Rheology and filling characteristics of particulate dispersions in polymer melt formulations for liquid fill hard gelatin capsules

OBJECTIVE: In the postmenopausal years, women develop a central pattern of fat distribution and an increased risk of developing cardiovascular disease (CVD). The possibility that these events are related has not been extensively investigated. The object of the present study was to test the hypotheses that, 1) menopause-related differences in lipids are associated with greater estimated intra-abdominal adiposity, and 2) the relationship between individual adipose depots and plasma lipids differs with menopausal status. DESIGN: Cross-sectional. SUBJECTS: 141 healthy pre- and postmenopausal women aged 35-65 y. MEASUREMENTS: Total body fat by hydrodensitometry was used as an index of whole-body adiposity, the sum of five central skinfold measurements as an index of subcutaneous upper-body adiposity, and estimated intra-abdominal adipose tissue (IAF) as an index of visceral adiposity. Fasting plasma concentrations of total cholesterol (total-C), high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), and triglycerides were used as indices of CVD risk. RESULTS: Postmenopausal women had greater total body fat (P < 0.001), summed central skinfolds (P < 0.01), estimated IAF (P < 0.001), higher plasma concentrations of total-C (P < 0.001), LDL-C (P < 0.001) and triglycerides (P < 0.001), than premenopausal women. The relationship between central skinfolds and LDL-C differed with menopausal status, being significant in pre- but not postmenopausal women. Adjustment for estimated IAF with analysis of covariance decreased menopause-related differences in levels of total-C, LDL-C and triglycerides by approx 40-70%. CONCLUSION: These observations suggest that, 1) menopause-related changes in IAF may adversely affect the plasma lipid profile, and 2) menopausal status affects the relationship between central subcutaneous fat and LDL-C. Studies with measured IAF are needed to confirm present results.     

Transferable, plasmid-mediated vanB-type glycopeptide resistance in Enterococcus faecium

An approximately 60-kb transferable, vanB-carrying plasmid has been identified in a clinical Enterococcus faecium strain. A similar plasmid has been observed in an unrelated E. faecium strain, suggesting that plasmid transfer of vanB operons occurs in nature and plays a role in the dissemination of VanB-type resistance among strains of E. faecium.     

Compartmentation of [14C]glutamate and [14C]glutamine oxidative metabolism in the rat hippocampus as determined by microdialysis

Metabolic compartmentation of amino acid metabolism in brain is exemplified by the differential synthesis of glutamate and glutamine from the identical precursor and by the localization of the enzyme glutamine synthetase in glial cells. In the current study, we determined if the oxidative metabolism of glutamate and glutamine was also compartmentalized. The relative oxidation rates of glutamate and glutamine in the hippocampus of free-moving rats was determined by using microdialysis both to infuse the radioactive substrate and to collect 14CO2 generated during their oxidation. At the end of the oxidation experiment, the radioactive substrate was replaced by artificial CSF, 2 min-fractions were collected, and the specific activities of glutamate and glutamine were determined. Extrapolation of the specific activity back to the time that artificial CSF replaced 14C-amino acids in the microdialysis probe yielded an approximation of the interstitial specific activity during the oxidation. The extrapolated interstitial specific activities for [14C]glutamate and [14C]glutamine were 59 +/- 18 and 2.1 +/- 0.5 dpm/pmol, respectively. The initial infused specific activities for [U-14C]glutamate and [U-14C]glutamine were 408 +/- 8 and 387 +/- 1 dpm/pmol, respectively. The dilution of glutamine was greater than that of glutamate, consistent with the difference in concentrations of these amino acids in the interstitial space. Based on the extrapolated interstitial specific activities, the rate of glutamine oxidation exceeds that of glutamate oxidation by a factor of 5.3. These data indicate compartmentation of either uptake and/or oxidative metabolism of these two amino acids. The presence of [14C]glutamine in the interstitial space when [14C]glutamate was perfused into the brain provided further evidence for the glutamate/glutamine cycle in brain.     

Experimental infection of chimpanzees with hepatitis C virus of genotype 5a: genetic analysis of the virus and generation of a standardized challenge pool

Six major genotypes (genotypes 1-6) of hepatitis C virus (HCV) have been identified. These genetic variants are being transmitted to chimpanzees, the only recognized animal model for the study of HCV. Genotype 5a (strain SA13), a variant found primarily in South Africa, has been transmitted to chimpanzees for the first time. Experimental infection of 2 chimpanzees was characterized by early appearance of viremia and peak virus titers of 10(5)-10(6) genome equivalents/mL. The HCV infection was resolved by week 15 after inoculation in 1 chimpanzee and persisted in the other. Both chimpanzees became anti-HCV-positive by week 14 after inoculation. Both chimpanzees developed viral hepatitis. The infectivity titer of a genotype 5a challenge pool prepared from the first passage of HCV in a chimpanzee was approximately 10(4) infectious doses/mL. Finally, sequence analysis of strain SA13 confirmed that genotype 5a is genetically distinct from other genotypes of HCV.     

