Epidemiology of drug resistance in malaria

In the late 1950's chloroquine resistance to Plasmodium falciparum occurred in South America and on the Indochina Subcontinent. Since then it has conquered most of the areas where the parasite species is endemic. This has necessitated the use of alternative drugs such as sulphonamide-pyrimethamine combinations, quinine/tetracyclines, mefloquine, halofantrine, and recently also artemisinin-based compounds. In wide areas of South-east Asia, western Oceania and South America sulphonamide-pyrimethamine combinations have lost adequate efficacy. The situation is most serious in the Thai/Cambodia and Thai/Myanmar border areas where multiresistance necessitated the shift to the last line drug, i.e., the artemisinin derivatives. Selection of resistant parasites due to drug pressure, and their subsequent propagation by local transmission and migration of reservoirs are key factors in the dynamics of drug resistance. Selection is the result of the interplay of parasite, drug and human host, and is largely influenced by immune factors and the pharmacokinetics and pharmacodynamics of the drug. Spread of resistance is determined by eco-epidemiological factors among which migration and vectorial parameters play a major role. Rational drug use, especially adequate, monitored, therapeutic administration according to strict criteria, should curb the onset and spread of resistance, but this concept may not be readily accepted by health services whose primary goal is clinical amelioration of the disease rather than the more stringent target of epidemiologically desirable results.     

Transformation of Plasmodium falciparum malaria parasites by homologous integration of plasmids that confer resistance to pyrimethamine

Plasmodium falciparum malaria parasites were transformed with plasmids containing P. falciparum or Toxoplasma gondii dihydrofolate reductase-thymidylate synthase (dhfr-ts) coding sequences that confer resistance to pyrimethamine. Under pyrimethamine pressure, transformed parasites were obtained that maintained the transfected plasmids as unrearranged episomes for several weeks. These parasite populations were replaced after 2 to 3 months by parasites that had incorporated the transfected DNA into nuclear chromosomes. Depending upon the particular construct used for transformation, homologous integration was detected in the P. falciparum dhfr-ts locus (chromosome 4) or in hrp3 and hrp2 sequences that were used in the plasmid constructs as gene control regions (chromosomes 13 and 8, respectively). Transformation by homologous integration sets the stage for targeted gene alterations and knock-outs that will advance understanding of P. falciparum.     

Mefloquine and sulfadoxine/pyrimethamine overdose in malaria tropica

Quantitative ultrastructural myocardial changes of myocardium of the japanese quail (Coturnix coturnix japonica) were studied during an immobilization stress (hypodynamia) lasting 9, 30, 60 and 90 days. Hypodynamic quails were fixed by waistcoats to the feeding place simulating conditions of long lasting space flight which the quails were determined for. The surveyed morphological parametres were: mitochondrial rate, mitochondrial volume in % of cytoplasm, volume of myofibres in % of cytoplasm, volume of single mitochondria, extent of cristolysis. Progressive mitochondrial hydratation and even local oedema were observed during the experiment. It led to a progressive increase of mitochondrial volume and simultaneous decrease of volume of myofilaments as a sign of intracellular atrophy of myofibres. The results correlated well with a decreased mass of myofibres observed in experimental quails from space flight on the orbital station MIR.     

Understanding and overcoming parent resistance to play therapy.

Explores the nature and sources of parent resistance to play therapy, questions the concept of resistance as it is often understood, and suggests ways the play therapist can prevent or overcome it, addressing common mistakes therapists make that actually increase client resistance. It is stated that play therapist's own attitudes and the therapist–parent relationship can be used to overcome resistance that might interfere with therapeutic progress. Showing respect and empathy for parents can go far in creating a trusting collaborative therapeutic relationship that is needed for optimum outcomes. Similarly, helping parents see the connections between their problems and the course of therapy being recommended can make it easier for them to engage as partners in the process of change. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

抗生素的耐药性与抗生素的应用

细菌对抗生素产生耐药性是一种自然生物现象,抗生素的广泛应用与滥用加速了耐药性过程.现就抗生素的耐药机理进行讨论,期望有助于进一步合理应用抗生素.     

Chloroquine treatment for uncomplicated childhood malaria in an area with drug resistance: early treatment failure aggravates anaemia

Using the polymerase chain reaction (PCR) and two primers for conserved regions of the small subunit ribosomal RNA (SSU-rRNA) of Microsporidia, a DNA segment about 1,195 base pairs long was amplified from a DNA template prepared from purified spores of the microsporidian species Pleistophora anguillarum. These spores had been isolated from adult eels (Anguilla japonica) with "Beko Disease." A comparison of sequence data from other microsporidian species showed P. anguillarum SSU-rRNA to be most similar to Vavraia oncoperae. When juvenile eels were artificially infected with P. anguillarum, enzyme-linked immunosorbent assay could detect a positive infection only 12 days post-infection. However, when suitable PCR primers were used, a DNA fragment of about 0.8 kb was detected from these juvenile eels after only 3 days post infection. No PCR product was obtained with templates prepared from clinically healthy control animals.     

Developing a patient education program: overcoming physician resistance

Scientific expertise in the management of diabetes was an important factor in overcoming physician resistance to the education program. Nurses have expertise, and their expertise must be acknowledged for them to be viewed as leaders. Not only are nurses responsible for sharing their expertise with other nurses, it is equally important for them to share their expertise with the physicians, who may appreciate receiving any information that can help them improve their patients' outcomes. The components that are essential for success in pioneering a new program are good listening skills, a willingness to cooperate, self-confidence, scientific knowledge, vigilance, determination, and a clear vision. Patient outcomes will improve when nurses use their scientific knowledge base and leadership skills through patient-centered nursing practice, planned change strategies, and advanced practice nursing.     

