Impact of Ultrafiltration on Back-Diffusion in Hemodialyzer

Abstract: Ultrafiltration of water from blood to dialysate decreases the rate of back–diffusion of solutes from dialysate to blood. Therefore, back–clearance ( bK ) of hemodialyzers may be expressed as bK = bK _o – bTrQ _u, where bK _o is the diffusive back–clearance, bTr is the "back–"transmittance coefficient, and Qu is the net ultrafiltration rate. A formula for bK was derived from the one–dimensional theory of hemodialyzer, and bTr was described as a function of bK _o and the Staverman reflection coefficient. The transport parameters, bK _o and bTr , for creatinine and vitamin B₁₂ were measured in two types of hemodialyzers with negligible back–filtration, using water solutions, and compared with the transport parameters, K _o and Tr , for the case of both diffusion and ultrafiltration from blood to dialysate. bK _o was in general equal to K_o. bTr was not different from Tr for creatinine whereas bTr was lower than Tr for vitamin B₁₂. Experimental values of bTr for vitamin B₁₂ were in general agreement with theoretical predictions. However, experimental values of bTr for creatinine were lower than predicted values. We conclude that the impact of ultrafiltration on back–clearance for slowly diffusing solutes is weaker than on their clearance.     

Anticancer Activity of Novel NF-kB Inhibitor DHMEQ by Intraperitoneal Administration

There have been great advances in the therapy of cancer and leukemia. However, there are still many neoplastic diseases that are difficult to treat. For example, it is often difficult to find effective therapies for aggressive cancer and leukemia. An NF- B inhibitor named dehydroxymethylepoxyquinomicin (DHMEQ) was discovered in 2000. This compound was designed based on the structure of epoxyquinomicin isolated from a microorganism. It was shown to be a specific inhibitor that directly binds to and inactivates NF- B components. Until now, DHMEQ has been used by many scientists in the world to suppress animal models of cancer and inflammation. Especially, it was shown to suppress difficult cancer models, such as hormone-insensitive breast cancer and prostate cancer, cholangiocarcinoma, and multiple myeloma. No toxicity has been reported so far. DHMEQ was administered via the intraperitoneal (IP) route in most of the animal experiments because of its simplicity. In the course of developmental studies, it was found that IP administration never increased the blood concentration of DHMEQ because of the instability of DHMEQ in the blood. It is suggested that inflammatory cells in the peritoneal cavity would be important for cancer progression, and that IP administration, itself, is important for the effectiveness and safety of DHMEQ. In the present review, we describe mechanism of action, its in vivo anticancer activity, and future clinical use of DHMEQ IP therapy.     

Interleukin-4 activates large-conductance, calcium-activated potassium (BKCa) channels in human airway smooth muscle cells

Large-conductance, calcium-activated potassium (BK_Ca) channels are regulated by voltage and near-membrane calcium concentrations and are determinants of membrane potential and excitability in airway smooth muscle cells. Since the T helper−2 (Th2) cytokine, interleukin (IL)-4, is an important mediator of airway inflammation, we investigated whether IL-4 rapidly regulated BK_Ca activity in normal airway smooth muscle cells. On-cell voltage clamp recordings were made on subconfluent, cultured human bronchial smooth muscle cells (HBSMC). Interleukin-4 (50 ng ml⁻¹), IL-13 (50 ng ml⁻¹) or histamine (10 μ m ) was added to the bath during the recordings. Immunofluorescence studies with selective antibodies against the α and β1 subunits of BK_Ca were also performed. Both approaches demonstrated that HBSMC membranes contained large-conductance channels (>200 pS) with both calcium and voltage sensitivity, all of which is characteristic of the BK_Ca channel. Histamine caused a rapid increase in channel activity, as expected. A new finding was that perfusion with IL-4 stimulated rapid, large increases in BK_Ca channel activity (77.2 ± 63.3-fold increase, P < 0.05, n = 18). This large potentiation depended on the presence of external calcium. In contrast, IL-13 (50 ng ml⁻¹) had little effect on BK_Ca channel activity, but inhibited the effect of IL-4. Thus, HBSMC contain functional BK_Ca channels whose activity is rapidly potentiated by the cytokine, IL-4, but not by IL-13. These findings are consistent with a model in which IL-4 rapidly increases near-membrane calcium concentrations to regulate BK_Ca activity.     

Choriocarcinoma presenting as a cutaneous metastasis

The rare presentation of choriocarcinoma as a cutaneous metastasis in a 23-year-old male is reported. Histological and immunohistochemical analysis of the biopsy material demonstrated two distinct cell populations, syncytiotrophoblasts and cytotrophoblasts, with syncytiotrophoblasts strongly positive for human chorionic gonadotropin antigen. Subsequent clinical evaluation revealed a testicular tumor with metastases to lungs, brain, liver and kidney and increased serum levels of human chorionic gonadotropin. The patient died shortly alter diagnosis due to complications of metastatic disease despite chemotherapy.     