A comparison of placebo response with major depressive disorder in patients recruited through newspaper advertising versus consultation referrals

Recent evidence indicates few differences between patients recruited through advertising and by consultation referral, and there is some suggestion that those recruited through advertising are more representative of the target community population. However little has been reported on differences in placebo response and compliance in these two patient groups. We conducted a retrospective chart review of 49 patients with major depressive disorder (MDD), recruited through advertising or consultation, randomized to placebo in five clinical trials. Variables included demographics, clinical history, efficacy, compliance, and completion data. Homogeneity was demonstrated for most variables. Differences in placebo groups included significantly lower Hamilton Rating Scale for Depression (HAM-D) scores for the advertisement group throughout the trials. Advertisement patients were also more likely to be early placebo responders and in remission at Days 14 and 28. No differences were found in completion rates or reasons for early termination. Compliance was excellent for both groups. Early placebo response of the advertisement group reinforces the need for trials of at least 8 weeks. In addition, consultation patients may have a more severe illness and be treatment resistant, suggesting they are less generalizable to community practice populations.     

Pigeon basal ganglia: insights into the neuroanatomy underlying telencephalic sensorimotor processes in birds

This paper reviews the organization of the avian and mammalian striatum. The striatum receives input from virtually the entire rostrocaudal and mediolateral expanse of the cerebral cortex. The corticostriatal projections appear to be glutamatergic, forming excitatory synapses in the striatum. Another major projection to the avian striatum that also appears to be glutamatergic stems from a set of nuclei in the dorsal zone of the avian thalamus that are comparable to the mammalian intralaminar, mediodorsal, and midline nuclei. Furthermore, the striatum receives a massive projection from dopaminergic neurons of the ventral tegmental area and substantia nigra in the midbrain tegmentum. In return, the midbrain tegmentum receives a direct GABAergic/substance P-ergic/ dynorphinergic projection from the striatum, as well as an indirect one formed by GABAergic/substance P-ergic/ dynorphinergic and GABA-ergic/enkephalinergic striatal neurons projecting to the pallidum in the first step, and pallidal GABAergic/LANT6/parvalbumin neurons projecting to the midbrain tegmentum in the second step. In addition to its projection neurons, the striatum possesses GABAergic and cholinergic interneurons. One motor output pathway of the striatum runs via the pallidum and dorsal thalamic ventral tier nulei to the motor cortex. In addition to this pathway, birds possess a major descending pathway from the basal ganglia to the tectum via the GABAergic nucleus spiriformis lateralis in the pretectum. On hodological and topological grounds, similar nuclei, although not GABAergic, can be found in mammals. Finally, an other striatal motor output is formed by a sequential GABAergic pathway from the basal ganglia via the substantia nigra to the tectum. In conclusion, it appears that the organization of the avian and mammalian basal ganglia is similar rather than different.     

Repetitive axonal stimulation of the same single motor unit: a longitudinal tracking study

We elicited three single motor unit action potentials (S-MUAPs) via multiple point stimulation and subjected them to repetitive stimulation (RS) in 3 healthy subjects. We tracked each S-MUAP and its RS trains over two separate sessions as well as the compound motor action potential (CMAP) RS trains obtained from the same muscle following whole nerve stimulation. Repetitive axonal stimulation yields consistent results when carefully performed with minimal variation in each S-MUAP RS train from session to session, providing previously unobtainable data regarding neuromuscular junction function in the same single motor unit over time. In this small, normative sample, no significant correlation between S-MUAP and CMAP RS responses was observed.     

Treatment of cutout of a lag screw of a dynamic hip screw in an intertrochanteric fracture

Sixteen consecutive patients with cutout of a lag screw of a dynamic hip screw fixation in an intertrochanteric fracture were treated with reinsertion of a lag screw, bone cement supplementation in the neck-trochanter, and subtrochanteric valgus osteotomy. Postoperatively, patients were permitted to ambulate with protected weight-bearing. Fourteen patients were followed-up for at least 1 year (median 2 years; range 1-3 years), and all had a solid union. The union period took a median of 5 months, with a range of 3-7 months. Usually, union of an intertrochanteric fracture was faster than that of subtrochanteric osteotomy (P < 0.01). There were no complications of wound infection, loss of reduction, cutout of a lag screw, or osteonecrosis of the femoral head. From clinical and theoretical considerations, we conclude that despite cutout of a lag screw of a dynamic hip screw fixation being difficult to treat, out technique still can provide an excellent outcome. Therefore, we strongly recommend its wide use.     

