The effect of age on the pharmacokinetics of the opioid antagonist nalmefene

1 The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1  mg ( n =18 young; n =11 elderly) or 2  mg ( n =8 young; n =15 elderly) intravenous bolus dose of nalmefene.
2 Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8±1.1 vs 3.9±1.1  l  kg⁻¹ for 1  mg dose). The elderly volunteers also had a significantly shorter distributional half-life ( t1/2λ1 ) than young volunteers (0.7±0.7 vs 1.3±0.8  h for 1  mg dose). No significant differences between groups were observed for the elimination half-life, clearance or steady-state apparent volume of distribution.
3 Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.     

An In Vitro Model for the Expansion of Vγ9δ2 T Lymphocytes During Development

The 7/γ/δTlymphocytes represent a minority of T lymphocytes in human peripheral blood. Although there have been reports of reactivity against (myco-) bacterial antigens and heat shock proteins, their function and antigen specificity remain ill defined. The biological role of γ/δ T cells has been related to functions within the 'first line of defense'. Similar to γ/δ T lymphocytes in the T-cell compartment, CD5 positive B cells represent a small subset of B lymphocytes, which is thought to be involved in the maintenance of natural immunity and autoimmunity. We provide evidence for the cooperation of γ/δ T cells and CD5 positive B cells in the proliferative response of γ/δ T cells to bacterial antigens. Our data indicate a strong proliferation of Vγ9δ2 T cells in response to gram-negative bacteria, which is dependent upon the presence of CD5 positive B-CLL or activated normal B lymphocytes. The selective stimulation of the Vγ9δ2 subpopulation by gram-negative bacteria is also confirmed by analysis of different γ/δ T-cell clones. The interaction of γ/δ T cells with activated B cells and gram-negative bacteria may prove to be a useful model similar to the expansion of the Vγ9δ2 subpopulation during development. In addition, our in vitro system should provide new insights in the interaction of CLL B cells with the immune system and the antigens recognized by γ/δ T cells.     

Coronary Reperfusion Following Experimental Myocardial Infarction

Numerous studies have shown that early coronary reperfusion is feasible in the setting of evolving acute myocardial infarction in man. While early reperfusion reduces myocardial infarct size, there are potentially deleterious consequences of reperfusion. The concept of "reperfusion injury", oxygen-free radical damage, no reflow phenomenon, and stunned myocardium are discussed.     

Release of chemoattractants and neutrophil activation in acute myocardial infarction immediately after successful recanalization of the infarct-related vessel by angioplasty

The study investigated inflamatory responses in evolving myocardialinfarction. Fifteen patients with acute myocardial infarction,who had undergone balloon recanalization of the infarct-relatedcoronary artery within 4 h after onset of symptoms, were examined.Blood samples were obtained through the guiding catheter andfrom the pulmonary artery before and immediately after successfulrecanalization. After recanalization, plas from the pulmonaryartery was 47% (quartiles: l9%, 78; P =0·001) more chemotacticto neutrophils from normal donors than before recanalization.Furthermore, significant changes in neutrophil function werefound in the pulmonary artery. Compared to the values beforerecanalization, the nitroblue tetrazolium score rose by 31%(quartiles: 4%, 37% P=0·003), FMLP-stimulated superoxideanion production by 10% (quartiles: 0%, 39% P=0·020),and chemotaxis by 46% (quartiles: 0%, 81%, P=0·011),while neutrophil filterability decreased by 28% (quartiles:15%, 47%; P=0·010). No significant changes in neutrophilparameters were found in the arterial blood The study indicatesthat chemoattractants are released in the early reperfusionperiod of evolving myocardial infarction. These chemoattractantsmay act as inflammatory mediators causing neutrophil activation.     

Eating despite severe difficulties: assessment of poststroke eating

• ? A programme for the assessment and nursing diagnoses of eating difficulties among stroke patients was tested. The patients' experiences regarding eating were expressed in interviews and dialogues. Eating was observed during both a test meal and regular meals.
• ? The assessments included the prerequisites for eating as well as oral, pharyngeal and oesophageal functions.
• ? General and specific nursing diagnoses as well as life consequences (handicap) were established, based on assessment of disabilities and impairments, and interviewing the patients and their families, respectively. The general nursing diagnoses were formulated on admission after the test meal and these were reformulated to form specific nursing diagnoses after assessments of the functions.
• ? The programme presented proved to be useful in clinical practice. It is emphasized that many assessments must be co-ordinated for each individual.

