The potential impact of geological environment on health status of residents of the Slovak Republic.

In order to assess the potential impact of the geological environment on the health of the population of the Slovak Republic, the geological environment was divided into eight major units: Paleozoic, Crystalline, Carbonatic Mesozoic and basal Paleogene, Carbonatic-silicate Mesozoic and Paleogene, Paleogene Flysch, Neovolcanics, Neogene and Quaternary sediments. Based on these geological units, the databases of environmental indicators (chemical elements/parameters in groundwater and soils) and health indicators (concerning health status and demographic development of the population) were compiled. The geological environment of the Neogene volcanics (andesites and basalts) has been clearly documented as having the least favourable impact on the health of Slovak population, while Paleogene Flysch geological environment (sandstones, shales, claystones) has the most favourable impact. The most significant differences between these two geological environments were observed, especially for the following health indicators: SMRI6364 (cerebral infarction and strokes) more than 70 %, SMRK (digestive system) 55 %, REI (circulatory system) and REE (endocrine and metabolic system) almost 40 % and REC (malignant neoplasms) more than 30 %. These results can likely be associated with deficit contents of Ca and Mg in groundwater from the Neogene volcanics that are only about half the level of Ca and Mg in groundwater of the Paleogene sediments.

A family of secreted pathogenesis-related proteins in Candida albicans.

Analysing culture supernatants of yeast and hyphal cells of Candida albicans, we found two close homologues of pathogenesis-related (PR-) 1 proteins, Rbe1p and Rbt4p, in the secretome. Due to sequence homology, three additional, yet not characterized open reading frames, ORF19.6200, ORF19.2787 and ORF19.2336, together with RBE1 and RBT4 were assigned to a novel family of CaPRY proteins. In a Δrbe1/Δrbt4 deletion strain, genome-wide transcriptional analysis revealed differential transcription of only a limited set of genes implicated in virulence and oxidative stress response. Single deletion of RBE1 or RBT4 in a clinical C. albicans isolate resulted in a moderate but significant attenuation in virulence in a mouse model for disseminated candidiasis. However, a synergistic effect was observed in a Δrbe1/Δrbt4 double deletion strain, where virulence was strongly affected. Remarkably, transcription of RBT4 and RBE1 was each upregulated in blastospores of Δrbe1 or hyphae of Δrbt4 deletion strains respectively, indicating functional complementation thereby compensating a potential virulence defect in the single deletion strains. Furthermore, the double deletion strain showed increased sensitivity to attack by polymorphonuclear leucocytes. Therefore, the crucial contribution of both C. albicans pathogenesis-related proteins to virulence might be vested in protection against phagocyte attack.

Influence of wheat ash on the MCPA immobilization in agricultural soils.

Burning of crop residues in the fields is a routine post-harvest practice and results in accumulation of ashes in soils. Recent studies have shown that the ashes may significantly contribute to the herbicide sorption in soils. This study was conducted to evaluate the potential role of wheat ash in immobilization of anionic herbicide MCPA in soils. The results showed that wheat ash is highly effective sorbent for herbicide MCPA. Amendment of Fluvi-Gleyic Phaeozem and Eutric Regosol with 1% wheat ash caused a 8-fold and 16-fold increase in MCPA sorption, respectively. Desorption of MCPA was also influenced by wheat ash in soils. The addition of wheat ash to both soils increased the resistant fraction to desorption up to 80%. Generally, the field burning of crop residues appears to increase the sorption of pesticides in agricultural soils and decrease their leaching.

[A 19-year-old patient with acute promyelocytic leukemia and knee swelling]. / 19-jährige Patientin mit akuter Promyelozytenleukämie und Knieschwellung.

We report on a case of a 19-year-old female patient with acute promyelocytic leukemia suffering from febrile monarthitis of the right knee during neutropenia after consolidation chemotherapy caused by Geotrichum capitatum. Apparently this infection occurred due to a hematological reactivation since the patient had already developed Geotrichum capitatum fungemia during induction therapy. Under antimycotic therapy with voriconazole, flucytosine, and caspofungin as well as after two arthroscopic synovectomies with cleansing of the right knee, the infection could be controlled and the full clinical function of the knee joint could be preserved.

[29-year-old female patient with pneumonia and enlarged abdominal lymph nodes]. / 29-jährige Patientin mit Pneumonie und grossen abdominellen Lymphknoten.

