Estimation of the biophase concentration of noradrenaline at presynaptic α2-adrenoceptors in brain slices

Summary The aim of the present study was to determine the local concentrations of noradrenaline existing at presynaptic ₂-adrenoceptors during electrical pulse train stimulation of brain slices at different frequencies. The experiments are based on the assumption that the concentration of released noradrenaline at the ₂-adrenoceptors exerting a certain autoinhibition should be equal to the concentration of exogenous noradrenaline causing the same inhibition under conditions in which any influence of the released transmitter is excluded. In order to avoid autoinhibition, hippocampus and cortex slices of the rabbit and the rat, prelabelled with [³H]noradrenaline and superfused in presence of an uptake inhibitor, were electrically stimulated using 4 pulses delivered at 100 Hz (POP stimulation). Exogenous noradrenaline diminished the overflow of tritium elicited by POP stimulation in a concentration-dependent manner. In rabbit brain tissues the EC₅₀ value and maximum inhibition of noradrenaline release were found to be approximately 6 nmol/l and more than 95%, respectively, whereas in rat tissues the corresponding values were between 20 and 30 nmol/l and approximately 90%. When electrical stimulation was performed with trains of 36 pulses delivered at 0.1, 0.3 or 3 Hz in absence or presence of an uptake inhibitor, the ₂-adrenoceptor antagonist yohimbine (1 or 10 mol/l) enhanced the evoked tritium overflow in a manner which was dependent on the frequency of stimulation and on blockade of the re-uptake mechanism. The facilitatory effects of yohimbine reflected an extent of autoinhibition which was between 53% (36 pulses/0.1 Hz, no uptake inhibitor) and 85% (36 pulses/3 Hz, uptake inhibitor present) in rabbit and between 16% (36 pulses/0.3 Hz, no uptake inhibitor) and 71% (36 pulses/3 Hz, uptake inhibitor present) in rat brain slices. Accordingly, the corresponding estimated biophase concentrations of noradrenaline were generally higher in rat than in rabbit tissues (they were between 32.5 and 74.5 or 5.1 and 51.6 nmol/l in the presence or absence of an uptake inhibitor, respectively, in the rat, and between 15 and 23.1 or 6.1 and 18.6 nmol/l in the rabbit). The observed frequency dependence of the effect of re-uptake blockade on the calculated biophase concentrations of noradrenaline would be compatible with the idea of a dependence of the effectiveness of the re-uptake mechanism on the firing rate of the neurone in being more effective at lower frequencies. Moreover, the stikingly low biophase concentrations of noradrenaline suggest that also in brain tissue noradrenaline causes lateral inhibition of release as has recently been shown for guinea-pig vas deferens. Send offprint requests to C. Allgaier at the above address     

Technetium-99m-MRP20, a potential brain perfusion agent: in vivo biodistribution and SPECT studies in non-primate animals

MRP20 (N-(2(1H pyrolylmethyl]N'-(4-pentene-3-one-2] ethane-1,2-diamine) complexes with technetium-99m, yielding a neutral, lipophilic species. This compound has been characterized as [TcO(MRP20)]. Biologic investigation of [99mTc][TcO(MRP20)] in female rats showed 2.35% ID in the brain 30 min p.i. with no significant wash-out over 3 hr. A single-photon emission computed tomography (SPECT) study in a dog demonstrated rapid tracer uptake in the brain, reaching a maximum within 1 min, with 2.24% i.d. 15 min p.i., decreasing to 1.7% after 4 hr. The complex undergoes hydrolysis in vitro forming a cationic species. This is possibly the trapping mechanism in the brain in vivo. The main excretory route of [99mTc][TcO(MRP20)] is via the hepatobiliary tract. There is evidence of some "in vivo" cell labeling and soft-tissue uptake.     

