Publications by authors named "C Robert Valeri"

519 Publications

Molecular mechanisms underlying AMH elevation in hyperoestrogenic states in males.

Sci Rep 2020 09 15;10(1):15062. Epub 2020 Sep 15.

Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD, Buenos Aires, Argentina.

Anti-Müllerian hormone (AMH) is secreted by Sertoli cells of the testes from early fetal life until puberty, when it is downregulated by androgens. In conditions like complete androgen insensitivity syndrome (CAIS), AMH downregulation does not occur and AMH increases at puberty, due in part to follicle-stimulating hormone (FSH) effect. However, other conditions like Peutz-Jeghers syndrome (PJS), characterised by low FSH, also have increased AMH. Because both CAIS and PJS may present as hyperoestrogenic states, we tested the hypothesis that oestradiol (E2) upregulates AMH expression in peripubertal Sertoli cells and explored the molecular mechanisms potentially involved. The results showed that E2 is capable of inducing an upregulation of endogenous AMH and of the AMH promoter activity in the prepubertal Sertoli cell line SMAT1, signalling through ERα binding to a specific ERE sequence present on the hAMH promoter. A modest action was also mediated through the membrane oestrogen receptor GPER. Additionally, the existence of ERα expression in Sertoli cells in patients with CAIS was confirmed by immunohistochemistry. The evidence presented here provides biological plausibility to the hypothesis that testicular AMH production increases in clinical conditions in response to elevated oestrogen levels.
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http://dx.doi.org/10.1038/s41598-020-71675-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492256PMC
September 2020

A mutation inactivating the distal SF1 binding site on the human anti-Müllerian hormone promoter causes persistent Müllerian duct syndrome.

Hum Mol Genet 2019 10;28(19):3211-3218

Inserm UMR_S938, Centre de Recherche Saint Antoine, Sorbonne Université, IHU ICAN, Paris, France.

The persistent Müllerian duct syndrome (PMDS) is a 46,XY disorder of sexual development characterized by the persistence of Müllerian duct derivatives, uterus and tubes, in otherwise normally masculinized males. The condition, transmitted as a recessive autosomal trait, is usually due to mutations in either the anti-Müllerian hormone (AMH) gene or its main receptor. Many variants of these genes have been described, all targeting the coding sequences. We report the first case of PMDS due to a regulatory mutation. The AMH promoter contains two binding sites for steroidogenic factor 1 (SF1), one at -102 and the other at -228. Our patient carries a single base deletion at -225, significantly decreasing its capacity for binding SF1, as measured by the electrophoresis mobility shift assay. Furthermore, by linking the AMH promoter to the luciferase gene, we show that the transactivation capacity of the promoter is significantly decreased by the mutation, in contrast to the disruption of the -102 binding site. To explain the difference in impact we hypothesize that SF1 could partially overcome the lack of binding to the -102 binding site by interacting with a GATA4 molecule linked to a nearby response element. We show that disruption of both the -102 SF1 and the -84 GATA response elements significantly decreases the transactivation capacity of the promoter. In conclusion, we suggest that the distance between mutated SF1 sites and potentially rescuing GATA binding motifs might play a role in the development of PMDS.
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http://dx.doi.org/10.1093/hmg/ddz147DOI Listing
October 2019

Evidence for the Detection of Subclinical Retinal Involvement in Systemic Lupus Erythematosus and Sjögren Syndrome: A Potential Association with Therapies.

Int Arch Allergy Immunol 2018 14;177(1):45-56. Epub 2018 Jun 14.

Ophthalmology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy.

Background: Retinal involvement in systemic lupus erythematosus (SLE) and Sjögren syndrome (SS) may be subclinical and thus underdiagnosed.

Objectives: We aimed at evaluating morphological and functional visual abnormalities in a cohort of SLE and SS patients in the absence of an overt clinical visual impairment. We also investigated potential associations between retinal disorders and disease activity, organ involvement, and treatment with steroid and/or hydroxychloroquine.

Methods: The study comprised 42 SLE and 36 primary SS patients and 76 healthy controls (HC). Ophthalmological examination, standard automated perimetry, spectral-domain optical coherence tomography, and fundus perimetry were performed.

Results: Retinal thickness of the posterior pole was not different between SLE and HC groups, but it was reduced in the SS group compared with both the HC and the SLE group. In SLE and SS patients, mean defect and pattern standard deviation by standard automated perimetry were higher than in HC. Visual field index values were lower in both SLE and SS patients than in HC. SLE patients with nephritis displayed increased mean defect and pattern standard deviation and reduced visual field index values compared to patients without nephritis. In SLE and SS patients, fundus perimetry differential sensitivity was reduced, and mean defect values were higher than in HC. Disturbances in fundus perimetry in the SLE group were more prevalent in steroid-naïve patients and in SS patients who received a cumulative hydroxychloroquine dose > 1,000 g.

