Characterization of the contractile 5-hydroxytryptamine receptor in the autoperfused kidney of L-NAME hypertensive rats.

We evaluated the renal vascular effects of serotonin in Nomega-Nitro-l-arginine-hypertensive rats (L-NAME, 30 mg/kg/day, administered over 21 days in drinking water), a model of systemic hypertension with glomerular capillary hypertension and renal disease due to chronic blockade of endogenous synthesis of nitric oxide (NO) and compared with those obtained in normotensive rats. Using several agonists and antagonists of 5-hydroxytryptamine (5-HT), we characterized the receptor subtypes involved in the contractile response to 5-HT in the in-situ autoperfused rat kidney. An intra-arterial (i.

[Quality of life of patients with breast cancer receiving hormonal therapy, depending on age and marital status].

Our study involved 247 patients with histologically verified breast tumors, aged 48-89, who had received hormones - tamoxifen as first-line therapy, exemestan (second-line) for 12 months. FACT-B and FACT-G questionnaires were used to assess quality of life. Worse results were reported in tamoxifen-treated patients older than 60 years.

Synthesis and enzymatic evaluation of 2- and 4-aminothiazole-based inhibitors of neuronal nitric oxide synthase.

Highly potent and selective inhibitors of neuronal nitric oxide synthase (nNOS) possessing a 2-aminopyridine group were recently designed and synthesized in our laboratory and were shown to have significant in vivo efficacy. In this work, analogs of our lead compound possessing 2- and 4-aminothiazole rings in place of the aminopyridine were synthesized. The less basic aminothiazole rings will be less protonated at physiological pH than the aminopyridine ring, and so the molecule will carry a lower net charge.

Alleviating perinatal depressive symptoms and stress: a nurse-community health worker randomized trial.

To determine whether a Nurse-Community Health Worker (CHW) home visiting team, in the context of a Medicaid enhanced prenatal/postnatal services (EPS), would demonstrate greater reduction of depressive symptoms and stress and improvement of psychosocial resources (mastery, self-esteem, social support) when compared with usual Community Care (CC) that includes Medicaid EPS delivered by professionals. Greatest program benefits were expected for women who reported low psychosocial resources, high stress, or both at the time of enrollment. Medicaid eligible pregnant women (N = 613) were randomly assigned to either usual CC or the Nurse-CHW team.

L337H mutant of rat neuronal nitric oxide synthase resembles human neuronal nitric oxide synthase toward inhibitors.

A common dichotomy exists in inhibitor design: should the compounds be designed to block the enzymes of animals in the preclinical studies or to inhibit the human enzyme? We report that a single mutation of Leu-337 in rat neuronal nitric oxide synthase (nNOS) to His makes the enzyme resemble human nNOS more than rat nNOS. We expect that the approach used in this study can unite the dichotomy and speed up the process of inhibitor design and development.

[Palliative resection in esophageal cancer].

A 20-year experience of treatment of 633 patients with cancer of the thoracic esophagus has been evaluated. Far advanced disease was diagnosed in 384 (60.7%).

Analogues of 2-aminopyridine-based selective inhibitors of neuronal nitric oxide synthase with increased bioavailability.

Overproduction of nitric oxide by neuronal nitric oxide synthase (nNOS) has been linked to several neurodegenerative diseases. We have recently designed potent and isoform selective inhibitors of nNOS, but the lead compound contains several basic functional groups. A large number of charges and hydrogen bond donors can impede the ability of molecules to cross the blood brain barrier and thereby limit the effectiveness of potential neurological therapeutics.

Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy.

Objective: To design a new class of selective neuronal nitric oxide synthase (NOS) inhibitors, and demonstrate that administration in a rabbit model for cerebral palsy (CP) prevents hypoxia-ischemia-induced deaths and reduces the number of newborn kits exhibiting signs of CP.

Methods: We used a novel computer-based drug design method called fragment hopping to identify new chemical entities, synthesized them, and conducted in vitro enzyme inhibition studies with the three isozymes of NOS and in vivo experiments to monitor cardiovascular effects on pregnant rabbit dams, NOS activity, and NO(x) (NO and NO(2)) concentration in fetal brain, and assess neurobehavioral effects on kits born to saline- and compound treated dams.

Results: The computer-based design led to the development of powerful and highly selective compounds for inhibition of neuronal NOS over the other isozymes.

Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study.

Purpose: Vascular endothelial growth factor is a key promoter of tumor progression in cervical carcinoma. The Gynecologic Oncology Group (GOG) conducted a phase II trial to assess the efficacy and tolerability of bevacizumab, a recombinant humanized anti-vascular endothelial growth factor monoclonal antibody.

Patients And Methods: Eligible patients had recurrent cervical cancer, measurable disease, and GOG performance status < or = 2.

Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping.

Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity but more druglike properties can be achieved by fragment hopping. On the basis of the structure of lead molecule 6, fragment hopping effectively extracted the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization.

Who participates in state sponsored Medicaid enhanced prenatal services?

Medicaid insures an estimated 43% of all births in Michigan and provides additional funding for enhanced prenatal services (EPS). The objectives of this study are to report on the (1) use of statewide administrative data to examine risk characteristics and EPS enrollment of Medicaid-insured pregnant women in Michigan; and (2) presence and extent of a broad range of risk factors in a sample of EPS participants in Michigan, using a newly developed two-tier, risk screener and assessment tool. This study uses Vital Records, Medicaid and other data to describe EPS participation by maternal risks in the statewide population of Medicaid-insured pregnant women (54,582 in the fiscal year 2005).

