Reacción granulomatosa en paciente con melanoma metastásico tratado con ipilimumab: primer caso descrito presentando clínica cutánea únicamente / Granulomatous Reaction in a Patient With Metastatic Melanoma Treated With Ipilimumab: First Case Reported With Isolated Cutaneous Findings

Las reacciones granulomatosas "sarcoidosis-like" secundarias a ipilimumab afectarán simultáneamente a múltiples órganos y característicamente se presentarán semanas o meses después de haber iniciado el tratamiento. Paciente varón de 67 años, quien consulta por reacción cutánea granulomatosa a nivel de tronco, extremidades y rostro. Esta se presentó 18 meses después de haber iniciado tratamiento con ipilimumab, medicamento pautado por el diagnóstico de un melanoma metastásico. Reportamos reacción granulomatosa de presentación exclusivamente cutánea, como efecto adverso medicamentoso tardío secundario al tratamiento con ipilimumab. Así mismo resaltamos la necesidad de realizar en los pacientes tratados con ipilimumab un seguimiento prolongado

Granulomatous sarcoidosis-like reactions affecting multiple organ systems at one time have infrequently been described within weeks to months after initiation of Ipilimumab. We present the first case of a 67-year-old man with isolated cutaneous granulomatous reaction involving the trunk, extremities, and face after eighteen months of treatment with ipilimumab for metastatic melanoma. This case documents the eruption of isolated cutaneous granulomatous reaction as a late treatment-related adverse effect of ipilimumab, highlighting the importance of adequate, prolonged follow-up

Granulomatous Reaction in a Patient With Metastatic Melanoma Treated With Ipilimumab: First Case Reported With Isolated Cutaneous Findings. / Reacción granulomatosa en paciente con melanoma metastásico tratado con ipilimumab: primer caso descrito presentando clínica cutánea únicamente.

Granulomatous sarcoidosis-like reactions affecting multiple organ systems at one time have infrequently been described within weeks to months after initiation of Ipilimumab. We present the first case of a 67-year-old man with isolated cutaneous granulomatous reaction involving the trunk, extremities, and face after eighteen months of treatment with ipilimumab for metastatic melanoma. This case documents the eruption of isolated cutaneous granulomatous reaction as a late treatment-related adverse effect of ipilimumab, highlighting the importance of adequate, prolonged follow-up.

Whole body physiologically based modelling of ß-blockers in the rat: events in tissues and plasma following an i.v. bolus dose.

BACKGROUND AND PURPOSE: Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible. EXPERIMENTAL APPROACH: Previous PBPK model development of enantiomers of a series of seven racemic ß-blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D-optimal design. KEY RESULTS: Closed-loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate-limited models. For some compounds in the testes and gut, a permeability rate-limited distribution model was required to best fit the data. Parameter estimates of the tissue-to-blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady-state experiments. CONCLUSIONS AND IMPLICATIONS: PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.

Identification of the effect of multiple polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid using a population-modeling approach.

The aim of this work was to develop a joint population pharmacokinetic model for simvastatin (SV) and its active metabolite, simvastatin acid (SVA), that incorporates the effects of multiple genetic polymorphisms and clinical/demographic characteristics. SV/SVA plasma concentrations, demographic/clinical data, and genotypes for 18 genetic variants were collected from 74 individuals (three clinical trials) and analyzed using a nonlinear mixed-effects modeling approach. The structural model that best described the data included a two- and a one-compartment disposition model for SV and SVA, respectively. Age, weight, Japanese ethnicity, and seven genetic polymorphisms-rs4149056 (SLCO1B1), rs776746 (CYP3A5), rs12422149 (SLCO2B1), rs2231142 (ABCG2), rs4148162 (ABCG2), rs4253728 (PPARA), and rs35599367 (CYP3A4)-were identified as significantly affecting model parameters. The developed model was used to assess combinations of these covariates, highlighting specific risk factors associated with altered SV/SVA pharmacokinetics, and consequently myopathy cases that cannot be solely attributed to the rs4149056 CC genotype.

Rapid microsatellite marker development for African mahogany (Khaya senegalensis, Meliaceae) using next-generation sequencing and assessment of its intra-specific genetic diversity.

