Population genetics of reef coral endosymbionts (Symbiodinium, Dinophyceae).

Symbiodinium is a diverse genus of unicellular dinoflagellate symbionts associating with various marine protists and invertebrates. Although the broadscale diversity and phylogenetics of the Symbiodinium complex is well established, there have been surprisingly few data on fine-scale population structure and biogeography of these dinoflagellates. Yet population-level processes contribute strongly to the biology of Symbiodinium, including how anthropogenic-driven global climate change impacts these symbionts and their host associations. Here, we present a synthesis of population-level characteristics for Symbiodinium, with an emphasis on how phylogenetic affinities, dynamics within and among host individuals, and a propensity towards clonality shape patterns on and across reefs. Major inferences include the following: (i) Symbiodinium populations within individual hosts are comprised mainly of cells belonging to a single or few genetic clones. (ii) Symbiont populations exhibit a mixed mode of reproduction, wherein at least one sexual recombination event occurs in the genealogy between most genotypes, but clonal propagation predominates overall. (iii) Mutualistic Symbiodinium do not perpetually persist outside their hosts, instead undergoing turnover and replacement via the continuous shedding of viable clonal cells from host individuals. (iv) Symbiont populations living in the same host, but on different reefs, are often genetically subdivided, suggesting low connectivity, adaptation to local conditions, or prolific asexual reproduction and low effective population sizes leading to disproportionate success within and among hosts. Overall, this synthesis forms a basis for future investigations of coral symbiosis ecology and evolution as well as delimitation of species boundaries in Symbiodinium and other eukaryotic microorganisms.

Mini-Review: Monosomy 1p36 syndrome: reviewing the correlation between deletion sizes and phenotypes.

The major clinical features of monosomy 1p36 deletion are developmental delay and hypotonia associated with short stature and craniofacial dysmorphisms. The objective of this study was to review the cases of 1p36 deletion that was reported between 1999 and 2014, in order to identify a possible correlation between the size of the 1p36-deleted segment and the clinical phenotype of the disease. Scientific articles published in the (National Center for Biotechnology Information; NCBI http://www.ncbi.nlm.nih.gov/pubmed) and Scientific Electronic Library Online (www.scielo.com.br) databases were searched using key word combinations, such as "1p36 deletion", "monosomy 1p36 deletion", and "1p36 deletion syndrome". Articles in English or Spanish reporting the correlation between deletion sizes and the respective clinical phenotypes were retrieved, while letters, reviews, guidelines, and studies with mouse models were excluded. Among the 746 retrieved articles, only 17 (12 case reports and 5 series of cases), comprising 29 patients (9 males and 20 females, aged 0 months (neonate) to 22 years) bearing the 1p36 deletions and whose clinical phenotypes were described, met the inclusion criteria. The genotype-phenotype correlation in monosomy 1p36 is a challenge because of the variability in the size of the deleted segment, as well as in the clinical manifestations of similar size deletions. Therefore, the severity of the clinical features was not always associated with the deletion size, possibly because of the other influences, such as stochastic factors, epigenetic events, or reduced penetration of the deleted genes.

TreeKDE: clustering multivariate data based on decision tree and using one-dimensional kernel density estimation.

In this paper, we present an algorithm for clustering multidimensional data, which we named TreeKDE. It is based on a tree structure decision associated with the optimization of the one-dimensional kernel density estimator function constructed from the orthogonal projections of the data on the coordinate axes. Among the main features of the proposed algorithm, we highlight the automatic determination of the number of clusters and their insertion in a rectangular region. Comparative numerical experiments are presented to illustrate the performance of the proposed algorithm and the results indicate that the TreeKDE is efficient and competitive when compared to other algorithms from the literature. Features such as simplicity and efficiency make the proposed algorithm an attractive and promising research field, which can be used as a basis for its improvement, and also for the development of new clustering algorithms based on the association between decision tree and kernel density estimator.

A systematic review of the intergenerational aspects and the diverse genetic profiles of Huntington's disease.