Conclusions: Functional eye impairment was demonstrated in SLE patients, possibly associated with kidney involvement. In SLE, corticosteroids might exert a protective role. Morphological alterations and functional impairment were detected in SS patients, which may be linked to hydroxychloroquine toxicity.
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http://dx.doi.org/10.1159/000488950DOI Listing
September 2018

Commentary on 50 years of research at the NBRL, Boston, Massachusetts.

Transfus Apher Sci 2016 Feb 22;54(1):16-20. Epub 2016 Jan 22.

NBRL Inc, 372 Ocean Ave, Marblehead, MA 01945, United States.

Research at the NBRL, Boston, MA over the past 50 years assessed the survival and function of RBC and platelets and the function of plasma clotting proteins. Liquid preserved RBC can be stored at 4 °C for only 2 weeks to maintain a 24-hour posttransfusion survival value of 75%, moderately impaired oxygen transport function after transfusion, exert a hemostatic effect, and increase the plasma volume. Liquid preserved platelets can be stored at room temperature with agitation for only 2 days to have acceptable in vivo survival 2 hours following transfusion, normal lifespan, and a hemostatic effect to reduce the bleeding time in thrombocytopenic patients. RBCs frozen with 40% W/V glycerol at -80 °C for at least 10 years, thawed, and deglycerolized in the Haemonetics ACP215 can be stored in Nutricel at 4 °C for 2 weeks with a 24-hour posttransfusion survival of 75%, moderately impaired oxygen transport function after transfusion, exert a hemostatic effect and increase the plasma volume. Leukoreduced single donor platelets treated with 6% DMSO, the supernatant DMSO removed prior to freezing at -80 °C for 2 years, thawed, and diluted with 0.9% NaCl or AB plasma have a bimodal population of platelets: one population has reduced in vivo survival, but increased hemostatic effect and the other has normal in vivo survival. AB plasma can be stored at -80 °C for at least 14 years, thawed, and stored at 4 °C for 24 hours with acceptable in vitro function of clotting proteins. The data reported by the NBRL, Boston, Mass. over the past 50 years and the 15-year experience by the Netherlands military now recommend that FDA, ARC, HHS and DOD should support the use of universal donor frozen group O Rh positive and group O Rh negative RBC, frozen group O platelets and frozen AB plasma from male donors. The frozen blood products will eliminate the severe adverse events of mortality and morbidity associated with the current FDA approved red blood cell products, platelet products, and plasma.
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http://dx.doi.org/10.1016/j.transci.2016.01.004DOI Listing
February 2016

Ovarian Stimulation Protocol in IVF: An Up-to-Date Review of the Literature.

Curr Pharm Biotechnol 2016 ;17(4):303-15

CIVF Center Doha Center Clinic Hospital Doha, Qatar.

The Assisted Reproductive Technology (ART) was born in order to help couples with infertility issues in having a baby. The first treatments of IVF used the spontaneous cycle of the women, with the retrieval of only one oocyte. Further studies have shown that it is possible to induce ovulation by administrating gonadotropins during the menstrual cycle, in order to obtain a higher number of oocytes. Many stimulation protocols have been introduced for controlled ovarian hyperstimulation of patients undergoing in vitro fertilization treatment. This review describe the different stimulation protocols using follicle-stimulating hormone (FSH) in combination with Gonadotropin releasing hormone (GnRH) either agonist or antagonist, oral supplementations and ovarian triggering. Using GnRH antagonist protocols have been demonstrated to improve significantly the clinical pregnancy rates for expected poor and high-responders, and in those women at high risk of developing ovarian hyperstimulation syndrome (OHSS). Two meta-analyses showed a better outcome in terms of the live birth rate when highly purified human menopausal gonadotropin (HMG) was used for ovarian stimulation compared with recombinant follicle stimulating hormone (rFSH) in the GnRH agonist long protocol. One of the most efficient stimulation protocol is the use of a combined protocol of human derived urinary FSH (uFSH) and rFSH. Combined protocol has resulted in a significant increase in the proportion of mature metaphase II oocytes and grade 1 embryos when compared to either rFSH or uFSH alone. A significantly higher delivery rate was achieved in rFSH+uFSH compared to the other protocols in poor and normal responders. Studying the combination of melatonin with myo-inositol and folic acid has also showed a higher percentage of mature oocytes in the melatonin group and a higher percentage of G1 embryos as well. However, It remains a crucial step to confirm the efficacy of such protocols for clinical application and it is still needs to comparison studies on larger scale with more focused on the differences in patients' response criteria and additional confounding variables, in order to draw more defined conclusions.
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http://dx.doi.org/10.2174/1389201017666160118103147DOI Listing
August 2016

Fas and Fas-Ligand in Eutopic and Ectopic Endometrium of Women With Endometriosis: The Possible Immune Privilege of Ectopic Endometrium.

