|
|
Post by Max on Jun 13, 2005 18:22:31 GMT -5
Observed wide ocular effects, short and also suggested long term degenerative effectsSome of the Accutane induced ocular side affects are not reversible when the drug is stopped [10 and more]. Hoffman la Roche itself sees the following associations related to vision in human subjects exposed to (Ro)accutane: corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia and visual disturbances [0]. Non published data suggest (Ro)accutane induced severe tunnelvision in a number of patients. The mechanism for this event is unknown. Lasting increased UV-sensitivity has been observed [10 and more].  Picture 1. Lissamine green corneal staining of a dry eye patient taking isotretinoin. Photo courtesy of Eric Donnenfeld, M.D.  Picture 2. Fluorescein staining of the central cornea in a patient taking isotretinoin. Photo courtesy of Eric Donnenfeld, M.D. Isotretinoin is currently used in human subjects for severe recalcitrant nodular acne and has a variety of by independent research well known associated ocular side effects [1 and more]. Observations demonstrate that some of the Accutane induced ocular side affects are not reversible when the drug is stopped [10 and more]. Accumulating evidence is also pointing out that eye-related side-effects may worsen with time after a (Ro)accutane exposure in human subjects. Subjects exposed to these drugs often show side effects resembling the symptoms of hypovitaminosis A, namely, among other things night blindness and decreased plasma retinol levels [5]. Possible oculomotor deficit developing with time after (Ro)accutane exposure in subjectsThyroid function is found to be altered in human subjects exposed to retinoic acid, and significant fall in plasma concentrations of thyroxine and triiodthyronine have been found in human subjects exposed to the toxin [6]. This fall is likely explained by a found significant inhibition of thyroid receptor expression in various cell lines in doses related to what could be expected in acne subjects [7]. The long term effects of a hypothyroid condition on vision are not fully evaluated. Thyroid function is suggested to be of importance for oculomotor function and is associtated with ophthalmopathy (ocular-motor deficit) [8, 9]. In adult cats, the Trk receptor isoforms are suggested to be of importance for oculomotor function and exert an influence on the normal operation of the oculomotor circuitry. A similiar function is likely to be present in human. TrkA, TrkB, and TrkC immunopositive cells were found in similar percentages in the oculomotor and in the trochlear nuclei. In the abducens nucleus, however, a significantly higher percentage of cells expressed TrkB than the other two receptors, among both motoneurons (81.8%) and internuclear neurons (88.4%) [11]. Trk receptor isoform gene-expression is suggested to be modulated by among other things thyroxin [12 and 13]. 1,25 dihydroxyvitamin D metabolites were found to be significantly lower in human subjects exposed to (Ro)accutane after exposure, implicating a clinical vitamin D deficiency [14 and more]. In the human eye the vitamin D receptor (VDR) was found to be expressed in several areas. Human retinal photoreceptors express vitamin D receptor (VDR), plasma membrane calcium pump and calcium-binding protein epitopes were detected in the outer nuclear layer. VDR epitopes were also seen in lens epithelium. Some immunostaining for VDR, PMCA and calbindin-D28k also was present in the endothelium and in the basal epithelium of the cornea. All three proteins were detected in some cells of the ganglion cell layer, the inner nuclear layer, and the retinal pigment epithelium [16]. Except for inducing the VDR receptor, vitamin D is found to induce Trk receptor isotypes in various tissue [15]. This may also be valid for Trk receptors that are related to the eye. The long-term effects of a clinically significant vitamin D-deficiency on the retinal photoreceptors, the eye-lens, and eye function are unknown. Little is known about possible long-term ocular side-effects, or possible additional ocular effects appearing with time after exposure. There are no studies showing how photreceptor cell maintenance and signaling is affected long term, no studies on how oculo-motor capacity is affected long term, and no studies of how the crystal lens structure is affected long-term in subjects exposed to retinoic acid. Degeneration of crystal lens structureVitamin A has been found to be inducing regeneration in the lens of adult mammals [17]. A state with vitamin A insufficiency, both circulating and lack of adequate metabolism may therefore affect the lens negative long term. Night blindnessIsotretinoin can cause nyctalopia (night blindness) [2, 5 and more]. Even a single dose of isotretinoin slowed the recovery of rod signaling after exposure to an intense bleaching light, and that rhodopsin regeneration was markedly slowed. When only a single dose was given, rod function recovered to normal within several days. Rods and cones both showed slow recovery from bleach after isotretinoin in rats and in mice [3]. Retinitis pigmentosa (RP) is a heterogeneous group of retinal dystrophies characterized by photoreceptor cell degeneration. RP causes night blindness, a gradual loss of peripheral visual fields, and eventual loss of central vision [4]. Dry eye syndromePersistent dry eye syndrome in human subjects has been observed [10 and more].
