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Nl 4th and 5th-09

Newsletter No 4 and 5/2009 (July and September 2009) 1. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair. The influence of peritoneal endometriotic lesions on the generation of endometriosis-related pain and pain reduction after surgical excision. Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study. Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis
1. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair.
INTRODUCTION: This study presents a unifying concept of the pathophysiology of
endometriosis and adenomyosis. In particular, a physiological model is proposed that
provides a comprehensive explanation of the local production of estrogen at the level of
ectopic endometrial lesions and the endometrium of women affected with the disease.
METHODS: In women suffering from endometriosis and adenomyosis and in normal
controls, a critical analysis of uterine morphology and function was performed using
immunohistochemistry,
molecular biology as well as clinical aspects. The relevant molecular biologic aspects were compared to those of tissue injury and repair (TIAR) mechanisms reported in literature. RESULTS AND CONCLUSIONS: Circumstantial evidence suggests that endometriosis and adenomyosis are caused by trauma. In the spontaneously developing disease, chronic uterine peristaltic activity or phases of hyperperistalsis induce, at the endometrial-myometrial interface near the fundo-cornual raphe, microtraumatizations with the activation of the mechanism of 'tissue injury and repair' (TIAR). This results in the local production of estrogen. With ongoing peristaltic activity, such sites might increase and the increasingly produced estrogens interfere in a paracrine fashion with the ovarian control over uterine peristaltic activity, resulting in permanent hyperperistalsis and a self-perpetuation of the disease process. Overt auto-traumatization of the uterus with dislocation of fragments of basal endometrium into the peritoneal cavity and infiltration of basal endometrium into the depth of the myometrial wall ensues. In most cases of endometriosis/adenomyosis, a causal event early in the reproductive period of life must be postulated leading rapidly to uterine hyperperistalsis. In late premenopausal adenomyosis, such an event might not have occurred. However, as indicated by the high prevalence of the disease, it appears to be unavoidable that, with time, chronic normoperistalsis throughout the reproductive period of life leads to the same extent of microtraumatization. With the activation of the TIAR mechanism endometriosis/adenomyosis of the younger woman and premenopausal adenomyosis share in principle the same pathophysiology. In conclusion, endometriosis and adenomyosis result from the physiological mechanism of 'tissue injury and repair' (TIAR) involving local estrogen production in an estrogen-sensitive environment normally controlled by the ovary. Reference Leyendecker G, Wildt L, Mall G. The pathophysiology of endometriosis and adenomyosis: tissue injury and repair. http://www.ncbi.nlm.nih.gov/pubmed/19644696?ordinalpos=1&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum This is a chronological list of our published scientific work that was
performed by our group over the last 15 years to elucidate the
pathophysiology of endometriosis and adenomyosis.
The article “Endometriosis and Adenomyosis – a shared Pathophysiology”
is in press (Proceedings of the IVth International Congress on
Endometriosis, Rome May 29-30, 2009). In addition to the new concept of
“tissue injury and repair” (TIAR) it presents some historical remarks that
might be of interest to the reader.
http://www.gerhard-leyendecker.de/fileadmin/EndometriosisAndAdenomyosis.pdf
Leyendecker G, Wildt L, Mall G.
The pathophysiology of endometriosis and adenomyosis: tissue injury and repair.