Huntington's disease (HD) is a rare progressive and fatal neurogenetic degenerative disease, characterized by movement and personality disorders and by progressive dementia. Its prevalence varies by ethnic origin and different genetic profiles predisposing individuals to HD in each population. The prevalence of HD is 5-10 per 100,000 individuals in Caucasian populations of North America and Western Europe. It is an autosomal dominant disease associated with the expansion of CAG-type repetitive DNA sequences in the HTT gene. This gene, located on the short arm of chromosome 4, encodes the protein huntingtin. In this study, we reviewed 17 articles about HD that report data from 2400 affected individuals from various countries around the world, including Venezuela, China, Croatia, Turkey, Germany, Italy, Brazil, Spain, Taiwan, India, the Netherlands, Russia, and the USA, with a focus on genetic profiles and intergenerational expansions or contractions of expanded alleles responsible for causing HD. We discuss the genetic characteristics of HD in different populations and any atypical cases reported in these studies.

MulticlusterKDE: a new algorithm for clustering based on multivariate kernel density estimation.

In this paper, we propose the MulticlusterKDE algorithm applied to classify elements of a database into categories based on their similarity. MulticlusterKDE is centered on the multiple optimization of the kernel density estimator function with multivariate Gaussian kernel. One of the main features of the proposed algorithm is that the number of clusters is an optional input parameter. Furthermore, it is very simple, easy to implement, well defined and stops at a finite number of steps and it always converges regardless of the data set. We illustrate our findings by implementing the algorithm in R software. The results indicate that the MulticlusterKDE algorithm is competitive when compared to K-means, K-medoids, CLARA, DBSCAN and PdfCluster algorithms. Features such as simplicity and efficiency make the proposed algorithm an attractive and promising research field that can be used as basis for its improvement and also for the development of new density-based clustering algorithms.

Relations between soil attributes and the abundance of Bacillus thurigiensis in the Cerrado of Maranhão state, Brazil.

The influence of abiotic factors on the abundance of microorganism populations in soil has been sparsely studied, especially regarding Bacillus thuringiensis (Bt) bacteria. Therefore, this research was aimed at analyzing the relationship between the chemical and textural characteristics of the soil of the Cerrado (savanna) of Maranhão State on the abundance of Bacillus thuringiensis. Soil samples were collected in different municipalities in eastern Maranhão: São Mateus do Maranhão, Alto Alegre, Coroatá, Timbiras and Codó. The soil samples were obtained in the 0-0.1 m layer for soil fertility and texture analysis. Then, in the same area for the isolation of Bt, 1 g of soil was collected. The colonies obtained in the isolation that featured morphological characteristics of Bacillus spp. were visualized under phase contrast microscopy. Principal component analysis, clustering and correlations were peformed. Results: The sand content correlated positively with the Bacillus thuringiensis index (iBt). The cluster analysis allowed for verifying that the soils not showed iBt in function of high concentrations of aluminum (Al) and potential acidity (H+Al). Considering as these attributes (Al and H+Al) alter the availability of P in the soil, the abundance of Bacillus thuringiensis may have been impaired by the deficiency of this element in the environment. Conclusion: Bt has correlations with soil texture, and high concentrations of aluminum and potential acidity in the soil influencing the permanence of Bacillus thuringiensis in Maranhão eastern Cerrado.

Biological behavior of magnesium-substituted hydroxyapatite during bone repair.

The aim of this study was to analyze the biological behavior and osteogenic potential of magnesium (Mg) substituted hydroxyapatite (HA) microspheres, implanted in a critical bone defect, considering that this ion is of great clinical interest, since it is closely associated with homeostasis and bone mineralization. For the purpose of this study, 30 rats were used to compose three experimental groups: GI - bone defect filled with HA microspheres; GII - bone defect filled with HA microspheres replaced with Mg; GIII - empty bone defect; evaluated at biological points of 15 and 45 days. The histological results, at 15 days, showed, in all the groups, a discrete chronic inflammatory infiltrate; biomaterials intact and surrounded by connective tissue; and bone neoformation restricted to the borders. At 45 days, in the GI and GII groups, an inflammatory response of discrete granulomatous chronic type was observed, and in the GIII there was a scarce presence of mononuclear inflammatory cells; in GI and GII, the microspheres were seen to be either intact or fragmented, surrounded by fibrous connective tissue rich in blood vessels; and discrete bone neoformation near the edges and surrounding some microspheres. In GIII, the mineralization was limited to the borders and the remaining area was filled by fibrous connective tissue. It was concluded that the biomaterials were biocompatible and osteoconductive, and the percentage of Mg used as replacement ion in the HA did not favor a greater bone neoformation in relation to the HA without the metal.