Reprod Sci 2016 Jan 7;23(1):81-6. Epub 2015 Jul 7.

Praxi Provita, Praxis DS, Rome, Italy Department of Urologic and Gynaecologic Science, University of Sapienza, Rome, Italy.

The Fas/Fas-Ligand system is an important mediator of apoptosis. We analyzed their expression in tissue specimens obtained from 33 women with severe endometriosis and 18 women without endometriosis. Immunostaining for Fas-Ligand in the eutopic endometrium was stronger in the epithelial cells of secretory phase, while the epithelial cells of endometriotic lesions showed a significantly stronger staining for Fas-Ligand independently from the menstrual phase (P < 0.01). Immunostaining for Fas in the eutopic endometrium showed a reduced staining during the proliferative phase, whereas it was strong in the secretory phase. The epithelial cells of the ectopic endometrium showed a reduced staining for Fas independently from the menstrual phase with respect to the eutopic tissue (P < 0.01). The reduced expression of Fas in the ectopic endometrium with the contemporary higher expression of Fas-Ligand in the corresponding cells suggests a possible immune privilege of this tissue.
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http://dx.doi.org/10.1177/1933719115594019DOI Listing
January 2016

Response to the Article on Dimethyl Sulfoxide-Cryopreserved Platelets Published in Transfusion Medicine Reviews Volume 28(4).

Transfus Med Rev 2015 Jul 26;29(3):205-6. Epub 2015 Mar 26.

Naval Blood Research Laboratory, Plymouth, MA.

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http://dx.doi.org/10.1016/j.tmrv.2015.03.005DOI Listing
July 2015

In situ evidence of pulmonary endothelial activation in patients with granulomatosis with polyangiitis and systemic sclerosis.

Lung 2015 Jun 19;193(3):355-9. Epub 2015 Mar 19.

Pulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, Av Dr Eneas de Carvalho Aguiar, 44 - 5º andar, Bloco II (secretaria de pneumologia), São Paulo, SP, 05403-900, Brazil,

Introduction: The aim of this study was to investigate the in situ pulmonary endothelial activation in lung lesions of granulomatosis with polyangiitis (GPA) and systemic sclerosis (SScl).

Methods: We examined the endothelial expression of ICAM-1, VCAM-1, and E-selectin using immunohistochemistry on formalin-fixed, paraffin-embedded sections of lung lesions of GPA, interstitial lung disease associated with SScl and controls.

Results: A significantly enhanced expression of ICAM-1 and E-selectin was observed in GPA and SScl pulmonary endothelium compared to controls. VCAM-1 was more pronouncedly expressed in GPA compared to SScl.

Conclusion: These observations are an evidence of in situ pulmonary vascular endothelial activation in lesions of GPA and SScl, adding information to the pathogenic knowledge of both diseases.
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http://dx.doi.org/10.1007/s00408-015-9718-6DOI Listing
June 2015

Spreading the clinical window for diagnosing fetal-onset hypogonadism in boys.

Front Endocrinol (Lausanne) 2014 7;5:51. Epub 2014 May 7.

Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET, FEI, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez , Buenos Aires , Argentina.

In early fetal development, the testis secretes - independent of pituitary gonadotropins - androgens and anti-Müllerian hormone (AMH) that are essential for male sex differentiation. In the second half of fetal life, the hypothalamic-pituitary axis gains control of testicular hormone secretion. Follicle-stimulating hormone (FSH) controls Sertoli cell proliferation, responsible for testis volume increase and AMH and inhibin B secretion, whereas luteinizing hormone (LH) regulates Leydig cell androgen and INSL3 secretion, involved in the growth and trophism of male external genitalia and in testis descent. This differential regulation of testicular function between early and late fetal periods underlies the distinct clinical presentations of fetal-onset hypogonadism in the newborn male: primary hypogonadism results in ambiguous or female genitalia when early fetal-onset, whereas it becomes clinically undistinguishable from central hypogonadism when established later in fetal life. The assessment of the hypothalamic-pituitary-gonadal axis in male has classically relied on the measurement of gonadotropin and testosterone levels in serum. These hormone levels normally decline 3-6 months after birth, thus constraining the clinical evaluation window for diagnosing male hypogonadism. The advent of new markers of gonadal function has spread this clinical window beyond the first 6 months of life. In this review, we discuss the advantages and limitations of old and new markers used for the functional assessment of the hypothalamic-pituitary-testicular axis in boys suspected of fetal-onset hypogonadism.
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http://dx.doi.org/10.3389/fendo.2014.00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019849PMC
June 2014

The prepubertal testis: biomarkers and functions.

