Effects of cardiac and renal disease on clinical pharmacokinetics]

In this oral presentation, the author emphasized the need for individualization of drug treatment, reviewing the most known factors of variability in drug response. The importance of studies of clinical pharmacokinetics was focused. The main parameters for a judgement on the efficacy and virtual tolerability of a medicine, on the basis of its sequential concentrations in the blood after administration, were briefly outlined. The influence of congestive heart failure on the volume of distribution, systemic clearance, elimination half-life and bioavailability, was discussed. The changes that renal failure makes in drug elimination were equally presented, having been pointed the modification of protein binding, volume of distribution, and hepatic elimination. A selection of eight clinical cases was summarily presented, to illustrate the important contribute that can be afforded to practice by pharmacokinetics. The dosing of aminoglycosides and of other drugs with narrow therapeutic ranges was evaluated through some of the examples. A case of complex interferences of heart failure, renal failure and therapeutic hemoperfusion on the kinetics of an antibiotic drug was included. Two cases of intoxications (phenytoin and theophylline), whose management has been greatly improved by repeated drug dosing in blood, were discussed, too. A special call of attention was made to the need the currently practicing physician has of being aware of kinetic characteristics of the drugs he prescribes, and of how can disease modify the body fate of those medicines, and their therapeutic and nontherapeutic effects.     

Type 2 diabetes: assessment of endothelial lesion and fibrinolytic system markers.

This study aimed to investigate whether endothelial cells are damaged and to evaluate fibrinolytic system function in patients with type 2 diabetes. For this proposal, plasma levels of von Willebrand factor (an endothelial marker of injury), homocysteine (an inductor of endothelial injury), D-dimer (a marker of coagulation cascade activation) and plasminogen activator inhibitor-1 (a fibrinolysis marker) were measured in individuals with both type 2 diabetes and high blood pressure, with type 2 diabetes, with high blood pressure and in healthy control individuals. No significant differences among groups were observed for von Willebrand factor and homocysteine plasma levels. The type 2 diabetes and high blood pressure group presented a significant difference to the other groups for D-dimer and also presented high values for plasminogen activator inhibitor-1. The high blood pressure group and type 2 diabetes group presented separately higher values of plasminogen activator inhibitor-1 compared with the control group. High levels of D-dimer and plasminogen activator inhibitor-1 in patients with type 2 diabetes and high blood pressure with normoalbuminuria therefore indicate a state of hypercoagulability and hypofibrinolysis, despite no evident microvascular injury supported by normal levels of von Willebrand factor and homocysteine.     

Using Queueing Theory to Increase the Effectiveness of Emergency Department Provider Staffing

Objectives: Significant variation in emergency department (ED) patient arrival rates necessitates the adjustment of staffing patterns to optimize the timely care of patients. This study evaluated the effectiveness of a queueing model in identifying provider staffing patterns to reduce the fraction of patients who leave without being seen. Methods: The authors collected detailed ED arrival data from an urban hospital and used a Lag SIPP queueing analysis to gain insights on how to change provider staffing to decrease the proportion of patients who leave without being seen. The authors then compared this proportion for the same 39‐week period before and after the resulting changes. Results: Despite an increase in arrival volume of 1,078 patients (6.3%), an average increase in provider hours of 12 hours per week (3.1%) resulted in 258 fewer patients who left without being seen. This represents a decrease in the proportion of patients who left without being seen by 22.9%. Restricting attention to a four‐day subset of the week during which there was no increase in total provider hours, a reallocation of providers based on the queueing model resulted in 161 fewer patients who left without being seen (21.7%), despite an additional 548 patients (5.5%) arriving in the second half of the study. Conclusions: Timely access to a provider is a critical dimension of ED quality performance. In an environment in which EDs are often understaffed, analyses of arrival patterns and the use of queueing models can be extremely useful in identifying the most effective allocation of staff.     

Thermic effect of a meal. 2. Role in chronic undernutrition.

