The thyroid hormone-αvß3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation.

Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvß3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvß3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvß3) and A2780 (low αvß3) cells promoted αv and ß3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvß3 antibodies, excluding T3-induced ß3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of ß3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvß3-deficient HEK293 cells treated with αvß3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the ß3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical role for thyroid hormones as potent αvß3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.

Increased bone marrow toxicity of doxorubicin bound to nanoparticles.

The in vivo myelosuppressive effects of free and polyalkylcyanoacrylate-bound doxorubicin were compared in a mouse model. After intravenous administration of 11 mg/kg body weight of doxorubicin either free or bound to polyisobutyl (doxo-PIBCA) or polyisohexylcyanoacrylate (doxo-PIHCA) nanoparticles, we studied the total and differential counts of blood, bone marrow and spleen cells; the number of granulocyte progenitors (CFU-GM) was determined by culture. Doxorubicin concentrations were measured with an HPLC method in the bone marrow and the spleen. Doxo-PIHCA nanoparticles showed the highest and longest myelosuppressive effects which correlated well with a high concentration of the drug in the bone marrow and the spleen. Moreover, it was found that PIHCA nanoparticles induced the release of colony stimulating factors, which might account for the observed increase of toxic effects of doxorubicin on bone marrow progenitors. These data also indicate that a more precise evaluation of the myelosuppressive effects of targeted formulations of anticancer drugs is needed, which may be attained by studies on bone marrow progenitors.

Medical care in a geriatric psychiatry unit: impact on psychiatric outcome.

The medical care of 49 randomly selected patients admitted to a geriatric psychiatry evaluation unit was assessed to determine the impact on psychiatric care and outcome. Medical factors were identified as directly causing psychiatric symptoms in 12 of the 49 cases, whereas psychiatric decompensation was precipitated by medical illness in 25. Previously undiagnosed significant medical problems were found in ten patients. In 25 cases concomitant medical illness had a major effect on psychiatric treatment, and in 23 the course of the medical illness affected psychiatric outcome. Seventy-nine per cent of the patients had at least moderately improved at the time of discharge, and most were able to return to their homes. Improvement in medical condition was correlated significantly with psychiatric improvement. Implications for the care of geriatric psychiatry patients are discussed.

Polyalkylcyanoacrylate nanoparticles as carriers for granulocyte-colony stimulating factor (G-CSF).

The human recombinant granulocyte colony-stimulating factor (rhG-CSF) is largely used in the treatment of neutropenia occurring during chemotherapy. After injection, this glycoprotein distributes through the whole body. Thus, to obtain high and durable bone marrow concentrations, targeting with polyalkylcyanoacrylate nanoparticles was considered. Two methods of preparation were investigated: anionic polymerization and precipitation of the preformed polymer. By anionic polymerization, it was possible to associate more than 66% of rhG-CSF with nanoparticles (polyisobutyl- or polyisohexylcyanoacrylate nanoparticles) when the glycoprotein was added at the end of the polymerization process. It has been shown that the rhG-CSF was mainly adsorbed on the surface of the nanoparticles and most of the colony stimulating activity was conserved. Using precipitation of performed polyisohexylcyanoacrylate, 90% of rhG-CSF was associated with nanoparticles, the protein being mainly adsorbed onto the nanoparticle surface. In this case, a decrease of the colony stimulating activity was however observed. Whatever the method used, the in vitro release of rhG-CSF from the polyisohexylcyanoacrylate nanoparticles, was progressive during 8 h in seric conditions. Nevertheless, using mice as an animal model, it has been shown that the short-term effects of intravenously injected rhG-CSF were not increased by its association with polyisohexylcyanoacrylate nanoparticles.

A pharmacoeconomic analysis of neuromuscular blocking agents in the operating room.