Curr Opin Endocrinol Diabetes Obes 2013 Jun;20(3):224-33

Centro de Investigaciones Endocrinológicas (CEDIE), División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.

Purpose Of Review: Biomarkers of prepubertal testicular function have become widely available only in recent years. The aim of this review is to update the knowledge on key biomarkers used to assess hypogonadism in boys.

Recent Findings: Sertoli cells are the most representative cells of the prepubertal testis. Anti-Müllerian hormone and inhibin B are essential biomarkers of Sertoli cell function. Also, INSL3 arises as an additional marker of Leydig cell dysfunction.

Summary: The widespread use of these biomarkers has enhanced our knowledge on the pathophysiology and diagnosis of prepubertal male hypogonadism. Beyond their well known germ-cell toxicity, oncologic treatments may also affect Sertoli cell function. Pathophysiology is not the same in all aneuploidies leading to infertility: while hypogonadism is not evident until mid-puberty in Klinefelter syndrome, it is established in early infancy in Down syndrome. In Noonan syndrome, the occurrence of primary hypogonadism depends on the existence of cryptorchidism, and Prader-Willi syndrome may present with either primary or combined forms of hypogonadism. Prepubertal testicular markers have also provided insights into the effects of environmental disruptors on gonadal function from early life, and helped dissipate concerns about testicular function in boys born preterm or small for gestational age or conceived by assisted reproductive technique procedures.
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http://dx.doi.org/10.1097/MED.0b013e328360be2cDOI Listing
June 2013

The mitochondrial permeability transition pore provides a key to the diagnosis and treatment of traumatic brain injury.

IUBMB Life 2012 Feb;64(2):203-7

Laboratory of Metabolic Control, NIAAA, NIH, Rockville, MD 20852, USA.

The pathological consequences of traumatic head injury result largely from the opening of the mitochondrial permeability transition pore (mPTP). The mPTP opens due to a decrease in brain phosphorylation energy resulting in a further decrease in brain ATP production and a measurable increase in brain heat generation and temperature. The increase in brain temperature can be measured transcranially by near infrared spectroscopy which can be used to diagnose traumatic brain injury (TBI) and to monitor treatment. Effective therapy of TBI can be achieved by closure of the mPTP by administration of cyclosporine A or by oral administration of ketone body esters. While ketosis has previously been known to prevent damage from TBI, the availability of oral ketone esters presents the first practical modality of achieving therapeutic levels of ketone bodies.
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http://dx.doi.org/10.1002/iub.590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272646PMC
February 2012

Poly-N-acetyl glucosamine fibers induce angiogenesis in ADP inhibitor-treated diabetic mice.

J Trauma 2011 Aug;71(2 Suppl 1):S183-6

Department of Plastic Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.

Background: It has been previously demonstrated that short-fiber poly-N-acetyl-glucosamine (sNAG) nanofibers specifically interact with platelets, are hemostatic, and stimulate diabetic wound healing by activating angiogenesis, cell proliferation, and reepithelialization. Platelets play a significant physiologic role in wound healing. The influence of altered platelet function by treatment with the ADP inhibitor Clopidogrel (CL) on wound healing and the ability of sNAG to repair wounds in diabetic mice treated with CL were studied.

Methods: Dorsal 1 cm2 skin wounds were excised on genetically diabetic 8-week to 12-week-old, Lep/r-db/db male mice, and wound healing kinetics were determined. Microscopic analysis was performed for angiogenesis (PECAM-1) and cell proliferation (Ki67). Mice were either treated with CL (P2Y12 ADP receptor antagonist, CL) or saline solution (NT). CL wounds were also treated with either a single application of topical sNAG (CL-sNAG) or were left untreated (CL-NT).

Results: CL treatment did not alter wound healing kinetics, while sNAG induced faster wound closure in CL-treated mice compared with controls. CL treatment of diabetic mice caused an augmentation of cell proliferation and reduced angiogenesis compared with nontreated wounds. However, sNAG reversed the effects of CL on angiogenesis and partially reversed the effect on cell proliferation in the wound beds. The sNAG-treated wounds in CL-treated mice showed higher levels of cell proliferation and not did inhibit angiogenesis.

Conclusions: CL treatment of diabetic mice decreased angiogenesis and increased cell proliferation in wounds but did not influence macroscopic wound healing kinetics. sNAG treatment did not inhibit angiogenesis in CL-treated mice and induced faster wound closure; sNAG technology is a promising strategy to facilitate the healing of complex bleeding wounds in CL-treated diabetic patients.
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http://dx.doi.org/10.1097/TA.0b013e318225585bDOI Listing
August 2011

Poly-N-acetyl glucosamine fibers are synergistic with vacuum-assisted closure in augmenting the healing response of diabetic mice.