Research and the clinical dietitian: perceptions of the research process and preferred routes to obtaining research skills

The art and science of dietetics are rooted in research, yet clinical dietitians do not generally participate in the research process. Focus group methodology was used to identify clinical dietitians' perceptions about incorporating research into clinical practice and to identify potential barriers to participation in research. In a series of 9 focus group sessions with 50 registered dietitians and 3 dietetic interns, attendees recognized the importance that research findings play in their practice. Barriers such as lack of time and low comfort levels with initiating and conducting research were discussed, and possible solutions to these barriers were suggested. Collaboration with academic dietitians or with research mentors was viewed as a useful and realistic pathway to increased participation in the research process. According to participants, increased involvement in research could also be facilitated by a supportive administrative structure within the facility, clinical management that is supportive of the research process, and collaboration among members of the dietetics staff. The findings of this qualitative investigation indicate that the central tenet of successful integration of clinical practice and research is collaboration-within dietetics departments, across the strata of facilities, and in particular, between clinical and research-oriented registered dietitians.     

Immunogenicity and reactogenicity of a Haemophilus influenzae type b tetanus conjugate vaccine when administered separately or mixed with concomitant diphtheria-tetanus-toxoid and acellular pertussis vaccine for primary and for booster immunizations

With an increasing number of new vaccines available for routine childhood immunization, combination vaccines are needed in order to maintain or achieve a high compliance with recommended immunization programmes. In a prospective, randomized, comparative, multi-centre study, 822 healthy infants were enrolled to receive three doses of either a candidate or a commercially available Haemophilus influenzae type b (Hib) vaccine concomitantly with diphtheria-, tetanus- acellular pertussis (DTaP) vaccine. Study subjects were randomly allocated to one of the following groups: (1) separate, or (2) mixed injection of DTaP and candidate Hib vaccine, or (3) separate injection of DTaP and commercial Hib vaccine. One year later the first 189 study subjects received either separate or mixed injections of the same Hib and DTaP vaccines as booster doses. Evaluation of reactogenicity was based on diary cards completed by parents. Immunogenicity was documented by measuring IgG antibody concentrations in serum samples taken before and 4 weeks after primary and booster vaccination. No serious adverse events occurred and most local and systemic reactions were mild to moderate. Booster doses were more reactogenic than primary doses with all groups. Antibody concentrations against pertussis antigens were similar to those seen with DTaP alone. All but one subject had protective antibody concentrations against diphtheria and tetanus. Primary immune response to the Hib vaccine was significantly lower in the group receiving the mixed Hib-DTaP vaccine, however, ≥95% of vaccinees had anti-Hib antibody concentrations ≥0.15 μg/ml and there was a marked booster response (>100-fold) in all groups. Conclusions Mixing DTaP and Hib vaccines for primary immunization caused a decrease in anti-Hib antibody response, although after primary immunization as after booster doses, all subjects showed antibody concentrations considered to be protective for invasive Hib disease. Mixing of the vaccines did not result in increased reactogenicity. Received: 13 June 1997 / Accepted in revised form: 4 September 1997     

Brain trauma in aged transgenic mice induces regression of established abeta deposits

Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known if TBI affects the progression of AD. To address this question, we studied the neuropathological consequences of TBI in transgenic (TG) mice with a mutant human Abeta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter resulting in overexpression of mutant APP (V717F), elevated brain Abeta levels, and AD-like amyloidosis. Since brain Abeta deposits first appear in 6-month-old TG (PDAPP) mice and accumulate with age, 2-year-old PDAPP and wild-type (WT) mice were subjected to controlled cortical impact (CCI) TBI or sham treatment. At 1, 9, and 16 weeks after TBI, neuron loss, gliosis, and atrophy were most prominent near the CCI site in PDAPP and WT mice. However, there also was a remarkable regression in the Abeta amyloid plaque burden in the hippocampus ipsilateral to TBI compared to the contralateral hippocampus of the PDAPP mice by 16 weeks postinjury. Thus, these data suggest that previously accumulated Abeta plaques resulting from progressive amyloidosis in the AD brain also may be reversible.     

