Drug abuse and depression: possible models for geriatric anorexia

The central biochemical pathology of anorexia and the natural aging of the brain is similar. Biochemical models for drug withdrawal and depression may also assist in understanding geriatric anorexia. Norepinephrine, corticotropin releasing factor and beta-endorphin may key neurotransmitters in all of these conditions.     

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a component of tobacco smoke, modulates mediator release from human bronchial and alveolar epithelial cells

Respiratory epithelial cells are known to contribute to immune responses through the release of mediators. The aim of this study was to characterize the immunomodulatory effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco carcinogen, on respiratory epithelial cells and to compare two metabolic pathways, alpha-methylhydroxylation and alpha-methylenehydroxylation, involved in these effects using selective precursors, 4-(acetoxy-methylnitrosamino)-1-(3-pyridil)-1-butanone (NNKOAc) and N-nitroso (acetoxymethyl) methylamine (NDMAOAc), respectively. Human bronchial and alveolar epithelial cell lines, BEAS-2B and A549, respectively, were treated with NNK, NNKOAc and NDMAOAc for 24 h with and without tumour necrosis factor (TNF) and mediators released in cell-free supernatants were measured by enzyme-linked immunosorbent assay (ELISA). NNK significantly inhibited interleukin (IL)-8, IL-6 and monocyte chemoattractant protein-1 (MCP-1) production in both cell types. Similar results were observed with primary bronchial and alveolar epithelial cells. Although NNK increased prostaglandin E(2) (PGE(2)) production by A549 cells, its immunomodulatory effects were not mediated by PGE(2) according to the results with cyclo-oxygenase inhibitors. NNKOAc mimicked NNK effects, whereas NDMAOAc significantly inhibited IL-8 production in BEAS-2B cells and MCP-1 in both cell types. These results demonstrate that NNK and its reactive metabolites have immunosuppressive effects on respiratory epithelial cells, which could contribute to the increased respiratory infections observed in smokers and the development and/or the progression of lung cancer.     

Assisted hatching improves implantation rates on cryopreserved-thawed embryos. A randomized prospective study

Sir, Gabrielsen et al. (2004) evaluated the impact of assisted hatchingin cryopreserved human embryo transfers and reported an implantationrate of 11.4% in the assisted hatching group and 5.8% in thecontrol group (P<0.05; Table I     

Prevalence and associations of symptoms of upper extremities,repetitive strain injuries (RSI) and 'RSI-like condition'. A cross sectional study of bank workers in Northeast Brazil

Background  

The repetitive strain injury syndrome (RSI) is a worldwide occupational health problem affecting all types of economic activities. We investigated the prevalence and some risk factors for RSI and related conditions, namely 'symptoms of upper limbs' and 'RSI-like condition'.     

Upper and lower eyelid saccades describe a harmonic oscillator function

PURPOSE: To determine whether experimentally measured upper and lower eyelid saccades can be fitted to a mathematical function. METHODS: A charge-coupled device video camera connected to a personal computer was used to record upper and lower eyelid saccades accompanying 20 degrees and 40 degrees of vertical eye rotation in 19 normal adult subjects. Movement analysis was performed with software that calculated the center of a blue spot in each frame. The damped harmonic oscillator model was used to fit all saccadic functions obtained. RESULTS: All downward and upward saccades of both upper and lower eyelids were fitted with the underdamped solution of the model with correlation coefficients ranging from 0.980 to 0.999 (mean = 0.995). It was possible to measure maximum velocity at any time, amplitude, and duration of the saccade movements. For the upper eyelid, downward saccades were faster than upward saccades, a difference that was not observed for the lower eyelid. For both the upper and lower eyelids, the velocity of upward and downward movements reached a peak at approximately 0.05/0.06 second and then decreased. For both the upper and lower eyelid saccades, there was good linear correlation between amplitude and velocity. Overshoots were detected in the downward saccades of both lids. CONCLUSIONS: Normal upper and lower saccades are described by functions that are extremely well fitted by the underdamped solution of the harmonic oscillator model. Overshooting is a typical feature of normal downward saccades and can be explained by the elastic properties of the tissues.     