A cost-minimization analysis was performed to compare the direct costs of various neuromuscular blocking agents (NMBAs) in procedures of specific durations. Secondary objectives were to review the role of the NMBAs studied with respect to their place on our hospital formulary, and to develop a pharmacoeconomic methodology to be applied to other formulary decisions. Patients were stratified according to estimated length of surgical procedure; group 1 (55 patients) included surgeries estimated to take less than 2 hours, and group 2 (55 patients) included those estimated to be 2-4 hours long. Patients were then randomized to one of three intermediate-acting NMBAs: atracurium, vecuronium, or rocuronium. Anesthesia records were used to obtain all anesthetic agents administered in the operating room, and drug costs were calculated from hospital drug acquisition costs as of December 1994. Postanesthesia care unit (PACU) costs were estimated from patient charges and converted to costs using our hospital's cost-to-charge ratio. Costs that were common to all study treatments or unrelated to the use of NMBAs were excluded from the analysis. Two time-adjusted costs were calculated to determine the cost of neuromuscular blockade/hour and the total anesthesia drug costs/hour. In group 1 there were no statistical differences in NMBA cost/hour, anesthesia cost/hour, or PACU times or costs. In group 2, a significant difference was found in NMBA cost/case between atracurium ($54.23 +/- 41.26, mean +/- SD) and vecuronium ($31.95 +/- 15.33, p = 0.046). Atracurium was also significantly more costly than either vecuronium or recuronium/hour ($21.95 +/- 7.42 vs $14.39 +/- 7.02 and $16.07 +/- 8.15, respectively, p = 0.011) and anesthesia cost/hour ($28.77 +/- 7.43 vs $ 22.82 +/- 7.46 and $23.32 +/- 6.54, respectively, p = 0.03). There were no differences in PACU times or costs. Based on these results, vecuronium or rocuronium is preferred over atracurium in procedures with an estimated duration of 2-4 hours. In the patient population evaluated, there were no significant cost differences among the three NMBAs in surgeries with an estimated duration of less than 2 hours.

Thromboembolic prophylaxis in moderate-risk patients undergoing elective abdominal surgery: decision and cost-effectiveness analyses.

We conducted a retrospective, literature-based decision analysis to compare the cost-effectiveness of conventional low-dose heparin, dalteparin, and intermittent pneumatic compression (IPC) as thromboembolic prophylaxis to a no-prophylaxis option in patients at moderate risk of developing thromboembolic complications after major elective abdominal surgery. The analysis was conducted through an institutional perspective. Probability and incidence rate data were summarized from the literature. Cost data were obtained from the Detroit Medical Center's cost accounting systems and from national diagnosis-related group estimates. Mortality and complications avoided were the main outcome measures on which cost-effectiveness was based. Overall costs associated with conventional low-dose heparin, dalteparin, intermittent pneumatic compression, and no prophylaxis were $84, $122, $102, and $112, respectively in the primary analysis, which included costs of labor. Corresponding cost-effectiveness ratios in terms of costs/complication-free patient were $86, $124, $103, and $118, respectively. Compared with no prophylaxis, incremental cost-effectiveness analysis in terms of cost/mortality avoided involved savings of $6087 and $3125 with conventional low-dose heparin and IPC, respectively, and expenses of $2857 with dalteparin. A secondary analysis excluding costs of labor showed similar results. The results of the study consistently showed conventional low-dose heparin to provide the most cost-effective thromboembolic prophylaxis of the methods considered in terms of reducing both morbidity and mortality in the patient population studied.

Omeprazole-induced exfoliative dermatitis.

A 41-year-old man being treated for severe esophageal reflux disease developed red, exfoliative scaling on his back, trunk, and legs after taking omeprazole 20 mg twice/day for 3 months. He also had redness and extreme sloughing of the skin on his hands. Even after he discontinued omeprazole and after several courses of topical and systemic steroids, symptoms continued to occur 18 months after treatment, mostly localized to the hands. Exfoliative dermatitis is associated with many drugs, but omeprazole has been implicated only once before in the literature.

A pharmacist-initiated program of intravenous to oral antibiotic conversion.