     

Near‐Fatal ICD Lead Dysfunction with Implications for ICD Testing

A 31‐year‐old male patient with an implantable cardioverter defibrillator (ICD) experienced ventricular fibrillation. After resuscitation, no communication between the device and an ICD programmer was possible. The ICD was explanted, no signs of destruction were visible, and the ICD leads revealed normal values. A new ICD was implanted, interrogation values were stable. However, immediately after defibrillation testing the connection between programmer and ICD was interrupted and could not be established again. The device showed burn marks and a hole in the can. Analysis revealed an isolation defect of the ICD lead, which was not detectable with standard interrogation.     

Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1

Aim Difficulties in neurocognition and social interaction are the most prominent causes of morbidity and long‐term disability in children with neurofibromatosis type 1 (NF1). Symptoms of attention‐deficit–hyperactivity disorder (ADHD) have also been extensively recognized in NF1. However, systematic evaluation of symptoms of autism spectrum disorder (ASD) in children with NF1 has been limited. Method We present a retrospective, cross‐sectional study of the prevalence of symptoms of ASD and ADHD and their relationship in a consecutive series of 66 patients from our NF1 clinic. The Social Responsiveness Scale and the Vanderbilt ADHD Diagnostic Parent Rating Scale were used to assess symptoms of ASD and ADHD. Results Sixty‐six participants (42 males, 24 females) were included in this study. Mean age at assessment was 10 years 11 months (SD 5y 4mo). Forty percent of our NF1 sample had raised symptom levels reaching clinical significance on the Social Responsiveness Scale (T ≥ 60), and 14% reached levels consistent with those seen in children with ASDs (T ≥ 75). These raised levels were not explained by NF1 disease severity or externalizing/internalizing behavioral disorders. There was a statistically significant relationship between symptoms of ADHD and ASD (χ²=9.11, df=1, p=0.003, φ=0.56). Particularly salient were the relationships between attention and hyperactivity deficits, with impairments in social awareness and social motivation. Interpretation We found that symptoms of ASD in our NF1 population were raised, consistent with previous reports. Further characterization of the specific ASD symptoms and their impact on daily function is fundamental to the development and implementation of effective interventions in this population, which will probably include a combination of medical and behavioral approaches.     

MUTATION OF THE VHL GENE IS ASSOCIATED EXCLUSIVELY WITH THE DEVELOPMENT OF NON-PAPILLARY RENAL CELL CARCINOMAS

To define the possible role of the VHL gene in the development of sporadic renal cell carcinomas, 91 different parenchymal tumours of the kidney have been investigated for mutation of the VHL gene by single strand conformation polymorphism (SSCP) and/or heteroduplex (HD) techniques. Chromosome 3p deletion was detected in 98 per cent of non-papillary renal cell carcinomas and in 25 per cent of chromophobe renal cell carcinomas. In 22 of the 43 non-papillary renal cell carcinomas, abnormally migrating DNA bands were detected by SSCP and/or HD analysis. No mobility shift was seen in any of the 23 chromophobe renal cell carcinomas. In addition, 15 papillary renal cell tumours and ten renal oncocytomas, which are characterized by genetic changes other than loss of chromosome 3p sequences, were analysed for mutation of the VHL gene. None of these tumours showed abnormal migration patterns. The results indicate that mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinoma.     

Estrogen receptor β– an independent prognostic marker in estrogen receptor α and progesterone receptor‐positive breast cancer?

Both subtypes of estrogen receptor (ER), ERα and ERβ, are normally present in the mammary gland. The role of ERα as a prognostic marker in breast cancer is well established due to the beneficial effect of providing tamoxifen as adjuvant therapy. The role of ERβ, however, is less clear. To gain insight into the importance of ERβ in breast cancer, 145 primary breast cancers were examined by immunohistochemistry for ERβ, and the expression level was compared with ERα and progesterone receptor (PR) status. Especially, we wanted to examine the significance of ERβ in the contrasting ERα+/PR+ and ERα?/PR? subgroups. In the ERα+/PR+ subgroup (dual positive), the survival difference between patients with low, medium and high ER β level was statistically significant (p = 0.004), with more than 70% of patients with medium and high ERβ levels surviving 100 months, compared with less than 30% in the group with low ERβ level. Further, for ERα+/PR+ patients there was a reduced risk of fatal outcome by multivariate analysis with increasing ERβ levels (p(trend) < 0.01 [univariate analysis]; p(trend) = 0.05 [multivariate analysis]). The risk was 31% and 27% for medium and high ERβ levels, respectively, compared with low ERβ level, adjusting for standard prognostic factors such as tumor diameter, nuclear tumor grade (quantified by mean nuclear area), lymph node status, and patient age at operation. For patients with ERα?/PR? tumors (dual negative), however, there was no association between ERβ levels and patient outcome. Our findings indicate that ERβ expression provides independent prognostic information for breast cancers with ERα/PR‐positive status, a feature typical among screen‐detected breast cancers. The role of ERβ needs to be further evaluated especially in this group of breast cancers.