Grafting aminocyclopentane carboxylic acids onto the RGD tripeptide sequence generates low nanomolar alphaVbeta3/alphaVbeta5 integrin dual binders

Eleven gamma-aminocyclopentane carboxylic acid (Acpca) platforms, including four dihydroxy representatives (19-22), three hydroxy analogues (34-36), and four deoxy derivatives (30-33), were prepared in a chiral nonracemic format. These simple units were then grafted onto an Arg-Gly-Asp (RGD) tripeptide framework by a mixed solid phase/solution protocol delivering an ensemble of 11 macrocyclic analogues of type cyclo-[-Arg-Gly-Asp-Acpca-], 1-11. The individual compounds were evaluated for their binding affinity toward the alphaVbeta3 and alphaVbeta5 integrin receptors. The analogue 10 exhibited a very interesting activity profile (IC50/alphaVbeta3= 1.5 nM; IC50/alphaVbeta5= 0.59 nM), comparable to that of reference compounds EMD121974 and ST1646. Closely related congeners 6, 8, and 9 also proved to be excellent dual binders with activity levels in the low nanomolar range. The three-dimensional (3D) NMR solution structures were determined, and docking studies to X-ray crystal structure of the extracellular segment of integrin alphaVbeta3 in complex with the reference compound EMD121974 were performed on selected analogues to elucidate the interplay between structure and function in these systems and to evidence the subtle bases for receptorial recognition. The results prove that the principle of isosteric dipeptide replacement for peptidomimetics design and synthesis can be violated, without detriment to the development of highly effective integrin binders.     

Heterocyclic and phenyl double-bond-locked combretastatin analogues possessing potent apoptosis-inducing activity in HL60 and in MDR cell lines

Two new series of combretastatin (CA-4) analogues have been prepared. The alkenyl motif of CA-4 was replaced either by a five-membered heterocyclic (isoxazoline or isoxazole) or by a six-membered ring (pyridine or benzene). The new compounds have been evaluated for their effects on tubulin assembly and for cytotoxic and apoptotic activities. Five compounds (18b, 20a, 21a, 34b, and 35b) demonstrated an attractive profile of cytotoxicity (IC50 < 1 microM) and apoptosis-inducing activity but poor antitubulin activity. The isoxazoline derivatives 18b, 20a, and 21a, demonstrated potent apoptotic activity different from that of natural CA-4. Their ability to block most cells in the G2 phase suggests that these compounds could act on targets different from the mitotic spindle. This would indicate activation of both the intrinsic and the extrinsic apoptotic pathways. The data suggest unambiguously that structural alteration of the stilbene motif of CA-4 can be extremely effective in producing potent apoptosis-inducing agents.     

Influence of pupillary diameter, ciliary muscle tone, and ambient light on nerve fiber layer measurements with scanning laser polarimetry

PURPOSE: To evaluate the influence of the pupillary diameter, ciliary muscle tone, and room light on nerve fiber layer measurements with the scanning laser polarimeter (GDx). METHODS: One randomly selected eye of ten normal volunteers was examined with the GDx in a two-day protocol under eight testing conditions (pilocarpine 1%, phenylephrine 10%, tropicamide 1%, or no drops with room lights on or off). The twelve parameters, obtained by the GDx, were compared under the eight testing conditions, using two way ANOVA for repeated measurements and Tukey HSD post hoc test. RESULTS: Ten of the twelve parameters were statistically significantly different (P < 0.05) when measured under the three medication or no medication conditions, controlling for the ambient light status. There were no significant differences when measured with the light on or off, controlling for use of drops. CONCLUSIONS: Nerve fiber layer measurements with the GDx were influenced by drugs affecting pupillary diameter, but not by the status of room light or ciliary muscle tone.