Association of Paclitaxel pharmacokinetics with the development of peripheral neuropathy in patients with advanced cancer.

PURPOSE: The shortening of infusion time from 3 to 1 hour decreases the systemic exposure (area under the curve, AUC) of total and unbound paclitaxel but increases the AUC of its vehicle Cremophor EL, whereas the time above total paclitaxel concentrations of 0.05 micromol/L (T >0.05) remains almost constant. As both Cremophor EL and paclitaxel are neurotoxic, we evaluated their pharmacodynamic effects on the development of peripheral neuropathy as the most important nonhematologic toxicity. EXPERIMENTAL DESIGN: Patients with advanced cancer of different origin were randomized to receive a maximum of 12 weekly-given 1- or 3-hour infusions of 100 mg/m2 paclitaxel (Taxol). Twenty-four patients were assessable for both pharmacokinetics and peripheral neuropathy development evaluated by a clinical scoring system including sensory symptoms, strength, tendon reflexes, and vibratory sense. RESULTS: Patients with peripheral neuropathy development (n=14) received more weeks of therapy (P=0.056) and showed significantly higher T(>0.05) (P=0.022) and overall systemic drug exposures (weeks of therapy x AUC) for total paclitaxel (P=0.002) and unbound paclitaxel (P=0.003) than those without peripheral neuropathy. In Kaplan-Meier analyses, T(>0.05) > or = 10.6 hours (P=0.023), AUC of total paclitaxel > or = 4.7 microg/mL x hour (P = 0.047), and AUC of unbound paclitaxel > or = 0.375 microg/mL x hour (P = 0.095) were identified as being potential factors for peripheral neuropathy development. In a Cox regression analysis, only T(>0.05) > or = 10.6 hours remained as an independent risk factor (relative risk, 18.43; P = 0.036) after adjusting for prior vincamycin (relative risk, 11.28; P = 0.038). CONCLUSIONS: From the results obtained in this study, it is concluded that exposure to paclitaxel but not Cremophor EL is associated with peripheral neuropathy development.     

Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women.

PURPOSE: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. EXPERIMENTAL DESIGN: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [-889 C/T polymorphism of the IL1alpha gene (IL1A), -511 C/T polymorphism of the IL1beta promoter (IL1B promoter), a polymorphism of IL1beta exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the -174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. RESULTS: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. CONCLUSIONS: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.     

Epidemiology of Travelers— Diarrhea: Details of a Global Survey

Background Recent epidemiologic data on travelers— diarrhea (TD) are essential for the evaluation of conventional and future prophylactic and therapeutic measures.
Methods To determine the epidemiology, including risk factors, impact and quality-of-life evaluation of TD, a cross-sectional survey was conducted over 12 months at the airports of Mombasa (Kenya), Goa (India), Montego Bay (Jamaica) and Fortaleza (Brazil) by distributing questionnaires to visitors just prior to their flying home. The study period was March 1996 to July 1998.
Results Overall, 73,630 short-term visitors completed a questionnaire. The total diarrhea attack rate varied between a high of 54.6% in Mombasa and a low of 13.6% in Fortaleza, but only between 31.5% and 5.4% of all travelers had classic TD. The 14-day incidence rates varied between 19.5% and 65.7%. Few travelers meticulously avoided potentially dangerous food items, although in India and Kenya most travelers avoided those considered most dangerous. Risk factors were stays exceeding 1 week, age between 15 and 30 years, and residence in the UK. The impact, measured as incapacity or quality-of-life scores, was very considerable.
Conclusions TD continues to affect vacationers and business travelers as frequently as it did some 20 years ago. Compliance with recommendations to reduce exposure to pathogens by avoiding dangerous food items is poor among travelers from all countries. Implementation of food safety education programs may be difficult to achieve.