Genetic population structure of an anchialine shrimp, Metabetaeus lohena (Crustacea: Alpheidae), in the Hawaiian Islands.

Anchialine habitats in the Hawaiian Islands, characterized as coastal bodies of land-locked salt or brackish water that fluctuate with the tides due to subterranean connections, are the only ecosystems of this type found within the United States. These habitats are currently subject to anthropogenic impacts that threaten their future existence. Previous research has shown strong genetic population structure of an endemic atyid shrimp, Halocaridina rubra, in these habitats. The native alpheid shrimp, Metabetaeus lohena, whose known range entirely overlaps that of H. rubra, has feeding and reproductive behaviors that are biologically distinct from H. rubra. Its historic scarcity and status as a candidate for the US Fish and Wildlife Department's Endangered Species List, make M. lohena an ideal species to compare against the known genetic structure of H. rubra. We investigated the population structure of this native anchialine shrimp to test the hypothesis that genetic population structure differs between the two shrimp species and that M. lohena is genetically unstructured across its range. A survey of 605 bp of the mitochondrial cytochrome c oxidase subunit I (COI) gene from 127 individuals collected at 7 sites spanning the islands of O'ahu, Maui and Hawaii revealed 43 haplotypes. The most common haplotype was represented in similar proportions from all sites sampled, accounting for 44% of the surveyed sequences. Analyses of molecular variation (AMOVA), pairwise PhiST values, Bayesian estimates of migration (M), Mantel tests and Nested Clade Analyses (NCAs) all failed to reveal evidence of major barriers to gene flow among most populations separated by inter-island channels. This lack of genetic structure in M. lohena is found to be in stark contrast with the highly structured population of H. rubra, and may be attributed to oceanic dispersal strategies and/or a recent introduction to the Hawaiian Islands.

Toxicological and phytochemical studies of Aspidosperma subincanum Mart. stem bark (Guatambu).

Aspidosperma subincanum Mart. is widely used in Brazilian folk medicine to treat digestive disorders. In this study, acute and subchronic toxicity and cytotoxicity of stem bark ethanolic extract of Aspidosperma subincanum (EEAs) have been evaluated. In addition, phytochemical analysis was performed. The EEAs had low acute toxicity in mice with LD50 =1129 +/- 154mg/kg p.o. and 397 +/- 15 mg/kg i.p. The LC50 was 1340 +/- 428 microg/mL in the brine shrimp assay. There was no relevance of serious changes in behavioral, hematological and biochemical parameters and no deleterious effect on vital organs of rats that resulted after 30 days daily exposure to 5 and 100 mg/kg of EEAs. Phytochemical analysis of stem bark of A. subincanum revealed the presence of indole alkaloids, saponins, terpenoids, steroids and tannins and resulted in the isolation of oleic acid and guatambuine as major constituents. Using the method of the dose by factor approach, the human safe dose was 210 mg/70 kg/day. The EEAs appears to be safe and non-toxic in low doses in rodents and domestic preparations used by population have relatively security.

Rheumatic Heart Disease: Pathogenesis and Vaccine.

Rheumatic fever (RF) and rheumatic heart disease (RHD) follow untreated S. pyogenes throat infections in children who present susceptible genes that favor the development of autoimmune reactions. In this review, we focus on the genes that confer susceptibility and on the autoimmune reactions that occur due to molecular mimicry between human-tissue proteins and streptococcal M protein. Polyarthritis is the initial manifestation, which can evolve to carditis and severe valve damage; these culminate in rheumatic heart disease (RHD) or Sydenham's chorea, which affects the central nervous system. A perspective on vaccine development to prevent the disease is also discussed.

Simultaneous determination of cefepime, vancomycin and imipenem in human plasma of burn patients by high-performance liquid chromatography.

A liquid chromatographic method with UV detection for simultaneous determination of cefepime, vancomycin and imipenem has been developed. Cefuroxime was used as internal standard. After the clean up of samples by plasma protein precipitation, 5 microl of the extract were injected into the chromatograph and peaks were eluted from the Sulpelcosil LC-18 column using a mobile phase consisting of 0.075 M acetate buffer:acetonitrile (92:8, v/v), pH 5.0 at low rate (0.8 ml/min). The detection wavelength was 230 nm. The limit of detection was 0.4 microg/ml for cefepime and 0.2 microg/ml for vancomycin and imipenem. The method was applied to plasma samples of burn patients, and only small volumes of plasma were required for the simultaneous determination of those antimicrobial agents.