Choline kinase inhibitors as a novel approach for antiproliferative drug design

Recent progress in deciphering the molecular basis of carcinogenesis is of utmost importance to the development of new anticancer strategies. To this end, it is essential to understand the regulation of both normal cell proliferation and its alterations in cancer cells. We have previously demonstrated that in ras-transformed cells there is an increased level of phosphorylcholine (PCho) resulting from a constitutive activation on choiline kinase (ChoK). The importance of ChoK for the regulation of cell proliferation has also been proposed since an inhibitor for this enzyme, hemicholinium-3 (HC-3), drastically reduces entry into the S phase after stimulation with growth factors. Here we report the synthesis of several new compounds which are highly specific inhibitors for ChoK, with up to 1000-fold or 600-fold increased inhibitory activity, compared to HC-3 under ex vivo or in vitro conditions respectively. These novel compounds also drastically reduce entry into the S phase after stimulation with specific growth factors. A more profound inhibition of cell proliferation was observed in ras-, src- and mos-transformed cells in the presence of ChoK inhibitors, compared to their parental, untransformed NIH3T3 cells. By contrast, this effect was not observed in fos-transformed cells. While ras, src and mos transformation is associated with elevated levels of ChoK activity, fos-induced transformation does not affect ChoK activity. The inhibitory effect on proliferation of the new compounds correlates with their ability to inhibit the production of phosphorylcholine in whole cells, a proposed novel second messenger for cell proliferation. These results strongly support a critical role of choline kinase in the regulation of cell growth and makes this enzyme a novel target for the design of new antiproliferative and anticancer drugs.     

Rational approach to postoperative transfusion in high-risk patients

An appropriate threshold for transfusion in patients with coronary artery disease has not been defined. Our purpose was to determine: (1) the effects of preoperative volume loading; (2) postoperative function and oxygen delivery (DO2); (3) an appropriate transfusion threshold based on observed DO2 in high-risk patients undergoing abdominal aortic aneurysm (AAA) repair, bypass of aortoiliac disease (AOD), distal bypass, or carotid endarterectomy (CEA). Preoperative volume loading increased cardiac output (CO) in all groups by 15% to 22%. Postoperative CO was unchanged from optimal preoperative values except in the CEA group, in which it decreased. Systemic vascular resistance decreased in the AAA and AOD groups. The decrease in postoperative DO2 in all groups (25% to 31%) was related to a decrease in hemoglobin. Despite marginal (less than 11 mL/kg/min) postoperative DO2 in more than a third of patients, there was no compensatory increase in CO. Thus, after optimization of function by volume loading, red cell transfusion may be the only way to increase DO2. Hemoglobin levels of 10 to 12 g/dL may be required for adequate DO2 when ventricular function is markedly impaired.     

Anaemia in malaria control: a practical approach

Mortality from malarial anaemia and malarial infection in those who are already anaemic yet have some degree of compensation is now beginning to receive the attention it deserves. It is of particular concern in Africa and especially in young children and pregnant women. The asymptomatic parasitaemia remaining after poor response to full antimalarial treatment may lead to life-threatening anaemia; as drug-resistant strains of the malarial parasite proliferate this is becoming increasingly important. It is now possible to estimate haemoglobin levels, simply, cheaply, easily and safely, using a haemoglobin colour scale which is being developed by the World Health Organization. The potential and practical value of this scale in malaria-control programmes was demonstrated in a small, preliminary trial in 1995. Estimation of anaemia should become an additional parameter in the traditional malariometric survey. Haemoglobin concentrations should also be taken into consideration in the management of malaria patients at the primary-care level, particularly in deciding whether a patient should be referred to an appropriate treatment centre. The accurate prediction of clinical outcome of malaria and anaemia, and indication of the appropriate action (determined by a case-based reasoning device) should be possible in the near future.     

Mycobacterium tuberculosis drug resistance: a call to action

One of the mutants of Streptomyces cholesterol oxidase with the Val121Ala mutation (V121A) was kinetically analysed. Although the reaction rate-substrate concentration curve of wild type follows a simple Michaelis-Menten equation, that of V121A is sigmoidal. The cooperativity was apparent and caused by non-ionic detergents that were used as a solvent of cholesterol. The concentration dependence of V121A on detergents was more significant than that of wild type, although the reaction rates of both enzymes decrease as the concentrations of detergents increase. Further experiments suggested that less hydrophobic interactions between V121A and detergents should be responsible for the apparent cooperativity. Since Val121 is in a hydrophobic loop located near the active site, the mutational effect is structurally discussed.     

Tyrosine kinase inhibition: an approach to drug development

Protein tyrosine kinases (PTKs) regulate cell proliferation, cell differentiation, and signaling processes in the cells of the immune system. Uncontrolled signaling from receptor tyrosine kinases and intracellular tyrosine kinases can lead to inflammatory responses and to diseases such as cancer, atherosclerosis, and psoriasis. Thus, inhibitors that block the activity of tyrosine kinases and the signaling pathways they activate may provide a useful basis for drug development. This article summarizes recent progress in the development of PTK inhibitors and demonstrates their potential use in the treatment of disease.