Prognostic significance of del(20q) in patients with hematological malignancies

Deletions of the long arm of chromosome 20 represent a common chromosomal abnormality associated with myeloid malignancies, in particular with myeloproliferative disorders (MPD), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Using G-banding cytogenetic techniques, we found clones with del(20q) in 36 patients with hematological malignancies examined in our laboratory during the years 2001–2003: in 23 patients as a sole cytogenetic aberration and in 13 patients together with other chromosomal changes. Fluorescence in situ hybridization (FISH) with a probe specific for the 20q12 region was used in all cases to confirm the presence of the clone with deletion. For patients with additional or complex chromosomal rearrangements, multicolor FISH (M-FISH) analysis was performed. Statistical evaluation of the prognostic impact of sex, age, diagnosis, and karyotype was performed. The survival time correlated with the type of chromosomal aberration; no significant differences in survival were found for sex, age, and diagnosis.     

Leukocyte-derived inhibitory activity in patients with myelodysplastic syndrome

Summary Leukocyte-derived inhibitory activity inhibiting the entry of normal progenitor cells of granulocytes and macrophages (CFU-GM) into the S-phase of a cell cycle was investigated in 16 patients with different forms of myelodysplastic syndrome (MDS). The presence of this inhibitory activity was analysed in medium conditioned with low-density cells obtained from peripheral blood of MDS patients. The inhibition rate was measured by ³H-thymidine suicide technique with subsequent cultivation of pretreated cells in semisolid agar medium. Low-density cells from MDS patients of various types were studied: from the twelve patients with refractory anaemia (RA or RAS) only three were positive, one patient with chronic myelomonocytic leukaemia (CMML) was negative while one patient with refractory anaemia with excess of blasts (RAEB) and two patients with RAEB in transformation (RAEB-T) were positive with respect of the described test. In two patients with RA, who underwent a long-term investigation, the production of leukocyte-derived inhibitory activity preceded the development of disease into RAEB or RAEB-T. In five positive cases, supernatants were incubated with antiserum against human placental ferritin; with one exception, the inhibitory activity was neutralized.     

Effect of voice therapy with or without transcutaneous electrical stimulation on recovery of injured macroscopically intact recurrent laryngeal nerve after thyroid surgery

European Archives of Oto-Rhino-Laryngology - Electrical stimulation-supported therapy is an often used modality. However, it still belongs to experimental methods in the human larynx. Data are...     

Myelodysplastic and myeloproliferative type of chronic myelomonocytic leukemia--distinct subgroups or two stages of the same disease?

Several authors have tried to solve the problems in the classification of CMML. A fully suitable classification does not exist. The goal of our study was to determine common and different signs of MD and MP type of CMML and to observe frequency of shifts from MD to MP-CMML. Sixty nine CMML patients were divided according to FAB proposal into two groups: 31 patients into the MD group (WBC < or = 13 x 10(9)/l) and 38 patients into the MP group (WBC < or = 13 x 10(9)/l). Presenting features and the course of the disease in both groups were evaluated. The median age of patients was not different in both groups (71.5 and 74 years, respectively), male/female ratio was 1.1 and 2.4, respectively. The median follow-up time was 15.5 months (1-58.8) in MP group and 24 months (2-118) in MD group. In MP group splenomegaly, hepatomegaly, lymphadenopathy, abnormal karyotype and skin involvement were found more often than in MD group. Median LDH value was higher in MP group. Probability of survival was higher in the MD group than in MP group (median 30 and 11 months, respectively). Leukaemia transformation frequency was similar in both groups. In 12 out of 24 (50%) MD group patients WBC increased during the course of the disease over 13 x 10(9)/l. Oscillation of WBC values below and over 13 x 10(9)/l was observed in three patients. During the follow-up time number of patients with splenomegaly and/or immature granulocytes in the PB increased. After inclusion of 12 patients who shifted from MD to MP group a new CMML group resulted characterised by longer median survival (17 months) due to a higher number of patients in an earlier stage of the disease. Failure of evolution of myeloproliferative signs and lower frequency of AL in the remaining group might be explained by an early stage of CMML, untimely deaths due to unrelated causes and/or by patients suffering of RA with monocytosis rather than of CMML. In summary, our data suggest, that evolution from MD-CMML to MP-CMML is a frequent event and that MD-CMML could be the early stage of CMML in most of cases. The WBC at diagnosis as the single criterion for subclassification of CMML does not seem to be fully justified. We propose that CMML should not be divided in MD and MP types and that monitoring of patients and search for other signs of myeloproliferation such as PB immature granulocytes, splenomegaly, lymphadenopathy, skin involvement, pleural or peritoneal effusions, spontaneous growth of CFU-GM in vitro should be taken in consideration for a better classification of CMML, which would have an impact on the therapeutic approach.     