|
|
|
|
Post by Max on Jun 23, 2005 15:49:07 GMT -5
Location alkaline phosphatase: 2q37.1
Ophthalmic Genet. 2001 Sep;22(3):133-54. Related Articles, Links
Update on the molecular genetics of retinitis pigmentosa.
Wang Q, Chen Q, Zhao K, Wang L, Wang L, Traboulsi EI.
Center for Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA. wangq2@ccf.org
Retinitis pigmentosa (RP) is a heterogeneous group of retinal dystrophies characterized by photoreceptor cell degeneration. RP causes night blindness, a gradual loss of peripheral visual fields, and eventual loss of central vision. Advances in molecular genetics have provided new insights into the genes responsible and the pathogenic mechanisms of RP. The genetics of RP is complex, and the disease can be inherited in autosomal dominant, recessive, X-linked, or digenic modes. Twenty-six causative genes have been identified or cloned for RP, and an additional fourteen genes have been mapped, but not yet identified. Eight autosomal dominant forms are due to mutations in RHO on chromosome 3q21-24, RDS on 6p21.1-cen, RP1 on 8p11-21, RGR on 10q23, ROM1 on 11q13, NRL on 14q11.1-11.2, CRX on 19q13.3, and PRKCG on 19q13.4. Autosomal recessive genes include RPE65 on chromosome 1p31, ABCA4 on 1p21-13, CRB1 on 1q31-32.1, USH2A on 1q41, MERTK on 2q14.1, SAG on 2q37.1, RHO on 3q21-24, PDE6B on 4p16.3, CNGA1 on 4p14-q13, PDE6A on 5q31.2-34, TULP1 on 6p21.3, RGR on 10q, NR2E3 on 15q23, and RLBP1 on 15q26. For X-linked RP, two genes, RP2 and RP3 (RPGR), have been cloned. Moreover, heterozygous mutations in ROM1 on 11q13, in combination with heterozygous mutations in RDS on 6p21.1-cen, cause digenic RP (the two-locus mechanism). These exciting molecular discoveries have defined the genetic pathways underlying the pathogenesis of retinitis pigmentosa, and have raised the hope of genetic testing for RP and the development of new avenues for therapy.
Publication Types:
Review
PMID: 11559856 [PubMed - indexed for MEDLINE]
|
|
|
|
Post by Max on Jun 29, 2005 12:32:58 GMT -5
References:[0] No author Roche official complete US Accutane Product information www.rocheusa.com/products/accutane/pi.pdf [1] Fraunfelder FW. Ocular side effects associated with isotretinoin. (2004) Drugs Today (Barc). Jan;40(1):23-7. [2] Danby FW. Night blindness, vitamin A deficiency, and isotretinoin psychotoxicity. (2003) Dermatol Online J. Dec;9(5):30. [3] Sieving PA, Chaudhry P, Kondo M, Provenzano M, Wu D, Carlson TJ, Bush RA, Thompson DA. Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy.
(2001) Proc Natl Acad Sci U S A. Feb 13;98(4):1835-40. [4] Wang Q, Chen Q, Zhao K, Wang L, Wang L, Traboulsi EI. Update on the molecular genetics of retinitis pigmentosa. (2001) Ophthalmic Genet. Sep;22(3):133-54. [5] Dew SE, Wardlaw SA, Ong DE. Effects of pharmacological retinoids on several vitamin A-metabolizing enzymes. (1993) Cancer Res. Jul 1;53(13):2965-9. [6] Marsden JR, Trinick TR, Laker MF, Shuster S. Effects of isotretinoin on serum lipids and lipoproteins, liver and thyroid function. (1984) Clin Chim Acta. Nov 30;143(3):243-51. [7] [8] Ye X, Yan J, Chen Q, Su J, Lin Z. [The clinic value of fixed visual field examination in patients with thyroid-associated ophthalmopathy] (2004) Yan Ke Xue Bao. Jul;20(2):101-3. [9] Thacker NM, Velez FG, Demer JL, Rosenbaum AL.
