Ultrasensitive analysis of the intestinal absorption and compartmentalization of aluminium in uraemic rats: a 26Al tracer study employing accelerator mass spectrometry

BACKGROUND: Developments in accelerator mass spectrometry (AMS) now permit the determination of femtogram amounts of 26Al in blood and in various tissues with good precision and free of external contamination. METHODS: In the present study we used trace quantities of 26Al to investigate the intestinal absorption and compartmentalization of aluminium in rats with renal failure (Nx, 5/6 nephrectomy) and in pair- fed controls (C). Single oral doses of 20 ng 26Al were administered to six animals in each group and, subsequently, 24-h post-load 26Al was analysed in serum, urine, bone, liver, and spleen by means of AMS. RESULTS: Serum concentrations of 26Al were significantly lower in uraemic rats compared to controls, whereas urinary excretion was comparable (Nx, 7.11 +/- 5.78 pg/day vs C, 9.46 +/- 6.10 pg/day), suggesting a higher fraction of ultrafiltrable serum 26Al in uraemia. The target tissues of cellular transferrin-mediated 26Al uptake, liver and spleen, tended to show a larger degree of aluminium accumulation in controls (0.26 +/- 0.31 pg/g vs Nx, 0.14 +/- 0.10 pg/g and 0.37 +/- 0.27 pg/g vs Nx, 0.25 +/- 0.27 pg/g respectively). In contrast, in bone, a site of extracellular aluminium deposition, 26Al concentrations were more elevated in uraemia (1.22 +/- 0.59 pg/g vs C: 0.68 +/- 0.30 pg/g). Estimated total 26Al accumulation in all measured target tissues was significantly higher in uraemic rats (28.15 +/- 9.90 pg vs C: 17.03 +/- 7.03 pg) and total recovery of 26Al from tissue and urine was 26.58 +/- 6.74 pg in controls and 35.75 +/- 7.03 pg in uraemic animals, suggesting a fractional absorption of 0.133% and 0.175% respectively. CONCLUSIONS: Our data suggest that fractional absorption from a dietary level dose of 26Al is about 0.13%. Compartmentalization occurs in transferrin-dependent target tissues such as liver and spleen; however, in quantitative terms extracellular deposition in bone is more important. Uraemia has a significant effect on the intestinal absorption and compartmentalization of aluminium. It enhances fractional absorption and increases subsequent extracellular deposition of aluminium in bone. However, at the same time uraemia does not increase transferrin-dependent cellular accumulation of aluminium in liver and spleen.      

Investigation of the aluminium biokinetics in humans: a 26Al tracer study.

Despite the well-known toxicity of aluminium in chronic renal failure, a solid database on its biokinetics has been difficult to establish. A highly sensitive method using (26)Al as tracer and accelerator mass spectrometry (AMS) for detection was used. No perturbing background and saturation effects were taken into account using a delta function input of aluminium in time. Aluminium absorption, distribution, speciation and excretion in six healthy volunteers and in two patients with chronic renal failure were investigated following administration of a single oral or i.v. dose of (26)Al. Serial samples of blood and urine were taken. In a speciation study, the time dependence of the binding of (26)Al to low-molecular weight molecules in serum was investigated. The measured data were compared and interpreted with simulations in an open compartmental model. Fractional absorption, distribution, excretion and time constants for the aluminium transport were determined. Typical intestinal absorption rates for AlCl(3) were found to be in the range of 10(-3). The ultrafiltrable percentage of aluminium in serum of one volunteer was estimated to be 5.6+/-0.8%. Differences between healthy volunteers and patients with chronic renal failure were deduced. The employed method using (26)Al and ams has proven to be highly sensitive for investigations of aluminium biokinetics at the ultra-trace element level. With the model, the measured values of (26)Al in serum and urine were used to precisely determine absorption, speciation, distribution, retention and excretion of aluminium in humans.     

