Comparison of 177Lu-octreotate and 177Lu-octreotide for treatment in human neuroblastoma-bearing mice.

Background: Patients with high-risk neuroblastoma (NB) have a 5-year event-free survival of less than 50 %, and novel and improved treatment options are needed. Radiolabeled somatostatin analogs (SSTAs) could be a treatment option. The aims of this work were to compare the biodistribution and the therapeutic effects of 177Lu-octreotate and 177Lu-octreotide in mice bearing the human CLB-BAR NB cell line, and to evaluate their regulatory effects on apoptosis-related genes. Methods: The biodistribution of 177Lu-octreotide in mice bearing CLB-BAR tumors was studied at 1, 24, and 168 h after administration, and the absorbed dose was estimated to tumor and normal tissues. Further, animals were administered different amounts of 177Lu-octreotate or 177Lu-octreotide. Tumor volume was measured over time and compared to a control group given saline. RNA was extracted from tumors, and the expression of 84 selected genes involved in apoptosis was quantified with qPCR. Results: The activity concentration was generally lower in most tissues for 177Lu-octreotide compared to 177Lu-octreotate. Mean absorbed dose per administered activity to tumor after injection of 1.5 MBq and 15 MBq was 0.74 and 0.03 Gy/MBq for 177Lu-octreotide and 2.9 and 0.45 Gy/MBq for 177Lu-octreotate, respectively. 177Lu-octreotide treatment resulted in statistically significant differences compared to controls. Fractionated administration led to a higher survival fraction than after a single administration. The pro-apoptotic genes TNSFS8, TNSFS10, and TRADD were regulated after administration with 177Lu-octreotate. Treatment with 177Lu-octreotide yielded regulation of the pro-apoptotic genes CASP5 and TRADD, and of the anti-apoptotic gene IL10 as well as the apoptosis-related gene TNF. Conclusion: 177Lu-octreotide gave somewhat better anti-tumor effects than 177Lu-octreotate. The similar effect observed in the treated groups with 177Lu-octreotate suggests saturation of the somatostatin receptors. Pronounced anti-tumor effects following fractionated administration merited receptor saturation as an explanation. The gene expression analyses suggest apoptosis activation through the extrinsic pathway for both radiopharmaceuticals.

Specific binding and uptake of 131I-MIBG and 111In-octreotide in metastatic paraganglioma--tools for choice of radionuclide therapy.

Tumor-specific uptake of the radiolabeled nor-epinephrine analogue meta-iodobenzylguanidine via norepinephrine transporter or radiolabeled somatostatin analogues octreotide/octreotate via somatostatin receptors offers possibilities to diagnose and treat metastatic pheochromocytoma/paraganglioma. High uptake of 123I-meta-iodobenzylguanidine is dependent on high expression of vesicular monoamine transporters responsible for mediating uptake of biogenic amines into dense core granules. A patient with metastatic paraganglioma (liver and bone metastases) underwent surgical removal of the primary after injection of 131I-meta-iodobenzylguanidine and 111In-octreotide. Radioactivity was determined in biopsies from tumor and normal tissue biopsies. The tumor/blood concentration value was high: 180 for 131I-meta-iodobenzylguanidine 3 h after injection and 590 for 111In-octreotide 27 h after injection. Studies of primary tumor cell cultures demonstrated increased cell membrane binding and internalization over time for 131I-meta-iodobenzylguanidine. The vesicular monoamine transporter antagonist reserpine and the norepinephrine transporter inhibitor clomipramine reduced internalization by 90% and 70%, respectively, after 46 h of incubation. The results demonstrated increased cell membrane binding and internalization over time also for 111In-octreotide. Internalization was highest for a low concentration of 111In-octreotide. Excess of octreotide reduced internalization of 111In-octreotide with 75% after 46 h of incubation. In conclusion, uptake and tumor/blood concentration values of radiolabeled meta-iodobenzylguanidine and somatostatin analogues can be determined for metastatic pheochromocytoma/paraganglioma to evaluate the possibility to use one or both agents for therapy. For this patient, the high tumor/blood values clearly demonstrated that therapy using both radiopharmaceuticals would be most beneficial. In vitro studies verified specific cell-membrane binding and internalization in tumor cells of both radiopharmaceuticals.

Hospital registered nurse shortages: environmental, patient, and institutional predictors.

