Production and characterisation of mucoadhesive nanosuspensions for the formulation of bupravaquone

Bupravaquone is a new naphthoquinone antibiotic against Cryptosporidium parvum and other parasites. It has attracted interest for the treatment of C. parvum infections, because of the lack of a drug in the treatment of mostly AIDS patients. The bioavailability of bupravaquone is limited when given orally. To overcome the problem of the high elimination rate caused by diarrhoea, typical for C. parvum infections, bupravaquone was formulated as a mucoadhesive nanosuspension, i.e. combining the properties of mucoadhesive drug delivery systems, in this case hydro gels, with nanosuspensions. In this study different polymers/hydro gels were employed to create a prolonged retention time for the drug in the infected gastrointestinal tract (GIT). The second step to improve the bioavailability of bupravaquone was the formulation as nanosuspension. Therefore various concentrations of bupravaquone with different surfactants were tested. The production of these nanosuspensions was carried out by high pressure homogenisation. In addition to the classical stepwise production, about a new one step production method is described.     

Personality traits in young patients with Parkinson's disease

OBJECTIVES: It has been hypothesized that the dopaminergic deficit of older patients with Parkinson's disease (PD) is associated with a reduction in the dopamine-dependent personality trait "novelty seeking". It is unknown whether this may also be found in younger patients with PD whose dopaminergic deficit is considered to be purely motor. MATERIAL AND METHODS: We interviewed 122 patients below 51 years of age and 122 age- and sex-matched healthy controls with regard to clinical and sociodemographic data. Both groups had to fill out the Tridimensional Personality Questionnaire (TPQ) of Cloninger. Neuropsychological testing of formal intelligence and depression was also applied. RESULTS: "Novelty seeking" was not different between both groups. Patients were more often depressed than controls, explaining their difference in "harm avoidance" on the TPQ. "Persistence", a sub-scale of the third TPQ dimension "reward dependence", was significantly higher in patients. Neither sex, nor age, nor educational status were correlated with one of the three personality traits. CONCLUSIONS: The higher rate of depression explains our finding of more "harm avoidance" among young PD patients. According to a literature review the choice and performance of controls is crucial whether personality traits in PD patients may be assessed as abnormal.     

Regional dendritic and spine variation in human cerebral cortex: a quantitative golgi study

The present study explored differences in dendritic/spine extent across several human cortical regions. Specifically, the basilar dendrites/spines of supragranular pyramidal cells were examined in eight Brodmann's areas (BA) arranged according to Benson's (1993, Behav Neurol 6:75-81) functional hierarchy: primary cortex (somatosensory, BA3-1-2; motor, BA4), unimodal cortex (Wernicke's area, BA22; Broca's area, BA44), heteromodal cortex (supple- mentary motor area, BA6beta; angular gyrus, BA39) and supramodal cortex (superior frontopolar zone, BA10; inferior frontopolar zone, BA11). To capture more general aspects of regional variability, primary and unimodal areas were designated as low integrative regions; heteromodal and supramodal areas were designated as high integrative regions. Tissue was obtained from the left hemisphere of 10 neurologically normal individuals (M(age) = 30 +/- 17 years; five males, five females) and stained with a modified rapid Golgi technique. Ten neurons were sampled from each cortical region (n = 800) and evaluated according to total dendritic length, mean segment length, dendritic segment count, dendritic spine number and dendritic spine density. Despite considerable inter-individual variation, there were significant differences across the eight Brodmann's areas and between the high and low integrative regions for all dendritic and spine measures. Dendritic systems in primary and unimodal regions were consistently less complex than in heteromodal and supramodal areas. The range within these rankings was substantial, with total dendritic length in BA10 being 31% greater than that in BA3-1-2, and dendritic spine number being 69% greater. These findings demonstrate that cortical regions involved in the early stages of processing (e.g. primary sensory areas) generally exhibit less complex dendritic/spine systems than those regions involved in the later stages of information processing (e.g. prefrontal cortex). This dendritic progression appears to reflect significant differences in the nature of cortical processing, with spine-dense neurons at hierarchically higher association levels integrating a broader range of synaptic input than those at lower cortical levels.     