Increased Hypothalamic Somatostatin Expression in Mice Transgenic for Bovine or Human GH

Acute studies of GH removal by hypophysectomy or GH replacement in adult rats have shown that GH has a positive influence on its hypothalamic inhibitory hormone somatostatin (SRIH). The present study was undertaken to assess the effect of lifelong exposure to elevated GH on the development and differentiation of SRIH-producing hypothalamic neurons, including comparison of differing GH levels and heterologous species of GH. Expression of somatostatin peptide and mRNA was evaluated using respective immunocytochemistry and in situ hybridization in brains of transgenic mice bearing constructs of either human (hGH) or bovine (bGH) linked to metallothionein (MT) promoter or bGH linked to phosphoenolpyruvate carboxykinase (PEPCK) promoter. Nontransgenic littermates served as controls. All transgenic constructs resulted in high levels of circulating heterologous GH and significantly elevated body weights. Both bGH levels and body weights were higher in PEPCK-bGH than in MT-bGH mice; mean weights were not different between MT-bGH and MT-hGH mice. Numbers of SRIH-immunoreactive neurons in the hypophysiotropic periventricular nucleus (PeN) of transgenic mice showed a two-fold increase (P<0.01) relative to control animals; the number of SRIH-positive cells in the medial basal hypothalamus (MBH) was comparable for transgenic and control mice. Total SRIH mRNA in situ hybridization intensity also showed a two-fold increase (P<0.05) in the PeN of all transgenic mice compared with controls, and was not elevated in the MBH. The higher levels of GH produced in PEPCK-bGH transgenic mice led to greater weight gain, but not to greater SRIH expression than in other GH-transgenic mice, suggesting that the increased SRIH cell number and mRNA in the PeN of MT-GH-transgenic mice may represent a plateau of maximal feedback stimulation. The results indicate that lifelong elevated heterologous GH in mice stimulates hypothalamic SRIH expression markedly. It is not known whether this mechanism is direct or indirect via a mediator of GH such as IGF, but the heterologous GH appears to be specific to these hypophysiotropic neurons.     

Transplantation of peripheral blood progenitor cells from HLA-identical sibling donors

Transplantation of peripheral blood progenitor cells (PBPCs) has largely replaced autologous bone marrow transplantation. The same might occur in the allogeneic setting if the favourable initial experience with allogeneic PBPCT is confirmed. We analysed all primary transplants utilizing unmodified PBPC from HLA-identical sibling donors reported to the European Group for Blood and Marrow Transplantation (EBMT) for 1994. 59 patients with a median age of 39 years received myeloablative therapy for acute myelogenous leukaemia (23 patients), acute lymphoblastic leukaemia (13), chronic myelogenous leukaemia (nine), lymphoma (seven), or other diagnoses (seven) mostly of advanced stages followed by transplantation of allogeneic PBPC. Three patients died soon after grafting, the others showed prompt haemopoietic recovery with median times to recover an absolute neutrophil count (ANC) above 0.5 and 1.0×10⁹/l of 15 (range 9–27) and 17 d (range 10–28) respectively. Time to platelet recovery above 20 or 50×10⁹/l was 16 (range 9–76) and 18 d (range 12–100) respectively. 27 patients (46%) developed no or mild acute graft-versus-host disease (GVHD). The incidence of moderate (grade II) disease was 27%; 24% of the patients developed severe acute GVHD (grades III or IV). 55% of patients who were alive 90 d after transplantation developed chronic GVHD, the probability to develop extensive chronic GVHD was 32% (95% confidence interval 22–42) with a median follow-up of 14 months. Overall and event-free survival (EFS) at 1 year were 54% (CI 48–60) and 50% (CI 43–57), respectively, the relapse incidence was 23% (CI 17–29). EFS was 67% (CI 55–79) in patients transplanted for acute leukaemias in first complete remission, chronic myelogenous leukaemia in first chronic phase, or severe aplastic anaemia. Transplantation of allogeneic PBPC resulted in prompt and durable engraftment. The incidence and severity of acute and chronic GVHD seemed comparable to that observed after allogeneic BMT. Overall and event-free survival in this cohort of patients, most of whom suffered from advanced leukaemia or lymphoma, is encouraging, suggesting that the high numbers of T lymphocytes and/or natural killer cells contained in a typical PBPC collection product exert a vigorous graft-versus-leukaemia effect. Further evaluation of allogeneic PBPCT is highly desirable.     

Malaria as an Occupational Disease in Polish Citizens

Background: Since 1963, malaria has been exclusively recognized in Poland as an imported disease, which has become increasingly frequent in recent years. When associated with performing duties in malaria-endemic areas, malaria is acknowledged as an occupational disease.
Methods: Ninety five cases of malaria recognized as an occupational disease in Polish citizens in the years 1984–1993 were studied retrospectively in terms of working conditions, epidemiologic and clinical features, and permanent disability sequelae.
Results: Among patients examined, young and professionally active persons who called at tropical ports or who worked in rural areas or in the regions of military conflict were predominant. Most infections were contracted in Africa during the first few months of the stay. The observed morbidity and recrudescence rates were mainly attributable to Plasmodium falciparum. Disregard of prevention and chemoprophylaxis of malaria were key risk factors. In 33% of the patients, severe symptoms and complications occurred and these required long-term therapy. In seven cases, disturbances of the central nervous system, hepatic, renal, or cardiac system occurred 6 months after termination of treatment, and these occurrences resulted in permanent disability and an inability to work.
Conclusions :The disability and inability to work and its legal consequences, such as indemnity, demonstrate that malaria may present a serious socioeconomic problem, even in the country where it is an imported disease.     

Theoretical Description of Mass Transport in Medical Membrane Devices

Abstract: The application of the one-dimensional theory of mass transport to the derivation of mathematical formulas for clearances of a variety of membrane mass exchangers, namely hemodialyzers, hemofilters, plasma separators, and the cascade filtration procedure, has been reviewed. The applied theory predicts that clearances depend approximately on fluid inlet flow rates but not on concentrations, and with constant fluid flow rates, clearances are constant. Also, the application of device clearance in kinetic modeling has been discussed.