Khaya senegalensis (African mahogany or dry-zone mahogany) is a high-value hardwood timber species with great potential for forest plantations in northern Australia. The species is distributed across the sub-Saharan belt from Senegal to Sudan and Uganda. Because of heavy exploitation and constraints on natural regeneration and sustainable planting, it is now classified as a vulnerable species. Here, we describe the development of microsatellite markers for K. senegalensis using next-generation sequencing to assess its intra-specific diversity across its natural range, which is a key for successful breeding programs and effective conservation management of the species. Next-generation sequencing yielded 93,943 sequences with an average read length of 234 bp. The assembled sequences contained 1030 simple sequence repeats, with primers designed for 522 microsatellite loci. Twenty-one microsatellite loci were tested with 11 showing reliable amplification and polymorphism in K. senegalensis. The 11 novel microsatellites, together with one previously published, were used to assess 73 accessions belonging to the Australian K. senegalensis domestication program, sampled from across the natural range of the species. STRUCTURE analysis shows two major clusters, one comprising mainly accessions from west Africa (Senegal to Benin) and the second based in the far eastern limits of the range in Sudan and Uganda. Higher levels of genetic diversity were found in material from western Africa. This suggests that new seed collections from this region may yield more diverse genotypes than those originating from Sudan and Uganda in eastern Africa.

Influences of activity wheel access on the body temperature response to MDMA and methamphetamine.

Recreational ingestion of the drug 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") can result in pathologically elevated body temperature and even death in humans. Such incidents are relatively rare which makes it difficult to identify the relative contributions of specific environmental and situational factors. Although animal models have been used to explore several aspects of MDMA-induced hyperthermia and it is regularly hypothesized that prolonged physical activity (e.g., dancing) in the nightclub environment increases risk, this has never been tested directly. In this study the rectal temperature of male Wistar rats was monitored after challenge with doses of MDMA and methamphetamine (MA), another drug frequently ingested in the rave/nightclub environment, either with or without access to an activity wheel. Results showed that wheel activity did not modify the hyperthermia produced by 10.0mg/kg MDMA. However, individual correlations were observed in which wheel activity levels after a locomotor stimulant dose of MDMA were positively related to body temperature change and lethal outcome. A modest increase in the maximum body temperature observed after 5.6mg/kg MA was caused by wheel access but this was mostly attributable to a drop in temperature relative to vehicle treatment in the absence of wheel activity. These results suggest that nightclub dancing in the human Ecstasy consumer may not be a significant factor in medical emergencies.

Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1.

BACKGROUND: This trial describes a first-in-man evaluation of RH1, a novel bioreductive drug activated by DT-diaphorase (DTD), an enzyme overexpressed in many tumours. PATIENTS AND METHODS: A dose-escalation phase I trial of RH1 was carried out. The primary objective was to establish the maximum tolerated dose (MTD) of RH1. Secondary objectives were assessment of toxicity, pharmacokinetic determination of RH1 and pharmacodynamic assessment of drug effect through measurement of DNA cross linking in peripheral blood mononuclear cells (PBMCs) and tumour, DTD activity in tumour and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphism status. RESULTS: Eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 µg/m(2)/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t(1/2) = 12.3 min), with AUC increasing proportionately with dose. The comet-X assay demonstrated dose-related increases in DNA cross linking in PBMCs. DNA cross linking was demonstrated in tumours, even with low levels of DTD. Only one patient was homozygous for NQO1 polymorphism precluding any conclusion of its effect. CONCLUSIONS: RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 µg/m(2)/day is the dose recommended for phase II trials. The biomarkers of DNA cross linking, DTD activity and NQO1 status have been validated and clinically developed.

In situ ATR-FTIR characterization of primary cement interfaces of the barnacle Balanus amphitrite.

A method is presented for characterizing primary cement interfaces of barnacles using in situ attenuated total reflection-Fourier transform infrared spectroscopy. Primary cement of the barnacle, Balanus amphitrite (Amphibalanus amphitrite), was characterized without any disruption to the original cement interface, after settling and growing barnacles directly on double sided polished germanium wafers. High-quality IR spectra were acquired of live barnacle cement interfaces, providing a spectroscopic fingerprint of cured primary cement in vivo with the barnacle adhered to the substratum. Additional spectra were also acquired of intact cement interfaces for which the upper portion of the barnacle had been removed leaving only the base plate and cement layer attached to the substratum. This allowed further characterization of primary cement interfaces that were dried or placed in D(2)O. The resulting spectra were consistent with the cement being proteinaceous, and allowed analysis of the protein secondary structure and water content in the cement layer. The estimated secondary structure composition was primarily beta-sheet, with additional alpha-helix, turn and unordered components. The cement of live barnacles, freshly removed from seawater, was estimated to have a water content of 20-50% by weight. These results provide new insights into the chemical properties of the undisturbed barnacle adhesive interface.