Superior oblique muscle involvement in thyroid ophthalmopathy. (2005) J AAPOS. Apr;9(2):174-8. [10] Lerman S. Ocular side effects of accutane therapy. (1992) Lens Eye Toxic Res. 9(3-4):429-38. [11] Benitez-Temino B, Morcuende S, Mentis GZ, de la Cruz RR, Pastor AM. Expression of Trk receptors in the oculomotor system of the adult cat. (2004) J Comp Neurol. Jun 7;473(4):538-52. [12] [13] [14] Rodland O, Aksnes L, Nilsen A, Morken T. Serum levels of vitamin D metabolites in isotretinoin-treated acne patients.
(1992) Acta Derm Venereol. 72(3):217-9. [15] [16] Johnson JA, Grande JP, Roche PC, Campbell RJ, Kumar R. Immuno-localization of the calcitriol receptor, calbindin-D28k and the plasma membrane calcium pump in the human eye. (1995) Curr Eye Res. Feb;14(2):101-8. [17] Jangir OP, Modi D, Manshi S. Effect of vitamin A on lens regeneration in pigs. (2005) Indian J Exp Biol. Aug;43(8):679-85.
|
|
|
|
Post by Max on Jun 30, 2005 7:45:56 GMT -5
Dev Growth Differ. 2002 Oct;44(5):391-4. Related Articles, Links
Expression and role of retinoic acid receptor alpha in lens regeneration.
Tsonis PA, Tsavaris M, Call MK, Chandraratna RA, Del Rio-Tsonis K.
Laboratory of Molecular Biology, Department of Biology, University of Dayton, Dayton, OH 45469-2320, USA. Panagiotis.Tsonis@notes.udayton.edu
The role of retinoids in eye development has been well studied. Retinoids and their receptors regulate gene expression and morphogenesis of the eye. In this study, a highly specific antagonist of retinoic acid receptor (RAR)-alpha was used in an attempt to study its function in lens regeneration. It was found that this antagonist inhibited lens regeneration and lens fiber differentiation. It was also shown that RAR-alpha is expressed in the lens during the process of regeneration. These results indicate that different RAR might have unique as well as redundant effects and patterns of expression in the regenerating lens.
PMID: 12392572 [PubMed - indexed for MEDLINE]
|
|
|
|
Post by Max on Jun 30, 2005 7:58:27 GMT -5
J Cataract Refract Surg. 2005 Mar;31(3):595-606. Related Articles, Links
Upregulation of alphavbeta6 integrin, a potent TGF-beta1 activator, and posterior capsule opacification.
Sponer U, Pieh S, Soleiman A, Skorpik C.
Department of Ophthalmology and Optometrics, General Hospital, University of Vienna, Austria.
PURPOSE: To identify the predominant activation pathway of transforming growth factor (TGF)-beta1 in the lens capsule, studying the spatial and temporal expression pattern of alphavbeta6 and thrombospondin-1. Other PCO-related proteins were also studied. SETTING: Departments of Ophthalmology and Optometrics and Clinical Pathology, Medical School, University of Vienna, Vienna, Austria. METHODS: The lens capsules of 12 human donor eyes were cultivated in a protein-free medium for up to 28 days (cultivated lens capsules [CLCs]) after lens extraction. Ten intact lenses (ILs) served as the control group and were also cultured. During the culture period, cell dynamics were observed by phase-contrast microscopy. Proteins were detected by double immunofluorescence on frozen sections. RESULTS: In ILs, alphavbeta6 was absent but 91.6% of the CLCs showed extensive staining. Remnant lens epithelial cells (LECs) expressed alphavbeta6 immediately after lens extraction. The alphavbeta6 was detected throughout the culture period in all regions of the capsule. Thrombospondin-1 was absent in ILs and CLCs, suggesting that this protein is not significant in TGF-beta1 activation in the lens. Transforming growth factor-beta1 was abundantly expressed in all ILs and CLCs, slightly decreasing during intensive LEC proliferation and migration. The TGF-beta receptor II (RII) was expressed equally in all specimens, decreasing with culture time. Nonresident extracellular matrix proteins and alpha-smooth muscle actin were partially detected in CLCs but not in ILs. Latent TGF-beta binding protein 1 and collagen III were absent in all specimens. All cells found in the cultures expressed vimentin and alphaB-crystallin (LEC markers). CONCLUSION: Alphavbeta6 is the main activator of TGF-beta1 in the lens capsule and represents a new target for PCO prevention.