Inhibitor of normal granulopoiesis produced by cells of MDS patients

Low-density blood cells from patients with refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-T) release a high molecular weight inhibitory substance that reduces the entry of normal progenitor cells of granulocytes and macrophages (CFU-GM) into the S-phase. Out of 20 patients with refractory anemia (RA and RAS) only 3 were positive. One patient with CMML was negative. Serial examination of 3 patients (two RA and one CMML) revealed that the production of the inhibitory activity preceded the development of the disease into RAEB, RAEB-T, or AML. With one exception, the inhibitory activity in positive cases was neutralized by antiserum against human placental ferritin.     

Differentiation of human myeloid leukemia cell line ML-1 induced by retinoic acid and 1,25-dihydroxyvitamin D3.

Human myeloblastic leukemia cell line ML-1 was induced to differentiate by 1 mumol/l all-trans-retinoic acid (RA) or by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). After 4-6 days of the induction several differentiation-associated characteristics were observed: (1) Ability to stimulate respiration burst in the ML-1 induced cells as detected by nitroblue tetrazolium (NBT) test or by chemiluminescence (CL). (The percentage of the NBT-positive cells was up to 99% in the RA-induced cells and up to 85% in the 1,25(OH)2D3-induced cells.) (2) Substantially higher phagocytosis of colloid iron, latex or Staphylococcus particles was found in the induced cells. (3) The 1,25(OH)2D3-induced ML-1 cells expressed the monocytic enzyme NaF-inhibitable alpha-naphthyl butyrate esterase and the surface monocytic antigen CD-14. (4) A majority of the induced cells lost the morphological features of blast cells; while the 1,25(OH)2D3-treated cells acquired certain features of monocyte-macrophage differentiation, the RA-treated cells displayed several granulocytic characteristics. (5) Cytofluorometric DNA assay after treatment of the cells with colcemid showed that the decline observed in the growth rate of the induced cells was connected with their arrest in G1/G0 phase of the cell cycle. The obtained results indicate granulocytic differentiation of the RA-induced ML-1 cells and monocyto/macrophage differentiation of the 1,25-(OH)2-D3 induced cells.     

Agranulocytosis in a patient with primary Sjögren's syndrome

Summary The authors describe a case of primary Sjögren's syndrome, which was complicated with severe autoimmune agranulocytosis quite sensitive to immunosuppressive therapy. Agranulocytosis is a very rare complication of this autoimmune rheumatic disease as opposed to leucopenia. A remarkable feature of the presented case is the fact that correct diagnosis of primary Sjögren 's syndrome has not been settled for almost 25 years. The disease has manifestated only in the form of arthropathy imitating rheumatoid arthritis.     

Prenatal dietary load of Maillard reaction products combined with postnatal Coca-Cola drinking affects metabolic status of female Wistar rats

Aim

To assess the impact of prenatal exposure to Maillard reaction products (MRPs) -rich diet and postnatal Coca-Cola consumption on metabolic status of female rats. Diet rich in MRPs and consumption of saccharose/fructose sweetened soft drinks is presumed to impose increased risk of development of cardiometabolic afflictions, such as obesity or insulin resistance.

Methods

At the first day of pregnancy, 9 female Wistar rats were randomized into two groups, pair-fed either with standard rat chow (MRP-) or MRPs-rich diet (MRP+). Offspring from each group of mothers was divided into two groups and given either water (Cola-) or Coca-Cola (Cola+) for drinking ad libitum for 18 days. Oral glucose tolerance test was performed, and circulating markers of inflammation, oxidative stress, glucose and lipid metabolism were assessed.

