor is possible. This model will be valuable for studies focusing on general physiologic aspects of antibody-to-tumor cell localization and critical as a guide to the evaluation of various A33 antibody constructs and combinations with other therapies for the treatment of colon cancer.

Correction of amino acid metabolism by recombinant human erythropoietin therapy in hemodialysis patients.

We assessed the effect of correction of anemia with recombinant human erythropoietin (rhEPO) on plasma amino acid levels in maintenance hemodialysis patients. The plasma amino acid pattern was estimated by high performance liquid chromatography in 18 healthy persons and 14 hemodialysis patients before and up to 12 weeks after rhEPO therapy. There was a correction of the plasma serine values (67 +/- 16 to 87 +/- 22; P less than 0.05) and a corresponding decrease in the serine precursors, glycine (317 +/- 113 to 228 +/- 56; P less than 0.05) and hydroxyproline (26 +/- 21 to 15 +/- 13; P less than 0.10). The low plasma branched-chain amino acids, valine (137 +/- 33 to 154 +/- 50; P less than 0.10) and leucine (72 +/- 22 to 80 +/- 27; P less than 0.20), also were corrected. The elevated values of ornithine (78 +/- 16 to 62 +/- 19; P less than 0.1) and arginine (94 +/- 14 to 72 +/- 14; P less than 0.1) fell. The diminished glutamine values (470 +/- 125 to 563 +/- 115; P less than 0.1) and the decreased tyrosine/phenylalanine ratio (0.78 +/- 0.17 to 0.98 +/- 0.21; P less than 0.05) rose. Thus, the administration of rhEPO not only affects erythropoiesis, but also corrects the plasma amino acid pattern towards normal.

Increased reduction of dimethylarginines and lowered interdialytic blood pressure by the use of biocompatible membranes.

Hypertension contributes to cardiac and cerebrovascular complications in HD patients. Endogenous inhibitors of nitric oxide synthase accumulate in renal failure and may interfere with the regulation of vascular tone. We investigated the elimination of asymmetric dimethylarginine (ADMA) by using biocompatible Polyamide Strade mark membranes in low-flux (Polyflux 6L) or high-flux (Polyflux 14S) hemodialysis or hemodiafiltration (HDF) compared with hemodialysis with cellulosic membranes. Removal rates for ADMA, symmetric dimethylarginine (SDMA), and beta2-microglobulin significantly increased in HDF. The plasma total amino acid concentration and the arginine/ADMA ratio increased, and the mean 24-hour blood pressure decreased during the study. In a second study, we investigated whether plasma amino acids and interdialytic blood pressure are influenced by the use of a biocompatible membrane and HDF. Seventeen end-stage renal disease patients were treated for six weeks with hemodialysis using cellulosic membranes, six weeks with low-flux hemodialysis using Polyflux 6L, and six weeks with HDF using Polyflux 14S. Only in the diabetic patients were the hemoglobin concentration (from 10.6 +/- 1.5 to 11.9 +/- 0.6 mg/dL) and hematocrit (from 33.6 +/- 1.9 to 36.2 +/- 1.5%) increased significantly, whereas the mean 24-hour systolic blood pressure decreased (from 154 +/- 22 to 129 +/- 18 mm Hg). No significant changes were observed in nondiabetic patients. We conclude that primarily diabetic patients seem to benefit from the use of biocompatible membranes--most in HDF--after a period of six weeks. The regulation of nitric oxide pathways by ADMA removal and changed ADMA/arginine ratio might be contributing factors. Further prospective studies are required to show whether the long-term application of HDF or other changes of dialysis treatment modalities may help to improve well-being, morbidity, and mortality in hemodialysis patients.

Cellular kinetics of prednimustine versus chlorambucil plus prednisolone in vitro.