Pegylated asparaginase in combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in first remission: a pilot study

The German Multicentre acute lymphoblastic leukaemia (ALL) study group (GMALL) performed a pilot study using pegylated asparaginase (PEG-ASP) in combination with high-dose methotrexate as consolidation therapy in the 05/93 protocol. The aim of the study was an intra-individual comparison of two different doses of PEG-ASP in 26 patients, with regard to the depletion of asparagine in serum and toxicity. 'Pharmacokinetic' monitoring was performed to evaluate the effect of an intra-individual dose escalation of PEG-ASP from 500 to 1000 U/m2 intravenously in successive doses. Serum asparaginase activity was targeted at > or =100 U/l for 1 week and > or =50 U/l for 10 d. The second course of PEG-ASP was administered to 23 patients. Due to hypersensitivity reactions in five patients, only 18 patients were evaluable for pharmacokinetic monitoring. With respect to the PEG-ASP activity, an effective depletion of asparagine could be postulated in the majority of patients during 10 d after the first administration. The effect of an intraindividual dose escalation form 500 to 1000 U/m2 was evaluable in 17 of 22 patients. An increment in peak PEG-ASP activity >70% was observed in 65% of the patients. PEG-ASP was well tolerated. Despite the long half-life of PEG-ASP, neither pancreatic nor central nervous toxicities occurred among the 26 adult patients treated in this pilot study.     

Serum Aspergillus galactomannan for the management of disseminated histoplasmosis in AIDS

Abstract. Disseminated histoplasmosis is an emerging infection in patients with cellular immune deficiency in non-endemic countries, caused by the migration from endemic regions and the development of travels. Diagnosis can be challenging in this context because rapid diagnostic tools such as Histoplasma antigen detection or appropriate molecular tools are generally unavailable, serology is often negative in immunosuppressed patients, and isolation of the fungus from cultures often takes several weeks. Here, we report the contribution of galactomannan serum detection for the management of an HIV-infected patient with disseminated histoplasmosis.     

Healthcare-associated mucormycosis

Mucormycosis is a severe emerging invasive fungal infection that occurs as a consequence of environmental exposure. We exhaustively reviewed all the cases of mucormycosis (European Organisation for Research and Treatment of Cancer/Mycoses Study Group 2008 criteria) attributed to healthcare procedures that occurred between 1970 and 2008. A total of 169 cases were studied (29% children, 61% male). Major underlying diseases were solid organ transplantation (24%), diabetes mellitus (22%), and severe prematurity (21%). Skin was the most common localization (57%), followed by gastrointestinal tract (15%). Culture results were available in 75% (92% positive), and results of histological examination were positive in 95%. Rhizopus was the most frequent genus (43%). Infection portal of entry included surgery and presence of medical devices such as catheters or adhesive tape. Outbreaks and clusters were related to adhesive bandages (19 cases), wooden tongue depressors (n = 5), ostomy bags (n = 2), water circuitry damage (n = 2), and adjacent building construction (n = 5). Thorough investigations are mandatory to identify healthcare-associated mucormycosis, notably in neonatology, hematological, and transplantation units.     

DROP-OUT FROM CHRONIC PAIN TREATMENT PROGRAMMES: IS RANDOMIZATION JUSTIFIED IN BIOPSYCHOSOCIAL APPROACHES?