Common variable immunodeficiency (CVID) is the most common clinically manifested primary immunodeficiency disease. A 29-year-old female patient presented with pneumonia and enlarged thoracal and abdominal lymph nodes. Frequently recurring infections, especially in the respiratory tract were observed in the patient's history. A hypogammaglobulinaemia could be detected. By exclusion of other disorders and a complete analysis of the immune status a CVID Ib/B was diagnosed. Regular ambulatory treatment with immune globulin substitution reduced the incidence and severity of infections.

[21-year-old patient with myocardial infarct, transient cerebral ischemia and thrombocytopenia]. / 21-jährige Patientin mit Myokardinfarkt, TIA und Thrombozytopenie.

We report on a case of a young female soccer player who first experienced a transient ischemic attack at the age of 21 and then suffered an acute myocardial infarction accompanied by thrombocytopenia 6 months later. The underlying cause was antiphospholipid syndrome. This clinical picture is caused by a very heterogeneous group of antiphospholipid antibodies, which interfere with plasmatic coagulation at various sites and are able to activate thrombocytes, endothelial cells, and monocytes. This leads to a thrombophilic condition with clinical manifestation of recurrent venous thromboses, arterial embolisms, or premature birth or miscarriage. The main therapeutic options are thus anticoagulation, heparins, and aspirin. Steroids are recommended for cases of pronounced thrombocytopenias; if treatment fails, immunosuppressants are also advisable. The antiphospholipid syndrome should be kept in mind especially in cases of young patients with thromboembolic events since the presence of antiphospholipid antibodies can be detected in 10-20% of this patient group and effective therapy after diagnosis lowers the rate of recurrence.

The impact of antithymocyte globulin on short-term toxicity after allogeneic stem cell transplantation.

Antithymocyte globulin (ATG) is commonly used in allogeneic haematopoietic stem cell transplantation (HSCT). Little information is available, however, as to the optimal protocol for use and the side-effects occurring if ATG is administered in high daily doses (10-30 mg/kg). We report our experience with ATG Fresenius (ATG-F) in conditioning for allogeneic HSCT. During a period of 3 days, 47 patients received doses between 10 and 30 mg/kg either over 4 h preceded by 1-1.5 mg/kg prednisolone 30 min before the start of ATG-F (protocol A) or alternatively, over 12 h with 3-4 mg/kg prednisolone being administered before and 6 h after start of ATG (protocol B). During treatment with ATG-F, the side-effects observed included inflammation, disseminated intravascular coagulation, hyperdynamic circulation and renal dysfunction. Although these complications caused substantial morbidity, they were reversible within a few days. Side-effects were significantly more severe in patients treated according to protocol A than in those treated according to protocol B. As prolonged infusion of ATG-F does not reduce T cell clearance due to the long half-life of ATG-F, and since less cytokine release during conditioning might have beneficial long-term effects, we recommend administering ATG-F over 12 h preceded by high-dose steroid treatment.

Flow cytometric findings in platelets of patients following allogeneic hematopoietic stem cell transplantation.

Following allogeneic hematopoietic stem cell transplantation (HSCT) patients may have an increased bleeding tendency in spite of a normal platelet count. Moreover, an association between chronic graft-versus-host disease (cGVHD) and a thrombophilic state has been observed. Platelet receptors and granules from 27 patients following HSCT (13 without cGVHD, 14 with cGVHD) were evaluated by flow cytometric analysis and compared to 62 healthy controls. Platelets from HSCT patients stained weakly with mepacrine indicating a reduced content of dense bodies, whereas no significant degranulation reaction of alpha granules and lysosomes was detectable. In addition, a lower surface expression of GP Ia/IIa was observed, indicating an acquired thrombocytopathy. The surface receptors are activated in HSCT patients, which could be seen by the lower surface expression of GP Ib internalized during the activation process and elevated levels of LIBS-1 and PAC-1 antibody binding. Patients with cGVHD had a seven-fold increased ratio of microparticles. This study demonstrates platelet receptor and granule defects in patients following HSCT. The key role of platelets in HSCT-associated hemostatic disorders is underscored by the high levels of circulating microparticles in cGvHD patients which might explain the thrombophilic state in these patients.

Platelet flow cytometric findings in patients undergoing conditioning therapy for allogeneic hematopoietic stem cell transplantation.