Intracellular concentrations of prednimustine (PM), chlorambucil (CLB), phenylacetic acid mustard (PAAM) and prednisolone (P) were measured in different experimental tumor cell lines that had been incubated with either PM or CLB + P. For intracellular analytical determination, we modified a high-pressure liquid chromatographic method for the detection of these substances in plasma. Intact PM could be detected in the intracellular compartment of the incubated tumor cells. PM-incubated cells from PM-injected rats exhibited a higher intracellular concentration-time integral (PAAM) and longer concentration-time profiles for drugs with alkylating capacity than did cells exposed to the CLB + P mixture or to CLB. PAAM was not detectable after incubation of cells with PM, whereas in CLB-incubated cells the AUC of PAAM exceeded that of the parent drug CLB. Our in vitro results therefore favour the concept of a facilitated intracellular uptake and an increased antiproliferative effect for PM versus CLB and CLB + P.

Long-term effects of rhEPO therapy on erythrocyte rheology in dialysis patients with different target hematocrits.

UNLABELLED: Successful treatment of renal anemia with recombinant erythropoietin (rhEPO) raises the question of whether the renal anemia symptom complex requires complete correction. Current arguments against increasing hemoglobin (Hb) levels above 10-11 g/dl are impaired hemodynamics, increased risk of vascular access occlusion, unmanageable hypertension and dialysis complications. The aim of the study was to determine whether sustained Hb normalization using long-term rhEPO causes hemorheological changes with a potentially negative hemodynamic impact. The study was conducted in 42 rhEPO-treated dialysis patients with stable Hb > 11.0 g/dl for at least 20 weeks. The mean Hb of the total study group was 12.8 1.1 g/dl. To study the effect of Hb as a risk indicator in greater detail, the patients were divided into two groups, with hematocrits above and below 0.40. Hemorheology (erythrocyte deformability and aggregation, plasma viscosity) showed no significant changes, including vs a healthy control group. Throughout the period of increased rhEPO administration, no increase was observed in the incidence of hypertension or vascular thrombosis. CONCLUSION: the marked additional quality-of-life benefit achieved by complete correction of renal anemia harbors no substantial increase in treatment risk.

Complete correction of renal anemia by recombinant human erythropoietin.

The target-hematocrit (Hct) for the correction of renal anemia by recombinant human erythropoeitin (rhEPO) therapy is discussed controversially. A normalization of the Hct that could lead to a further improvement of the patients status, is often rejected, because of possible side effects as a result of an increase in blood viscosity. Hemodialysis (HD) induces an acute hemoconcentration due to ultrafiltration that might influence these risk factors negatively and therefore conflict with the normalization of Hct. The aim of this study was to investigate the changes in rheological and biochemical parameters in chronic HD patients with a normal initial Hct before hemodialysis. Results in 39 patients are given as mean +/- SD before/after HD: Hct 0.42 +/- 0.05/0.45 +/- 0.05 (p < 0.001), hemoglobin (g/dI) 13.3 +/- 1.0/14.4 +/- 1.3 (p < 0.001), MCV (fl) 99.3 +/- 5.7/99.1 +/- 5.5, MCHC (mM/l) 19.9 +/- 0.6/20.1 +/- 0.6 (p < 0.01), red blood cell (RBC) elongation (%) 60.97 +/- 3.67/60.99 +/- 3.73, RBC aggregation index AI0 0.52 +/- 0.12/0.50 +/- 0.12, AI4 0.52 +/- 0.14/0.51 +/- 0.12, plasma viscosity 1.74 +/- 0.14/1.92 +/- 0.20 (p < 0.001), whole blood viscosity (WBV), etaabs.100(mPas) 5.91 +/- 0.78/6.80 +/- 1.2 (p < 0.001), etaabs.0.01(mPas) 75.81 +/- 35.48/167.656 +/- 98.686 (p < 0.05), ultrafiltration (FM) 2.1 +/- 1.1. The biochemical parameters protein, albumin, IgG, IgA, IgM, cholesterol, transferrin and fibrinogen are significantly increased after HD. The hemoconcentration during HD is associated with a significant increase in WBV, mainly associated with the increase in Hct (r = 0.83), but not exceeding the normal range compared to healthy controls. The increase in plasma viscosity is correlated mainly with an increase in protein (r = 0.80), albumin (r = 0.74), and fibrinogen (r = 0.54). No significant changes in RBC aggregation and deformability were observed during the HD session. In conclusion, from the rheological point of view it is unlikely that the normalization of the Hct will contribute to an increased risk in access thrombosis or thromboembolic events in HD patients.

