Mass, Spectroscopy, and Two-Neutron Decay of

The structure and decay of the most neutron-rich beryllium isotope, ^{16}Be, has been investigated following proton knockout from a high-energy ^{17}B beam. Two relatively narrow resonances were observed for the first time, with energies of 0.84(3) and 2.15(5) MeV above the two-neutron decay threshold and widths of 0.32(8) and 0.95(15) MeV, respectively. These were assigned to be the ground (J^{π}=0^{+}) and first excited (2^{+}) state, with E_{x}=1.31(6) MeV. The mass excess of ^{16}Be was thus deduced to be 56.93(13) MeV, some 0.5 MeV more bound than the only previous measurement. Both states were observed to decay by direct two-neutron emission. Calculations incorporating the evolution of the wave function during the decay as a genuine three-body process reproduced the principal characteristics of the neutron-neutron energy spectra for both levels, indicating that the ground state exhibits a strong spatially compact dineutron component, while the 2^{+} level presents a far more diffuse neutron-neutron distribution.

Surface Localization of the Dineutron in

The formation of a dineutron in the ^{11}Li nucleus is found to be localized to the surface region. The experiment measured the intrinsic momentum of the struck neutron in ^{11}Li via the (p,pn) knockout reaction at 246 MeV/nucleon. The correlation angle between the two neutrons is, for the first time, measured as a function of the intrinsic neutron momentum. A comparison with reaction calculations reveals the localization of the dineutron at r∼3.6 fm. The results also support the density dependence of dineutron formation as deduced from Hartree-Fock-Bogoliubov calculations for nuclear matter.

Extraction of the Landau-Migdal Parameter from the Gamow-Teller Giant Resonance in

The key parameter to discuss the possibility of the pion condensation in nuclear matter, i.e., the so-called Landau-Migdal parameter g^{'}, was extracted by measuring the double-differential cross sections for the (p,n) reaction at 216 MeV/u on a neutron-rich doubly magic unstable nucleus, ^{132}Sn with the quality comparable to data taken with stable nuclei. The extracted strengths for Gamow-Teller (GT) transitions from ^{132}Sn leading to ^{132}Sb exhibit the GT giant resonance (GTR) at the excitation energy of 16.3±0.4(stat)±0.4(syst) MeV with the width of Γ=4.7±0.8 MeV. The integrated GT strength up to E_{x}=25 MeV is S_{GT}^{-}=53±5(stat)_{-10}^{+11}(syst), corresponding to 56% of Ikeda's sum rule of 3(N-Z)=96. The present result accurately constrains the Landau-Migdal parameter as g^{'}=0.68±0.07, thanks to the high sensitivity of the GTR energy to g^{'}. In combination with previous studies on the GTR for ^{90}Zr and ^{208}Pb, the result of this work shows the constancy of this parameter in the nuclear chart region with (N-Z)/A=0.11 to 0.24 and A=90 to 208.

Single nucleotide polymorphisms in long noncoding RNA, ANRIL, are not associated with severe periodontitis but with adverse cardiovascular events among patients with cardiovascular disease.

BACKGROUND AND OBJECTIVE: Biological plausibility of an association between severe periodontitis and cardiovascular disease (CVD) has been proven. Genetic characteristics play an important role in both complex inflammatory diseases. Polymorphisms (single nucleotide polymorphisms [SNPs]) in the long noncoding RNA, antisense noncoding RNA in the INK4 locus (ANRIL), were shown to play a leading role in both diseases. The primary objectives of the study were to assess, among cardiovascular (CV angiographically proven ≥50% stenosis of a main coronary artery) patients, the impact of ANRIL SNPs rs133049 and rs3217992 on the severity of periodontitis and the previous history of coronary events, as well as on the occurrence of further adverse CV events. MATERIAL AND METHODS: The prevalence of severe periodontitis was analyzed in 1002 CV patients. ANRIL SNPs rs133049 and rs3217992 were genotyped. The prognostic value of both ANRIL SNPs for combined CV endpoint (stroke/transient ischemic attack [TIA], myocardial infarction, death from a CV-related event, death from stroke) was evaluated after a 3-year follow-up period. Hazard ratios (HRs) were adjusted for established CV risk factors applying Cox regression. RESULTS: ANRIL SNPs rs133049 and rs3217992 were not associated with severe periodontitis or history of CVD in CV patients. In the Kaplan-Meier survival curve including the log rank-test (P = .036) and Cox regression (hazard ratio = 1.684, P = .009) the AA genotype of rs3217992 was shown to be an independent predictor for adverse CV events after 3 years of follow-up. CONCLUSION: SNPs in ANRIL are not risk modulators for severe periodontitis and history of CVD in CV patients. The AA genotype of ANRIL SNPs rs3217992 possesses prognostic power for further CV events within 3 years of follow-up.