J Trauma 2011 Aug;71(2 Suppl 1):S187-93

Division of Plastic and Reconstructive Surgery, University Hospitals of Basel and Lausanne, Switzerland.

Background: Vacuum-assisted closure (VAC) has become the preferred modality to treat many complex wounds but could be further improved by methods that minimize bleeding and facilitate wound epithelialization. Short fiber poly-N-acetyl glucosamine nanofibers (sNAG) are effective hemostatic agents that activate platelets and facilitate wound epithelialization. We hypothesized that sNAG used in combination with the VAC device could be synergistic in promoting wound healing while minimizing the risk of bleeding.

Methods: Membranes consisting entirely of sNAG nanofibers were applied immediately to dorsal excisional wounds of db/db mice followed by application of the VAC device. Wound healing kinetics, angiogenesis, and wound-related growth factor expression were measured.

Results: The application of sNAG membranes to wounds 24 hours before application of the VAC device was associated with a significant activation of wounds (expression of PDGF, TGFβ, EGF), superior granulation tissue formation rich in Collagen I as well as superior wound epithelialization (8.6% ± 0.3% vs. 1.8% ± 1.1% of initial wound size) and wound contraction.

Conclusions: The application of sNAG fiber-containing membranes before the application of the polyurethane foam interface of VAC devices leads to superior healing in db/db mice and represents a promising wound healing adjunct that can also reduce the risk of bleeding complications.
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http://dx.doi.org/10.1097/TA.0b013e318225583cDOI Listing
August 2011

Poly-N-acetyl glucosamine fibers accelerate hemostasis in patients treated with antiplatelet drugs.

J Trauma 2011 Aug;71(2 Suppl 1):S176-82

Francis Owen Blood Research Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27516, USA.

Background: Nanofibers consisting of poly-N-acetyl glucosamine (pGlcNAc), as the functional component of products for surface hemostasis, have been shown to activate platelets and thereby the clotting mechanism. The nanofiber-activated platelets provide a catalytic surface for acceleration of the intrinsic coagulation cascade, thrombin generation, and fibrin polymerization.

Methods: Thromboelastographic analysis was undertaken to study the role of the pGlcNAc nanofibers in platelet activation and acceleration of fibrin polymerization. Thromboelastographic studies were performed without added activators of coagulation.

Results: The pGlcNAc nanofibers were found to accelerate fibrin polymerization in whole blood and platelet-rich plasma. Treatment with eptifibatide (an inhibitor of the platelet GPIIbIIIa receptor) and corn trypsin inhibitor inhibited clotting of whole blood and platelet-rich plasma. The inhibition was reversed by treatment with pGlcNAc nanofibers. Inhibition was not observed after treatment with aspirin alone, MRS2359 (platelet ADP receptor inhibitor), or by a combination of aspirin and MRS2359. The pGlcNAc nanofibers accelerate clotting in normal blood treated with aspirin and MRS2359. Clopidogrel (Plavix) and aspirin did not affect the kinetics of pGlcNAc-mediated fibrin polymerization in blood from patients treated with antiplatelet drugs compared with nontreated blood.

Conclusions: These results provide evidence that pGlcNAc nanofibers activate platelets and accelerate the clotting of blood, and on how best to achieve surface hemostasis when patients are coagulopathic because of shock and/or to treatment with antiplatelet drugs.
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http://dx.doi.org/10.1097/TA.0b013e318225570dDOI Listing
August 2011

mRDH bandage for surgery and trauma: data summary and comparative review.

J Trauma 2011 Aug;71(2 Suppl 1):S162-6

Naval Blood Research Laboratory, Inc., Boston, Massachusetts, USA.

Background: Bleeding often poses significant life-threatening situations to surgeons. After trauma, a one-third of civilian casualties and one-half of combat casualties die as a result of exsanguination. Recent advances have provided promising new hemostatic dressings that are applied directly to severely bleeding wounds in the pre-hospital period.

Methods: The modified Rapid Deployment Hemostat (mRDH) trauma/surgery bandage, containing fully acetylated, diatom-derived, poly-N-acetyl-glucosamine fibers, has a unique multifactorial hemostatic action that incorporates vasoconstriction, erythrocyte agglutination, and platelet and RBC activation.

Results: Animal studies have shown that the mRDH bandage quickly and completely stops both venous and arterial bleeding, even in the presence of a coagulopathy. A prospective study in humans is in accord with these findings.