Arch
http://www.ncbi.nlm.nih.gov/pubmed/19644696?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Kunz G, Herbertz M, Beil D, Huppert P, Leyendecker G. Adenomyosis as a disorder of the early and late human reproductive period Reprod Biomed Online. 2007 Dec;15(6):681-5. . http://www.ncbi.nlm.nih.gov/pubmed/18062865?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Kunz G, Beil D, Huppert P, Leyendecker G. Oxytocin--a stimulator of directed sperm transport in humans. Reprod Biomed Online. 2007 Jan;14(1):32-9. http://www.ncbi.nlm.nih.gov/pubmed/17207329?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Leyendecker G, Kunz G, Kissler S, Wildt L. Adenomyosis and reproduction Best Pract Res Clin Obstet Gynaecol. 2006 Aug;20(4):523-46. http://www.ncbi.nlm.nih.gov/pubmed/16520094?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum G, Kunz G, Herbertz M, Beil D, Huppert P, Mall G, Kissler S, Noe M, Wildt L. Uterine peristaltic activity and the development of endometriosis.Leyendecker Ann N Y Acad Sci. 2004 Dec;1034:338-55. http://www.ncbi.nlm.nih.gov/pubmed/15731324?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Kunz G, Beil D, Huppert P, Noe M, Kissler S, Leyendecker G Adenomyosis in endometriosis--prevalence and impact on fertility. Evidence from magnetic resonance imaging. Hum Reprod. 2005 Aug;20(8):2309-16. Epub 2005 May 26 http://www.ncbi.nlm.nih.gov/pubmed/15919780?ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Leyendecker G, Herbertz M, Kunz G, Mall G. Endometriosis results from the dislocation of basal endometrium Hum Reprod. 2002 Oct;17(10):2725-36. http://www.ncbi.nlm.nih.gov/pubmed/12351554?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Leyendecker G. Redefining endometriosis: Endometriosis is an entity with extreme pleiomorphism Hum Reprod. 2000 Jan;15(1):4-7. Review. No abstract available. http://humrep.oxfordjournals.org/cgi/reprint/15/1/4 .Kunz G, Beil D, Huppert P, Leyendecker G. Structural abnormalities of the uterine wall in women with endometriosis and infertility visualized by vaginal sonography and magnetic resonance imaging Hum Reprod. 2000 Jan;15(1):76-82. http://www.ncbi.nlm.nih.gov/pubmed/10611192?ordinalpos=16&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Noe M, Kunz G, Herbertz M, Mall G, Leyendecker G. The cyclic pattern of the immunocytochemical expression of oestrogen and progesterone receptors in human myometrial and endometrial layers: characterization of the endometrial-subendometrial unit. Hum Reprod. 1999 Jan;14(1):190-7. http://www.ncbi.nlm.nih.gov/pubmed/10374119?ordinalpos=18&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Leyendecker G, Kunz G, Noe M, Herbertz M, Mall G. Endometriosis: a dysfunction and disease of the archimetra.Leyendecker G, Kunz G, Noe M, Herbertz M, Mall G. Hum Reprod Update. 1998 Sep-Oct;4(5):752-62. Review. http://www.ncbi.nlm.nih.gov/pubmed/10027630?ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Kunz G, Herbertz M, Noe M, Leyendecker G. Sonographic evidence for the involvement of the utero-ovarian counter-current system in the ovarian control of directed uterine sperm transport. Hum Reprod Update. 1998 Sep-Oct;4(5):667-72. http://www.ncbi.nlm.nih.gov/pubmed/10027620?ordinalpos=20&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Kunz G, Noe M, Herbertz M, Leyendecker G. Uterine peristalsis during the follicular phase of the menstrual cycle: effects of oestrogen, antioestrogen and oxytocin. Hum Reprod Update. 1998 Sep-Oct;4(5):647-54 http://www.ncbi.nlm.nih.gov/pubmed/10027618?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Leyendecker G, Kunz G, Wildt L, Beil D, Deininger H. Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertility. Hum Reprod. 1996 Jul;11(7):1542-51. http://www.ncbi.nlm.nih.gov/pubmed/8671502?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Kunz G, Beil D, Deininger H, Wildt L, Leyendecker G The dynamics of rapid sperm transport through the female genital tract: evidence from vaginal sonography of uterine peristalsis and hysterosalpingoscintigraphy. Hum Reprod. 1996 Mar;11(3):627-32 http://www.ncbi.nlm.nih.gov/pubmed/8671281?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
2. The influence of peritoneal endometriotic lesions on the generation of
endometriosis-related pain and pain reduction after surgical excision.