Cytogenetic Effects of Chronic Methylphenidate Treatment and Chronic Social Stress in Adults with Attention-Deficit/Hyperactivity Disorder.

INTRODUCTION: Methylphenidate (MPH) is widely used to treat childhood and adult attention-deficit/hyperactivity disorder (ADHD). However, there are still safety concerns about side effects in long-term treatment. The aim of this study was to assess cytogenetic effects of chronic MPH treatment in adult ADHD and to find out if chronic social stress is attenuated by medication and to investigate whether chronic psychosocial stress leads to mutagenic effects by itself. METHODS: Lymphocytes for micronucleus assay and saliva samples for cortisol measurement were collected from adult ADHD patients and healthy controls. Stress exposure of the last 3 months was assessed by TICS (Trier Inventory for Chronic Stress). RESULTS: We could not detect an influence of MPH treatment on cytogenetic markers. ADHD patients displayed significantly higher chronic stress levels measured by TICS compared to healthy controls which were influenced by duration of MPH treatment. ADHD patients also showed significantly lower basal cortisol levels. DISCUSSION: We could corroborate that there are neither cytogenetic effects of chronic stress nor of chronic MPH intake even after several years of treatment.

Maternal telomere length inheritance in the king penguin.

Telomeres are emerging as a biomarker for ageing and survival, and are likely important in shaping life-history trade-offs. In particular, telomere length with which one starts in life has been linked to lifelong survival, suggesting that early telomere dynamics are somehow related to life-history trajectories. This result highlights the importance of determining the extent to which telomere length is inherited, as a crucial factor determining early life telomere length. Given the scarcity of species for which telomere length inheritance has been studied, it is pressing to assess the generality of telomere length inheritance patterns. Further, information on how this pattern changes over the course of growth in individuals living under natural conditions should provide some insight on the extent to which environmental constraints also shape telomere dynamics. To fill this gap partly, we followed telomere inheritance in a population of king penguins (Aptenodytes patagonicus). We tested for paternal and maternal influence on chick initial telomere length (10 days old after hatching), and how these relationships changed with chick age (at 70, 200 and 300 days old). Based on a correlative approach, offspring telomere length was positively associated with maternal telomere length early in life (at 10 days old). However, this relationship was not significant at older ages. These data suggest that telomere length in birds is maternally inherited. Nonetheless, the influence of environmental conditions during growth remained an important factor shaping telomere length, as the maternal link disappeared with chicks' age.

Use of floss/interdental brushes is associated with lower risk for new cardiovascular events among patients with coronary heart disease.

BACKGROUND AND OBJECTIVE: Periodontitis has been found to be associated with coronary heart disease (CHD) and stroke. However, only little is known about whether periodontitis and associated confounders are associated with new cardiovascular events among patients with CHD. MATERIAL AND METHODS: A total of 942 inpatients with CHD were examined regarding periodontitis, oral care habits, bacteria in the subgingival biofilm and the expression of interleukin-(IL)-6 c. (coding DNA)-174 genotypes (rs 1800793) to determine whether these confounders are associated with new cardiovascular events within a 1-year follow-up period. Adjusted hazard ratios (HR) with respect of age, gender, smoking, body mass index, use of aids for interdental hygiene, plaque index, occurrence of severe periodontitis and further internal diseases such as diabetes, hypertension, dyslipoproteinemia, number of missing teeth, serological parameters and IL-6 genotypes were generated with Cox regression. RESULTS: In all, 941 cardiovascular patients completed the 1-year follow up and 7.3% of the patients achieved the primary endpoint (myocardial infarction: 2.1%, stroke/transient ischemic attack: 1.8%, cardiovascular deaths: 3.4%). Patients who reported practicing interdental cleaning were younger, less likely to be male or to have severe periodontitis, had a reduced tobacco exposure, had fewer missing teeth, less indices for plaque and bleeding on probing and a significant decreased adjusted risk for new cardiovascular events (HR = 0.2, CI 0.06-0.6, p = 0.01) than those patients with CHD who did not report practicing interdental cleaning. We did not obtain significant increased HR for patients with severe periodontitis (HR = 1.2, CI 0.7-2.1, p = 0.53), carriers of the IL-6 genotypes GC or CC (HR = 1.4, CI 0.8-2.5, p = 0.24) and did not find a significant association between the number of detected various oral species and the incidence of the combined endpoint (HR = 0.9, CI 0.8-1.01, p = 0.07). CONCLUSIONS: These findings suggest that flossing and brushing of interdental spaces might reduce the risk for new cardiovascular events among patients with CHD. The hypothesis that interdental cleaning per se reduces the risk of new cardiovascular events should be examined in an interventional study.