Conclusion: The mRDH trauma/surgery bandage was able to increase survival of patients after high-grade liver trauma with an associated coagulopathy. Additional clinical studies support this result.
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http://dx.doi.org/10.1097/TA.0b013e31822555e9DOI Listing
August 2011

The experience of Stinner, et al.

Authors:
C Robert Valeri

Mil Med 2011 May;176(5):ii; author reply ii-iii

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May 2011

Correlation of oocyte morphometry parameters with woman's age.

J Assist Reprod Genet 2011 Jun 6;28(6):545-52. Epub 2011 Apr 6.

Genesis Centre for Reproductive Medicine, via Velletri 7, 00198, Rome, Italy.

Purpose: Aim of this study was to evaluate morphometric parameters of metaphase II oocytes, including cytoplasm diameter (CD), zona pellucida thickness (ZPT) and width of the perivitelline space (PS), in relation with zona pellucida birefringence, spindle presence and age of the woman.

Methods: Oocytes were classified into groups according to zona birefringence (low or high zona birefringence, LZB and HZB, respectively) and presence or absence of a visible spindle (SP and aSP, respectively).

Results: HZB oocytes showed a thicker zona (17.7 ± 0.3 μm) than LZB oocytes (16.7 ± 0.3 μm, p < 0.01). Moreover, PS was narrower in HZB and SP oocytes than in LZB (p < 0,001) and aSP (p < 0,05) oocytes. Finally, we found that CD and ZPT linearly decrease with age of the woman (CD r = 0.028: p < 0.01; ZPT r = 0.050: p < 0.0001).

Conclusion: Our results evidence an association in human oocytes between zona pellucida and spindle birefringence and defined morphometric parameters and a decrease of oocyte size and ZPT as a function of women's age.
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http://dx.doi.org/10.1007/s10815-011-9555-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158254PMC
June 2011

The rheologic properties of leukoreduced red blood cells.

Transfusion 2010 Nov;50(11):2506; author reply 2506

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http://dx.doi.org/10.1111/j.1537-2995.2010.02810.xDOI Listing
November 2010

Ablation of the Sam68 gene impairs female fertility and gonadotropin-dependent follicle development.

Hum Mol Genet 2010 Dec 29;19(24):4886-94. Epub 2010 Sep 29.

Department of Public Health and Cell Biology, University of Rome Tor Vergata, 00133 Rome, Italy.

Sam68 is a multifunctional RNA-binding protein highly expressed in the gonads, whose ablation causes male infertility. Herein, we have investigated Sam68 expression in the adult ovary and its function in female fertility. Immunohistochemistry showed that Sam68 was localized in the nucleus of oocytes and follicular cells at all stages of folliculogenesis. Sam68(-/-) females were severely subfertile, and they showed a delay in the age of first pregnancy, increased breeding time for successful pregnancy and yielded smaller litters. Morphological analyses indicated a significant reduction in the number of secondary and pre-antral follicles in the ovary. These defects were associated with alteration of oestrous cycles and a reduced number of ovulated oocytes, which were only partially restored by the administration of exogenous gonadotropins. Crosslinking/immunoprecipitation experiments showed that Sam68 directly binds the mRNAs for the follicle-stimulating hormone (FSH) and the luteinizing hormone receptors (Fshr and Lhcgr), which were downregulated in ovaries of adult knockout females. Stimulation of immature females with FSH-like pregnant mare serum gonadotropin (PMSG), or of follicular cells with the FSH second messenger analogue 8Br-cAMP, caused the upregulation of Sam68. The increase in Sam68 levels paralleled that of the Fshr and Lhcgr mRNAs in the pre-ovulatory follicle and was required to allow accumulation of these transcripts in follicular cells. These studies identify a new crucial function for Sam68 in the regulation of female fertility and indicate that this protein is required to insure proper expression of the gonadotropin receptor transcripts in pre-ovulatory follicles in adult ovary.
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http://dx.doi.org/10.1093/hmg/ddq422DOI Listing
December 2010

Prophylactic platelet transfusions.

N Engl J Med 2010 Jun;362(22):2141; author reply 2141-2

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June 2010

An approach to prevent the severe adverse events associated with transfusion of FDA-approved blood products.

Transfus Apher Sci 2010 Jun 13;42(3):223-33. Epub 2010 Apr 13.

NBRL, Inc., Plymouth, MA 02360, USA.