PMID: 15811751 [PubMed - indexed for MEDLINE]
|
|
|
|
Post by Max on Jun 30, 2005 8:00:13 GMT -5
Prog Retin Eye Res. 2005 Jan;24(1):87-138. Related Articles, Links
The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina.
SanGiovanni JP, Chew EY.
Division of Epidemiology and Clinical Research, National Eye Insitute, National Institutes of Health, 31 Center Drive, Building 31, Room 6A52, MSC 2510, Bethesda, MD 20892-2510, USA. jpsangio@nei.nih.gov
In this work we advance the hypothesis that omega-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) exhibit cytoprotective and cytotherapeutic actions contributing to a number of anti-angiogenic and neuroprotective mechanisms within the retina. omega-3 LCPUFAs may modulate metabolic processes and attenuate effects of environmental exposures that activate molecules implicated in pathogenesis of vasoproliferative and neurodegenerative retinal diseases. These processes and exposures include ischemia, chronic light exposure, oxidative stress, inflammation, cellular signaling mechanisms, and aging. A number of bioactive molecules within the retina affect, and are effected by such conditions. These molecules operate within complex systems and include compounds classified as eicosanoids, angiogenic factors, matrix metalloproteinases, reactive oxygen species, cyclic nucleotides, neurotransmitters and neuromodulators, pro-inflammatory and immunoregulatory cytokines, and inflammatory phospholipids. We discuss the relationship of LCPUFAs with these bioactivators and bioactive compounds in the context of three blinding retinal diseases of public health significance that exhibit both vascular and neural pathology. How is omega-3 LCPUFA status related to retinal structure and function? Docosahexaenoic acid (DHA), a major dietary omega-3 LCPUFA, is also a major structural lipid of retinal photoreceptor outer segment membranes. Biophysical and biochemical properties of DHA may affect photoreceptor membrane function by altering permeability, fluidity, thickness, and lipid phase properties. Tissue DHA status affects retinal cell signaling mechanisms involved in phototransduction. DHA may operate in signaling cascades to enhance activation of membrane-bound retinal proteins and may also be involved in rhodopsin regeneration. Tissue DHA insufficiency is associated with alterations in retinal function. Visual processing deficits have been ameliorated with DHA supplementation in some cases. What evidence exists to suggest that LCPUFAs modulate factors and processes implicated in diseases of the vascular and neural retina? Tissue status of LCPUFAs is modifiable by and dependent upon dietary intake. Certain LCPUFAs are selectively accreted and efficiently conserved within the neural retina. On the most basic level, omega-3 LCPUFAs influence retinal cell gene expression, cellular differentiation, and cellular survival. DHA activates a number of nuclear hormone receptors that operate as transcription factors for molecules that modulate reduction-oxidation-sensitive and proinflammatory genes; these include the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and the retinoid X receptor. In the case of PPAR-alpha, this action is thought to prevent endothelial cell dysfunction and vascular remodeling through inhibition of: vascular smooth muscle cell proliferation, inducible nitric oxide synthase production, interleukin-1 induced cyclooxygenase (COX)-2 production, and thrombin-induced endothelin 1 production. Research on model systems demonstrates that omega-3 LCPUFAs also have the capacity to affect production and activation of angiogenic growth factors, arachidonic acid (AA)-based vasoregulatory eicosanoids, and MMPs. Eicosapentaenoic acid (EPA), a substrate for DHA, is the parent fatty acid for a family of eicosanoids that have the potential to affect AA-derived eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and inflammation. EPA depresses vascular endothelial growth factor (VEGF)-specific tyrosine kinase receptor activation and expression. VEGF plays an essential role in induction of: endothelial cell migration and proliferation, microvascular permeability, endothelial cell release of metalloproteinases and interstitial collagenases, and endothelial cell tube formation. The mechanism of VEGF receptor down-regulation is believed to occur at the tyrosine kinase nuclear factor-kappa B (NFkappaB). NFkappaB is a nuclear transcription factor that up-regulates COX-2 expression, intracellular adhesion molecule, thrombin, and nitric oxide synthase. All four factors are associated with vascular instability. COX-2 drives conversion of AA to a number angiogenic and proinflammatory eicosanoids. Our general conclusion is that there is consistent evidence to suggest that omega-3 LCPUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, and age-associated pathology of the vascular and neural retina.
