bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreasing Hair Cell Counts in Aging Humans
Authors: RAUCH STEVEN D. , VELAZQUEZ‐VILLASEÑOR LUIS , DIMITRI PAUL S. , MERCHANT SAUMIL N.
Published: July 2010

Abstract: Deterioration of balance with advancing age is a well‐known fact of life. Some investigators have reported a 50% prevalence of dizziness in the elderly. Clinically, progressive dysequilibrium of aging presents as gradually worsening balance due to age‐related decline in function of the peripheral vestibular system, central nervous system, vision, and musculoskeletal system. Vestibular function testing has shown clear evidence of age‐related changes in peripheral and central sites. Histopathologic changes in the vestibular sensory organs include progressive hair cell degeneration, otoconial degeneration in the otolith organs, and decreasing number of Scarpa's ganglion neurons. Recently, a new quantitative method of assessing vestibular otopathology has been described, utilizing Nomarski differential interference contrast microscopy. This technique has been applied to 67 human temporal bones of individuals from birth to age 100 to create a normative database of total, type I, and type II hair cell counts as a function of age. Results show a highly significant continuous decrease in all counts from birth to age 100, best fit by a linear regression model. Type I hair cell counts in all three semicircular canal cristae decrease at a similar rate, significantly faster than the degeneration observed in type I hair cells of the maculae. Type II hair cell counts decline at the same rate for all 5 sensory epithelia. These normative data provide the basis for comparisons to hair cell counts made in temporal bones from subjects with known vestibular disorders. They also provide a basis for drawing correlations between vestibular function testing and vestibular otopathology.
Symptoms and Signs in Superior Canal Dehiscence Syndrome
Authors: MINOR LLOYD B. , CREMER PHILLIP D. , CAREY JOHN P. , DELLA SANTINA CHARLES C. , STREUBEL SVEN‐OLRIK , WEG NOAH
Published: July 2010

Abstract: Patients with superior canal dehiscence (SCD) syndrome experience vertigo and oscillopsia in response to loud sounds and to stimuli that result in changes in middle ear or intracranial pressure. They may also experience hyperacusis to bone‐conducted sounds. The evoked eye movements in this syndrome align with the plane of the dehiscent superior canal. The symptoms and signs can be understood in terms of the effect of the dehiscence in creation of a third mobile window into the inner ear. The SCD syndrome has been diagnosed in 28 patients who were examined in the neuro‐otology clinics at the Johns Hopkins Medical Institutions from May 1995 through January 2001. The diagnosis is best established based upon the symptoms that are characteristic for the syndrome, the vertical‐torsional eye movements evoked by sound or pressure stimuli noted on examination performed with Frenzel goggles, the lowered thresholds for responses to vestibular‐evoked myogenic potentials, and CT imaging of the temporal bones.
Vestibulospinal Control of Reflex and Voluntary Head Movement
Authors: BOYLE R.
Published: July 2010

Abstract: Secondary canal‐related vestibulospinal neurons respond to an externally applied movement of the head in the form of a firing rate modulation that encodes the angular velocity of the movement, and reflects in large part the input “head velocity in space” signal carried by the semicircular canal afferents. In addition to the head velocity signal, the vestibulospinal neurons can carry a more processed signal that includes eye position or eye velocity, or both (see Boyle1 on ref. list).

To understand the control signals used by the central vestibular pathways in the generation of reflex head stabilization, such as the vestibulocollic reflex (VCR), and the maintenance of head posture, it is essential to record directly from identified vestibulospinal neurons projecting to the cervical spinal segments in the alert animal. The present report discusses two key features of the primate vestibulospinal system. First, the termination morphology of vestibulospinal axons in the cervical segments of the spinal cord is described to lay the structural basis of vestibulospinal control of head/neck posture and movement. And second, the head movement signal content carried by the same class of secondary vestibulospinal neurons during the actual execution of the VCR and during self‐generated, or active, rapid head movements is presented.
Dynamic and Kinematic Strategies for Head Movement Control
Authors: PETERSON BARRY W. , CHOI HYEONKI , HAIN TIMOTHY , KESHNER EMILY , PENG GRACE C.Y.
Published: July 2010

Abstract: This paper describes our analysis of the complex head‐neck system using a combination of experimental and modeling approaches. Dynamical analysis of head movements and EMG activation elicited by perturbation of trunk position has examined functional contributions of biomechanically and neurally generated forces in lumped systems with greatly simplified kinematics. This has revealed that visual and voluntary control of neck muscles and the dynamic and static vestibulocollic and cervicocollic reflexes preferentially govern head‐neck system state in different frequency domains. It also documents redundant control, which allows the system to compensate for lesions and creates a potential for substantial variability within and between subjects. Kinematic studies have indicated the existence of reciprocal and co‐contraction strategies for voluntary force generation, of a vestibulocollic strategy for stabilizing the head during body perturbations and of at least two strategies for voluntary head tracking. Each strategy appears to be executed by a specific muscle synergy that is presumably optimized to efficiently meet the demands of the task.
What Can Posturography Tell Us About Vestibular Function?
Authors: BLACK F. OWEN
Published: July 2010