Amino acid and alpha-keto acid metabolism depends on oxygen availability in chronic hemodialysis patients.

Amino acid and alpha-keto acid metabolism depends on oxygen availability in chronic hemodialysis patients. Malnutrition in hemodialysis (HD) patients with renal anemia is reflected in an abnormal plasma amino acid profile. We wished to determine the extent to which malnutrition can be improved by correcting anemia with recombinant human erythropoietin (rhEPO) and supplemental iron. As specific parameters we measured and compared the plasma concentrations of the branched-chain amino acids valine, leucine and isoleucine and their transamination products - major participants in proteolysis and protein biosynthesis - using HPLC with fluorescence detection in 45 severely anemic HD patients (group A: Hb 7.2 +/- 0.8 g/dl), 34 patients with partially corrected anemia (group B: Hb 10.3 +/- 0.6 g/dl) and 35 HD patients with totally corrected anemia (group C: Hb 13.5 +/- 0.7 g/dl). Sixty healthy subjects (group N: Hb 14.2 +/- 1.1 g/dl) served as controls. Correlating with the degree of correction (A/B/C/N), a significant shift to anabolic metabolism was observed in the plasma levels of valine: 130/146/155/205 micromol/l; leucine: 73/71/80/110 micromol/l and alpha-ketoisocaproate (KIC): 11.4/11.8/15.1/ 30.4 micromol/l. It is concluded that energy metabolism becomes increasingly anabolic as hemoglobin levels are normalized.

Atherosclerosis: current concepts of pathophysiology and pharmacological intervention based on trial outcomes.

Atherosclerosis related cardiovascular diseases are the leading cause of death in western societies. The clinical manifestations are chronic arterial obstructions or acute arterial occlusions in various vascular territories. The pathogenesis is only understood in part as yet. Arterial wall abnormalities, blood composition abnormalities and hemodynamic alterations are generally accepted to be causative (Virchow's triad). The key role is played by macrophages in the subendothelial space that are activated immunologically by oxidized LDL particles via the scavenger receptor pathway. Recently, endothelial dysfunction due to oxidative stress was identified as a priming factor in the course of the development of atherosclerotic plaques. Shear stress-induced microinjuries of the endothelium in hemodynamically compromised regions together with local coagulation activation associated with microinflammation of the plaque are currently thought to cause plaque rupture. This event is the reason for local clot formation and ultimate organ infarction. Treatment success is still insufficient, however some progress during the last decade is reflected by the improving outcome of atherosclerosis associated cardiovascular diseases. Evidence from clinical trials supports the efficacy of statins, antiplatelet agents, antihypertensive agents if necessary and omega-fatty acids in patients with overt atherosclerosis. The reduction of mortality achieved by those drugs amounts to: omega-fatty acids -21%, statins -16%, anti-platelet agents -14%, treatment of hypertension -13%. It is impossible to calculate the combined effect of these modalities since in each trial participants received co-medication containing agents tested in other trials.

Oxidation parameters in complete correction of renal anemia.