Publication Types:
Review
PMID: 15555528 [PubMed - indexed for MEDLINE]
|
|
|
|
Post by Max on Jul 12, 2005 16:40:10 GMT -5
Brain Res. 2005 Jun 7;1046(1-2):207-15. Related Articles, Links
Calpain and N-methyl-d-aspartate (NMDA)-induced excitotoxicity in rat retinas.
Chiu K, Lam TT, Ying Li WW, Caprioli J, Kwong Kwong JM.
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong.
Calpain-mediated proteolysis has been implicated as a major process in neuronal cell death in both acute insults and the chronic neurodegenerative disorders in the central nerves system. However, activation of calpain also plays a protective function in the early phase of excitotoxic neuronal death. The exact role of calpains in neuronal death and recovery after exposure to N-methyl-D-aspartate (NMDA) is not clearly known. The purpose of present study was to examine the involvement of mu- and m-calpain in NMDA-induced excitotoxicity in the adult rat retina. Increased immunoreactivity of mu-calpain was noted in RGC layer cells and in the inner nuclear layer with maximal expression at 12 h after NMDA injection. This was further confirmed with Western blotting. TdT-mediated biotin-dUTP nick end labeling (TUNEL) positive cells in the inner retina co-localized with moderate or intense mu-calpain immunoreactivity. In contrast, there was no remarkable change in m-calpain immunoreactivity at any time point after NMDA injection. Simultaneous injection of 2 nmol of a calpain inhibitor (calpain inhibitor II) significantly reduced the number of TUNEL-positive cells in the inner retina at 18 h after NMDA injection and preserved RGC-like cells counted at 7 days after injection. The results of this study showed that mu-calpain may be involved in mediating NMDA-induced excitotoxicity in the rat retina and calpain inhibitors may play a therapeutic role in NMDA related disease.
PMID: 15878434 [PubMed - in process]
|
|
|
|
Post by Max on Jul 12, 2005 16:41:20 GMT -5
Cell Death Differ. 2005 Jul;12(7):796-804. Related Articles, Links
Multiple death pathways in retina-derived 661W cells following growth factor deprivation: crosstalk between caspases and calpains.
Gomez-Vicente V, Donovan M, Cotter TG.
1Cell Development and Disease Laboratory, Department of Biochemistry, Biosciences Research Institute, University College Cork, Cork, Ireland.
During development of the mammalian retina, neurons that do not succeed in establishing functional synaptic connections are eliminated by apoptosis, allowing the formation of a finely tuned network. Growth factors play a crucial role in controlling the balance between apoptosis and survival signals not only at developmental stages but also in long-term preservation of retinal functions. In the present work, we explore the apoptotic mechanisms triggered by growth factor deprivation of retina-derived 661W cells. Under serum starvation conditions, these cone photoreceptors underwent cell death with participation of caspase-9, -3 and -12. Interestingly, inhibition of caspases did not prevent apoptosis but only resulted in a temporary delay. We show m-calpain activation in parallel with caspases, indicating that more than one execution pathway is available to cone photoreceptors. Moreover, crosstalk of the caspase and calpain pathways was detected, suggesting a loop that may act to amplify the apoptotic cascade.Cell Death and Differentiation (2005) 12, 796-804. doi:10.1038/sj.cdd.4401621 Published online 22 April 2005.
PMID: 15846377 [PubMed - in process]
|
|
|
|
Post by Max on Jul 12, 2005 16:46:07 GMT -5
Photochem Photobiol. 2004 Jul-Aug;80:61-71. Related Articles, Links
Identification of genes responsive to UV-A radiation in human lens epithelial cells using complementary DNA microarrays.