A prospective program to convert patients from parenteral to oral antibiotics was evaluated over 12 months to determine its pharmacoeconomic impact on antibiotic acquisition and length of hospital stay. Physicians of patients meeting predetermined clinical criteria for mild and moderate infections were contacted to discuss potential oral alternative therapy. Clinical end points and economic data were followed in 242 patients (200 converted and 42 not converted but meeting criteria). No significant differences were noted between the groups with regard to demographic data, infection diagnosis, clinical outcome, or adverse effects. The average number of days of therapy for patients converted was 1.53 days shorter than that of patients who were not converted to oral therapy (p < 0.003). Cost savings for drug acquisition and length of stay were $15,149.24 and $161,071.88, respectively. The intervention program appeared to provide a cost-effective conversion from parenteral to oral antimicrobial administration without compromising patient care. It is anticipated that expansion of the program to include additional antibiotics will result in even greater cost savings for the institution.

Evaluation of Acinetobacter baumannii infection and colonization, and antimicrobial treatment patterns in an urban teaching hospital.

In 1990 there was a sudden increase in the incidence of colonization and infection due to Acinetobacter baumannii (AB) in our intensive care units (ICUs). The isolates were multiply resistant to beta-lactam and aminoglycoside antibiotics, but remained susceptible to imipenem, amikacin, and ampicillin-sulbactam. We examined the frequency of infection and colonization with AB and the effects of increased imipenem and amikacin therapy on Pseudomonas aeruginosa. We also used disease-matched controls to determine the clinical and financial impacts of treating colonization. All patients with at least one AB isolate from January-December 1992 were identified retrospectively and classified as infected or colonized based on published Centers for Disease Control criteria; the control group was selected from a computerized medical records data base matching primary diagnostic codes (102 patients both groups). The 102 patients yielded 140 isolates, 124 resistant AB and 16 sensitive AB. Thirty three patients were infected, 69 colonized. Mortality correlated with APACHE II scores. Patients acquired the organism approximately 2 weeks after admission; they had a mean ICU stay of 27.35 days, compared with 5.53 days for controls. Patients with positive AB cultures required significantly more use of ventilators than those with negative AB cultures. They also had significantly longer hospital stay, more bed transfers, greater duration and number of antibiotics, and higher hospital and pharmacy charges. Unnecessary treatment for colonization with either imipenem or amikacin resulted in a substantial decrease of P. aeruginosa susceptibility to each agent. The financial impact of treating colonization was significant and is a potential area for cost avoidance. Our results emphasize the need to extubate and move patients to non-ICU beds as soon as possible to decrease the risk of nosocomial infection. It also highlights the need to avoid treating colonization, thus avoiding unnecessary antibiotic therapy.

Magnetically responsive microspheres for the pulsed delivery of insulin.

This paper describes a new formulation for triggered delivery of insulin which consisted of magnetic particles dispersed in alginate spheres. When magnetic field was applied to that system, the release rate of insulin was about 50 times higher than in the absence of magnetic field. The influence of oscillating magnetic field was tested, in the same experimental conditions, on polyethylenimine cross-linked alginate spheres. In that case, the pulsed delivery of insulin occurred not immediately but during the period just after applying the magnetic field. The proposed magnetically responsive alginate spheres open new perspectives for the rhythmically delivery of peptides.

In vitro evaluation of nanoparticles spleen capture.

After intravenous injection, the main part of nanoparticles trapped by the spleen are concentrated in the marginal zone. The first step of this capture is the adhesion of the particles to the marginal zone macrophages. As classical techniques of cell suspension preparation did not allow to isolate without damage these actively capturing cells, tightly bound to a well-developed reticular meshwork, we designed a tissue slice incubation method, in order to study in vitro the interaction of nanoparticles with these particular macrophages, in conditions close to in vivo. In a serum supplemented medium, this in vitro model was able to give similar uptake profile than after intravenous injection of nanoparticles thus proving its validity. Surprisingly, no significant decrease of nanoparticles capture was observed when the medium was depleted from complement, immunoglobulins or proteins affine for heparin, while substitution of serum by purified albumin allowed a near optimal uptake. Addition of competitive ligands for lectin-like receptors did not show any clear inhibition of spleen capture. On the other hand, the scavenger receptor blocking agents, such as maleylated albumin or polyinosinic acid, induced a strong reduction of the spleen nanoparticles uptake. Thus, this paper proposes an in vitro binding assay as a reliable method to investigate the spleen capture of a large variety of nanoparticulate drug carriers. It is also a useful methodology to highlight the interactions between spleen cells and nanoparticles. The data obtained suggest that capture of nanoparticles depends on a multifactorial and complex phenomenon involving for a part albumin and the scavenger receptor.