Urgency priority in kidney transplantation in Rio Grande do Sul.

In 2002, it was established a system of urgency priority for kidney transplantations in cases with no vascular or peritoneal access for dialysis. The aims of this article are to describe the system in the organ donation and procurement agency (CNCDO) as well as to show the results to date. We reviewed cases of urgency priority request for kidney transplantation addressed to the CNCDO from May 2002 to August 2005. Within this period the CNCDO received 35 urgency priority requests for kidney transplantation (mean, 1 every 1.2 months). Thirty-one (88%) were accepted as urgent, and only 4 (11%) were refused. Among the 31 accepted, 26 (83%) had the transplantation performed in an average time of 19.6 days (range, 1-90), representing only 3.2% of all cadaveric kidney transplantations during that period.

Multifunctional catalysts based on carbon nanotubes and titanate nanotubes for oxidation of organic compounds in biphasic systems.

Amphiphilic catalysts composed of carbon nanotubes (CNTs) and titanate nanotubes (TiNTs) have been successfully synthesized by refluxing anatase TiO2 and functionalised CNTs in concentrated NaOH solution. The prepared materials were characterized by transmission electron microscopy, scanning electron microscopy, X-ray diffraction, thermogravimetric analysis (TGA), and N2 physisorption isotherms. The catalytic activity of the synthesized composites was first evaluated in the oxidation of methyl yellow (MY) using H2O2 as oxidant in a single liquid phase system and in a biphasic water/oil mixture. The results of these experiments indicated that the catalytic activities of nanocomposites were very similar in the single liquid-phase oxidation. However, the modification of TiNTs with CNTs led to a substantially enhanced MY oxidation in the biphasic system. The nanocomposites show excellent interaction with both hydrophilic and hydrophobic compounds and thus stabilise emulsions. Under biphasic conditions, the catalysts can be easily separated and recycled, retaining catalytic activity even after eight runs. Additionally, the hybrid materials show superior catalytic activity and selectivity in the biphasic oxidation of benzyl alcohol with H2O2, as compared to pure TiNTs.

Biological behavior of magnesium-substituted hydroxyapatite during bone repair / Comportamento biológico de hidroxiapatita substituída com magnésio durante o reparo ósseo

Abstract The aim of this study was to analyze the biological behavior and osteogenic potential of magnesium (Mg) substituted hydroxyapatite (HA) microspheres, implanted in a critical bone defect, considering that this ion is of great clinical interest, since it is closely associated with homeostasis and bone mineralization. For the purpose of this study, 30 rats were used to compose three experimental groups: GI - bone defect filled with HA microspheres; GII - bone defect filled with HA microspheres replaced with Mg; GIII - empty bone defect; evaluated at biological points of 15 and 45 days. The histological results, at 15 days, showed, in all the groups, a discrete chronic inflammatory infiltrate; biomaterials intact and surrounded by connective tissue; and bone neoformation restricted to the borders. At 45 days, in the GI and GII groups, an inflammatory response of discrete granulomatous chronic type was observed, and in the GIII there was a scarce presence of mononuclear inflammatory cells; in GI and GII, the microspheres were seen to be either intact or fragmented, surrounded by fibrous connective tissue rich in blood vessels; and discrete bone neoformation near the edges and surrounding some microspheres. In GIII, the mineralization was limited to the borders and the remaining area was filled by fibrous connective tissue. It was concluded that the biomaterials were biocompatible and osteoconductive, and the percentage of Mg used as replacement ion in the HA did not favor a greater bone neoformation in relation to the HA without the metal.