PURPOSE: To investigate the influence of different kinds of endometriotic lesions, especially
peritoneal endometriotic implants in pain generation and the pain reduction after surgical
excision in a prospective study. METHODS: Fifty-one pre-menopausal patients underwent
surgical laparoscopy due to chronic pelvic pain, dysmenorrhoea and/or for ovarian cysts. In
44 patients, endometriosis was diagnosed. The pre- and post-operative pain score was
determined using a standardized questionnaire with a visual analogue scale. Patients with
peritoneal endometriosis were divided into two different groups depending on their pre-
operative pain score: group A had a pain score of 3 or more, while group B a pain score of 2
or less. Patients without peritoneal endometriosis were classified as group C, and patients
without endometriosis were classified as group D. The pre- and post-operative pelvic pain
and/or dysmenorrhoea was analysed according to the different types of endometriotic
lesions. RESULTS: In groups A and C, the post-operative pain score decreased by at least 2
grades or more (p < 0.0). In group D, the post-operative pain score showed no significant
reduction. CONCLUSION: The present study suggests that the surgical excision of
endometriotic lesions -- including peritoneal implants -- is an effective treatment of
endometriosis-associated pelvic pain and/or dysmenorrhoea.

Reference
Kaiser A, Kopf A, Gericke C, Bartley J, Mechsner S.
The influence of peritoneal endometriotic lesions on the generation of endometriosis-related
pain and pain reduction after surgical excision.
Arch Gynecol Obstet. 2009 Sep;280(3):369-73. Epub 2009 Jan 16.
http://www.ncbi.nlm.nih.gov/pubmed/19148660?ordinalpos=2&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
3. Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis
surgery may indicate adenomyosis
OBJECTIVE: To evaluate whether persistence of pelvic pain after excision of endometriosis
was associated with adenomyosis as defined by a thickened uterine junctional zone (JZ) on
magnetic resonance (MR) imaging. DESIGN: Prospective clinical trial. SETTING:
Government research hospital. PATIENT(S): Fifty-three women with chronic pelvic pain.
INTERVENTION(S): Preoperative MR imaging to measure uterine JZ thickness, surgical
excision, and pathologic diagnosis of endometriosis. Those with biopsy-proven
endometriosis were randomized to raloxifene or placebo. Visual analog scale (VAS) was
used to rate dysmenorrhea and nonmenstrual pain severity before surgery and 3 months
later. MAIN OUTCOME MEASURE(S): Comparison of JZ thickness and pain severity before
and 3 months after surgery in women with endometriosis controlling for medical treatment.
RESULT(S): Forty of the 53 patients had biopsy-proven endometriosis, and 6 of these 40
women with endometriosis had a thickened JZ. Overall, dysmenorrhea at 3 months was
positively correlated with preoperative JZ thickness (r = 0.47, P=.01). Dysmenorrhea pain
severity showed no significant decrease in those patients whose JZ measured >or=11 mm
compared with those with JZ <8 mm (P<.0001; VAS decreased 4.3 +/- 0.6), or >or=8 and
<11 mm (P<.02; VAS decreased 4.8 +/- 1.3). Nonmenstrual pain severity was correlated with
JZ thickness (r = 0.51, P=.004) at 3 months with a significant decrease in nonmenstrual pain
only in women with a JZ <8 mm (VAS decreased 4.0 +/- 0.7, P<.0001). The association
between dysmenorrhea and nonmenstrual pain reduction and thinner JZ remained after
controlling for medical treatment. CONCLUSION(S): Following surgical excision of
endometriosis, chronic pelvic pain was significantly more likely to persist with JZ thickness
>11mm on preoperative MR imaging. This suggests that myometrial JZ abnormalities or
adenomyosis may contribute to chronic pelvic pain in women with endometriosis.
Parker JD, Leondires M, Sinaii N, Premkumar A, Nieman LK, Stratton P.
Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery
may indicate adenomyosis
Fertil Steril 2006 Sep;86(3):711-5. Epub 2006 Jun 1
http://www.ncbi.nlm.nih.gov/pubmed/16782099?ordinalpos=19&itool=EntrezSystem2.PEntre
z.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
4. Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a
double blind study.