Abstract: Patients with balance disorders want answers to the following basic questions: (1) What is causing my problem? and (2) What can be done about my problem? Information to fully answer these questions must include status of both sensory and motor components of the balance control systems. Computerized dynamic posturography (CDP) provides quantitative assessment of both sensory and motor components of postural control along with how the sensory inputs to the brain interact. This paper reviews the scientific basis and clinical applications of CDP. Specifically, studies describing the integration of vestibular inputs with other sensory systems for postural control are briefly summarized. Clinical applications, including assessment, rehabilitation, and management are presented. Effects of aging on postural control along with prevention and management strategies are discussed.
Inhibin, Activin, and Follistatin in Human Fetal Pituitary and Gonadal Physiology
Authors: BLUMENFELD ZEEV , RITTER MARINA
Published: July 2010

Background: Activin has been previously demonstrated to directly stimulate the synthesis of gonadotropin‐releasing hormone (GnRH) receptors and to increase follicle‐stimulating hormone (FSH) secretion in nonhuman pituitary cell cultures (PCCs). Currently, knowledge of the physiological role of these peptides in primates is still far from complete. Moreover, several results in macaque monkeys failed to support an unequivocal role for inhibin in FSH suppression. Whereas the bioactivity of inhibin and activin has been demonstrated in rat PCCs, no data exist on human pituitary response to these peptides either in vivo or in vitro. Methods: We studied the secretion of FSH and luteinizing hormone (LH) by dispersed human fetal pituitary cells from midtrimester abortions in response to recombinant human (rh‐) activin‐A, inhibin‐A, and other secretagogues. After mechanical and enzymatic dispersion, the human fetal pituitary cells were cultured on an extracellular matrixlikematerial‐coated 24‐well plate. After 3 days' incubation in serum‐containing medium, the PCCs were washed and preincubated for 90 min in serum‐free medium and incubated with activin‐A, inhibin‐A, TGF‐β, follistatin, sex steroids, and GnRH, in quadruplicate. Results: Activin‐A was a potent secretagogue for FSH secretion. GnRH (20 ng/ml) was more potent than rh‐activin‐A for LH secretion. Nevertheless, a significant increase in LH secretion into the medium was brought about by rh‐activin‐A. Inhibin decreased FSH and LH secretion, but the LH response to inhibin was less prominent than that of FSH. GnRH opposed the inhibitory effect of inhibin on LH secretion. In dynamic, short‐term, repetitive exposure of fetal pituitary fragments to rh‐activin‐A (superfusion), we could not receive a similar increase in LH and FSH as in static incubations, as opposed to a short GnRH exposure. In addition to their endocrine, paracrine, and autocrine effects, and in addition to their role as possible markers, the TGF‐β superfamily members may affect embryogenesis and possibly immunomodulation of the embryo and fetus. The role of activin and inhibin as intragonadal regulators is hypothesized. The pro‐αC inhibin precursor may act as an FSH receptor antagonist. Conclusions: Human fetal PCCs express the previously reported physiologic responses to activin and inhibin generated in nonhuman experiments on gonadotropin secretion in vitro and may serve as a physiologic model for studying human gonadotrope responses to the TGF‐β family of peptides.
Design and Conduct of Clinical Trials in Hormone Replacement Therapy
Authors: HOLINKA CHRISTIAN F.
Published: July 2010

Postmenopausal hormone replacement therapy represents an area of outstanding importance in preventive medicine that greatly affects personal well‐being as well as public health. The number of women living in the United States who are 50 years or older has been estimated at nearly 50 million.1 Many of those women are likely to be eligible for postmenopausal hormone replacement, which may consist either of estrogen replacement therapy (ERT) in women without a uterus or, more frequently, estrogen/progestin combination therapy (HRT) in women with a uterus. This chapter first presents an overview of general regulatory requirements pertaining to the design and conduct of clinical studies in support of marketing approval for a drug product. These requirements include, but are not restricted to, studies in HRT. The chapter next discusses the design and conduct of clinical trials in support of marketing approval for the indications: treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy; prevention of osteoporosis; and protection by adjunctive progestin against estrogen‐induced endometrial hyperplasia/cancer in women with a uterus. Finally, data related to the potential cardioprotective action of HRT and its protection against Alzheimer's disease and colon cancer are discussed.
Endometrial Anomalies in Women with Endometriosis
Authors: SHARPE‐TIMMS KATHY L.
Published: July 2010

Endometriotic lesions are defined by extrauterine growth of endometrial glands and stroma. Retrograde menstruation with subsequent attachment, invasion, and neovascularization are believed to give rise to the endometriotic lesions. As most women exhibit some degree of retrograde menstruation, some other unidentified factor(s) must render certain women susceptible to attachment and growth of ectopic endometrial tissue. A variety of theories have been proposed to account for this susceptibility, including genetic predisposition, aberrant immunological response, and an altered peritoneal environment. Ectopic endometriotic lesions are histologically similar to their putative eutopic precursors, yet significant biochemical differences exist between these two tissues. Less information is available regarding differences between eutopic endometrium from women with or without endometriosis. This report describes anomalies in structure, proliferation, immune components, adhesion molecules, proteolytic enzymes and inhibitors, steroid and cytokine production and responsiveness, and gene expression and protein production that have been identified in eutopic endometrium from women with endometriosis.
Biochemistry and Molecular Biology of Trophoblast Invasion
Authors: BISCHOF P. , MEISSER A. , CAMPANA A.
Published: July 2010