Resumo O objetivo deste estudo foi analisar o comportamento biológico de microesferas de hidroxiapatita (HA) substituída com magnésio (Mg) durante o reparo de defeito ósseo crítico, tendo em vista que este íon é de grande interesse clínico, pois está intimamente associado à homeostasia e à mineralização óssea. Para tanto, utilizou-se 30 ratos para compor três grupos experimentais: GI - defeito ósseo preenchido com microesferas de HA; GII - defeito ósseo preenchido com microesferas de HA substituída com Mg; GIII (controle) - defeito ósseo vazio; avaliados nos pontos biológicos de 15 e 45 dias. Os resultados histológicos evidenciaram, aos 15 dias, discreto infiltrado inflamatório crônico e neoformação óssea restrita às bordas, em todos os grupos. Nos grupos GI e GII, os biomateriais mantiveram-se íntegros e circundados por tecido conjuntivo frouxo. Aos 45 dias, notou-se resposta inflamatória do tipo crônica granulomatosa discreta nos grupos GI e GII, e no GIII presença escassa de células inflamatórias mononucleares. As microesferas implantadas no GI e GII mantiveram-se, em sua maioria, íntegras e envolvidas por tecido conjuntivo fibroso. Notou-se discreta neoformação óssea próxima às bordas e circunjacente a algumas microesferas. No GIII, a mineralização limitou-se às bordas e a área remanescente foi preenchida por tecido conjuntivo fibroso. Conclui-se que os biomateriais foram biocompatíveis, bioativos, osteocondutores e apresentaram biodegradação lenta, indicando seu grande potencial para em aplicações clínica como biomaterial de preenchimento.

Systemic availability of prophylactic cefuroxime in patients submitted to coronary artery bypass grafting with cardiopulmonary bypass.

Cardiopulmonary bypass and hypothermia (HCPB) is a procedure commonly used during heart surgery, representing a risk factor for the patient by promoting extensive haemodilution and profound physiological changes. Cefuroxime is used for the prevention of infection following heart surgery, and several dose schemes have been suggested for prophylaxis with cefuroxime. The objective of the present study was to assess, in a comparative manner, the systemic availability of cefuroxime administered intravascularly as a bolus dose of 1.5 g to 17 patients having heart surgery with or without HCPB. Plasma cefuroxime concentrations were determined by high-pressure liquid chromatography-UV, and the following values, expressed as medians, were obtained for the study group compared with controls: 69.1 vs. 62.7 mg/L (1st h), 35.8 vs. 26.0mg/L (3rd h), 14.6 vs. 8.7 mg/L (6th h, P<0.05), 6.1 vs. 3.0mg/L (9th h, P<0.05) and 2.6 vs. 1.0mg/L (12th h, P<0.05). Despite the differences recorded during the study period as a consequence of HCPB, low antibiotic concentrations were found as early as 6h post dose for both groups investigated. Thus, the low systemic availability of cefuroxime after the administration of a 1.5-g dose may not protect against postoperative infections. The data obtained permit us to recommend a change in the dose scheme in order to maintain adequate plasma levels of cefuroxime.

Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery.

The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB), resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG) by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 +/- 8 years, mean weight 75.4 +/- 11.9 kg and mean body surface area 1.83 +/- 0.19 m(2)), receiving propranolol before surgery (80-240 mg a day) and postoperatively (10 mg a day). Plasma propranolol levels were measured before and after CPB by high-performance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre- and postoperatively. There was an increase of biological half-life from 4.5 (95% CI = 3.9-6.9) to 10.6 h (95% CI = 8.2-14.7; P < 0.01) and an increase in volume of distribution from 4.9 (95% CI = 3.2-14.3) to 8.3 l/kg (95% CI = 6.5-32.1; P < 0.05), while total clearance remained unchanged 9.2 (95% CI = 7.7-24.6) vs 10.7 ml min(-1) kg(-1) (95% CI = 7.7-26.6; NS) after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

Higher salt consumption, digoxin-like factor, and nifedipine response are associated with salt sensitivity in essential hypertension.

In addition to demonstrating evidences of increased sympathetic nervous system activity and marked left ventricular hypertrophy in salt-sensitive hypertensives, our group has also reported increased weight gain with salt overload in these patients. The increased weight gain suggests volume expansion, a situation already shown to increase plasma levels of a Na, K-ATPase inhibitor. Therefore, in the present study, digoxin-like factor (DLF) serum levels, spontaneous salt ingestion, nifedipine hypotensive effect, and plasma renin activity were evaluated in essential hypertensive subjects. Thirteen essential hypertensive outpatients were studied sequentially on an ad lib diet, a low salt diet (LSD = 30 mEq Na/day), and a high salt diet (HSD = LSD + 171 mmol/L NaCl/day), 1 week each. On the seventh day of LSD and HSD, DLF levels, mean blood pressure (MBP) response to nifedipine (10 mg sublingual), and plasma renin activity were measured. The MBP percent change from the seventh day of LSD to the seventh day of HSD (salt sensitivity) ranged from -13.7 to 20.9%. A positive correlation (r = 0.64, P < .01) was observed between salt sensitivity and 24-h urinary sodium excretion with an ad lib diet. The DLF serum levels correlated with the salt sensitivity both on LSD (r = 0.50, P < .05) and on HSD (r = 0.53, P < .05). Salt sensitivity was positively correlated with the difference of response to nifedipine between HSD and LSD (r = 0.78, P < .001). Plasma renin activity correlated inversely with DLF on LSD (r = -0.51, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Simplified micromethod for the HPLC measurement of diclofenac in plasma.