[Investigation of metabolic parame- ters in high yielding dairy cows in pasture based production systems]. / Stoffwechseluntersuchungen bei Hochleistungskühen in Vollweidehaltung.

In the present study differences in metabolism between New Zealand Holstein-Friesian (NZHF) and Brown Swiss (CH-BV) or Swiss Holstein-Friesian (CH-HF) were investigated in a grassland based milk production system in Switzerland. Therefore 14 pairs of CH-BV/NZHF and 11 pairs of CH-HF/NZHF were available. The parameters glucose, insulin, non-esterified fatty acids (NEFA), ß-hydroxybutyrate (ß-HB), urea and cholesterol were analysed at the times 5-3 weeks before the calculated partus and 2, 3, 5, 7, 10 and 18-22 weeks post partum. Only ß-HB showed significantly higher concentrations (P = 0.0059) for both Swiss breeds compared to the NZ-HF. Regarding all other physiological parameters during early lactation New Zealand Holstein-Friesians were not different from Swiss breeds.

Carbogen inhalation during non-convulsive status epilepticus: A quantitative exploratory analysis of EEG recordings.

OBJECTIVE: To quantify the effect of inhaled 5% carbon-dioxide/95% oxygen on EEG recordings from patients in non-convulsive status epilepticus (NCSE). METHODS: Five children of mixed aetiology in NCSE were given high flow of inhaled carbogen (5% carbon dioxide/95% oxygen) using a face mask for maximum 120s. EEG was recorded concurrently in all patients. The effects of inhaled carbogen on patient EEG recordings were investigated using band-power, functional connectivity and graph theory measures. Carbogen effect was quantified by measuring effect size (Cohen's d) between "before", "during" and "after" carbogen delivery states. RESULTS: Carbogen's apparent effect on EEG band-power and network metrics across all patients for "before-during" and "before-after" inhalation comparisons was inconsistent across the five patients. CONCLUSION: The changes in different measures suggest a potentially non-homogeneous effect of carbogen on the patients' EEG. Different aetiology and duration of the inhalation may underlie these non-homogeneous effects. Tuning the carbogen parameters (such as ratio between CO2 and O2, duration of inhalation) on a personalised basis may improve seizure suppression in future.

The del/del genotype of the nuclear factor-kappaB -94ATTG polymorphism and its relation to aggressive periodontitis.

BACKGROUND AND OBJECTIVE: Periodontitis is influenced by specific host-dependent immune responses. Periodontopathogens induce innate immune responses, amongst others, via toll-like receptor 2 (TLR2), resulting in activation of the nuclear transcription factor nuclear factor-kappaB (NF-kappaB). The aim of this case-control study was to evaluate links between genetic variants of these genes and chronic/aggressive periodontitis in a multivariate model. MATERIAL AND METHODS: A total of 141 patients with periodontitis (63 with chronic periodontitis and 78 with aggressive periodontitis) and 81 controls without periodontitis were included in the study. Polymorphisms in TLR2 (Arg677Trp, Arg753Gln) and in NF-kappaB (-94ins/delATTG) were determined by restriction fragment length polymorphism and fragment length analyses, respectively. Subgingival bacterial colonization was evaluated using a PCR/DNA probe test (micro-Ident). RESULTS: Although there was no association of the TLR2 polymorphism Arg753Gln with periodontitis, heterozygous carriers (Arg/Gln) were at a higher risk for colonization with bacteria of the 'red complex' (corrected p-value = 0.042). The del/del genotype of the NF-kappaB polymorphism was associated with aggressive periodontitis considering age, gender, smoking and approximal plaque index as potential confounders (odds ratio = 2.81, p = 0.035, 95% confidence interval: 1.08-7.33). del/del carriers had a higher risk for subgingival colonization with Aggregatibacter actinomycetemcomitans (odds ratio = 2.36, p = 0.030, 95% confidence interval: 1.09-5.1; adjusted for age, gender, smoking and pocket depth(bacteria)). CONCLUSIONS: The del/del genotype of NF-kappaB was shown to be associated with the occurrence of aggressive periodontitis.

Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy.

Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs1, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. 2) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.

Interleukin-2 -330 and 166 gene polymorphisms in relation to aggressive or chronic periodontitis and the presence of periodontopathic bacteria.

BACKGROUND AND OBJECTIVE: As a pro-inflammatory cytokine, interleukin-2 mediates the activation, growth and differentiation of T and B lymphocytes and natural killer cells. Promoter polymorphisms of the interleukin-2 gene have been associated with altered interleukin-2 production or identified as prognostic markers for various infectious diseases. Therefore, the aim of this study was to evaluate two polymorphisms at positions -330 T/G and 166 G/T in patients with generalized chronic periodontitis (n = 58) or generalized aggressive periodontitis (n = 73) in comparison with periodontitis-free controls (n = 69). MATERIAL AND METHODS: Both interleukin-2 polymorphisms were analyzed using the polymerase chain reaction with sequence-specific primers. Distributions of single alleles, genotypes and haplotypes were calculated using the chi-square test. Risk factor analyses were carried out by logistic regression with respect to established cofactors for periodontitis. The presence of subgingival bacteria in an individual were analyzed using a molecular biological method (the micro-Ident test). RESULTS: The interleukin-2 genotype -330 TG occurred less frequently in patients with chronic periodontitis (25.9% vs. 49.3%). Moreover, this genotype decreased the adjusted odds ratio for chronic periodontitis (odds ratio = 0.394), whereas the interleukin-2 genotype 166 TT and the haplotype combination interleukin-2 -330,166 TT : TT were associated with an increased adjusted odds ratio (odds ratio = 2.82 or 2.97). For the latter interleukin-2 combination, a positive association for the subgingival presence of Porphyromonas gingivalis (81.3% vs. 59.5%) and bacteria of the 'red complex' (78.1% vs. 56.0%) was shown. CONCLUSION: The interleukin-2 genotypes -330 TG and 166 TT, as well as the combination genotype interleukin-2 TT : TT, could be putative prognostic factors for chronic periodontitis.

The interleukin-10 promoter haplotype ATA is a putative risk factor for aggressive periodontitis.

BACKGROUND AND OBJECTIVE: Interleukin-10 has been described as an anti-inflammatory cytokine and a B-cell proliferation factor. Promoter polymorphisms of the interleukin-10 gene have been associated with altered interleukin-10 expression. Therefore, the aim of this study was to evaluate three polymorphisms at positions -1082G>A, -819C>T and -590C>A in patients with generalized chronic periodontitis (n = 27) and generalized aggressive periodontitis (n = 32) in comparison with periodontitis-free controls (n = 34). MATERIAL AND METHODS: Interleukin-10 promoter polymorphisms were analyzed by polymerase chain reaction with sequence-specific primers (PCR-SSP). Distributions of single alleles, genotypes and haplotypes were calculated by the chi-square test. Risk factor analyses were carried out by logistic regression. Subgingival bacteria were subjected to molecular biological analyses using the micro-Ident test. RESULTS: The combination ATA/ATA was found only in patients with aggressive periodontitis (15.6 vs. 0.0%, p = 0.023). Taking into account age, gender, smoking and plaque level, an increased odds ratio (3.7, p = 0.04) for aggressive periodontitis was shown for subjects with the haplotype ATA. Prevotella intermedia was found to be decreased in ACC- positive (41.3 vs. 66.7%, p = 0.022), ATA-positive (33.3 vs. 57.1%, p = 0.032) and ACC/ATA-positive (20.0 vs. 55.9%, p = 0.002) individuals. In GCC/GCC-positive subjects, P. intermedia occurred more frequently (86.7 vs. 42.3%, p = 0.002). CONCLUSION: The haplotype ATA, which is known as a 'low interleukin-10 producer' is a putative risk indicator for generalized aggressive periodontitis.