A six-year evaluation of methadone prescribing practices at a substance misuse treatment centre in the UK.

OBJECTIVES: To document changes in prescribing practice at a specialized substance misuse service in the UK occurring since the introduction of the 1999 UK National Guidelines on the management of drug misuse, and to explore a possible link between the length of time spent in methadone maintenance therapy (MMT) and the dosage prescribed. METHODS: A retrospective analysis of a computerized prescription database between 1996 and 2002 obtained from Sheffield Care Trust Substance Misuse Service was performed. The relationship between various measures of dosage and the length of time spent in MMT was investigated. RESULTS: In accordance with the 1999 UK National Guidelines, the proportion of injectable methadone prescribed decreased from 22% to 16%. This was offset by an increase in the prescribing of methadone elixir from 74% to 79%. The 'maximum dose' of methadone prescribed correlated significantly with patient retention, explaining 14% of the variation in time spent in MMT. CONCLUSIONS: Our findings indicate that publication of the UK National Guidelines had a measurable effect on prescribing practice at the Service. We found that a higher methadone dose is associated with increased patient retention in MMT. However, as only a maximum of 14% of the variation in the length of stay is related to methadone dose, the importance of other aspects of treatment such as counselling and rehabilitation programmes, should be considered for the successful treatment of opioid abusers.

Utility of blood cultures in the management of adults with community acquired pneumonia discharged from the emergency department.

STUDY OBJECTIVE: To assess the clinical value of blood cultures (BCs) in the management of adult patients discharged from the emergency department (ED) with a diagnosis of community acquired pneumonia (CAP). METHODS: The courses of antibiotic regimens and outcomes of patients with positive BC results were examined to assess their influence on BCs. RESULTS: BCs were obtained from 289 outpatients. Six clinically significant organisms were identified (a yield of 2.1%). Outpatients with CAP who had blood cultures performed had a 0.69% (2 of 289) chance of having a change of treatment directed by the results of the culture. CONCLUSION: BCs have little utility in the ambulatory management of CAP.

Effect of physician specialty on counseling practices and medical referral patterns among physicians caring for disadvantaged human immunodeficiency virus-infected populations.

Data regarding the care and management of human immunodeficiency virus (HIV)-infected patients provided by infectious diseases (ID)-trained physicians, compared with data for care and management provided by other specialists, are limited. Here, we report results of a self-administered survey sent to 317 physicians (response rate, 76%) in 4 metropolitan areas of the United States who were identified as providing care to disadvantaged HIV-infected patients. ID-trained physicians who responded that they strongly agreed or somewhat agreed that they had enough time to care for their HIV-infected patients were more likely than were non-ID-trained physicians to provide therapy-adherence counseling. Physicians with >or=50 patients in care and ID-trained physicians were less likely to always discuss condom use and risk reduction for HIV transmission. Factors significantly associated with referring rather than treating HIV-infected patients with hypertension or diabetes included having <50 patients in care, being an ID-trained physician, and practicing in a private practice. These results suggest the need for targeted physician training on the importance of HIV transmission prevention counseling, increasing the duration of patient visits, and improving strategies for generalist-specialist comanagement of HIV-infected patients.

Using the national registry of HIV-infected veterans in research: lessons for the development of disease registries.

Disease-specific registries have many important applications in epidemiologic, clinical and health services research. Since 1989 the Department of Veterans Affairs has maintained a national HIV registry. VA's HIV registry is national in scope, it contains longitudinal data and detailed resource utilization and clinical information. To describe the structure, function, and limitations of VA's national HIV registry, and to test its accuracy and completeness. The VA's national HIV registry contains data that are electronically extracted from VA's computerized comprehensive clinical and administrative databases, called Veterans Integrated Health Systems Technology and Architecture (VISTA). We examined the number of AIDS patients and the number of new patients identified to the registry, by year, through December 1996. We verified data elements against information obtained from the medical records at five VA sites. By December 1996, 40,000 HIV-infected patients had been identified to the registry. We encountered missing data and problems with data classification. Missing data occurred for some elements related to the computer programming that creates the registry (e.g., pharmacy files), and for other elements because manual entry is required (e.g., ethnicity). Lack of a standardized data classification system was a problem, especially for the pharmacy and laboratory files. In using VA's national HIV registry we have learned important lessons, which, if taken into account in the future, could lead to the creation of model disease-specific registries.