There have been several retrospective studies reporting severe adverse events of mortality and morbidity associated with blood transfusions. Mortality and morbidity associated with posttransfusion infection, transfusion related acute lung injury (TRALI), and systemic inflammatory response syndrome (SIRS) have been reported in patients undergoing cardiac surgery, after massive transfusions for severe traumatic injuries, and after transfusions for elective and emergency indications. After 35 days of storage at 4 degrees C in additive solutions, RBC have 24-h posttransfusion survival values of 75% but do not function satisfactorily. For RBC to function satisfactorily shortly after transfusion, they should be stored at 4 degrees C for no more than 2 weeks. Yet while the FDA requires a 24-h posttransfusion survival value of 75%, there is no requirement for the function of the transfused RBC. It has been shown that red blood cells that circulate and function immediately or shortly after transfusion exert a very important hemostatic effect to reduce the bleeding time and nonsurgical blood loss in anemic and thrombocytopenic patients. Greater restoration of hemostasis is seen with viable and functional RBC transfusions than with platelets or plasma even though the platelets and plasma proteins may have satisfactory viability and function. The length of storage of the blood products affects their survival and function and the transfusion of nonviable compatible RBC, antibodies to granulocytes and WBC HLA antigens and biologically active substances affects the patient's clinical outcome. One of the easiest ways to prevent the severe adverse events that have been observed is to ensure that the transfused blood products survive and function at an optimum level and that the levels of antibodies to granulocytes and WBC HLA antigens and biologically active substances are eliminated or reduced. The best way to ensure this is to store liquid-preserved leukoreduced human red blood cells at 4 degrees C in additive solutions for no more than 2 weeks and leukoreduced platelets at room temperature for no more than 2 days. These liquid-preserved blood products can be used in conjunction with frozen RBC, platelets, and plasma stored in -80 degrees C mechanical freezers and will avoid the need for fresh whole blood and prevent the severe adverse events associated with the transfusion of blood products.
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http://dx.doi.org/10.1016/j.transci.2009.08.001DOI Listing
June 2010

Quiescent platelets stimulate angiogenesis and diabetic wound repair.

J Surg Res 2010 May 10;160(1):169-77. Epub 2008 Oct 10.

Division of Plastic Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Introduction: Platelets partake in hemostasis, wound healing, and tumor growth. Although platelet-rich-plasma (PRP) has been used in surgery for several years, its mechanism of action and application methods are still poorly characterized.

Materials And Methods: A single unit of human platelets obtained by plateletpheresis was diluted in plasma and divided into three equal volumes. One volume was stored at room temperature as fresh platelets (RT), another volume was frozen by storage at -80 degrees C (FZ), and the third volume was frozen at -80 degrees C with 6% DMSO (FZ6). Plasma (PL) was used as control. Using flow cytometry, platelets were tested for platelet glycoprotein GPIb and annexin V binding, as survival and activation markers, respectively. Hemostatic function was assessed by thromboelastometry. In vivo, platelets were topically applied on 1 cm,(2) full-thickness wounds on db/db mice (n = 10/group) and healing was staged microscopically and macroscopically.

Results: All platelet preparations showed hemostatic ability. RT platelets were GPIb positive (nonactivated-quiescent platelets) and stimulated angiogenesis by threefold, and cell proliferation by fourfold in vivo. FZ platelets were positive for annexin V, indicating activated platelets and, in vivo, increased only wound granulation. FZ6 platelets contained 30% nonactivated-quiescent and 50% activated platelets and stimulated granulation, angiogenesis, cell proliferation, and promoted re-epithelialization in vivo.

Conclusions: Platelets showed distinct mechanisms to induce hemostasis and wound healing. Quiescent platelets are required to induce angiogenesis in vivo. Platelets stored at room temperature and frozen with 6% DMSO and stored at -80 degrees C achieved optimal wound healing in diabetic mice.
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http://dx.doi.org/10.1016/j.jss.2008.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881478PMC
May 2010

Role of nitric oxide in the prevention of severe adverse events associated with blood products.

Authors:
C R Valeri G Ragno

Transfus Apher Sci 2008 Dec 26;39(3):241-5. Epub 2008 Oct 26.

Naval Blood Research Laboratory, 195 Bournehurst Drive, Plymouth, MA 02360, USA.

The reduction in vitro of nitric oxide binding to the globin portion of hemoglobin (SNOHb) in fresh and liquid preserved red blood cells has been reported to be responsible for the severe adverse events (SAEs) associated with red blood cell transfusion. No in vivo data were reported that the reduction in SNOHb in red blood cells following transfusion was irreversible. In addition, no clinical data were reported that the reduction in SNOHb in red blood cells produced severe adverse events (SAEs) in recipients.
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http://dx.doi.org/10.1016/j.transci.2008.09.011DOI Listing
December 2008

Non-classical processes in surface hemostasis: mechanisms for the poly-N-acetyl glucosamine-induced alteration of red blood cell morphology and surface prothrombogenicity.

Biomed Mater 2008 Mar 6;3(1):015009. Epub 2008 Feb 6.