Impact of genetic variants of CD14 and TLR4 on subgingival periodontopathogens.

CD14 and toll-like receptor 4 (TLR4) are involved in host's immune response to bacterial pathogens including periodontal bacteria. Functional important gene polymorphisms are described for both genes. The aim of this study was to evaluate links between genetic polymorphisms of CD14 and TLR4 and risk markers of periodontitis in a multivariate model. One hundred and thirty-three periodontitis patients (chronic: n = 60, aggressive: n = 73) and 80 healthy controls without periodontitis were included in the study. Polymorphisms in CD14 c.-159C>T and in TLR4 Asp299Gly, Thr399Ile were determined by restriction fragment length polymorphism analyses. The clinical investigation included smoking status, plaque and bleeding indexes, pocket depth and attachment loss. Subgingival bacterial colonization was analysed molecularbiologically using the micro-Ident test. Prevotella intermedia occurred less frequently in individuals positive for the TT genotype of CD14 in bivariate analysis (odds ratio = 0.36%, confidence interval: 0.14-0.91, P = 0.045). In binary logistic regression analyses, the occurrence of this bacterium was significantly decreased in TT carriers (odds ratio = 0.31%, confidence interval: 0.81-0.12, P = 0.017) considering age, smoking and maximum clinical attachment loss at microbial test site as confounding factors. However, no significant association with chronic and or aggressive periodontitis and polymorphisms in CD14 and TLR4 could be proven. Although the CD14 c.-159C>T polymorphism could be shown to be associated with subgingival colonization with P. intermedia, there is no evidence that CD14 and TLR4 polymorphisms investigated are independent risk factors for chronic or aggressive periodontitis in German periodontitis patients.

[Pulmonary auscultation in the era of evidence-based medicine]. / L'auscultation pulmonaire à l'ère de la médecine factuelle.

BACKGROUND: Distinction between normal and abnormal respiratory sounds is important for accurate diagnosis. CURRENT DATA: This paper describes the state of the art, scientific publications and ongoing research related to the respiratory sounds. The study includes a description of the various techniques that are being used to record auscultatory sounds and a physical description of known pathological sounds (wheezes and crackles) for which automatic detection tools have been developed. VIEWPOINTS: The next stage will include exploiting all the qualities of the sounds. This augmentation of the spectrum studied, linked to signal analysis techniques, will allow the definition of new characteristic markers.

The mitochondrial permeability transition pore and nitric oxide synthase mediate early mitochondrial depolarization in astrocytes during oxygen-glucose deprivation.

Recent studies suggest that the degree of mitochondrial dysfunction in cerebral ischemia may be an important determinant of the final extent of tissue injury. Although loss of mitochondrial membrane potential (psi(m)), one index of mitochondrial dysfunction, has been documented in neurons exposed to ischemic conditions, it is not yet known whether astrocytes, which are relatively resistant to ischemic injury, experience changes in psi(m) under similar conditions. To address this, we exposed cortical astrocytes cultured alone or with neurons to oxygen-glucose deprivation (OGD) and monitored psi(m) using tetramethylrhodamine ethyl ester. Both neurons and astrocytes exhibited profound loss of psi(m) after 45-60 min of OGD. However, although this exposure is lethal to nearly all neurons, it is hours less than that needed to kill astrocytes. Astrocyte psi(m) was rescued during OGD by cyclosporin A, a permeability transition pore blocker, and (G)N-nitro-arginine, a nitric oxide synthase inhibitor. Loss of mitochondrial membrane potential in astrocytes was not accompanied by depolarization of the plasma membrane. Recovery of astrocyte psi(m) after reintroduction of O(2) and glucose occurred over a surprisingly long period (>1 hr), suggesting that OGD caused specific, reversible changes in astrocyte mitochondrial physiology beyond the simple lack of O(2) and glucose. Decreased psi(m) was associated with a cyclosporin A-sensitive loss of cytochrome c but not with activation of caspase-3 or caspase-9. Our data suggest that astrocyte mitochondrial depolarization could be a previously unrecognized event early in ischemia and that strategies that target the mitochondrial component of ischemic injury may benefit astrocytes as well as neurons.