UK geriatricians' attitudes to active voluntary euthanasia and physician-assisted death.

AIM: To describe the views of British geriatricians on active voluntary euthanasia and physician-assisted death. METHOD: Postal questionnaire to 742 consultant members of the British Geriatrics Society. RESULTS: 81% considered active voluntary euthanasia never to be justified ethically, although 23% supported legalization in some situations and 13% would be willing to administer active voluntary euthanasia in some situations. With regard to physician-assisted death, 68% opposed it on ethical grounds and 24% supported its legalization in some instances, with 12% stating they would be willing to provide such assistance in some situations. Free text comments frequently cited good palliative care as an important response to such issues in clinical practice.

Effects of sonic toothbrush use on permanent dental luting cements.

The aim of this project was to assess the effects of sonic toothbrushes on commonly used permanent luting cements. While results showed differences between the tensile bond strengths of the three cements, the differences were similar between the two groups: sonic and nonsonic toohbrush exposure. These findings suggest that the sonic toothbrush had no significant effect on the tensile bond strengths of any of the three tested cements.

Food-dependent exercise-induced anaphylaxis.

Food-dependent exercise-induced anaphylaxis (FDEIA) is a specific variant of exercise-induced anaphylaxis that requires both vigorous physical activity and the ingestion of specific foods within the preceding several hours. When patients present to the emergency department (ED) with allergic reactions, careful history regarding these 2 factors is required to establish the correct diagnosis. Correct diagnosis of FDEIA will allow patients to take control of their lifestyles and avert repeated events and ED visits. Two cases of FDEIA are presented, and the diagnosis, pathophysiology and therapy of food-dependent exercise-induced anaphylaxis are reviewed.

A survey of emergency medicine in 36 countries.

OBJECTIVE: To assess the current level of development of emergency medicine (EM) systems in the world. DESIGN: Survey of EM professionals from 36 countries during a 90-day period from Aug. 25 to Nov. 24, 1998. PARTICIPANTS: Thirty-six EM professionals from 36 countries and 6 continents completed the survey. Thirty-five (97%) were physicians, of whom 25 (69%) gave presentations at 1 of 4 international EM conferences during the study period. Three potential participants from 3 countries were excluded because of language barriers. Five additional participants from 5 other countries did not respond within the study period and were excluded. MEASUREMENTS: Respondents completed a 103-question questionnaire about the presence of EM specialty, academic, patient care, information and management systems and the factors influencing the future of EM in their countries. RESULTS: The overall response rate was 88%. Nearly all respondents (97%) stated that their countries had hospital-based emergency departments (EDs). More than 80% of respondents reported that their countries have emergency medical services (EMS), national EMS activation phone numbers and ED systems for pediatric emergency care. More than 70% stated that their countries had national EM organizations, EM research, ED systems for patient transfer and peer review and emergency physician (EP) training in Advanced Cardiac Life Support (ACLS) and the ability to perform rapid sequence intubation. More than 60% reported ED systems for trauma care and triage and EP training in Advanced Trauma Life Support (ATLS) and the ability to perform thrombolysis for acute myocardial infarction. Fifty percent reported EM residency training programs, official recognition of EM as an independent specialty, and EM journals. CONCLUSIONS: Basic emergency medicine components now exist in the majority of countries surveyed. These include many specialty, academic, patient care and administrative systems. The foundation for further EM development is widely established throughout the world.

Gram-Positive Pneumonia.

Gram-positive pneumonia is a leading cause of morbidity and mortality throughout the world. Of the gram-positive pathogens that cause pneumonia, Streptococcus pneumoniae and Staphylococcus aureus are the most common. The diagnosis of gram-positive pneumonia remains less than satisfactory, and newer diagnostic techniques such as antibody- and polymerase chain reaction-based antigen detection have yet to prove themselves. Drug resistance among gram-positive organisms is now endemic throughout the world and remains a serious therapeutic problem despite the availability of new antimicrobials. Efforts to control the spread of resistant strains include, in the case of S. aureus, stringent isolation policies and topical treatment to reduce carriage and, for S. pneumoniae, increased use of available vaccines and the develop- ment of more immunogenic vaccines.