Cytotrophoblastic cells (CTBs) from first‐trimester placenta form columns of invasive CTBs. This invasive behavior is due to the ability of CTBs to secrete matrix metalloproteinases (MMPs), since tissue inhibitor of MMPs (TIMP) inhibits their invasiveness in the extracellular space. Although CTBs behave like metastic cells, in vivo they are only transiently invasive (first trimester), and their invasion is normally limited only to the endometrium and to the proximal third of the myometrium. This temporal and spatial regulation of trophoblast invasion is believed to be mediated in an autocrine way by trophoblastic factors and in a paracrine way by uterine factors. Several types of regulators have been investigated: hormones, extracellular matrix glycoproteins, and cytokines or growth factors. This review is not intended to be an exhaustive catalogue of potential regulators of trophoblast invasion but is aimed at summarizing the most important categories of factors affecting trophoblast‐endometrium interactions.
Uterine Contractility: Vaginal Administration of the β‐Adrenergic Agonist, Terbutaline
Authors: BULLETTI CARLO , DE ZIEGLER DOMINIQUE , DE MOUSTIER BEATRICE , POLLI VALERIA , BOLELLI GIANFRANCO , FRANCESCHETTI FRANCA , FLAMIGNI C.
Published: July 2010

Spontaneous uterine contractility during the menstrual cycle is required for menstruation, gamete transport, and, most likely, embryo nidation. Abnormal uterine contractility has been linked to dysmenorrhea, a condition associated with painful uterine cramping. Based on previous studies with progesterone, we have postulated the existence of a portal system that is responsible for some degree of direct vagina‐to‐uterus transport of administered compounds (i.e., the “first uterine pass effect”). It is possible that treatment with uterorelaxing substances, particularly β‐adrenergic agonists, may alleviate the uterine discomfort that accompanies dysmenorrhea. However, side effects encountered with oral administration of β‐agonists limit their utility. Alternatively, vaginal delivery of β‐agonists could solve this dilemma by enhancing their efficacy and reducing side effects. Therefore, in the current study we used hysterectomy specimens and an in vitro uterine perfusion system to test the vagina‐to‐uterus transport of [3H]terbutaline, a well‐known β‐agonist. With the use of autoradiographic and scintillation counting techniques, our results clearly show progressive diffusion of labeled terbutaline from the rim of vaginal tissue through the uterus during the first 12 hours of perfusion. This indicates that uterine targeting of terbutaline can be accomplished through vaginal administration, suggesting a new therapeutic modality in women's health care.
Contractility of the Nonpregnant Uterus
Authors: DE ZIEGLER D. , BULLETTI C. , FANCHIN R. , EPINEY M. , BRIOSCHI P.‐A.
Published: July 2010

Recent renewed interest in uterine contractility stems from the possibility of directly visualizing uterine contractility on images generated by high‐resolution ultrasound probes. During the menstrual cycle, three typical patterns of uterine contractility have been recognized. During the luteofollicular transition and early follicular phase (menses), the contractile event involves all layers of the myometrium and exerts antegrade (from fundus to cervix) expulsive forces. Characteristically, uterine contractions are often perceived by women at the time of menses, sometimes reaching the level of painful cramps (dysmenorrhea). In the late follicular phase, uterine contractility involves only the subendometrial layers of the myometrium and is never perceived by women. The primary function of uterine contractility in the late follicular phase is to facilitate the retrograde (cervix to fundus) transport of sperm towards the distal end of the fallopian tubes where fertilization normally takes place. Finally, the uterus reaches a stage of quiescence after ovulation (under the influence of progesterone) that characterizes the major part of the luteal phase. The present review summarizes our understanding of the physiological role of uterine contractility during the follicular phase and the possible implications in pathological circumstances such as endometriosis and dysmenorrhea.
Assessing Uterine Receptivity in 2001
Authors: FANCHIN RENATO
Published: July 2010

The understanding and control of embryo implantation represents the major challenge for assisted reproductive technologies. Along with developments in basic research and efforts to optimize embryo quality, the improvement of noninvasive and reliable methods to assess uterine receptivity constitutes an important step toward meeting such a challenge. Today, ultrasound‐based approaches to evaluate endometrial echogenicity and uterine perfusion and contractility are available for practical use. Increasing evidence indicates that echogenic patterns of the endometrium reflect histologic processes that are involved in the establishment of receptivity. This constitutes a possible explanation for the reported association between premature hyperechogenic patterns of the endometrium and poor implantation rates. Nevertheless, additional studies aiming at correlating further morpho‐biochemical events in the endometrium with its echogenicity patterns are needed. Further, developments in vascular assessment by Doppler, Doppler‐related, and vascular detection technologies will also be instrumental in monitoring and improving vascular changes that lead to uterine receptivity. Finally, data supporting the hypothesis that uterine contractility, as visualized by ultrasound, influences in vitro fertilization‐embryo transfer (IVF‐ET) pregnancy rates encourage further investigation on both the regulation and control of uterine contractions. This article discusses some of the advantages and limitations of ultrasonographic assessments of uterine receptivity in the perspective of the new millennium.
Methods and Devices for the Management of Term and Preterm Labor
Authors: GARFIELD R. E. , MAUL H. , SHI L. , MANER W. , FITTKOW C. , OLSEN G. , SAADE G. R.
Published: July 2010