The mismatch negativity cortical evoked potential elicited by speech in cochlear-implant users.

The mismatch negativity (MMN) event-related potential is a non-task related neurophysiologic index of auditory discrimination. The MMN was elicited in eight cochlear implant recipients by the synthesized speech stimulus pair /da/ and /ta/. The response was remarkably similar to the MMN measured in normal-hearing individuals to the same stimuli. The results suggest that the central auditory system can process certain aspects of speech consistently, independent of whether the stimuli are processed through a normal cochlea or mediated by a cochlear prosthesis. The MMN shows promise as a measure for the objective evaluation of cochlear-implant function, and for the study of central neurophysiological processes underlying speech perception.

Cells involved in the capture of nanoparticles in hematopoietic organs.

The affinity of nanoparticles for hematopoietic organs could be valuable for the targeting of certain stimulating factors to those tissues, but this affinity should also be taken into account in the toxicological evaluation of those carriers, especially when they are loaded with antimitotic compounds such as doxorubicin. However, the cells responsible for the capture of the nanoparticles and their localization in these organs is an important point to know before trying to modulate the nanoparticle's tissue distribution. Thus, we have studied, in this paper, the capture, the localization, and the retention in the bone marrow and in the spleen of biodegradable poly(isohexyl cyanoacrylate) nanoparticles as well as of nonbiodegradable polystyrene nanoparticles. The histological localization of these nanoparticles has been completed by cytological localization with a method used in cytochemistry for the evaluation of intracellular accumulation of various substances, such as iron deposits in bone marrow sideroblasts. These data indicate that, in the bone marrow, after a quick passage through the endothelium, nanoparticles were dispersed throughout in the tissue and captured by all types of phagocytizing cells. In the spleen, nanoparticles were mainly localized in large angular capturing cells in the marginal zone of the lymphoid follicles.

Snare uvulopalatoplasty.

Single-stage outpatient treatment of snoring with snare dissection uvulopalatoplasty (UPP) has been developed and found to be safe and effective. Single-stage snare dissection UPP (SUPP) was performed on 25 habitual loud snorers with readily available instrumentation in an ambulatory setting. Fourteen had associated septoplasty. When only SUPP was performed, local and topical anesthesia and minimal oral premedication were used in most cases. No significant immediate or delayed bleeding occurred. Postoperative discomfort persisted for 3 to 12 days and required only oral analgesics. No postoperative complications occurred. Ninety-one percent of patients reported satisfactory reduction or elimination of snoring after surgery. Preoperative and postoperative acoustic analysis of sleeping respiration (SNAP testing) was used to document the effects of SUPP in eight patients. SUPP is a safe, cost-effective method of treating patients with habitual snoring.

Urokinase activity after freezing: implications for thrombolysis in intraventricular hemorrhage.

The retention of urokinase activity after frozen storage was studied. Urokinase powder was reconstituted aseptically in sterile water for injection or preservative-free 0.9% sodium chloride injection to a final concentration of 5000 IU/mL. Samples were stored in 5-mL plastic syringes at -20 or -70 degrees C for up to six months. Samples containing urokinase 25,000 IU/mL were similarly prepared by using sodium chloride injection as the diluent and were stored frozen at the same temperatures for up to 93 days. Urokinase activity was measured with a chromogenic assay at each test interval. Samples were also cultured after thawing to evaluate their potential to support microbial growth. The activity of urokinase at either concentration did not change appreciably during the study period. The method of thawing-at room temperature or in a refrigerator-had no effect on urokinase activity. No microbial growth was observed. Urokinase 5000 IU/mL did not show any changes in activity when reconstituted with sterile water for injection or 0.9% sodium chloride injection and frozen for up to six months. Urokinase 25,000 IU/mL in sodium chloride injection was also stable after 93 days of frozen storage.