Physicians' attitudes about prescribing and knowledge of the costs of common medications.

BACKGROUND: Compliance with medical therapy is often compromised because patients cannot afford to pay for medications. Inadequate physician knowledge of drug costs may unwittingly contribute to this problem. OBJECTIVE: To measure attitudes about prescribing and knowledge of medication costs and compare differences among attending physicians and residents. DESIGN/PARTICIPANTS: Written survey of internal medicine house staff and general medicine attending physicians in an urban hospital-based primary care center. RESULTS: One hundred thirty-four of 189 physicians responded (71% response rate). Seventy percent of respondents were house officers and 30% were attending physicians. Eighty-eight percent of physicians felt the cost of medicines was an important consideration in the prescribing decision, and 71% were willing to sacrifice some degree of efficacy to make drugs more affordable for their patients. However, 80% often felt unaware of the actual costs. Only 33% had easy access to drug cost data, and only 13% had been formally educated about drug costs. Regarding insurance coverage, 94% of physicians gave strong consideration to the cost of medications when patients were self-paying, 68% when patients had Medicare, and 30% when patients had Medicaid or were participants in a health maintenance organization with a prescription plan. Physicians' estimates of the cost of a month's supply of 33 commonly used medications were accurate in 45% of cases, too low for 40%, and too high for 15%. The costs of brand-name and expensive drugs were most likely to be underestimated. House officers were less cost-conscious than attending physicians. CONCLUSIONS: Physicians were predisposed to being cost-conscious in their prescribing habits, but lacked accurate knowledge about actual costs and insurance coverage of drugs. Interventions are needed to educate physicians about drug costs and provide them with reliable, easily accessible cost information in real-world practice.

Deletion of 11 amino acids in tuberin associated with severe tuberous sclerosis phenotypes: evidence for a new essential domain in the first third of the protein.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder displaying a large spectrum of symptoms. Linkage studies have shown two loci, TSC1 in 9q34 and TSC2 in 16p13.3, to be involved in the disease. The TSC2 gene, composed of 41 exons, has been isolated and is shown to encode a protein, tuberin, from a 5.5-kb transcript. Mutation screening for both clinical diagnosis and identification of functional domains within the tuberin is in progress. In this study we identify a 33-bp in-frame deletion (1462del33) in the mRNA which segregates in two unrelated French families with severe TSC phenotypes. The corresponding 11 amino acids deletion (aa 482-492) is shown to result from two different splice site mutations at exon 14 and, when compared with the position of two previously described missense mutations, indicates a novel functionally important region of the protein.

Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours.

Alkylphosphocholines are a novel class of antitumour agents structurally related to ether lipids that interact with the cell membrane and influence intracellular growth signal transduction pathways. We performed a phase I trial with an analogue of miltefosine, perifosine (D-21266), which was expected to induce less gastrointestinal toxicity. Objectives of the trial were: to determine the maximum-tolerated dose (MTD) for daily administration, to identify the dose-limiting toxicity (DLT) of this schedule, to assess drug accumulation and to determine the relevant pharmacokinetic parameters. 22 patients with advanced solid tumours were treated at doses ranging from 50 to 350 mg/day for 3 weeks, followed by 1 week of rest. Toxicity consisted mainly of gastrointestinal side-effects: nausea was reported by 11 patients (52%, 10 patients Common Toxicity Criteria (CTC) grades 1-2 and 1 patient CTC grade 3), vomiting by 8 (38%, all CTC grades 1-2), and diarrhoea by 9 (43%, 8 patients CTC grades 1-2 and 1 patient CTC grade 3). The severity of these side effects appeared to increase with increasing doses. Another common side-effect was fatigue, occurring in 9 patients (43%). No haematology toxicity was observed. Dose-limiting toxicity (DLT) was not reached, but gastrointestinal complaints led to an early treatment discontinuation in an increasing number of patients at the higher dose levels. Therefore, MTD was established at 200 mg/day. The pharmacokinetic studies suggested dose proportionality.