A simple and sensitive micromethod based on HPLC is described for the measurement of diclofenac in 200 microliters plasma. A single extraction with dichloromethane in acidic medium was an essential clean-up step. Diclofenac and its internal standard (cyclohexendiphenyl propionic acid) was eluted at 3.3 and 6.5 min from a 4-micron C18 reverse-phase column using a mobile phase consisting of 0.75 M sodium acetate buffer, pH 5.0, and acetonitrile (55:45, v/v) at a flow rate of 0.9 ml/min with detection at 282 nm. The method, validated on the basis of parameters evaluated for the confidence limits of diclofenac measurements in spiked plasma, presented 1 ng/ml sensitivity, 10-10,000 ng/ml linearity, and 3.5% and 5.7% intra- and interassay precision, respectively. Peak plasma diclofenac levels ranging from 177 to 841 ng/ml and from 276 to 1008 ng/ml were obtained for two slow-release formulations. A wide range (1 ng/ml-3 micrograms/ml) was observed for plasma diclofenac levels of volunteers during a 24-h study period.

Ranitidine increases the bioavailability of nitrendipine in patients with arterial hypertension.

1. In a randomized placebo-controlled study, 12 hypertensive patients were treated po for one week with 20 mg nitrendipine once daily plus placebo, twice daily and later with the same dose of nitrendipine plus 300 mg ranitidine (150 mg twice a day). 2. When ranitidine was coadministered, plasma nitrendipine levels (0-24 h) were significantly increased (P < 0.001), although no significant increase in peak plasma nitrendipine level (Cmax) was observed due to the wide range of variation of this parameter (Cmax) in hypertensive patients. 3. Ranitidine coadministration increased the area under the curve for 24-h (AUC0-24) plasma concentration vs time, from 49.07 +/- 6.28 micrograms.h/l to 82.35 +/- 2.57 micrograms.h/l (P < 0.01). This significant increase caused a reduction in total body clearance from 2008.33 +/- 246.33 to 1284.00 +/- 182.16 ml/min (P < 0.002). 4. Nitrendipine bioavailability was increased by 89% when ranitidine was coadministered but the kinetic effect of this drug interaction is unlikely to be of clinical relevance since no adverse effects were observed in patients evaluated after ranitidine association.

Theophylline-ranitidine interaction in elderly COPD patients.

Most controlled studies in humans indicate that ranitidine does not alter theophylline metabolism, even at high doses. However, there have been several case reports published recently which demonstrate the development of theophylline toxicity mostly in older patients receiving stable oral doses of this drug when ranitidine was administered simultaneously. We studied eleven elderly (mean age, 69.0 +/- 6.2 years) patients with chronic obstructive pulmonary disease (COPD). During one week the patients took slow-release theophylline, 200 mg every 12 h, followed by one week intake of the same dose of theophylline plus ranitidine tablets, 150 mg every 12 h. At the end of each period, blood samples were obtained 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12 h after the morning dose for the determination of serum theophylline levels. The peak theophylline concentration (Tmax) was achieved after 4.1 +/- 0.9 h while the patients were taking theophylline, and after 2.9 +/- 1.4 h with the combined regimen. This difference was statistically significant (P < 0.01). In only 3/11 subjects did Tmax remain unchanged during both phases of the study. The mean theophylline clearance rates while the patients were receiving theophylline alone (39.58 +/- 19.89 ml/min) and when they were receiving both medications (34.42 +/- 10.55 ml/min) were similar. The mean serum levels while the patients were receiving theophylline alone were slightly higher but not statistically different. These results suggest that the reported increases in serum theophylline levels in older patients receiving theophylline and ranitidine cannot be ascribed to slower theophylline metabolism in the geriatric patients with COPD who is also given ranitidine.