In this review, we outline studies showing that the uterus (myometrium) and cervix pass through a conditioning step in preparation for labor. This step is not easily identifiable with present methods designed to assess the uterus or cervix. In the uterus, this seemingly irreversible step consists of changes in the electrical properties that make muscle more excitable and responsive and produce forceful contractions. In the cervix, the step consists of softening of the connective tissue components. Progesterone and nitric oxide appear to have important roles in these processes. The progress of labor can be assessed noninvasively using electromyographic (EMG) signals from the uterus (the driving force for contractility) recorded from the abdominal surface. Uterine EMG bursts detected in this manner characterize uterine contractile events during human and animal pregnancy. A low uterine EMG activity, measured transabdominally throughout most of pregnancy, rises dramatically during labor. EMG activity also increases substantially during preterm labor in humans and rats and may be predictive of preterm labor. A quantitative method for assessing the cervix is also described. A collascope estimates cervical collagen content from a fluorescent signal generated when collagen crosslinks are illuminated with an excitation light of about 340 nm. The system has proved useful in rats and humans at various stages of pregnancy and indicates that cervical softening occurs progressively in the last one‐third of pregnancy. In rats, collascope readings correlate with resistance measurements made in the isolated cervix, which may help to assess cervical function during pregnancy and indicate controls and treatments.
Ectopic Pregnancy
Authors: LUCIANO ANTHONY A. , ROY GERARD , SOLIMA EUGENIO
Published: July 2010

During the past 25 years, the incidence of ectopic pregnancy has progressively increased while the morbidity and mortality have substantially decreased, and the treatment has progressed from salpingectomy by laparotomy to conservative surgery by laparoscopy and more recently to medical therapy. This therapeutic transition from surgical emergency to medical management has been attributed to early diagnosis through the use of sensitive assays for hCG and the high definition of vaginal ultrasound. By using these sensitive diagnostic tools, we are now able to select those patients who are most likely to respond to medical management versus those who are at high risk of rupture and require surgery. Besides being less invasive and associated with significantly lower risks, medical therapy with methotrexate results in significant cost savings, which have been calculated to be approximately $3,000 per treated patient. Our goal is to identify those patients with ectopic pregnancy who are most likely to respond to methotrexate therapy and least likely to develop significant side effects. Recent studies have helped us define the predictors of success with methotrexate treatment in women with ectopic pregnancy. The reported success rates of treating ectopic pregnancy with methotrexate vary from 71% to 100%. The highest success rates have been reported from institutions that have detailed diagnostic and therapeutic protocols, readily available assays for serum hCG levels, high‐resolution vaginal probe ultrasound, and support staff that can closely monitor clinical response. The importance of developing specific protocols to create a clinical environment that supports the effective use of medical therapy for ectopic pregnancy is confirmed by the associated cost savings, decreased morbidity, and patient preference. Modern diagnostic advances and minimally invasive treatments coupled with improved success rates for assisted reproductive technologies should reduce the morbidity and mortality associated with ectopic pregnancy and offer the affected couple a much more optimistic outlook for subsequent reproductive potential.
Role of Exogenous and Endogenous Hormones in Endometrial Cancer
Authors: AKHMEDKHANOV ARSLAN , ZELENIUCH‐JACQUOTTE ANNE , TONIOLO PAOLO
Published: July 2010

Endometrial carcinoma is the most common cancer of the female reproductive organs in the United States. International comparisons reveal that the incidence of endometrial cancer vary widely between different countries with the highest rates observed in North America and Northern Europe, intermediate rates in Eastern Europe and Latin America, and lowest rates in Asia and Africa. International variation in endometrial cancer rates may represent differences in the distribution of known risk factors, which include obesity, postmenopausal estrogen replacement, ovarian dysfunction, diabetes mellitus, infertility, nulliparity, and tamoxifen use. Most of the risk factors for endometrial cancer can be explained within the framework of the unopposed estrogen hypothesis, which proposes that exposure to estrogens unopposed by progesterone or synthetic progestins leads to increased mitotic activity of endometrial cells, increased number of DNA replication errors, and somatic mutations resulting in malignant phenotype. Although the impact of exogenous hormone replacement was intensively studied during the last two decades, less is known about the effects of endogenous hormones in endometrial cancer. A review of available experimental, clinical, and epidemiologic data suggests that in addition to estrogens, other endogenous hormones, including progesterone, androgens, gonadotropins, prolactin, insulin, and insulin‐like growth factors, may play a role in the pathogenesis of different histopathologic types of endometrial cancer.
Doppler Investigation in Intrauterine Growth Restriction—From Qualitative Indices to Flow Measurements
Authors: FERRAZZI ENRICO , BELLOTTI MARIA , GALAN HENRY , PENNATI GIANCARLO , BOZZO MADDALENA , RIGANO SERENA , BATTAGLIA FREDERICK C.
Published: July 2010