Results

MRP+ groups had higher weight gain, significantly so in the MRP+/Cola- vs MRP-/Cola-. Both prenatal and postnatal intervention increased carboxymethyllysine levels and semicarbazide-sensitive amine oxidase activity, both significantly higher in MRP+/Cola + than in MRP-/Cola-. Total antioxidant capacity was lower in MRP+ groups, with significant decrease in MRP+/Cola + vs MRP-/Cola+. Rats drinking Coca-Cola had higher insulin, homeostatic model assessment of insulin resistance, heart rate, advanced oxidation of protein products, triacylglycerols, and oxidative stress markers measured as thiobarbituric acid reactive substances compared to rats drinking water, with no visible effect of MRPs-rich diet.

Conclusion

Metabolic status of rats was affected both by prenatal and postnatal dietary intervention. Our results suggest that combined effect of prenatal MRPs load and postnatal Coca-Cola drinking may play a role in development of metabolic disorders in later life.Maillard reaction products (MRPs), first described by French biochemist C. Maillard in the beginning of 20th century (1), are formed by nonenzymatic reactions of reactive sugars and proteins, giving thermally processed food its typical color, taste, and odor.Eight decades later Brownlee et al. recognized that same substances are formed naturally in human body, and named the in vivo analogues of MRPs “advanced glycation end products” (AGEs) (2,3). Except for classical pathway of their formation under hyperglycemic conditions, there are alternative pathways of AGEs formation effective – under oxidative- and carbonyl-stress, utilizing reactive aldehydes formed during lipid peroxidation and autooxidation of glucose. AGEs are implicated in pathophysiology of aging and different non-communicable diseases: AGE-modification alters the structure (physical and chemical properties) and thus function (biological properties) of proteins (4). Discovery of specific cell-surface receptor for AGEs (RAGE) enabled characterization of indirect harmful pathways leading to enhanced oxidative stress and pro-inflammatory, diabetogenic, and atherogenic effects (5,6).In 1997, Koschinsky et al (7) showed that dietary MRPs partially absorbed into the bloodstream were chemically and biologically active, exerting harmful health effects, which is why they were called “glycotoxins.” This finding prompted extensive research confirming that consumption of large amounts of dietary MRPs might induce or aggravate insulin resistance, renal impairment or atherosclerosis, activate inflammatory and oxidative stress pathways, and contribute to development of complications in diabetes and nephropathies (8-11). These findings raise the question on the role of MRPs-rich diet in prenatal programming. Evidence strongly suggests that maternal obesity and improper prenatal nutrition provide maladaptive intrauterine cues to developing offspring, predisposing organs for chronic disease later in life (12,13). Maternal dietary habits affect the fetus, outcome of pregnancy, and long term health of the child (14-16). Mericq et al found a direct relationship between newborn’s and maternal serum levels of several AGEs at the time of delivery, suggesting maternal transmission of AGEs (17). AGEs/RAGE axis activates in pregnancy-associated pathologies impacting fetus development, such as preeclampsia and preterm birth (18-20).Rising prevalence of obesity and obesity-associated (particularly metabolic) complications in youth (21,22) was linked, among others, to rising consumption of sugar-sweetened carbonated drinks such as cola beverages (23,24). Effects are attributed to multiple factors, including higher caloric intake, high fructose content rendering less satiety and compensation and resulting in elevated plasma uric acid, and a general effect of consuming refined carbohydrates (25,26). Moreover, cola beverages also contain MRPs and reactive AGE-precursors, most abundantly hydroimidazolone derived from arginine residues modified by methylglyoxal (27,28).To the best of our knowledge potential effects of MRPs-rich diet during pregnancy on prenatal programming have yet not been investigated. In this study we investigated the metabolic status of young adult rats – offspring of mothers consuming MRPs-rich diet during pregnancy. As drinking of cola beverages is increasingly popular among children and adolescents, our second aim was to investigate the additional impact of Coca-Cola consumption on prenatally affected young adult rats.