Andley UP, Patel HC, Xi JH, Bai F.
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8096, St. Louis, MO 63110, USA. andley@vision.wustl.edu
UV-A radiation produces cataract in animals, enhances photoaging of the lens and skin and increases the phototoxicity of drugs. However, the nature of genes that are activated or repressed after cellular exposure to UV-A radiation remains enigmatic. Because lens epithelial cells exposed to UV-A radiation undergo apoptosis 4 h after exposure to the stress, we sought to establish the change in gene expression in cells by UV-A radiation using gene expression profiling using complementary DNA microarrays containing about 12 000 genes. We identified 78 genes abnormally expressed in UV-A-irradiated cells (showing >2.5-fold change at P < 0.05). These genes are implicated in various biological processes, including signal transduction and nucleic acid binding, and genes encoding enzymes. A majority of the genes were downregulated. Our analysis revealed that the expression of genes for the transcription factors ATF-3 and Pilot increased four-fold, whereas the gene for the apoptosis regulator NAPOR-1 decreased five-fold. These changes were confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction. The calpain large polypeptide 3 (CANP3) gene also increased nine-fold after UV-A radiation. In addition, peroxisomal biogenesis factor 7, glucocorticoid receptor-alpha and tumor-associated calcium signal transducer genes decreased three- to eight-fold. Western blot analysis further confirmed the increase in protein expression of ATF-3 and CANP3 and decreased expression of glucocorticoid receptor-alpha in the irradiated cells. Surprisingly, most of these genes had not been previously shown to be modulated by UV-A radiation. Our results show that human lens epithelial cells respond to a single dose of UV-A radiation by enhancing or suppressing functionally similar sets of genes, some of which have opposing functions, around the time at which apoptosis occurs. These studies support the intriguing concept that activation of competing pathways favoring either cell survival or death is a means to coordinate the response of cells to UV-A stress.
PMID: 15339208 [PubMed - indexed for MEDLINE]
|
|
|
|
Post by Max on Jul 12, 2005 16:52:31 GMT -5
J Zhejiang Univ Sci. 2004 Jun;5(6):743-8. Related Articles, Links
Expression and proteolytic activity of calpain in lens epithelial cells of oxidative cataract.
Xu W, Yao K, Sun ZH, Wang KJ, Shentu XC.
Eye Center, Second Affiliated Hospital, Medical College, Zhejiang University, Hangzhou 310009, China.
OBJECTIVE: To study the role of calpain in the mechanism of oxidative cataract through detecting the level of intracellular free Ca(2+), the expression and proteolytic activity of calpain in the lens epithelial cells (LECs) of H(2)O(2)-induced cataract. METHODS: Rat lenses were cultured in vitro and cataract was induced by H(2)O(2). The level of intracellular free Ca(2+) was measured by fluorescence determination with fura-2/AM. The expression of m-calpain protein in LECs was detected with immunohistochemical method. The proteolytic activity in LECs was measured using a fluorogenic synthetic substrate. RESULTS: There were significant differences of the level of intracellular free Ca(2+) (P=0.001, 0.000, 0.000), the expression of m-calpain (P=0.001, 0.000, 0.000) and the proteolytic activity of calpain (P=0.001, 0.000, 0.000) between H(2)O(2)-induced and control group at 6, 12 and 24 h, respectively. CONCLUSIONS: H(2)O(2) can increase intracellular free Ca(2+), then enhance the expression and proteolytic activity of calpain which may play a role in the mechanism of oxidative cataract of rat.
PMID: 15101113 [PubMed - indexed for MEDLINE]
|
|
|
|
Post by adfa on May 4, 2010 11:38:35 GMT -5
|
|
|
|
Post by adfa on May 4, 2010 11:41:08 GMT -5
|
|
|
|
Post by find on May 5, 2010 9:39:17 GMT -5
|
|
|
|
Post by jiejees on Oct 31, 2011 3:55:11 GMT -5
Straighteners cheap GHD cheap GHD stock all GHD Hair styles Low Price, GHD Outlet GHD Outlet Sale free shipping, Fast Delivery, High Quality GHD UK GHD UK sale. |
|
|
|
Post by kfkjfkf on Sept 7, 2018 19:36:48 GMT -5
|
|