BACKGROUND Diagnosis of endometriosis currently requires a laparoscopy and this need
probably contributes to the considerable average delay in diagnosis. We have reported the
presence of nerve fibres in the functional layer of endometrium in women with endometriosis,
which could be used as a diagnostic test. Our aim was to assess efficacy of nerve fibre
detection in endometrial biopsy for making a diagnosis of endometriosis in a double-blind
comparison with expert diagnostic laparoscopy. METHODS Endometrial biopsies, with
immunohistochemical nerve fibre detection using protein gene product 9.5 as marker, taken
from 99 consecutive women presenting with pelvic pain and/or infertility undergoing
diagnostic laparoscopy by experienced gynaecologic laparoscopists, were compared with
surgical diagnosis. RESULTS In women with laparoscopic diagnosis of endometriosis (n =
64) the mean nerve fibre density in the functional layer of the endometrial biopsy was 2.7
nerve fibres per mm(2) (+/-3.5 SD). Only one woman with endometriosis had no detectable
nerve fibres. Six women had endometrial nerve fibres but no active endometriosis seen at
laparoscopy. The specificity and sensitivity were 83 and 98%, respectively, positive
predictive value was 91% and negative predictive value was 96%. Nerve fibre density did not
differ between different menstrual cycle phases. Women with endometriosis and pain
symptoms had significantly higher nerve fibre density in comparison with women with
infertility but no pain (2.3 and 0.8 nerve fibre per mm(2), respectively, P = 0.005).
CONCLUSIONS Endometrial biopsy, with detection of nerve fibres, provided a reliability of
diagnosis of endometriosis which is close to the accuracy of laparoscopic assessment by
experienced gynaecological laparoscopists. This study was registered with the Australian
Clinical Trials Registry (ACTR) 00082242 (registered: 12/12/2007). The study was approved
by the Ethics Review Committee (RPAH Zone) of the Sydney South West Area Health
Service (Protocol number X05-0345) and The University of Sydney Human Research Ethics
Committee (Ref. No. 10761) and all women gave their informed consent for participation.
Reference
Al-Jefout M, Dezarnaulds G, Cooper M, Tokushige N, Luscombe GM, Markham R, Fraser IS.
Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study.
Hum Reprod. 2009 Aug 18. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/19690352?ordinalpos=1&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
5. Density of small diameter sensory nerve fibres in endometrium: a semi-invasive
diagnostic test for minimal to mild endometriosis
BACKGROUND The aim of our study was to test the hypothesis that multiple-sensory small-
diameter nerve fibres are present in a higher density in endometrium from patients with
endometriosis when compared with women with a normal pelvis, enabling the development
of a semi-invasive diagnostic test for minimal-mild endometriosis. METHODS Secretory
phase
laparoscopically/histologically confirmed minimal-mild endometriosis (n = 20) and from women with a normal pelvis (n = 20) were selected from the biobank at the Leuven University Fertility Centre. Immunohistochemistry was performed to localize neural markers for sensory C, Adelta, adrenergic and cholinergic nerve fibres in the functional layer of the endometrium. Sections were immunostained with anti-human protein gene product 9.5 (PGP9.5), anti-neurofilament protein, anti-substance P (SP), anti-vasoactive intestinal peptide (VIP), anti-neuropeptide Y and anti-calcitonine gene-related polypeptide. Statistical analysis was done using the Mann-Whitney U-test, receiver operator characteristic analysis, stepwise logistic regression and least-squares support vector machines. RESULTS The density of small nerve fibres was approximately 14 times higher in endometrium from patients with minimal-mild endometriosis (1.96 +/- 2.73) when compared with women with a normal pelvis (0.14 +/- 0.46, P < 0.0001). CONCLUSIONS The combined analysis of neural markers PGP9.5, VIP and SP could predict the presence of minimal-mild endometriosis with 95% sensitivity, 100% specificity and 97.5% accuracy. To confirm our findings, prospective studies are required. Reference
Bokor A, Kyama CM, Vercruysse L, Fassbender A, Gevaert O, Vodolazkaia A, De Moor B,
Fülöp V, D'Hooghe T.
Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic
test for minimal to mild endometriosis
Hum Reprod. 2009 Aug 18. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/19690351?ordinalpos=1&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Further reading on nerve fibers and endometriosis:

Wang G, Tokushige N, Markham R, Fraser IS.
Rich innervation of deep infiltrating endometriosis.Wang G, Tokushige N, Markham R, Fraser
IS.
Hum Reprod. 2009 Apr;24(4):827-34. Epub 2009 Jan 16.
http://www.ncbi.nlm.nih.gov/pubmed/19151028?ordinalpos=5&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Macrophages and nerve fibres in peritoneal endometriosis.
Tran LV, Tokushige N, Berbic M, Markham R, Fraser IS.
Hum Reprod. 2009 Apr;24(4):835-41. Epub 2009 Jan 9.
http://www.ncbi.nlm.nih.gov/pubmed/19136478?ordinalpos=6&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Macrophage expression in endometrium of women with and without endometriosis.
Berbic M, Schulke L, Markham R, Tokushige N, Russell P, Fraser IS.
Hum Reprod. 2009 Feb;24(2):325-32. Epub 2008 Dec 1.
http://www.ncbi.nlm.nih.gov/pubmed/19049988?ordinalpos=7&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Tokushige N, Markham R, Russell P, Fraser IS.
Effect of progestogens and combined oral contraceptives on nerve fibers in peritoneal
endometriosis.
Fertil Steril. 2008 Oct 29. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/18976764?ordinalpos=8&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Effects of hormonal treatment on nerve fibers in endometrium and myometrium in women
with endometriosis.
Tokushige N, Markham R, Russell P, Fraser IS.
Fertil Steril. 2008 Nov;90(5):1589-98. Epub 2007 Dec 3.
http://www.ncbi.nlm.nih.gov/pubmed/18061173?ordinalpos=12&itool=EntrezSystem2.PEntre
z.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Mechsner S, Kaiser A, Kopf A, Gericke C, Ebert A, Bartley J.
A pilot study to evaluate the clinical relevance of endometriosis-associated nerve fibers in peritoneal endometriotic lesions. Fertil Steril. 2008 Nov 1. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/18980761?ordinalpos=4&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Al-Jefout M, Andreadis N, Tokushige N, Markham R, Fraser I. A pilot study to evaluate the relative efficacy of endometrial biopsy and full curettage in making a diagnosis of endometriosis by the detection of endometrial nerve fibers. Am J Obstet Gynecol. 2007 Dec;197(6):578.e1-4. http://www.ncbi.nlm.nih.gov/pubmed/18060940?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Mechsner S, Schwarz J, Thode J, Loddenkemper C, Salomon DS, Ebert AD.Growth-associated protein 43-positive sensory nerve fibers accompanied by immature vessels are located in or near peritoneal endometriotic lesions. Fertil Steril. 2007 Sep;88(3):581-7. Epub 2007 Apr 6. http://www.ncbi.nlm.nih.gov/pubmed/17412328?ordinalpos=1&itool=EntrezSystem2.PEntrez.
Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis. Tokushige N, Markham R, Russell P, Fraser IS. Fertil Steril. 2007 Oct;88(4):795-803. Epub 2007 Apr 23. http://www.ncbi.nlm.nih.gov/pubmed/17451690?ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Tokushige N, Markham R, Russell P, Fraser IS. Nerve fibres in peritoneal endometriosis. Hum Reprod. 2006 Nov;21(11):3001-7. Epub 2006 Sep 1. http://www.ncbi.nlm.nih.gov/pubmed/16950827?ordinalpos=16&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum Tokushige N, Markham R, Russell P, Fraser IS. High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum Reprod. 2006 Mar;21(3):782-7. Epub 2005 Oct 27. http://www.ncbi.nlm.nih.gov/pubmed/16253968?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Source: http://www.kinderwunschzentrum-da.de/admin/upload/pdf/nl_4th_and_5th_09.pdf

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