The conditioning regimen preceding hematopoietic stem cell transplantation (HSCT) causes a rapid decrease in the platelet count and signs of disseminated intravascular coagulation, possibly indicating platelet activation. As impacts during the conditioning regimen may predict later transplantation-associated complications, we investigated changes in platelet membrane glycoproteins (GP) and the liberation of microparticles. Platelet receptors and granules of 49 patients undergoing HSCT were evaluated by flow cytometric analysis before and after the different phases of the conditioning regimen [chemotherapy, total body irradiation (TBI), therapy with antithymocyte globulin (ATG)] and final transplantation. Following chemotherapy a high surface expression of CD62P, a low mepacrine staining, and a reduced surface expression of CD42b (part of the GP Ib/V/IX complex) were found, indicating an irreversible activation of platelets. In addition, elevated levels of circulating microparticles were observed, which may reinforce the thrombosis risk in these patients. Treatment with ATG leads to an elevated surface expression of PAC-1 epitopes, which are neoepitopes appearing after activation of GP IIb/IIIa. However, a significant degranulation was not detectable, which may be the consequence of inhibitory influences on platelets during ATG-induced cytokine release syndrome. TBI and transplantation itself had no influence on platelets. This study was able to demonstrate activating effects on platelets by certain phases of the conditioning regimen in patients receiving HSCT. Chemotherapy, in particular, leads to a strong and irreversible platelet activation and a generation of microparticles, which may cause an increased thrombosis risk. Our findings underline the impact of platelets on the pathogenesis of hemostatic complications during HSCT.

Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester.

PROBLEM: Thrombophilic predisposition may be one of the underlying causes of recurrent spontaneous abortions (RSA). We studied the prevalence of five thrombophilic gene mutations in patients with RSA. METHOD OF STUDY: 102 patients with two or more consecutive abortions and 128 women without miscarriage were analyzed for factor V Leiden mutation (FVL), prothrombin G20210A mutation (PTM), C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, glycoprotein IIIa (GPIIIa) C1565T polymorphism, and beta-fibrinogen G-455A polymorphism by polymerase chain reaction (PCR) techniques. RESULTS: No differences in the prevalence of FVL, MTHFR T/T, GPIIIa and 1-fibrinogen polymorphism were detected. Heterozygous PTM occurred more often in patients with RSA. This effect was significant in a subgroup with abortions exclusively in the first trimester (6.7%, vs. 0.8%, P = 0.027, OR 8.5). CONCLUSIONS: In contrast to the other mutations and polymorphisms, heterozygous PTM is more common in patients with abortions in the first trimester. This might reflect an influence of PTM on pathogenesis of early pregnancy loss.

Levels of insulin-like growth factor after stem cell transplantation.

Some cytokines, i.e. tumor necrosis factor-, interleukin-6 and soluble interleukin-2 receptors are associated with complications of stem cell transplantation. Insulin-like growth factors (IGFs) are a family of peptides essential for the proliferation of normal and malignant cells. Recently increased levels of IGFs have been associated with the development of malignant tumors. In this communication we report on 96 measurements of insulin-like growth factor-I (IGF-1), insulin-like growth factor-II (IGF-2), and insulin-like growth factor-binding protein-3 (IGFBP-3) performed in 19 patients following stem cell transplants. Seventeen patients had allogeneic and 2 patients autologous transplants. Most IGF determinations were made at days 0, 7, 14, 21 and 28, some at other time points. The baseline values (day 0) of IGF-1 and IGFBP-3 were not different from controls. IGF-2 values were slightly lower than controls. Following transplantation, a consistent increase of IGF-1 was observed in 9/16 patients at days 7 and 14. Later the values decreased again. IGF-2 and IGFBP-3 did not change significantly after transplantation. No direct correlation could be established with the severity of graft-versus-host disease, levels of interleukin-6 and the time to hematopoietic recovery. A potential relevance of IGFs following stem cell transplantation may be the early diagnosis of liver damage and the development of second malignancies. More studies are necessary to investigate the pathophysiology and the clinical relevance of the increase of IGF-1 following stem cell transplantation.

[Laparoscopic splenectomy in thrombotic thrombocytopenic purpura. Surgical and hematological results in 2 patients]. / Laparoskopische Splenektomie bei thrombotisch-thrombozytopenischer Purpura. Operative und hämatologische Ergebnisse bei zwei Patienten.