ObjectiveTo identify profiles of patients who are at risk of dropping out from biopsychosocial approaches to chronic pain management.PatientsA total of 575 patients were included in the study. Of these, 203 were randomized into 4 treatment groups: self-hypnosis/self-care; music/self-care; self-care; and psychoeducation/cognitive behavioural therapy. The remaining 372 patients were not randomized, as they presented with the demand to learn self-hypnosis/self-care, and therefore were termed a “self-hypnosis/self-care demanders” group.MethodsSocio-demographics and behavioural data were included in the analyses. Univariates analyses, comparing early drop-outs (never attended treatment), late drop-outs (6/9 sessions’ treatment) and continuers were conducted in order to select variables to include in a multivariate logistic regression.ResultsUnivariate analyses yielded 8 variables, out of 18 potential predictors for drop-out, which were eligible for inclusion in the multivariate logistic regression. The model showed that having an intermediate or high educational level protects against dropping out early or late in the pain management process. Having to wait for more than 4 months before starting the treatment increases the risk of never starting it. Being randomized increases the risk of never starting the treatment.ConclusionIn a context in which randomization is considered a “gold standard” in evidence-based practice, these results indicate that this very principle could be deleterious to pain management in patients with chronic pain.LAY ABSTRACTThe aim of this study was to identify profiles of patients who are at risk of dropping out from biopsychosocial approaches to chronic pain management. A total of 575 patients were included in the study. Of these, 203 patients were randomized into 4 treatment groups: self-hypnosis/self-care; music/self-care; self-care; psychoeducation/cognitive behavioural therapy. The remaining 372 patients were not randomized, as they presented with the demand to learn self-hypnosis/self-care, and hence formed a “self-hypnosis/self-care demanders” group. Analyses of socio-demographics and behavioural data were conducted, comparing early drop-outs (never attended treatment), late drop-outs (6/9 sessions’ treatment) and continuers. Results showed that having an intermediate or high educational level protects against dropping out early or late in the management process. Having to wait for more than 4 months before starting the treatment, and being randomized, increases the risk of never starting it. Thus, in a context in which randomization is considered as a “gold standard” in evidence-based practice, these results indicate that this very principle could be deleterious to pain management in patients with chronic pain.Key words: chronic pain, non-pharmacological treatment, randomization, drop-out, loss to follow-up, attrition

Chronic pain is a complex disorder in which pain appears persistent and prolonged (> 3 months) and includes biological, psychological and socio-professional factors that undermine patients’ everyday life. Patients and healthcare providers are increasingly turning to non-pharmacological treatments, such as hypnosis and music therapy, combined with cognitive behavioural therapy (CBT) (1). The efficacy of these treatment in managing chronic pain has been demonstrated (2–4).A major problem in clinical research is drop-out, which ranges from 5% to 46%, in chronic pain management, depending on the study (5). The first issue concerns the definition of drop-out, since this varies between authors: some regard drop-out as patients ending therapy before the agreed-end-of-treatment (6), others consider it as not attending therapy sessions even though patients have agreed to attend (7). The second issue is that few clinical studies in the field of chronic pain take drop-out into account, thus generating a bias in the overall results of clinical trials investigating the efficacy of such treatments (8). The lack of studies and the disagreement regarding definitions lead to a range of results in the study of drop-out predictors in chronic pain. Some authors have highlighted that a low educational level increases the risk of dropping out from therapy (cohort study (9)), while others have shown the contrary (randomized trial (10)). The same controversy can be seen when considering age, sex and personality (systematic review (5); randomized trial (10); retrospective study (11); non-randomized trial (12)). Predictors outside of patient-related factors have mostly been studied in the mental health literature. As the management of chronic pain and mental health is relatively similar, consideration of these factors seems relevant. A meta-analysis showed that, in psychotherapy settings, the therapist expertise had an influence on drop-out. The results demonstrated that when trainees (pre-degree attainment) lead the group therapy, patients tended to be more likely to drop-out (13). Another meta-analysis showed that patients’ motivational level predicted drop-out from psychotherapy (14). A further barrier to completing treatments is the waiting period between initial contact and the effective start of the treatment (retrospective study (15)). Another retrospective study highlighted that the longer the patients in a substance abuse treatment programme had to wait until the onset of treatment (≥8 days), the more likely they were not to attend the first session of the programme (16).Given the lack of consensus, a better understanding of the profile of drop-outs and contextual risk factors, is essential in order to prevent this phenomenon, enhance treatment adherence and, consequently, ameliorate the study of treatment efficacy in chronic pain.The aim of this study was to retrospectively identify patient- and context-related factors to explain drop-out from randomized biopsychosocial-based treatment programmes.     