Nursing interventions: caring for parents of a newborn transferred to a regional intensive care nursery--a challenge for low risk obstetric specialists.

Parents of infants transferred to a regional NICU have unique needs for support when the mother remains in the hospital of birth. Suddenly in a high risk situation and faced with family separation, these parents may display intense grief and crisis reactions related to their infant's status and transfer. The high risk interventions they require are frequently incongruent with the wellness orientation of staff specializing in care of the low risk clients. Nevertheless, low risk specialists have a critical role in assisting parents through this difficult transition to parenthood. Effective strategies are based upon: understanding that at some point infants requiring transfer to a regional NICU will be born; advance planning to prepare staff to assist parents during this type of crisis; establishing an ongoing relationship with staff from the regional NICU; and identification of crisis support networks available to parents and to staff within the low risk setting.

Ultrasonic tonsillectomy: rationale and technique.

Dissection using ultrasonic aspiration is characterized by its unique tendency to spare fibrous and vascular structures during removal of parenchymal lesions. This preliminary study was undertaken to evaluate the feasibility and efficiency of tonsillectomy using the ultrasonic aspirator. Tonsillectomy was performed on 23 patients using the ultrasonic aspirator. Pericapsular removal of the tonsil was easily accomplished with complete preservation of the tonsillar pillars and minimal peritonsillar trauma. The ability to identify significant vasculature before transection, and the constant aspiration integrated into the ultrasonic aspirator allowed excellent visualization of the operative field at all times. No postoperative complications were noted and recovery was typical for tonsillectomy patients. The ultrasonic aspirator may increase the efficiency and margin of safety of tonsillectomy.

Married mothers' perceptions of their premature or term infants and the quality of their relationships with their husbands.

Twenty-eight mothers of premature infants and 37 mothers of term infants were examined for their perceptions of their infants and of their relationships with their husbands at two to four postpartum days and at six to eight postpartum weeks. The mothers tended to perceive their infants positively, whether or not the infants were born prematurely. Preterm mothers who compared their infants to an average premature infant were more positive than term mothers who compared their infants to an average term infant. An association was not found in either group between mothers' perceptions of their infants and of the quality of their relationships with their husbands. However, mothers with negative perceptions of their infants also tended to have difficult marriages.

Measles: again an epidemic.

With the incidence of measles again on the rise in the United States, nurses have important roles in health promotion and education. Nurses and other health care providers need to be well informed about the potential severity of measles and the importance of immunization in preventing measles.

[Targeting bone marrow with the help of polyalkylcyanoacrylate nanoparticles]. / Ciblage de la moelle osseuse à l'aide de nanoparticules de polyalkylcyanoacrylate.

Using a mouse model, we examine drug targeting towards bone marrow. One cytotoxic (doxorubicin) and one stimulating (rhG-CSF), bound to polyalkylcyanoacrylate nanoparticles, were studied. Histological studies, using a fluorescence microscope, showed rapid capture of nanoparticles by bone marrow macrophages and granulocytes as soon as 15 minutes after injection into the blood stream. Doxorubicin nanoparticles, administered at a dose of 11 mg/kg were more toxic than free doxorubicin on all blood and marrow cell lines. Moreover, the choice of the nature of the polymer had an influence on toxicity: doxorubicin polyisohexylcyanoacrylate nanoparticles were more toxic than polyisobutylcyanoacrylate particles. Quantification of doxorubicin in bone marrow has confirmed these results. The bone marrow concentrations observed demonstrated that there was a high level of targeting towards the bone marrow that would be very interesting to use for a stimulating drug. Nevertheless, rhG-CSF nanoparticles did not show better efficacy than free rhG-CSF.