In 1997 we started a collaboration among three groups, combining our experience with Doppler examination of the human fetus, blood flow studies on fetal lamb, and mathematical modeling of human circulation. In preliminary investigations on fetal lambs, the same Doppler method designed for the human fetus was used to measure venous blood flow in the umbilical veins of seven fetal lambs. Doppler measurements and diffusion technique groups for umbilical venous flow were 210.8 ± 18.8 and 205.7 ± 38.5 ml/min/kg, respectively (p= 0.881). In human pregnancy the interobserver variabilities for the vein diameter, mean velocity, and absolute umbilical venous blood were 2.9%, 7.9%, and 12.7%, respectively. A cross‐sectional study allowed us to establish normal reference values. Venous blood flow/kg of estimated fetal weight showed a nonsignificant linear reduction with gestational age, from 128.7 ml/min/kg at 20 weeks to 104.2 ml/min/kg at 38 weeks. In a series of 37 growth‐restricted fetuses, the UV flow per kilogram was significantly lower in the more severe growth‐restricted fetuses (abdominal circumference below the second percentile and abnormal umbilical arterial p.i.) than in normal comparable fetuses (p < 0.001). In a series of 140 normal fetuses, we calculated that the absolute blood flow rate in the ductus venosus (DV) increases significantly with advancing gestational age from 20 to 38 weeks of gestation (from 23.2 ± 9.6 ml/min to 43.5 ± 21.5 ml/min). This means that the percentage of umbilical blood flow shunted through the DV decreases significantly during gestation (from 50% at midgestation to 20% at 38 weeks). In a series of 45 growthrestricted fetuses, delivered because of nonreactive fetal heart rate (group 2) and for other reasons but still with a normal heart rate pattern (group 1), we measured the ductal inlet diameter. In these fetuses, the diameters at the ductal isthmus, normalized for the dimension of the abdominal circumference (inlet diameter/abdominal circumference), were significantly larger (group 1 = 6.8 ± 2.3; group 29.4 ± 2.8) than in the control group (6.1 ± 0.3). This means that in this subset of fetuses the amount of blood shunted can be increased as a compensatory mechanism.
Ethical Issues in Selecting Embryos
Authors: RHODES ROSAMOND
Published: July 2010

People involved in assisted reproduction frequently make decisions about which of several embryos to implant or which of several embryos to reduce from a multiple pregnancy. Yet, others have raised questions about the ethical acceptability of using sex or genetic characteristics as selection criteria. This paper reviews arguments for rejecting embryo selection and discusses the subject of choosing offspring in terms of the centrality of liberty and autonomous choice in ethics. It also presents a position on the acceptable scope of embryo selection and the professional responsibilities of those who practice reproductive medicine.
In Vitro Maturation of Neonatal Porcine Islets
Authors: BINETTE TANYA M. , DUFOUR JANNETTE M. , KORBUTT GREGORY S.
Published: July 2010

Abstract: The mechanisms involved in islet neogenesis have remained largely unexplored due to lack of an appropriate model. Furthermore, with the recent advances in islet transplantation, the need for alternative islet tissue sources is greater than ever. Therefore, the authors have refined a neonatal porcine islet (NPI) maturation model that offers an ideal tool to gain insight into islet growth as well as an alternative source of transplantable tissue. Recent knowledge in islet growth has resulted in endocrine tissue being derived from human pancreatic precursor tissue in vitro. The potential for large scale production of endocrine tissue in vitro has been indicated, however, more investigation must be done on the various signals and pathways involved in pancreatic development to optimize this technique. The authors believe that their NPI in vitro maturation model provides an ideal tool to study islet growth and maturation. Transduction of the NPI to overexpress genes of interest (i.e., PDX‐1) or exposure of the NPI to various culture conditions will allow us to determine the effects on islet maturation. An understanding of NPI development gained will not only allow us to mature this unlimited tissue source for optimal xenotransplantation, but also elude to how human pancreatic endocrine precursor cells may be used to solve the current islet tissue supply problem.
Preclinical Development of the Islet Sheet
Authors: STORRS RICHARD , DORIAN RANDY , KING SCOTT R. , LAKEY JONATHAN , RILO HORACIO
Published: July 2010

Abstract: The Islet Sheet is a thin planar bioartificial endocrine pancreas fabricated by gelling highly purified alginate and islets of Langerhans. Acellular alginate layers form a uniform immunoprotective barrier to host rejection of the encapsulated cells, with the tissue nourished by passive diffusion from adjacent host tissue. The overall thickness of the Islet Sheet, 250 μm, is chosen to maximize nutrient diffusion. In this paper we describe the early development of the Islet Sheet, including purification and fractionation of the alginates used, difficulties in maintaining sheet planarity, and preliminary metabolic studies in pancreatectomized dogs. In a key experiment, approximately 75,000 allogeneic islet equivalents in six Islet Sheets were sutured to the omentum of a 7‐kg female beagle dog at the time of pancreatectomy. Fasting euglycemia was maintained for 84 days. Fed blood sugars were usually below 150 mg/dL. A single injection of 2 U insulin was administered on day 9, and antibiotics were administered for two weeks. No other drugs were used. IVGTT post implant was not normal, but seemed to improve between 30 and 60 days. Upon omentectomy and sheet removal the metabolic parameters deteriorated to a frankly diabetic state within seven days. The sheets did not remain flat, but fragments were recovered within hard, mostly acellular capsules. Dithizone staining showed islets within alginate sheets recovered from the interior of these capsules, suggesting that allogeneic islet tissue survived 84 days and was responsible for maintaining fasting euglycemia.
Engineering Tolerance into Transplanted β Cell Lines
Authors: THORENS BERNARD , DUPRAZ PHILIPPE , COTTET SANDRA
Published: July 2010

