Tau immunoreactivity detected in human plasma, but no obvious increase in dementia

Tau proteins are central to the neuropathology of Alzheimer's disease and tau levels in cerebrospinal fluid are elevated in affected individuals. In this study, we investigated the presence of tau in plasma from subjects with Alzheimer's disease (n = 16), frontotemporal dementia (n = 10), vascular dementia (n = 16) and from healthy controls (n = 15). By using an ELISA with monoclonal tau antibodies, tau immunoreactivity was detected in approximately 20% of the subjects. However, no difference between the disease and control groups was seen. After gel filtration of tau immunopositive plasma, the peak reactivity was found in the 160-kD fraction, indicating the source to be tau-like molecules of high-molecular-weight or polymers of low-molecular-weight tau isoforms. We conclude that measurements of tau in plasma cannot be utilized diagnostically for Alzheimer's disease or for the other dementias investigated. Copyrightz1999S.KargerAG,Basel     

Alpine skiing and acute beta-blockade

The effect of acute unselective (propranolol) and beta 1-selective (atenolol) beta-adrenoceptor blockade was studied on alpine skiing in six leisure and seven elite skiers. Prior to the skiing tests a short time "all out" cycle ergometer test (Wingate muscle power test) was performed to confirm whether a beta-blocking effect (80 mg propranolol and 100 mg atenolol orally) was present or not. Peak and average power of the Wingate test showed an impairment in the order of 4%--6% (P less than 0.05--0.001). Peak blood lactate was only reduced after propranolol (0.05 greater than P greater than 0.01). During leisure skiing under submaximal exercise conditions peak blood lactate was increased (P less than 0.05) as compared to placebo, but rated perceived exertion (RPE) was unchanged as well as the estimated skiing technique. The elite skiers showed prolonged performance times (P less than 0.05) after beta-blockade and in the case of propranolol also reduced peak and mean blood lactates (P less than 0.05). It is suggested that during intense exercise propranolol reduced lactate formation, which is in line with previous reports. This might impair short time, "explosive" type muscular exercise. If there is a risk factor for injury during beta-blockade and alpine skiing, it might be connected to the impaired performance and metabolism in relation to intense exercise and propranolol treatment.     

Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist

BACKGROUND AND PURPOSE: Based on neuroprotective efficacy in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a studies. METHODS: Two pivotal phase 3 ischemic stroke trials tested the hypothesis, by double-blind, randomized, placebo-controlled parallel design, that a single intravenous 1.5 mg/kg dose of Selfotel, administered within 6 hours of stroke onset, would improve functional outcome at 90 days, defined as the proportion of patients achieving a Barthel Index score of >/=60. The trials were performed in patients aged 40 to 85 years with acute ischemic hemispheric stroke and a motor deficit. RESULTS: The 2 trials were suspended on advice of the independent Data Safety Monitoring Board because of an imbalance in mortality after a total enrollment of 567 patients. The groups were well matched for initial stroke severity and time from stroke onset to therapy. There was no difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83; P=0.15). However, early mortality was higher in the Selfotel-treated patients (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke, mortality imbalance was significant throughout the trial (P=0.05). CONCLUSIONS: Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggests that the drug might have a neurotoxic effect in brain ischemia.     

The CINOD, AZD3582, exhibits an improved gastrointestinal safety profile compared with naproxen in healthy volunteers

COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs in development for the treatment of acute and chronic pain. They comprise a COX-inhibiting moiety linked to a nitric-oxide-donating component and are designed to provide an innovative mechanism of action of balanced COX inhibition and controlled nitric oxide donation. Through these pathways, CINODs should provide analgesic and anti-inflammatory efficacy, while offering gastrointestinal safety through the tissue-protective effects of nitric oxide donation. AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] is the first agent in the CINOD class to enter extensive clinical development. Pre-clinical studies demonstrate that AZD3582 has a superior gastrointestinal safety profile to naproxen, while demonstrating analgesic and anti-inflammatory efficacy. In healthy human volunteers, AZD3582 caused little gastrointestinal damage compared with equimolar doses of naproxen. Studies to evaluate the longer-term gastrointestinal safety of AZD3582, alongside its efficacy in alleviating chronic and acute pain, are ongoing.     

Intensity modulated radiation therapy with electrons using algorithm based energy/range selection methods.

BACKGROUND AND PURPOSE: In recent years photon intensity modulated radiation therapy (IMRT) has gained attention due to its ability to improve conformity of dose distributions. A potential advantage of electron-IMRT is that the dose fall off in the depth dose curve makes it possible to modulate the dose distribution in the direction of the beam by selecting different electron energies. This paper examines the use of a computer based energy selection in combination with the IMRT technique to optimise the electron dose distribution. MATERIALS AND METHODS: One centimetre square electron beamlets ranging from 2.5 to 50 MeV were pre-calculated in water using Monte Carlo methods. A modified IMRT optimisation tool was then used to find an optimum mix of electron energies and intensities. The main principles used are illustrated in some simple geometries and tested on two clinical cases of post-operated ca. mam. RESULTS: It is clearly illustrated that the energy optimisation procedure lowers the dose to lung and heart and makes the dose in the target more homogeneous. Increasing the energy at steep gradients compensates for lack of target coverage at beam edges and steep gradients. Comparison with a clinically acceptable four segment plan indicates the advantage of the used electron IMRT technique. CONCLUSIONS: Using an intensity optimised mix of computer selected electron energies has the potential to improve electron treatments for mastectomy patients with good target coverage and reduced dose to normal tissue such as lung and heart.     