Screening calcaneal ultrasound and risk factors for osteoporosis among lesbians and heterosexual women

We compared calcaneal ultrasound measurements (speed of sound [SOS], broadband ultrasound attenuation [BUA], and stiffness index [SI]) of lesbian and heterosexual women to examine the medical and lifestyle risk factors for osteoporosis in each group. This was an exploratory, community-based, cross-sectional study. Subjects were mailed food frequency, health, and physical activity questionnaires. Weight, height, and calcaneal ultrasound measurements were taken at one office visit. In communities in southern and eastern Maine, 71 lesbians and 77 heterosexual women between the ages of 30 and 50 with regular menses and in good general health were the subjects. Statistical analysis used t-tests and chi-square tests to evaluate differences between study groups. Linear regression models were used to evaluate risk factors for low calcaneal ultrasound measurements. There were no differences between the lesbian and heterosexual women in age, body mass index (BMI), exercise, calcium intake, alcohol use, or calcaneal ultrasound measurements. There was a positive association between BUA and both BMI and alcohol consumption (p < 0.01). Antidepressant use significantly reduced SOS and SI (p < 0.05). There were no differences in calcaneal ultrasound measurements between lesbian and heterosexual women. BMI was strongly and positively associated with BUA. Antidepressant use in both populations was associated with a significant reduction in calcaneal bone mass. Studies are needed to define the relationship of depression and its treatment to bone mineral density and the future risk of osteoporosis.     

Functional maturation of the primate fetal adrenal in vivo: 3. Specific zonal localization and developmental regulation of CYP21A2 (P450c21) and CYP11B1/CYP11B2 (P450c11/aldosterone synthase) lead to integrated concept of zonal and temporal steroid biosynthesis

Previous studies in the primate fetal adrenal gland have indicated that the gland is comprised of three functional zones: 1) the inner fetal zone (FZ), which has the enzymes necessary for dehydroepiandrosterone sulfate (DHEAS) production beginning early in gestation; 2) the transitional zone (TZ), which possesses enzymes necessary for cortisol production; and 3) the outer, definitive zone (DZ), which appears to function as a reservoir of progenitor cells that may populate the remainder of the gland and does not acquire a steroidogenic phenotype with the capacity to produce mineralocorticoids until near term. The enzymes CYP21A2 (P450 21 hydroxylase, or P450c21), CYP11B1 (11beta hydroxylase or P450c11) and CYP11B2 (aldosterone synthase) are necessary for glucocorticoid and mineralocorticoid synthesis but have not been localized previously in an ontogenic manner in the primate fetal adrenal gland. Therefore, we used immunocytochemistry (ICC) to assess specific zonal localization and developmental regulation of CYP21A2 and CYP11B1/CYP11B2 in the human (13-24 weeks' gestation) and rhesus monkey (109 d-term) fetal adrenal gland. In the fetal rhesus, ICC was performed with and without metyrapone administration to the fetus to assess the effects of endogenously increased fetal ACTH. In the human fetal adrenal, CYP21A2 immunoreactivity (IR) was present in only a few isolated cells in the DZ but was detectable in almost all cells in the TZ and FZ. In the fetal rhesus, CYP21A2-IR was present in cells throughout the DZ and TZ and, to a lesser degree, in the FZ. Staining intensity increased with advancing gestational age and was up-regulated in the DZ and TZ, but not the FZ, of the metyrapone-treated fetuses. In the human fetal adrenal gland, CYP11B1/CYP11B2-IR was absent in the DZ but present in the TZ and FZ. In the fetal rhesus monkey adrenal, CYP11B1/CYP11B2-IR was present in all cells of the TZ and FZ but was absent from the DZ until near term. After metyrapone, CYP11B1/CYP11B2-IR was induced in the DZ and was up-regulated in the TZ and FZ. Taken together, these data indicate that in the primate fetal adrenal gland, the FZ has the capacity to synthesize DHEA and DHEAS beginning early in development, the TZ has the capacity to synthesize cortisol after midgestation, and the DZ has the capacity to synthesize mineralocorticoids, but not until near term. The spatial localization of steroid metabolizing enzymes and steroid products in the human and rhesus monkey fetal adrenal suggests analogies of the three functional zones of the fetus (DZ, TZ, and FZ) to their adult counterparts (zona glomerulosa, zona fasciculata, and zona reticularis) and their steroid products (mineralocorticoids, glucocorticoids and androgens, respectively), although the reason for the presence of CYP11B1/CYP11B2- and CYP21A2-IR in the FZ remains to be elucidated.