Brain function in the vegetative state

Positron emission tomography (PET) techniques represent a useful tool to better understand the residual brain function in vegetative state patients. It has been shown that overall cerebral metabolic rates for glucose are massively reduced in this condition. However, the recovery of consciousness from vegetative state is not always associated with substantial changes in global metabolism. This finding led us to hypothesize that some vegetative patients are unconscious not just because of a global loss of neuronal function, but rather due to an altered activity in some critical brain regions and to the abolished functional connections between them. We used voxel-based Statistical Parametric Mapping (SPM) approaches to characterize the functional neuroanatomy of the vegetative state. The most dysfunctional brain regions were bilateral frontal and parieto-temporal associative cortices. Despite the metabolic impairment, external stimulation still induced a significant neuronal activation (i.e., change in blood flow) in vegetative patients as shown by both auditory click stimuli and noxious somatosensory stimuli. However, this activation was limited to primary cortices and dissociated from higher-order associative cortices, thought to be necessary for conscious perception. Finally, we demonstrated that vegetative patients have impaired functional connections between distant cortical areas and between the thalami and the cortex and, more importantly, that recovery of consciousness is paralleled by a restoration of this cortico-thalamo-cortical interaction.     

Early rapid loss followed by long-term consolidation characterizes the development of lumbar bone mineral density after kidney transplantation

BACKGROUND: Bone mineral density (BMD) decreases significantly early after renal transplantation. This prospective study was designed to evaluate the long-term lumbar BMD development. METHODS: Sixty-three renal-transplant recipients (mean age 44 +/- 12 years, 37 [59%] male) underwent serial yearly posttransplant laboratory parameter and BMD measurements of the lumbar spine (dual energy x-ray absorptiometry). Combined maintenance immunosuppression included prednisolone in 95% of patients. The minimum number of consecutive scans was three; the maximum number seven (n = 15). Examinations were performed between 3 +/- 2 and 68 +/- 4 months posttransplant. RESULTS: BMD was significantly lower compared with healthy controls at all times after transplantation. t scores were below -1. BMD development revealed a biphasic pattern: between 3 +/- 2 and 10 +/- 2 months, a significant BMD decrease of -0.016 +/- 0.055 g/cm2 (-1.6%, P = 0.024) occurred. Later, a moderate increase resulting in BMD stability until the sixth year posttransplant was detected. Within the first year, posttransplant osteocalcin (from 19 +/- 15 to 32 +/- 23 microg/L) and calcitriol (from 24 +/- 15 to 43 +/- 24 ng/L) displayed a significant increase. Compared with patients with a pronounced decrease, patients with a substantial increase in early posttransplant BMD had a lower baseline BMD (0.989 +/- 0.131 vs. 1.149 +/- 0.202 g/cm2 [P = 0.0122]) and lower creatinine levels (105 +/- 23 vs. 141 +/- 53 mmol/L [P = 0.0227]). CONCLUSION: Our study confirms a significant decrease of lumbar BMD early after renal transplantation. Bone loss was less pronounced than previously described. The longitudinal follow-up verifies a previously assumed biphasic lumbar BMD development: after the first year, no further significant bone loss occurred, and bone density remained relatively stable at significantly lower levels compared with healthy controls.     

Staphylococcus aureus isolates with reduced susceptibility to glycopeptides belong to accessory gene regulator group I or II

We used multiplex PCR to determine the agr group membership of 18 European glycopeptide heterointermediate and intermediate-resistant Staphylococcus aureus strains. Of the 15 agr group I strains, 13 were resistant and 2 were susceptible to methicillin. The remaining three strains, like the United States and Japanese control strains, belonged to agr group II.