UNLABELLED: Chronic hemodialysis (HD) patients are more exposed to oxidative stress, with its adverse impact on many cell functions and not least on patient survival. There is evidence that partial correction of renal anemia by erythropoietin (rhEPO) therapy reduces oxidative stress. The aim of this study was to clarify whether complete correction of renal anemia with rhEPO reduces free radical generation in HD patients and increases antioxidant supply. The following parameters: malondialdehyde (MDA), reduced glutathione (GSH) and glutathione disulfide (GSSG) were investigated in patients with a hematocrit (Hct) normalized on rhEPO therapy (Hct > or = 0.4), and compared with those in anemic patients (Hct 0.3 - 0.39 and Hct < 0.3). The groups were similar in age, sex or body weight. Patients with normal Hct were significantly longer in the chronic HD program (74.0 +/- 70.3 vs. 23.0 +/- 30.9 and 30.6 +/- 34.8 months; p < 0.05) and received significantly lower doses of iron (35.7 +/- 19.5 vs. 55.4 +/- 26.0 and 80.0 +/- 47.1 mg/week; p < 0.05) and rhEPO (68.9 +/- 63.6 vs. 106.5 +/- 63.9 and 152.8 +/- 86.0 IU/kg/week; p < 0.05). MDA levels were significantly lower in the group with normal Hct than in the comparison groups (1.54 +/- 0.27 vs. 1.98 +/- 0.52 and 2.23 +/- 0.93 micromol/l; p < 0.01), but did not differ significantly between the anemic groups. GSH and GSSG concentrations corrected for erythrocyte levels showed no significant differences, but whole-blood levels in patients with Hct > or = 0.4 and 0.3 - 0.39 were significantly higher than in patients with Hct < 0.3 (GSH: 0.97 +/- 0.42 vs. 1.03 +/- 0.38 and 0.62 +/- 0.34 micromol/ml; GSSG: 14.57 +/- 6.06 vs 13.07 +/- 5.18 and 7.28 +/- 3.64 micromol/l; p < 0.05). CONCLUSION: After correction of renal anemia, MDA levels are significantly lower - reflecting decreased free radical generation - than in anemic HD patients. Whole-blood antioxidant capacity is significantly increased. Overall, rhEPO therapy has clearly positive effects on free radical metabolism.

Does treatment of renal anemia with recombinant erythropoietin influence oxidative stress in hemodialysis patients?

Patients with chronic renal failure (CRF) undergoing hemodialysis (HD) are exposed to constant oxidative stress, as shown by elevated malondialdehyde (MDA) plasma concentrations in HD patients. The aim of our study was to investigate the role of renal anemia in oxidative stress. To this end, MDA and 4-hydroxynonenal (HNE) were measured in three groups of patients. Group I comprised 8 patients with hemoglobin (Hb) < 10 g/dl (mean Hb 8.1 +/- 1.3 g/dl) and group II 8 patients with Hb > 10 g/dl (mean Hb 12.4 +/- 1.9 g/dl). None of these 16 patients had been previously treated with recombinant erythropoietin (rhEPO). Group III comprised 27 patients with mean Hb 10.5 +/- 1.6 g/dl after long-term treatment with rhEPO. The plasma concentrations of both MDA and HNE in all 43 HD patients were significantly higher (p < 0.0001) than in 20 healthy controls (MDA 2.85 +/- 0.25 vs 0.37 +/- 0.03 microM, HNE 0.32 +/- 0.03 versus 0.10 +/- 0.01 microM). Comparison between the three groups showed that the HD patients with Hb < 10 g/dl had significantly higher plasma concentrations of lipid peroxidation products (MDA 3.81 +/- 0.86 microM, HNE 0.45 +/- 0.07 microM) than either HD patients with Hb > 10 g/dl (MDA 2.77 +/- 0.58 microM, HNE 0.25 +/- 0.05 microM) or HD patients treated with rhEPO (MDA 2.50 +/- 0.12 microM, HNE 0.29 micro 0.03 microM). An inverse correlation was also demonstrated between plasma HNE and Hb (r= 0.62, p < 0.0001). It follows that a substantial part of the oxidative stress is due to renal anemia. Treatment with rhEPO can therefore effectively reduce oxidative stress in HD patients.