Desipramine restricts estral cycle oscillations in swimming

1. Desipramine (DMI) is a tricyclic antidepressant which reduces the immobility in rats forced to swim; however, it is unknown whether estral cycle phases impinge on DMI actions on immobility in daily swimming tests during several weeks. 2. In female wistar rats, vaginal smears taken before testing defined four estral phases. Afterwards, the authors assessed the latency for the first period of immobility in five-min forced swim tests practiced on 21-day DMI (DMI group), 21-day washout saline given after a 21-day DMI treatment (washout-saline group), or non-treated rats (control group). 3. We observed a longer latency for the first period of immobility in proestrus-estrus from the control and washout-saline groups. The 21-day treatment with DMI (2.1 mg/kg i.p., once a day) significantly (p < 0.001) increased the latency by about 160% from control regardless of the estral cycle phase. 4. It is concluded that proestrus-estrus relates to increased struggling behavior. DMI enhances struggling behavior independently of hormonal state.     

Cytotoxicity of curcuminoids and some novel compounds from Curcuma zedoaria

Bioassay-directed fractionation of an EtOH extract of Curcuma zedoaria led to isolation of an active curcuminoid, which was identified as demethoxycurcumin (2) by comparison of its 1H and 13C NMR spectra with literature data and by direct comparison with synthetic material. Curcumin (1) and bisdemethoxycurcumin (3) were also obtained. Curcuminoids (1-3) were synthesized and demonstrated to be cytotoxic against human ovarian cancer OVCAR-3 cells. The observed CD50 values of 1, 2, and 3 were 4.4, 3.8, and 3.1 microg/mL, respectively. Three additional novel compounds, 3, 7-dimethylindan-5-carboxylic acid (4), curcolonol (5), and guaidiol (6), were also isolated from the EtOH extract. The structures and relative stereochemistry of 4-6 were determined by spectroscopic methods and X-ray crystallographic analysis.     

The contribution of noncatalytic phosphate-binding subsites to the mechanism of bovine pancreatic ribonuclease A

The enzymatic catalysis of polymeric substrates such as proteins, polysaccharides or nucleic acids requires precise alignment between the enzyme and the substrate regions flanking the region occupying the active site. In the case of ribonucleases, enzyme-substrate binding may be directed by electrostatic interactions between the phosphate groups of the RNA molecule and basic amino acid residues on the enzyme. Specific interactions between the nitrogenated bases and particular amino acids in the active site or adjacent positions may also take place. The substrate-binding subsites of ribonuclease A have been characterized by structural and kinetic studies. In addition to the active site (p1), the role of other noncatalytic phosphate-binding subsites in the correct alignment of the polymeric substrate has been proposed. p2 and p0 have been described as phosphate-binding subsites that bind the phosphate group adjacent to the 3' side and 5' side, respectively, of the phosphate in the active site. In both cases, basic amino acids (Lys-7 and Arg-10 in p2, and Lys-66 in p0) are involved in binding. However, these binding sites play different roles in the catalytic process of ribonuclease A. The electrostatic interactions in p2 are important both in catalysis and in the endonuclease activity of the enzyme, whilst the p0 electrostatic interaction contributes only to binding of the RNA.     

Activation of T lymphocytes by syngeneic murine intestinal smooth muscle cells

BACKGROUND & AIMS: Intestinal smooth muscle cells (ISMCs) express major histocompatibility complex II (MCH II) and intercellular adhesion molecule 1 (ICAM-1) after exposure to interferon gamma (IFN-gamma). T lymphocytes invade the intestinal musculature during Crohn's disease or pseudoobstruction. The aim of this study was to determine whether ISMCs activate syngeneic T cells via MHC II and ICAM-1. METHODS: Cultured murine ISMCs were exposed to IFN-gamma for 72 hours and analyzed for Mac-1 (CD11B CD18) antigen, MHC II, and ICAM-1 expression using enzyme-linked immunosorbent assay and fluorescence-activated cell sorter scan. T lymphocytes from mesenteric lymph nodes of ovalbumin-sensitized mice were examined for their ability to proliferate after coculture with IFN-gamma-pretreated and ovalbumin-pretreated ISMCs using [3H]thymidine incorporation. RESULTS: ISMCs expressed smooth muscle alpha-actin before and after IFN-gamma exposure. No macrophages were identified in these cultures. Exposure to IFN-gamma and ovalbumin for 72 hours induced MHC II and ICAM-1 expression; these treated ISMCs induced T-cell proliferation, whereas untreated ISMCs did not. T-cell proliferation was markedly enhanced by adding interleukin 2 and was blocked by antibodies against MHC II and ICAM-1. CONCLUSIONS: ISMCs activate T lymphocytes in an MHC II-linked manner and thus possess the ability to modulate immune function in the gut.     

Icons improve older and younger adults' comprehension of medication information

We examined whether timeline icons improved older and younger adults' comprehension of medication information. In Experiment 1, comprehension of instructions with the icon (icon/text format) and without the icon (text-only format) was assessed by questions about information that was (a) implicit in the text but depicted explicitly by the icon (total dose in a 24 hour period), (b) stated and depicted in the icon/text condition (medication dose and times), and (c) stated but not depicted by the icon (e.g., side effects). In a separate task, participants also recalled medication instructions (with or without the icon) after a study period. We found that questions about dose and time information were answered more quickly and accurately when the icon was present in the instructions. Notably, icon benefits were greater for information that was implicit rather than stated in the text. This finding suggests that icons can improve older and younger adults' comprehension by reducing the need to draw some inferences. The icon also reduced effective study time (study time per item recalled). In Experiment 2, icon benefits did not occur for a less integrated version of the timeline icon that, like the text, required participants to integrate dose and time information in order to identify the total daily dose. The integrated version of the icon again improved comprehension, as in Experiment 1, as well as drawing inferences from memory. These findings show that integrated timeline icons improved comprehension primarily by aiding the integration of dose and time information. These findings are discussed in terms of a situation model approach to comprehension.     