Intrathecal labor analgesia with bupivacaine and sufentanil: the effect of adding 2.25 microg epinephrine

BACKGROUND AND OBJECTIVES: Epinephrine, 25 microg and 200 microg, has been found to prolong the duration of intrathecal labor analgesia when added to an opioid. In our hospital we use the standard epidural mixture, prepared by the pharmacist, containing epinephrine 1:800,000; i.e., 1.25 microg/mL for both spinal and epidural labor analgesia. We wanted to evaluate whether such a low dose, depending on its effect on duration or quality of analgesia, should be maintained or deleted in future mixtures. METHODS: Forty-five term parturients were randomly assigned to receive 1.8 mL intrathecally of a mixture containing bupivacaine 0.125% and sufentanil 0.75 microg/mL with or without epinephrine 1.25 microg/mL. The quality and duration of analgesia, side effects, and obstetric/neonatal outcome were compared. RESULTS: For both combinations, the onset until the first painless contraction was between 5 and 6 minutes. Most patients were pain free during the second uterine contraction. The duration of complete analgesia was 93.2 +/- 24.2 minutes in the epinephrine group and 79.3 +/- 18.1 minutes for patients not receiving epinephrine (P = .014). The quality of the block, bupivacaine consumption, side effects, and obstetric/neonatal outcome were not different between groups. CONCLUSIONS: It was concluded that epinephrine in a dose as low as 2.25 microg significantly prolonged the duration of intrathecal analgesia of bupivacaine-sufentanil by 15 minutes. No other differences were noticed. Diluting the commercially available bupivacaine 0.5% with epinephrine 1:200,000 may avoid the need of freshly prepared epinephrine solutions.     

Carcinomas in situ of the breast with indeterminate features: role of E-cadherin staining in categorization

Most breast carcinomas in situ (CIS) are easily categorized as ductal (DCIS) or lobular (LCIS). However, some CIS have indeterminate histologic features (CIS-IF). Prior studies have shown that E-cadherin protein expression is lost in lobular but not ductal carcinomas. Therefore, evaluation of examples of CIS-IF for E-cadherin expression by immunohistochemistry might be useful in helping to define their nature. To address this, we studied histologic features and E-cadherin expression by immunohistochemistry in 89 cases of breast CIS (28 LCIS, 33 DCIS, 28 CIS-IF). CIS-IF cases were divided into three groups based on histology: Group 1 cases had all the cytologic and architectural features typical of LCIS but showed areas of comedo-type necrosis (n = 6). Group 2 cases were CIS lesions characterized by small, uniform neoplastic cells either growing in a solid pattern with focal microacinar-like structures but with cellular dyshesion, or growing in a cohesive mosaic pattern but with occasional intracytoplasmic vacuoles (n = 17). Group 3 cases showed marked cellular pleomorphism and nuclear atypia but had the dyshesive growth pattern characteristic of LCIS (n = 5). E-cadherin staining was scored as negative, positive, or mixed (mixture of negative and positive tumor cells). All 28 cases of LCIS were E-cadherin negative, and all 33 DCIS cases were E-cadherin positive by immunohistochemistry. All cases from CIS-IF group 1 and group 3 were negative for E-cadherin, suggesting a closer kinship to LCIS than to DCIS. In contrast, CIS-IF group 2 cases were heterogeneous with respect to E-cadherin staining. Six (35.3%) cases were E-cadherin negative (more akin to LCIS), 5 (29.4%) cases were E-cadherin positive (akin to DCIS), and 6 (35.3%) cases had both E-cadherin-positive and E-cadherin-negative tumor cells, suggesting a mixed DCIS/LCIS phenotype. Our findings suggest that E-cadherin immunostaining is of value in helping to characterize breast carcinomas in situ with indeterminate features. However, validation of these observations will require clinical outcome studies.     

In vitro complement activation favoring soluble C5b-9 complex formation alters myocellular sodium homeostasis

BACKGROUND: Deranged Na(+) homeostasis in skeletal muscle is closely associated with excessive complement activation that is encountered during sepsis. Recent evidence suggests that soluble C5b-9 complexes (SC5b-9), which are readily detected in plasma during sepsis and have long been considered irrelevant nonmembrane binding end products of complement activation, may have numerous biologic effects. The purpose of this study, therefore, was to determine the effects of SC5b-9 on myocellular ion homeostasis and its mechanism(s) of action. METHODS: Hindlimb fast-twitch extensor digitorum longus (EDL) was freshly isolated from rats weighing 50 to 70 g and then incubated at 30 degrees C for 60 minutes in normal Krebs-Henseleit buffer (KHB, pH 7.4) containing 10% zymosan-activated rat serum (10 mg/mL at 37 degrees C for 60 minutes) as a source of SC5b-9. Zymosan particles were removed by centrifugation after activation to exclude any noncomplement direct effects. Heat-inactivated rat serum (56 degrees C for 30 minutes) was used as control. EDL muscle was also incubated with pertussis toxin (1 microg/mL), in Ca(2+)-free KHB, with thapsigargin (0.3 or 3 micromol/L), or with ouabain (0.01, 0.1 or 1 micromol/L) before and/or during incubation with 10% zymosan-activated or heat-inactivated rat serum. Intracellular Na(+) and K(+) contents ([Na(+)](i) or [K(+)](i)) of EDL muscle were determined by using flame photometry after washing in ice-cold Na(+)-free Tris-sucrose buffer. SC5b-9 in zymosan-activated human serum was determined by SC5b-9 enzyme-linked immunoassay. RESULTS: SC5b-9 in zymosan-activated human serum significantly increased by 400% as compared with nonactivated, normal human serum. Zymosan-activated rat serum markedly increased [Na+]i without affecting [K(+)](i) in fast-twitch EDL muscle, which was completely inhibited by pertussis toxin, removal of extracellular Ca(2+) or depletion of intracellular Ca(2+) with thapsigargin. The addition of ouabain (at micromolar concentrations) increased myocellular [Na(+)](i) and decreased myocellular [K(+)](i) in both the zymosan-activated and the heat-inactivated rat serum groups. The effects of ouabain on myocellular [Na(+)](i) and [K(+)](i) were equivalent in these 2 groups. Zymosan-activated and heat-inactivated rat serum had similar effects on myocellular [K(+)](i) in the presence or absence of pertussis toxin, removal of extracellular Ca(2+) or depletion of intracellular Ca(2+). CONCLUSIONS: Zymosan-activated rat serum (presumed SC5b-9 enriched) selectively alters Na(+) homeostasis in isolated fast-twitch skeletal muscle. The mechanisms for such effects may be linked to G-proteins, Ca(2+) flux and Na(+),K(+)-adenosine triphosphatase pump binding site blockade.     