Abstract: In this paper we explore the possibility of improving, by genetic engineering, the resistance of insulin‐secreting cells to the metabolic and inflammatory stresses that are anticipated to limit their function and survival when encapsulated and transplanted in a type 1 diabetic environment. We show that transfer of the Bcl‐2 antiapoptotic gene, and of genes specifically interfering with cytokine intracellular signaling pathways, greatly improves resistance of the cells to metabolic limitations and inflammatory stresses.
Derivation of Pharmacokinetics Equations for Quantitative Evaluation of Bioartificial Liver Functions
Authors: PARK Y.‐G. , IWATA H. , IKADA Y.
Published: July 2010

Abstract: A bioartificial liver (BAL) is an extracorporeal medical device incorporating living hepatocytes in a cartridge. A variety of BALs have been developed and new devices are being introduced. Some of them have been clinically applied and from the results obtained they are claimed to be useful devices for assisting the liver functions of patients. However, there is still uncertainty as to their efficacy and their limitations are not clear. It is important to establish methods to quantitatively evaluate the metabolic and synthetic functions of BAL. In this paper, we derive simple equations for the quantitative evaluation of BAL functions on the basis of pharmacokinetics. Pharmacokinetics was originally developed to understand the processes of absorption, distribution, and elimination of administered drugs. Metabolic functions of the natural liver have been analyzed using pharmacokinetics and values of the useful parameters, clearance (CL) and intrinsic clearance (CLint), have been reported. The metabolic functions of the BAL expressed using values of CL and CLint are easily compared with those of the normal human liver. We believe that our method provides a useful basis for estimating the clinical effectiveness of BAL.
Development of a Hybrid Liver Support System
Authors: SAUER I. M. , OBERMEYER N. , KARDASSIS D. , THERUVATH T. , GERLACH J. C.
Published: July 2010

Abstract: Hybrid liver systems are being developed as temporary extracorporeal liver support therapy. The overview given here emphasizes the development of both hepatocyte culture models for bioreactors and of systems for clinical therapy. In vitro studies demonstrate long term external metabolic function in isolated primary hepatocytes within bioreactors. These systems are capable of supporting essential liver functions. Animal experiments verify the possibility of upscaling bioreactors for clinical treatment. However, since there is no reliable animal model for investigating the treatment of acute liver failure, the promising results obtained from these studies have limited relevance to human beings. The small number of clinical studies performed thus far are not sufficient to enable any conclusions concerning improvements in the therapy of acute liver failure. Although important progress has been made in the development of these systems, multiple hepatocyte culture models and bioreactor constructions are being discussed in the literature, indicating competition in this field of medical research. For the use of hepatocytes and sinusoidal endothelial cells in coculture, a bioreactor has been designed. The construction is based on capillaries for hepatocyte aggregate immobilization. Four separate capillary membrane systems, each permitting a different function, are woven in order to create a three‐dimensional network. Cells are perfused via independent capillary membrane compartments. Decentralized oxygen supply and carbon dioxide removal with low gradients is possible. The parallel use of identical units enables easy upscaling. Initial studies on the use of discarded organs that are unsuitable for transplantation as a source for primary human liver cells seem to be promising.1
Present Status of Modified Hemoglobin as Blood Substitutes and Oral Therapy for End Stage Renal Failure Using Artificial Cells Containing Genetically Engineered Cells
Authors: CHANG THOMAS MING SWI
Published: July 2010

Abstract:Artificial cell or bioencapsulation has been developed for use in bioartificial organs, drug delivery, blood substitutes, and other areas. Recent rapid advances in modified hemoglobin blood substitutes have resulted in advance stages of Phase III clinical trials. Another area of use is in oral therapy, using artificial cells microencapsulated with genetically engineered cells for use in end stage renal failure and other conditions.
Hepatic Progenitors and Strategies for Liver Cell Therapies
Authors: SUSICK R. , MOSS N. , KUBOTA H. , LECLUYSE E. , HAMILTON G. , LUNTZ T. , LUDLOW J. , FAIR J. , GERBER D. , BERGSTRAND K. , WHITE J. , BRUCE A. , DRURY O. , GUPTA S. , REID L. M.
Published: July 2010

Abstract:Liver cell therapies, including liver cell transplantation and bioartificial livers, are being developed as alternatives to whole liver transplantation for some patients with severe liver dysfunction. Hepatic progenitors are proposed as ideal cells for use in these liver cell therapies given their ability to expand extensively, differentiate into all mature liver cells, have minimal immunogenicity, be cryopreservable, and reconstitute liver tissue when transplanted. We summarize our ongoing efforts to develop clinical programs of hepatic progenitor cell therapies with a focus on hepatic stem cell biology and strategies that have emerged in analyzing that biology.
Objectively Assessing Bioartificial Organs
Authors: HUNKELER D. , REHOR A. , CEAUSOGLU I. , SCHULDT U. , CANAPLE L. , BERNARD P. , RENKEN A. , RINDISBACHER L. , ANGELOVA N.
Published: July 2010

