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Biomedical subjects

Jeffrey Klein

Publications and source records attributed to Jeffrey Klein.

9 recordsLinked to original sources
PubMed2006

Single-chain bifunctional vascular endothelial growth factor (VEGF)-follicle-stimulating hormone (FSH)-C-terminal peptide (CTP) is superior to the combination therapy of recombinant VEGF plus FSH-CTP in stimulating angiogenesis during ovarian folliculogenesis.

Infertility technologies often employ exogenous gonadotropin therapy to increase antral follicle production. In an effort to enhance ovarian response, several long-acting FSH therapies have been developed including an FSH-C-terminal peptide (CTP), where the FSH subunits are linked by the CTP moiety from human chorionic gonadotropin, which is responsible for the increased half-life of human chorionic gonadotropin. We found that administration of FSH-CTP for ovarian hyperstimulation in rats blunted ovarian follicle vascular development. In women, reduced ovarian vasculature has been associated with lower pregnancy rates. We were interested in determining whether vascular endothelial growth factor (VEGF) therapy could enhance ovarian angiogenesis in FSH-CTP-treated rats. Coadministration of systemic FSH-CTP plus recombinant VEGF was compared with treatment with a novel, single-chain bifunctional VEGF-FSH-CTP (VFC) analog. For VFC, the FSH portion targets the protein to the ovary and stimulates follicle growth, whereas VEGF enhances local vascular development. Both in vitro and in vivo studies confirm the dual FSH and VEGF action of the VFC protein. Evaluation of ovarian follicle development demonstrates that administration of combination therapy using VEGF and FSH-CTP failed to increase follicle vasculature above levels seen with FSH-CTP monotherapy. However, treatment with VFC significantly increased follicle vascular development while concurrently increasing the number of large antral follicles produced. In conclusion, we report the production and characterization of a long-acting, bifunctional VEGF-FSH-CTP protein that is superior to combination therapy for enhancing VEGF activity in the ovary and stimulating follicular angiogenesis in rats.

Animals↗
PubMed2005

Effects of long-acting recombinant human follicle-stimulating hormone analogs containing N-linked glycosylation on murine folliculogenesis.

OBJECTIVE: To evaluate the efficacy of two novel long-acting rhFSH analogs, rhFSH-N2 and rhFSH-N4, in stimulating murine folliculogenesis. DESIGN: Experimental study. SETTING: Academic research environment. ANIMAL(S): Immature female mice. INTERVENTION(S): Recombinant hFSH-N2 and -N4 were administered via single IP injection to 3-week-old female mice (n = 10) who were killed 48 hours later for dissection and histologic examination of reproductive organs and serum inhibin A. Results were compared with other groups of mice who received either single or q 12 hour injections for 48 hours of commercial rhFSH, or a single injection of pregnant mare serum gonadotropin (PMSG). A subgroup of the mice receiving rhFSH-N4 was supplemented with daily injections of small doses of hCG to simulate LH add-back. MAIN OUTCOME MEASURE(S): Serum inhibin A levels, ovarian and uterine weights, and ovarian antral follicle counts. RESULTS(S): Recombinant human FSH-N2 and -N4 administration induced a statistically significant increase in ovarian weights, uterine weights, and inhibin A levels compared with single and twice-daily injection of rhFSH. PMSG induced the greatest increases in all three measured parameters. There was no statistical difference between rhFSH-N2 and rhFSH-N4 for any parameter analyzed. A single injection of rhFSH-N2 or -N4 induced a greater number of antral follicles than did either single or q 12 hour injections of rhFSH. The addition of small doses of hCG to rhFSH-N4 increased inhibin A levels and antral follicle number to reach statistical equivalence to PMSG treatment. CONCLUSION(S): Addition of a synthetic polypeptide containing two or four N-linked glycosylation sites to rhFSH increases in vivo bioactivity of the hormone compared to commercial rhFSH. After a single injection, both rhFSH-N2 and rhFSH-N4 effectively induced a greater follicular response in the mouse than did rhFSH.

Amino Acid Sequence↗
PubMed2003

Understanding the motivations, concerns, and desires of human immunodeficiency virus 1-serodiscordant couples wishing to have children through assisted reproduction.

OBJECTIVE: To survey the attitudes of human immunodeficiency virus (HIV)-serodiscordant couples interested in assisted reproduction and better characterize their motivations for reproducing. METHODS: A prospectively designed questionnaire and open-ended interview of 50 consecutive HIV-serodiscordant couples interested in undergoing assisted reproduction to avoid transmission of virus were studied. Demographic characteristics and attitudes regarding beginning a family were obtained. By design, males were HIV seropositive (age, 38.0 +/- 5.4 years, range 26-51 years) and healthy. Women were HIV seronegative (age, 34.5 +/- 5.1 years, range 24-45 years). Most couples were married (44 of 50) and in long-term relationships (duration of relationship, 8.9 +/- 4.9 years, range 1-20 years). RESULTS: Before presentation, nine of 50 couples had conceived and delivered a child (three of nine instances with knowledge of paternal HIV status). Previous timed intercourse occurred in 8% of couples (four of 50). Six individuals stated they would proceed with timed intercourse if no other alternatives existed. Forty-eight percent said they would prefer artificial insemination with donor sperm in lieu, if assisted reproduction failed or were unavailable. Forty-three percent of respondents would pursue "posthumous conception" if cryopreserved sperm or embryos were available in the event of the partner's death. Most couples discussed the possibility of single parenting (45 of 50; 90%) or the possibility for adoptive parenting (29 of 50; 58%). Couples were aware of risk, and 92% (46 of 50) understood that their child might contract HIV. CONCLUSION: Human immunodeficiency virus-serodiscordant couples are actively seeking reproductive assistance and often consider or practice unsafe measures to achieve pregnancy. Reproductive issues and concerns unique to these couples need to be addressed before treatment.