HISTORY: Case 1. Thrombotic-thrombocytopenic purpura (TTP, Moschkowitz' disease) in a 57-year-old woman had for one year been treated conservatively. But when daily plasmapheresis was temporarily discontinued she developed behavioural changes and impaired speech, providing an indication for splenectomy. Case 2. A 53-year-old woman with TTP had been similarly treated for one month. Splenectomy was indicated when neurological symptoms rapidly developed. INVESTIGATIONS: At admission, creatinine 110 mg/d, white cell count (WBC) 12.4 G/l haemoglobin 10.1 g/dl, haematocrit 0.29, platelets 91 G/l. Prothrombin time (PTT) and thromboplastin time were normal. Patient 2. At admission, platelet count was below 10 G/l and she had various neurological abnormalities. Haemoglobin was 9.0 f/dl, haematocrit 0.27. Platelet count, PTT, thromboplastin time and renal functions were normal. TREATMENT AND COURSE: Case 1. After plasmapheresis and administration of cryoprecipitate-free fresh frozen plasma (FFP) excess, laparoscopic splenectomy was performed. On the third postoperative day WBC count was 11.5 G/l, haemoglobin level was unchanged, but platelet count was now normal, as were PTT and thromboplastin time and renal functions. 8 and 32 months after the operation WBC count, haemoglobin, haematocrit and platelets were all normal. There were no neurological abnormalities postoperatively. Case 2. Laparoscopic splenectomy was performed after intensive haematological preparation. The pre- and postoperative course was uneventful and she was discharged on the 8th postoperative day, at which time her haemoglobin was 8.4 g/dl, haematocrit 0.25, while platelets, PTT, thromboplastin time and renal functions were all normal and remained so at follow-up 11 months later. There have been no neurological symptoms after the splenectomy. CONCLUSION: Laparoscopic splenectomy is a haematologically and surgically safe treatment of TTP and should be considered for all cases of TTP that fail to respond to conservative management.

IDEC-C2B8 (Rituximab) anti-CD20 antibody treatment in relapsed advanced-stage follicular lymphomas: results of a phase-II study of the German Low-Grade Lymphoma Study Group.

PURPOSE: The current study was initiated to assess the clinical efficacy and side effects of rituximab in patients with relapsed advanced stage follicular lymphoma. PATIENTS AND METHODS: The study was performed as an open-label non-randomized multicenter phase-II trial and included patients older than 18 years of age with relapsed advanced-stage follicular lymphomas (FL) grades I and II, according to the REAL classification, or with centroblastic/centrocytic (CB/CC lymphomas according to the Kiel classification. Four weekly doses of 375 mg/m2 rituximab were applied. RESULTS: 38 patients from eight centers were included between January 1997 and January 1998 and were evaluable for response and toxicity on an intention to treat basis. The median age was 55 years (range 26-75 years). Thirteen patients (35%) were in first relapse, 11 patients (30%) in second, and 13 patients (35%) in third relapse. The median time between primary diagnosis and study entry was 4.6 years (range 0.9-14.7 years). Twenty-three patients tolerated the application of rituximab without adverse events; in 13 cases the infusion rate had to be reduced because of side effects; in two patients the application was stopped because of pharyngeal edema and anaphylactoid reaction. The most frequent side effects were fever (13 patients) and rigor (13 patients); 65% of the side effects were observed after the first infusion. Twenty grade-III/IV side effects were considered to be related to treatment: lymphocytopenia (3), granalocytopenia (1), thrombocytopenia (2), fever (1), hyperglycermia (1), venous thrombosis (1), syncope (1), plasmatic coagulation disorder (1), shortness of breath (2), photosensitivity (1), cardiac failure (1), chills (1), sepsis (1), tumor lysis (1), anemia (1), and pharyngeal edema (1). Eight patients were not eligible for assessment of response because of non-follicular subtypes of low-grade lymphomas (n =6) or early termination of therapy at the first infusion because of severe side effects (n =2). From the 30 evaluable cases with follicular lymphomas, five patients achieved a complete remission (CR) (17%), nine patients a partial remission (PR) (30%), and two patients a minor response (MR) (7%). The overall response rate was 47%. The median time to treatment progression (TTP) was 201 days (range 64-293 days), with five patients experiencing long-lasting remissions of 214-293 days duration. In three patients, the rituximab-induced remission exceeded the preceding progression-free interval substantially. Bulky disease (P=0.058) and/or bone-mar row involvement (P=0.046) were associated with poor response. CONCLUSION: This study confirms the moderate treatment-related toxicity and the high antilymphoma activity of rituximab in patients with relapsed follicular lymphoma. Further studies are needed to determine the role of rituximab in the first-line treatment of these disorders and its combination with conventional chemotherapy.