Fixed effects, random effects and GEE: what are the differences?

For analyses of longitudinal repeated-measures data, statistical methods include the random effects model, fixed effects model and the method of generalized estimating equations. We examine the assumptions that underlie these approaches to assessing covariate effects on the mean of a continuous, dichotomous or count outcome. Access to statistical software to implement these models has led to widespread application in numerous disciplines.

Polymorphisms and clinical outcome in recurrent ovarian cancer treated with cyclophosphamide and bevacizumab.

Purpose: This study was designed to evaluate the associations between angiogenesis gene polymorphisms and clinical outcome in ovarian cancer patients treated with low-dose cyclophosphamide and bevacizumab.

Experimental Design: Seventy recurrent/metastatic epithelial ovarian cancer patients were enrolled in a phase II clinical trial. Genomic DNA was available from 53 blood samples.

Deletion of the autoregulatory insert modulates intraprotein electron transfer in rat neuronal nitric oxide synthase.

Comparative CO photolysis kinetics studies on wild-type and autoregulatory (AR) insert-deletion mutant of rat nNOS holoenzyme were conducted to directly investigate the role of the unique AR insert in the catalytically significant FMN-heme intraprotein electron transfer (IET). Although the amplitude of the IET kinetic traces was decreased two- to three-fold, the AR deletion did not change the rate constant for the calmodulin-controlled IET. This suggests that the rate-limiting conversion of the electron-accepting state to a new electron-donating (output) state does not involve interactions with the AR insert, but that AR may stabilize the output state once it is formed.

Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors.

Fragment hopping, a new fragment-based approach for de novo inhibitor design focusing on ligand diversity and isozyme selectivity, is described. The core of this approach is the derivation of the minimal pharmacophoric element for each pharmacophore. Sites for both ligand binding and isozyme selectivity are considered in deriving the minimal pharmacophoric elements.

Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia.

Purpose: Vascular endothelial growth factor (VEGF) plays an important role in the biology of ovarian cancer (OC). Inhibitors of VEGF suppress tumor growth in OC models. Metronomic chemotherapy, defined as frequent administration of low doses of cytotoxic chemotherapy, suppresses tumor growth, possibly by inhibiting angiogenesis.

Phase II clinical trial of docetaxel in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study.

Objective: A phase II study was conducted to evaluate the antitumor activity and adverse effects of docetaxel in patients with previously treated squamous cell carcinoma of the cervix.

Methods: Eligible patients were to have measurable disease and not more than one prior chemotherapy regimen. Docetaxel 100 mg/m was administered intravenously over 1 hour.

Oxygen metabolism by endothelial nitric-oxide synthase.

Nitric-oxide synthase (NOS) catalyzes both coupled and uncoupled reactions that generate nitric oxide and reactive oxygen species. Oxygen is often the overlooked substrate, and the oxygen metabolism catalyzed by NOS has been poorly defined. In this paper we focus on the oxygen stoichiometry and effects of substrate/cofactor binding on the endothelial NOS isoform (eNOS).

A phase II study of Hsp-7 (SGN-00101) in women with high-grade cervical intraepithelial neoplasia.

Objective: Approximately 2 million women worldwide are infected with high-risk human papillomaviruses (HPV), resulting in a substantial risk for the development of invasive lower genital malignancies. This study was undertaken to determine the effects of vaccination with a protein encoding a bacterial heat shock protein fused to sequences from the oncogenic E7 protein of HPV-16 in women with high-grade cervical intraepithelial neoplasia. Endpoints included lesion regression, immune response, and viral clearance.

Therapeutic vaccination for HPV induced cervical cancers.

Cervical Cancer is the second leading cause of cancer-related deaths in women worldwide and is associated with Human Papillomavirus (HPV) infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function.

Hydroxyethylene isosteres of selective neuronal nitric oxide synthase inhibitors.

Nitric oxide (NO) is an important second messenger molecule for blood pressure homeostasis, as a neurotransmitter, and in the immune defense system. Excessive NO can lead to neurodegeneration and connective tissue damage. Three different isozymes of the enzyme nitric oxide synthase regulate NO production in endothelial (eNOS), neuronal (nNOS), and macrophage (iNOS) cells.

Addressing mental health and stress in Medicaid-insured pregnant women using a nurse-community health worker home visiting team.

Objective: To describe the conceptual framework and program features of a nurse-community health worker (CHW) team home visiting intervention, the trial design to test the program, and the results of a comparative evaluation of prenatal program participation.

Design: In the context of a community-based, randomized trial, we compared participation in a nurse-CHW team intervention with the standard community care that included a state Medicaid program (enhanced prenatal services) with nurse home visiting.

Sample: Medicaid-eligible pregnant women (n=530), who maintained their pregnancies, had a live birth, retained custody of the child, completed more than an enrollment assessment, did not move out of the county, and were not lost to follow-up.

Structure-based design and synthesis of N(omega)-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. Displacement of the heme structural water.

The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the production of nitric oxide in the central nervous system, represents an attractive target for the treatment of various neurodegenerative disorders. X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-aminoethylamino]pentyl}-N'-nitroguanidine (1) and 4-N-(Nomega-nitro-l-argininyl)-trans-4-amino-l-proline amide (2), led to the discovery of a conserved structural water molecule that was hydrogen bonded between the two heme propionates and the inhibitors (Figure 2). On the basis of this observation, we hypothesized that by attaching a hydrogen bond donor group to the amide nitrogen of 2 or to the secondary amine nitrogen of 1, the inhibitor molecules could displace the structural water molecule and obtain a direct interaction with the heme cofactor.