More positive or less negative? Trends in research on adjustment of families rearing children with developmental disabilities

Breast cancer is one of the most common forms of cancer observed in women, and endogenous estrogen is thought to play a major role in its development. Because of this, any conditions or exposures which enhance estrogenic responses would result in an increased risk for breast cancer. The role of xenoestrogenic compounds, such as DDT, in the etiology of breast cancer is still very controversial. In the following paper we discuss recently-published observations by ourselves and others which indicate that xenoestrogens may play a significant role in the development of breast cancer. Specifically, we hypothesize that during periods of high growth rates and during breast development the sensitivity of breast cells to estrogenic compounds is sufficiently great for xenoestrogens to significantly enhance risk for breast cancer.     

The evaluation of women with schizophrenia

BACKGROUND AND PURPOSE: A diagnosis of cancer is a contraindication for the use of therapeutic ultrasound (US). Continuous US applied to murine tumors has resulted in larger and heavier tumors compared with controls. We compared tumor growth using low-power continuous US and energy-matched pulsed US. SUBJECTS: Female C57BL/6 mice (N = 174) were used. METHODS: Animals received subcutaneous injections of methylcholanthrene tumor cells. The mice were randomly divided into three groups: 60 mice that received low-power continuous US for 5 minutes at 0.75 W/cm2 (LC US group), 63 mice that received pulsed US for 12.5 minutes at 1.5 W/cm2 (pulsed US group), and 51 mice that served as a control group. The LC and pulsed US groups received equal US energy. Both experimental groups received 10 treatments of 3-MHz US, which was applied directly over the tumor. The control group received identical handling but no US. After treatment, the tumors were excised, weighed, and measured. A one-way analysis of variance, followed by Newman-Keuls post hoc testing, was used to analyze the data. RESULTS: Mean tumor weights (in grams) and volumes (in cubic millimeters) were 0.563 g and 564 mm3 for the LC US group, 0.560 g and 525 mm3 for the pulsed US group, and 0.516 g and 406 mm3 for the control group. CONCLUSION AND DISCUSSION: Reducing total US energy will result in less growth of murine tumors. When infusing equal energy, continuous and pulsed US will produce similar effects on tumor growth.     

A theoretical framework for sex-biased parental care

Strong anion-exchange (SAX) chromatography and reversed-phase liquid chromatography (RPLC) followed by different mass spectrometric techniques for the separation and identification of conjugated and unconjugated 14C-labelled eltanolone (5beta-Pregnan-3alpha-ol-20-one) metabolites in biological fluids are presented. Conjugates of estradiol were used as model compounds for the development of a SAX based group separation of neutral steroids, glucuronides, sulfates and di-conjugated steroids. The usefulness of the technique is demonstrated by the analysis of 14C-labelled eltanolone metabolites in dog urine. The analytical SAX column used prior to RPLC improved the capacity to separate the metabolites from each other and from endogenous components, compared to a single reversed-phase system. Liquid chromatography negative ion electrospray-mass spectrometry (LC-ESI-MS) was used for the molecular mass determination of conjugated eltanolone metabolites. Unconjugated metabolites and hydrolysed conjugates were identified using gas chromatography-mass spectrometry with an electron impact ion source (GC-MS) after trimethylsilyl (TMS) derivatization. An unexpected finding in dog urine was the diglucuronide formation of eltanolone (presumably after enolisation of its carbonyl group).     

Investigation of the N-substituent conformation governing potency and mu receptor subtype-selectivity in (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists

A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [35S]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor.     

Parathyroid hormone (1-34) increased total body bone mass in aged female rats

Daily subcutaneous administration of bovine parathyroid hormone (PTH)(1-34) stimulates bone formation and increases bone mass in rat tibiae, femora and lumbar spine. However, the effects of PTH on the whole body bone mineral content and density determined by dual energy x-ray absortiometry (DEXA) have not been previously reported in rats. Eighteen-month-old intact female rats were subcutaneously injected daily with 0, 40, 80 or 160 micrograms/kg/day of bovine PTH (1-34) for either 15 or 60 days. Whole body DEXA was performed at 1 day before autopsy, and bone area, bone mineral content (BMC) and bone mineral density (BMD) of the total body were determined. Total femoral, tibial and lumbar spine BMD was also determined ex vivo. Cancellous bone histomorphometry was performed on sections of double-labeled proximal tibial metaphyses. Whole body bone mineral content and density were significantly increased by 60 days, but not by 15 days, of PTH treatment at all dose groups compared with vehicle controls. Lumbar vertebral and total femoral BMD was significantly increased at all doses of PTH by 15 days of administration and further increased by 60 days. All doses of PTH increased trabecular bone area in proximal tibial metaphyses by 15 days and further increased by 60 days. All doses of PTH increased trabecular bone area in proximal tibial metaphyses by 15 days and further increased by 60 days. In proximal tibial cancellous bone, dose-dependent increases in percent labeled perimeter, mineral apposition rate and bone formation rate-bone volume referent were found between 40 and 160 micrograms/kg of PTH treatment by 15 days, and no further increases were found by 60 days. Our results showed that in aged female rats, bovine PTH(1-34) increased bone formation and total body bone mass.