Francis Owen Blood Research Laboratory, Department of Pathology and Laboratory Medicine, 125 University Lake Dr., CB# 3114, University of North Carolina at Chapel Hill, NC, USA.

It is well established that platelets and the intrinsic plasma coagulation pathway can be activated when blood contacts artificial surfaces. Experiments were performed to assess the effect of hemostatic poly-N-acetyl glucosamine (pGlcNAc) nanofibers on red blood cells. The pGlcNAc nanofibers, isolated from a marine diatom, interact with red blood cells (RBCs) to produce stomatocytes. The stomatocytes could be converted to echinocytes by treatment with echinocytic reagents, as measured by electron microscopy. Electrophoretic and Western blot analysis of RBC surface proteins demonstrated that pGlcNAc fibers were bound to band 3 of the RBC. An important and unique result of the interaction of RBCs with pGlcNAc fibers was the activation of the intrinsic coagulation cascade. This prothrombotic effect was associated with the presentation of phosphatidylserine on the outer layer of the surface membrane of nanofiber bound RBCs. The results demonstrate that RBCs can play a direct and important role in achieving surface hemostasis by accelerating the generation of thrombin, and add to the growing body of evidence that RBCs can strongly interact with hemostatic systems.
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http://dx.doi.org/10.1088/1748-6041/3/1/015009DOI Listing
March 2008

Effects of poly-N-acetyl glucosamine (pGlcNAc) patch on wound healing in db/db mouse.

J Trauma 2008 Mar;64(3):803-8

Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Poly-N-acetyl glucosamine (pGlcNAc) nanofiber-based materials, produced by a marine microalga, have been characterized as effective hemostatic agents. In this study, we hypothesized that a pGlcNAc fiber patch may enhance wound healing in the db/db mouse.

Methods: pGlcNAc patches were applied on 1-cm, full-thickness, skin wounds in the db/db mouse model. Wounds (n = 15 per group) were dressed with a pGlcNAc nanofiber patch for 1 hour, 24 hours, or left untreated. After the application time, patches were removed and wounds were allowed to heal spontaneously. The rate of wound closure was evaluated by digital analysis of unclosed wound area as a function of time. At day 10, wounds (n = 7 per group) were harvested and quantified with immunohistochemical markers of proliferation (Ki-67) and vascularization (platelet endothelial cell adhesion molecule).

Results: Wounds dressed with pGlcNAc patches for 1 hour closed faster than control wounds, reaching 90% closure in 16.6 days, 9 days faster than untreated wounds. Granulation tissue showed higher levels of proliferation and vascularization after 1-hour treatment than the 24-hour and left-untreated groups. Foreign body reaction to the material was not noted in applications up to 24 hours.

Discussion: In addition to its hemostatic properties, the pGlcNAc material also appears to accelerate wound closure in healing-impaired genetically diabetic mice. This material, with its combination of hemostatic and wound healing properties, has the potential to be effective agent for the treatment of complicated wounds.
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http://dx.doi.org/10.1097/01.ta.0000244382.13937.a8DOI Listing
March 2008

The effects of preserved red blood cells on the severe adverse events observed in patients infused with hemoglobin based oxygen carriers.

Artif Cells Blood Substit Immobil Biotechnol 2008 ;36(1):3-18

NBRL Inc, Boston, MA 02360, USA.

The severe adverse events observed in patients who received hemoglobin based oxygen carriers (HBOCs) were associated with the Ringer's D.L lactate resuscitative solution administered and to the excipient used in the HBOCs containing Ringer's D,L lactate and the length of storage of the preserved RBC administered to the patient at the time that the HBOCs were infused. This paper reports the quality of the red blood cells preserved in the liquid state at 4 degrees C and that of previously frozen RBCs stored at 4 degrees C with regard to their survival, function and safety. Severe adverse events have been observed related to the length of storage of the liquid preserved RBC stored at 4 degrees C prior to transfusion. The current methods to preserve RBC in the liquid state in additive solutions at 4 degrees C maintain their survival and function for only 2 weeks. The freezing of red blood cells with 40% W/V glycerol and storage at -80 degrees C allows for storage at -80 degrees C for 10 years and following thawing, deglycerolization and storage at 4 degrees C in the additive solution (AS-3, Nutricel) for 2 weeks with acceptable 24 hour posttransfusion survival, less than 1% hemolysis, and moderately impaired oxygen transport function with no associated adverse events. Frozen deglycerolized RBCs are leukoreduced and contain less than 5% of residual plasma and non-plasma substances. Frozen deglycerolized RBCs are the ideal RBC product to transfuse patients receiving HBOCs.
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http://dx.doi.org/10.1080/10731190701857736DOI Listing
April 2008