Heart rate and mortality in a Japanese general population: an 18-year follow-up study

The predictive power of elevated heart rate for total mortality was evaluated in a Japanese general population. A total of 573 male participants, aged 40 to 64, who underwent a health examination in 1977, were followed until 1994. Heart rate (beats per minute; bpm) was measured using an electrocardiogram. During the 18 years, 82 subjects died; 18 from cerebro-cardiovascular diseases and 36 from cancer. In a multivariate proportional hazards regression model, age, elevated systolic and diastolic blood pressures, antihypertensive medication, heart rate, uric acid, vital capacity (inversely), and serum cholesterol (inversely) were significantly associated with all-cause death. Of these variables, elevated heart rate was the strongest predictor of all-cause death after adjustment for age. Resting heart rate levels were classified into five groups: < 60 (G1), 60-69 (G2), 70-79 (G3), 80-89 (G4), and > or = 90 (G5) bpm. Heart rates of 60-69 (G2) bpm showed the lowest death rate (14.3%) and heart rate > or = 90 (G5) bpm showed the highest death rate (38.2%) after adjustments for age and other confounding factors. The relative risk of G2 versus G5 was 2.68. An increased mortality risk was shown in men whose heart rate was > or = 90 bpm. Moreover, a continuous model suggested a graded increase in risk, so that risk is likely elevated even for heart rates less than 90 bpm, and lowest risk may be around 60 bpm.     

Molecular characterization of multidrug-resistant Streptococcus pneumoniae isolates in Korea. The Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study Group

Pulsed-field gel electrophoresis, ribotyping, and fingerprinting analysis of 22 invasive isolates of multidrug-resistant (MDR) pneumococci from Korea showed that 59 to 82% were genetically related. DNA sequencing of the PBP 2B gene showed relatively uniform alterations in nucleotides (5.4 to 7.8%) and amino acids (3.0 to 4. 3%), while Asn-276-->Lys, Arg-285-->Cys and Ser-305-->Phe substitutions were unique to Korean MDR strains, suggesting the spread of a few epidemic clones of resistant pneumococci within Korea.     

Follicle-stimulating hormone or human menopausal gonadotropin for ovarian stimulation in in vitro fertilization cycles: a meta-analysis

OBJECTIVE: To reanalyze the results of using FSH alone and hMG during IVF treatment, taking into account the different protocols of administration of superactive GnRH agonist analogs. DESIGN: Meta-analysis. SETTING: The London Women's Clinic. PATIENT(S): Women undergoing IVF treatment. INTERVENTION(S): A meta-analysis of published randomized controlled trials from 1985 to 1999 of the use of FSH versus hMG for ovarian stimulation during IVF treatment. The common Peto odds ratio was calculated with use of a fixed effect model. The overall log odds ratio was estimated after demonstrating the consistency or homogeneity of the study results. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate per cycle of IVF. RESULT(S): The results suggested that in the "long and short GnRH agonists protocol" of IVF, FSH, and hMG were equally effective in achieving ovarian stimulation, and there were no differences in the clinical pregnancy rates per cycle of IVF. However, in protocols where no pituitary desensitization was used, FSH alone was more efficacious. CONCLUSION(S): The optimum choice of gonadotropin preparation for ovarian stimulation during IVF treatment is influenced by the regimen of pituitary desensitization used. The optimum gonadotropin to be used when GnRH antagonists are used has yet to be determined.