Adult↗
PubMed2003

Normal and variant arterial supply of the liver and gallbladder.

The vascular supply of the liver and gallbladder is characterized by a striking degree of polymorphism. The occurrence of variants that differ from the usual pattern is both surprisingly common and unpredictable. Knowledge of this variable anatomy is particularly important during surgical interventions in which preoperative imaging studies are not available, such as in organ procurements. In this report we consider various anatomical arterial configurations, and describe an unusual variant.

Arteries↗
PubMed2002

Bacterial expression of a natively folded extracellular domain fusion protein of the hFSH receptor in the cytoplasm of Escherichia coli.

We have expressed the extracellular domain of the hFSH receptor as a fusion protein with thioredoxin in the cytoplasm of an Escherichia coli strain that contains mutations in both the thioredoxin reductase and the glutathione reductase genes. The chimeric protein isolated following induction of expression was purified in a soluble form and binds hFSH with an affinity approximating that of native receptor. This truncated form of the receptor displays the same specificity as intact receptor and does not bind hCG. The protein is expressed at levels that exceed 5 mg/L in the bacterial cytoplasm. Expression of the properly folded extracellular domain of the hFSH receptor in the cytoplasm of E. coli allows the facile and economical purification of large quantities of material. This will facilitate the determination of the structure of the hormone-binding domain of this glycoprotein receptor as well as the production of epitope-specific antibodies.

Amino Acid Sequence↗
PubMed2002

Pharmacokinetics and pharmacodynamics of single-chain recombinant human follicle-stimulating hormone containing the human chorionic gonadotropin carboxyterminal peptide in the rhesus monkey.

OBJECTIVE: To compare the pharmacokinetics of a long-acting FSH analog containing the hCG-beta carboxyterminal peptide (recombinant hFSH-CTP) with native recombinant hFSH and describe the pharmacodynamics of recombinant hFSH-CTP after SC injection in female rhesus monkeys. DESIGN: Rhesus monkey study. SETTING: Academic research environment. ANIMAL(S): Ten female rhesus monkeys. INTERVENTION(S): Recombinant hFSH and recombinant hFSH-CTP were administered via a single SC or IV dose to rhesus monkeys, and serial phlebotomy was performed (n = 2 and n = 4 for SC recombinant hFSH and recombinant hFSH-CTP, respectively; for IV dosing, n = 1 in each group). An additional two monkeys were pretreated with SC ganirelix and received SC recombinant hFSH-CTP after confirmation of pituitary suppression. MAIN OUTCOME MEASURE(S): Plasma disappearance rate of recombinant hFSH and recombinant hFSH-CTP and serum estradiol levels. RESULT(S): The elimination half-life of recombinant hFSH-CTP was twofold and fourfold longer than that for recombinant hFSH after SC and IV dosing, respectively. The absorption half-life was approximately threefold longer for recombinant hFSH-CTP than for recombinant hFSH after SC administration. Recombinant hFSH-CTP stimulates estradiol secretion for 5-7 days after an isolated SC dose. CONCLUSION(S): Addition of the hCG-beta carboxyterminal peptide to hFSH-beta results in an FSH analog with longer absorption and elimination half-lives compared with native hormone. This analog is capable of prolonged ovarian stimulation in rhesus monkeys after an isolated SC injection.

Absorption↗
PubMed2002

Oocyte donation.

Oocyte donation affords women with ovarian failure, advanced reproductive age, heritable conditions or recurrent implantation failure the ability to conceive. Recipients must be medically screened carefully prior to attempting pregnancy. Egg donors should also be healthy and pose no infectious or genetic risk to the recipient or offspring. Donor and recipient menstrual cycles are synchronized so that embryos are transferred to a receptive endometrium. Donors are prescribed injectible gonadotrophins to achieve multifollicular growth. Recipient endometrial priming begins with 2 weeks (or more) of oestradiol, with progesterone added to the regimen 3-4 days prior to the transfer of embryos. Pregnancy rates following egg donation are among the highest observed following assisted reproduction. Despite advanced reproductive age, perinatal and obstetric outcomes are generally good. Techniques (i.e. germinal vesicle transfer, donor ooplasm, and ovarian cryopreservation and transplantation techniques) may permit the recipient to provide some genetic contribution to offspring and are currently under investigation.

Adult↗
PubMed2002

Cardiac resynchronization therapy for treatment of chronic heart failure.

Cardiac resynchronization therapy (CRT) by means of biventricular pacing is a fairly new procedure that has recently been approved by the United States Food and Drug Administration. Many promising studies have been published that suggest CRT improves patient quality of life (based on the Minnesota Living with Heart Failure Quality of Life Questionnaire), increases distance walked in 6 minutes, improves oxygen uptake, lowers New York Heart Association classification, decreases QRS duration, increases left ventricular ejection fraction, and increases peak oxygen consumption. These studies include the Multisite Stimulation in Cardiomyopathies (MUSTIC), the Multicenter InSync Randomized Clinical Evaluation (MIRACLE), the Pacing Therapy for Congestive Heart Failure (PATH-CHF) multicenter trial, the Medtronic Inc. InSync study, the Ventak CHF/Contak CD study, Vigor CHF and a small study conducted by Alonso and colleagues. There are also a number of studies that are still being conducted, such as the COMPANION trial, which will provide further insight into the effectiveness of cardiac resynchronization therapy.

Aged↗