No association between immunohistochemical expression of p53, c-erbB-2, Ki-67, estrogen and progesterone receptors in female papillary thyroid cancer and ionizing radiation

An association has previously been reported between exposure to medical diagnostic ionizing radiation and papillary thyroid cancer in women. To further evaluate potential mechanisms in carcinogenesis, the expression of p53, c-erbB-2, as well as Ki-67, estrogen and progesterone receptors were analyzed by immunohistochemistry in 19 women exposed to X-rays and for comparison in nine women without such reported exposure. They all had papillary thyroid cancer. No difference was found between these groups. The results of this study showed that p53, c-erbB-2, Ki-67, estrogen and progesterone receptors are not involved in papillary thyroid cancer associated with exposure to medical diagnostic ionizing radiation.     

Beta-cell activity and destruction in type 1 diabetes

Type 1 diabetes is the result of a chronic inflammatory process that causes elimination of insulin-producing beta-cells, resulting in insulin deficiency and hyperglycemia. The destruction is thought to be mediated by an autoimmune process involving cytotoxic T cells recognizing beta-cell autoantigens in the context of MHC class I-peptide complexes. Autoantibodies against insulin, glutamic acid decarboxylase (GAD) and and ICA 512 protein tyrosine phosphatase are frequently found. At the clinical onset of diabetes, some beta-cells remain and after initiation of insulin treatment, most patients enter a period of remission, a phenomenon that may reflect diminished autoimmune activity in the islets. There is evidence to suggest that a further loss of beta-cells can be curtailed, and that patients, who maintain endogenous insulin production, have better glycemic control and less risk of complications. This is the basis for our current research. We are characterizing the remission phenomenon in epidemiological studies in order to identify determinants of beta-cell survival. In randomized, prospective multicenter trials, we are evaluating the benefit of beta-cell secretory rest for rescue of insulin production in patients at onset of clinical disease. In experimental studies, we are investigating expression and regulation of the key molecules of an autoimmune process in the islets. Further, selective beta-cell damage is induced in rat islets and measures to enhance beta-cell resistance and repair are being examined. We have recently identified a remarkable, beta-cell protective effect of K(ATP)-channel opening.     

Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel.

PURPOSE: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). EXPERIMENTAL DESIGN: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m(2)). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with one-way ANOVA. RESULTS: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium. The population typical value of clearance of unbound paclitaxel was 301 L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. CONCLUSIONS: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics.     

Influence of <Emphasis Type="Italic">CYP2B6</Emphasis> 516G>T polymorphism and interoccasion variability (IOV) on the population pharmacokinetics of efavirenz in HIV-infected South African children

Objective

To investigate the influence of CYP2B6 516G>T polymorphism, as a covariate, and of interoccasion variability (IOV) on the oral clearance (CL/F) of efavirenz (EFV) in treatment-naïve black South African children over a period of 24 months post-antiretroviral therapy (ART) initiation.

Methods

HIV-infected black children (n?=?60, aged 3–16 years), with no prior exposure to ART, eligible to commence ART and attending an outpatient clinic were enrolled into this study. Blood samples were taken at mid-dose interval at 1, 3, 6, 12, 18 and 24 months post-ART initiation. EFV plasma samples were determined with an adapted and validated LC/MS/MS method. Genotyping of the CYP2B6 G516T single nucleotide polymorphism (SNP) was performed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). NONMEM was used for the population pharmacokinetic modelling.

Results

EFV concentrations below 1 μg/mL accounted for 18% (116/649), EFV concentrations >4 μg/mL accounted for 29.5% (192/649) and concentrations within the therapeutic range (1–4 μg/mL) represented 52.5% (341/649) of all the samples determined. The covariates age, weight and CYP2B6 G516Tgenotype were included in the final model with population estimates for CL/F determined as 2.46, 4.60 and 7.33 L/h for the T/T, G/T and G/G genotype groups respectively.

Conclusions

The inclusion of both age and weight to predict accurate EFV CL values for the respective genotype groups within this paediatric population was required, whereas the addition of gender and body surface area did not improve the predictions. The importance of introducing IOV in a PK model for a longitudinal study with sparsely collected data was again highlighted by this investigation.

     

Hearing-related,health-related quality of life in patients who have undergone otosclerosis surgery: A long-term follow-up study

Objectives: The aims of the study were to assess health-related quality of life and hearing-related disability in subjects with otosclerosis 30 years after surgery. Design: An observational study was performed. Medical records were reviewed, a clinical examination as well as audiometric assessments were performed. Generic health-related quality of life was assessed by the SF-36v2 and hearing disability by a shortened version of SSQ (speech spatial and qualities of hearing scale). Study sample: Sixty-five individuals, who had undergone stapedectomy in 1977-79 at a tertiary referral center. Results: Generic health-related quality of life according to SF-36 subscale scores was comparable to that of an age- and sex-matched reference population. The SF-36 mental component summary score (MCS) was, however, significantly better than that of the reference population. The mental and physical summary component scores correlated significantly to hearing disability measured by the SSQ but not to hearing impairment. Hearing disability was displayed in all SSQ sub-scores, especially in more complex listening situations and in the localization of sounds. Conclusions: This study shows that individuals with otosclerosis, 30 years after surgery, have a good generic health-related quality of life, despite moderate to severe hearing loss and significant hearing disabilities.