The thermic effect of a standard liquid meal (TEM; energy 2.5 MJ; containing (g/kg) protein 100, fat 150, carbohydrate 750; volume 350 ml) was measured in a chronically undernourished (UN; n 9) group of human subjects and was compared with results from two control groups, one normal weight (NW)-for-height (BMI greater than 20; n 10) and the other underweight (UW)-for-height (BMI less than 18, n 10), using a ventilated-hood system over a period of 6 h after ingestion of the meal. Results indicated that the UN subjects had lower values for body-weight, height, percentage fat and fat-free mass (FFM) compared with those of either control group. Basal metabolic rates were lowest in the UN group in absolute terms; however, there were no significant differences among groups on an analysis of covariance (ANACOVA) with FFM as the covariate. TEM responses in the UN group were significantly higher when expressed either in absolute terms or as a percentage of the energy density of the meal. The post-meal total energy output was significantly lower (P less than 0.05) in the UW and UN groups as compared with the NW group in absolute terms; however, on adjusting for differences in FFM (by ANACOVA) there were no significant differences among groups. This would suggest that in the chronically undernourished thermogenic responses to a meal are unlikely to contribute towards any energy saving and may not constitute a part of any adaptive response to the undernourished state.     

Clinical aspects of tumour involvement of the pulmonary vessels.

The involvement of the pulmonary vessels by tumour emboli may lead to a clinical picture defined as 'subacute cor pulmonale'. Information about this syndrome has been limited to case reports and a few series. A study of 214 autopsied cancer patients was undertaken to investigate the clinical signs and symptoms of tumour involvement of the pulmonary vessels (TIPV). The lungs were removed as a block and 15 sections (3 from each lobe) were analyzed. Clinical data about right ventricular failure, dyspnoea, cough, pleuritic chest pain, cyanosis, engorgement of jugular veins, peripheral oedema, haemoptysis and haemoptoic sputum were obtained from the medical records of each patient. Tumour emboli were detected in 89 cases, and no respiratory symptoms were recorded in 39. The presence of dyspnoea and cyanosis were highly significant in the group with TIVP, and right ventricular failure and peripheral oedema showed slight significant differences between the patients with and without TIPV. The classical picture of subacute cor pulmonale was observed in 13 patients and TIPV was considered to be the main cause of death in 29 cases. Our results indicate that although the development of subacute cor pulmonale was rare in patients with cancer, TIPV may be suspected when the patient presents respiratory distress and should be included in the differential diagnosis of dyspnoea in cancer patients.     

Accumulation of brown adipose tissue and nutritional status. A prospective study of 366 consecutive autopsies.

Increased amounts of brown adipose tissue have been reported to occur in association with several diseases. The objective of the present study was to determine whether brown adipose tissue accumulation is related to nutritional status. Histologic sections of periadrenal tissue prospectively obtained at consecutive autopsies from 366 adults were examined. The cases were separated into three groups: malnourished (101 autopsies), normotrophic (128 autopsies), and obese (137 autopsies), according to the Quetelet index. Of these patients, 89 had brown adipose tissue accumulation, 35 were malnourished, 32 were normotrophic, and 22 were obese. The results showed a correlation between brown adipose tissue and patient nutritional status and a higher brown adipose tissue accumulation in malnourished patients. Cardiovascular disease was the most common type of illness present in the cases with brown adipose tissue accumulation.     

Extended structural variation of a pentanucleotide repeat in the GSTP1 gene: characterisation in a normal population and in thyroid and gastric tumours

The promoter region of the human GSTP1 gene contains a polymorphic short tandem repeat (STR) locus consisting of pentanucleotide repeat units (ATAAA). In this work we report the existence of a total of 26 alleles in a Caucasian population. While differences in size (ranging from one to five base pairs) were responsible for the major variation, in five size-defined classes, two alternative sequences were found. Automatic fragment sizing and sequencing analysis revealed that this polymorphism is of a highly complex nature in contrast with previous reports. A genetic population study was carried out on a random sample from Portugal showing no deviation from Hardy-Weinberg equilibrium. Somatic instability studies were also performed on gastric and thyroid tumours using this STR: no instability was detected in thyroid tumour tissues when compared with their normal counterpart but in gastric tumour tissues microsatellite instability (MSI) was detected in 9.6% of the cases and loss of heterozygosity (LOH) also in 9.6% of the cases studied. The results obtained with GSTP1 in gastric cancer were compared with previously reported data on MSI using BAT-26 and several dinucleotide repeat markers.