Abstract: The metrics used, thus far, to assess bioartificial organ function are shown to be subjective and requiring validation. Therefore, four categories of correlations are proposed based on, respectively, device, in vitro and in vivo evaluations, and clinical function. Examples are presented whereby the correlations among individual indicators are used as a means to expedite the development of immunoisolated cells. Specifically, a case study illustrating the validation of in vitro indicators of in vivo graft function for the bioartificial pancreas (microencapsulated islets) is summarized. This has revealed thresholds with respect to given metrics relating to in vivo device function, the necessity to couple bioartificial organ design with transplant site selection, as well as the lack of objectivity involved in the evaluation and establishment of hypotheses. Specific quantitative indicators illustrate the need for quality‐controlled measures, for example, relating to the tolerance of microcapsule diameter and membrane thickness distributions. Qualitative indices representing fibrosis and device properties (e.g., sphericity) are also used to describe the need for in vitro experiments in the development of bioartificial organs.
Bioartificial Organs in the Twenty‐first Century
Authors: PROKOP ALEŠ
Published: July 2010

Abstract: Bioartificial organs involve the design, modification, growth and maintenance of living tissues embedded in natural or synthetic scaffolds to enable them to perform complex biochemical functions, including adaptive control and the replacement of normal living tissues. Future directions in this area will lead to an abandonment of the trial‐and‐error implant optimization approach and a switch to the rational production of precisely formulated nanobiological devices. This will be accomplished with the help of three major thrusts: (1) use of molecularly manipulated nanostructured biomimetic materials; (2) application of microelectronic and nanoelectronic interfacing for sensing and control; and (3) application of drug delivery and medical nanosystems to induce, maintain, and replace a missing function that cannot be readily substituted with a living cell and to accelerate tissue regeneration. Biomimetics involves employment of microstructures and functional domains of organismal tissue function, correlation of processes and structures with physical and chemical processes, and use of this knowledge base to design and synthesize new materials for health applications. Nanostructured materials should involve biological materials (rather then synthetic ones) because their prefabricated structure is suitable for modular control of devices from existing materials. Nanostructured tools should encompass surface patterned molecular arrays, nanoscale synthetic scaffolding mimicking the cell‐extracellular matrix microenvironment, precise positioning of molecules with specific signals to provide microheterogeneity, composites of bioinorganic and organic molecules, molecular layering (coating), and molecular and supramolecular self‐assembly and self‐organization (template‐directed) assembly. The nanoelectronic interface includes electronic or optoelectronic biointerfaced devices based on individual cells, their aggregates and tissues, organelles, and molecules, such as enzyme‐based devices, transport and ion‐channel membrane proteins, and receptor‐ligand structures, including nanostructured semiconductor chips and microfluidic components. Delivery nanosystems encompass both water and lipid core vehicles (for hydrophilic and lipophilic components) of various geometries: liposomes, micelles, nanoparticles, lipid shells (as imaging and contrasting agents), solid nanosuspensions, lipid nanospheres, and coated film surfaces (molecular layering), all for use in delivering drugs, proteins, cell modifiers, and genes. Nanoelectronic interface and delivery nanosystems will be used for sensing, feedback, control, and analysis of function of bioartificial organs.
Circulating Nucleic Acids in Plasma and Serum: An Overview
Authors: LO Y. M. DENNIS
Published: July 2010

Abstract: The recent interest in nucleic acids in plasma and serum has opened up numerous new areas of investigation and new possibilities for molecular diagnosis. In oncology, tumor‐derived genetic changes, epigenetic alterations, and viral nucleic acids have been found in the plasma/serum of cancer patients. These findings have important implications for the detection, monitoring, and prognostication of many types of malignancies. In prenatal diagnosis, the discovery of fetal DNA in maternal plasma and serum has provided a noninvasive source of fetal genetic material for analysis. This development has important implications for the realization of noninvasive prenatal diagnosis and has provided new methods for the monitoring of pregnancy‐associated disorders. Plasma DNA technology has also found recent applications in the fields of organ transplantation, posttrauma monitoring, and infectious agent detection. Future areas of study include circulating RNA in plasma and the elucidation of the biology of release, clearance, and possible functionality of plasma nucleic acids.
Quantitative Analysis of Epstein‐Barr Virus DNA in Plasma and Serum
Authors: LO Y. M. DENNIS
Published: July 2010

Abstract: The recent interest in cell‐free tumor‐derived DNA in the plasma and serum of cancer patients has opened up numerous diagnostic possibilities. One type of tumor‐derived DNA that has been detected in plasma/serum is viral DNA. One example of circulating viral nucleic acid is Epstein‐Barr virus (EBV) DNA, which has been found in the plasma and serum of patients with nasopharyngeal carcinoma (NPC), certain lymphomas, and gastric carcinoma. Quantitative analysis of circulating EBV DNA in NPC has demonstrated a positive correlation with disease stage and a strong relationship with clinical events, as well as being of prognostic importance. For EBV‐associated lymphomas, quantitative EBV DNA analysis has also been found to correlate closely with clinical progress. It is expected that plasma/serum EBV DNA analysis will soon be incorporated into the routine investigative protocol of EBV‐associated malignancies.
Circulating Nucleosomes in Serum
Authors: HOLDENRIEDER STEFAN , STIEBER PETRA , BODENMÜLLER HEINZ , BUSCH MARTIN , VON PAWEL JOACHIM , SCHALHORN ANDREAS , NAGEL DOROTHEA , SEIDEL DIETRICH
Published: July 2010

Abstract: In the nucleus of eukaryotic cells, DNA is associated with several protein components and forms complexes known as nucleosomes. During cell death, particularly during apoptosis, endonucleases are activated that cleave the chromatin into multiple oligo‐ and mononucleosomes. Subsequently, these nucleosomes are packed into apoptotic bodies and are engulfed by macrophages or neighboring cells. In cases of high rates of cellular turnover and cell death, they also are released into the circulation and can be detected in serum or plasma. As enhanced cell death occurs under various pathologic conditions, elevated amounts of circulating nucleosomes are not specific for any benign or malignant disorder. However, the course of change in the nucleosomal levels in circulation of patients with malignant tumors during chemotherapy or radiotherapy is associated with the clinical outcome and can be useful for the therapeutic monitoring and the prediction of the therapeutic efficacy.
Fetomaternal Cellular and Plasma DNA Trafficking
Authors: BIANCHI DIANA W. , LO Y. M. DENNIS
Published: July 2010

Abstract:In human pregnancy, multiple lines of evidence have indicated that there is trafficking of nucleated cells and cell‐free DNA between the mother and fetus. Diagnostically, fetal cells in maternal blood and fetal DNA in maternal plasma offer a noninvasive source of fetal material for prenatal diagnosis. Through the developments of methods for fetal cell isolation and fetal DNA detection, many fetal genetic characteristics and chromosomal abnormalities have been detected from maternal blood. Large‐scale clinical trials have been initiated that will facilitate the eventual application of these technologies. The presence of large quantities of cell‐free fetal DNA in maternal plasma challenges the conventional belief that the fetal and maternal circulations are separate entities. In addition, the recent demonstration of the persistence of fetal cells following delivery also opens up a new field of investigation and raises new physiologic and pathogenic implications. Like the Yin and Yang in Chinese mythology, we believe that fetal cells and fetal DNA transfer are closely related and should be studied and applied in a synergistic manner.
Circulatory Fetal and Maternal DNA in Pregnancies at Risk and Those Affected by Preeclampsia
Authors: ZHONG XIAO YAN , HOLZGREVE WOLFGANG , HAHN SINUHE
Published: July 2010

Abstract: Elevations in fetal cell traffic as well as increased release of cell‐free fetal DNA into the maternal periphery have previously been shown to occur in pregnancies affected by preeclampsia. Our own investigations have shown that manifestation of preeclampsia is associated with an increased accumulation of circulatory fetal DNA as well as cell‐free maternal DNA in maternal plasma. We further established that the increments in these two molecular genetic analytes corresponded to the severity of the disease and to each other. This latter phenomenon was evident in preeclamptic pregnancies, but not in normal ones. As we had recently performed a prospective study to investigate fetal cell traffic prior to onset of preeclamptic symptoms, we examined the levels of cell‐free fetal and maternal DNA in these samples. This analysis indicated that circulatory fetal DNA concentrations were significantly elevated prior to onset of the disease symptoms. No similar feature was observed for cell‐free maternal DNA levels.
Detection of Fetal NRBCs in Maternal Blood of Pregnant Carriers of β‐Thalassemia Using Anti‐γ and Anti‐ε Monoclonal Antibodies
Authors: MAVROU ARIADNI , KOLIALEXI AGGELIKI , ANTSAKLIS ARISTIDES , KRIKOS XENOFON , KORATZIS ASTERIS , METAXOTOU CATHERINE
Published: July 2010

Abstract: Fetal nucleated red blood cells (NRBCs) entering maternal circulation during pregnancy constitute a potential source of material for safe and reliable noninvasive prenatal diagnosis. The increased prevalence of β‐thalassemia mutations in countries like Greece may create a problem, making it difficult to distinguish between NRBCs of fetal or maternal origin. Use of Ab against embryonic hemoglobin ε may increase specificity for fetal NRBC detection. In the present study, Ab against embryonic hemoglobin ε was used in the first and second trimesters of pregnancy in order to determine if specificity for fetal NRBC detection could be increased.
Technical Optimization of RhD Zygosity Determination by Real‐Time Quantitative Polymerase Chain Reaction
Authors: CHIU ROSSA W. K. , MURPHY MICHAEL F. , FIDLER CARRIE , WAINSCOAT JAMES S. , LO Y. M. DENNIS
Published: July 2010

Abstract: We have recently reported the development of a multiplex, real‐time quantitative polymerase chain reaction (PCR) assay for RhD zygosity determination based on the coamplification and quantification of RHD‐specific sequences in relation to a reference gene, albumin. This paper discusses the optimization procedure and technical parameters of this multiplex assay.