OBJECTIVE: To examine the characteristics of acute-care hospitals that report registered nurse shortages when a widespread shortage exists and when a widespread shortage is no longer evident. DATA SOURCE: Secondary data from the American Hospital Association's Nursing Personnel Survey from 1990 and 1992 were used. The study population was all acute-care hospitals in the United States. STUDY DESIGN: Outcome variables included whether a hospital experienced a shortage in 1990, when many hospitals reported a nursing shortage, or whether a hospital reported a shortage in both 1990 and 1992. Predictor variables included environmental, patient, and institutional characteristics. Associations between predictor and outcome variables were investigated using probit analyses. PRINCIPAL FINDINGS: Location in the South, a high percentage of nonwhite county residents, a high percentage of patients with Medicaid or Medicare as payer, a higher patient acuity, and use of team or functional nursing care delivery consistently predicted hospitals reporting shortages both when there was a widespread shortage and when there was no widespread shortage. CONCLUSIONS: Although some characteristics under the direct control of hospitals, such as nursing care delivery model, are associated with their reporting a shortage of nurses, shortage is also strongly associated with broader population characteristics such as minority communities and a public insurance payer mix. Awareness of these broader factors may help inform policies to improve the distribution of nurse supply.

Physician incentives and the timing of cesarean sections: evidence from California.

OBJECTIVES: The timing of cesarean sections is studied to examine how physician convenience and financial incentives play a role in the decision to perform a cesarean section. METHODS: Using birth certificate and hospital financial data from California, the likelihood of cesarean sections being performed at particular times of day was examined, controlling for maternal characteristics and the mother's insurance coverage. Two diagnoses associated with cesarean sections are examined separately: fetal distress and prolonged/dysfunctional labor. The hypotheses are that cesarean sections performed for physician convenience are more likely to occur in the evening hours and that type of insurance will affect the incentive to perform cesarean sections to obtain leisure. RESULTS: The probability of cesarean sections for patients insured by a group-model HMO is more stable during the course of a day than that for patients insured by all other insurance plans. Group-model HMO patients with previous cesarean sections are less likely to have cesarean sections in the evening hours and are less likely to be diagnosed with fetal distress or prolonged/dysfunctional labor. CONCLUSIONS: The differences in cesarean sections and diagnosis rates between group-model HMO patients and other patients could arise from several mechanisms: group-model HMOs provide consistent financial incentives to their staff, they may be better able to guide physician practice, and they might provide staff support to physicians so there is less leisure-based incentive to perform cesarean sections. In contrast, nongroup-model HMOs do not appear to reduce the incentive of physicians to maximize leisure relative to traditional insurance.

What should we expect from California's minimum nurse staffing legislation?

In 1999, California passed the first legislation in the United States to establish minimum staffing levels in hospitals for registered nurses (RNs) and licensed vocational nurses. The author provides estimates of the increase in RN expenditures required by this mandate, by hospital size and for regions of California. Issues related to the implementation of minimum ratios also are discussed. Attention must be paid to other staffing regulations, special concerns of rural hospitals, the possibility that minimum ratios result in lower RN staffing, and the effect of the nursing shortage on the ability of hospitals to meet requirements.

Male fertility defects in mice lacking the serine protease inhibitor protease nexin-1.

Understanding infertility and sterility requires knowledge of the molecular mechanisms underlying sexual reproduction. We have found that male mice deficient for the gene encoding the protease inhibitor protease nexin-1 (PN-1) show a marked impairment in fertility from the onset of sexual maturity. Absence of PN-1 results in altered semen protein composition, which leads to inadequate semen coagulation and deficient vaginal plug formation upon copulation. Progressive morphological changes of the seminal vesicles also are observed. Consistent with these findings, abnormal PN-1 expression was found in the semen of men displaying seminal dysfunction. The data demonstrate that the level of extracellular proteolytic activity is a critical element in controlling male fertility.

Errors in data on hospital ownership.

In recent years, there has been increased public concern about changes in hospital ownership and consolidation in the hospital market. Numerous studies have examined the relationship between hospital ownership and prices, costs, organization, service mix, access to care and quality of care. However, the data on which these studies are based are often incomplete and inaccurate. In this paper, we examine several sources of data employed by researchers examining hospital ownership and discuss the degree of inaccuracy we found in each source. Substantial primary data collection is necessary to accurately account for changes in ownership and system affiliation.

Measuring shortages of hospital nurses: how do you know a hospital with a nursing shortage when you see one?

Lack of clarity in definitions of shortages of hospital registered nurses may cause problems for effective policy making, particularly if different measures for identifying a nurse shortage lead to different conclusions about which hospitals and regions are experiencing a shortage. The authors compared different methods of identifying hospitals and regions with a shortage of registered nurses, including both relatively subjective measures (e.g., a hospital administrator's report of a nurse shortage) and more objective measures (e.g., number of registered nurses per inpatient year). Associations were strongest between self-reported shortage status and nursing vacancy rates and weaker for self-reported shortage status and registered nurses per inpatient year and overall regional supply of nurses. Different definitions of nursing shortage are not equally reliable in discriminating between hospitals and regions with and without nursing shortages. When faced with reports sounding an alarm about a hospital nursing shortage, policy makers should carefully consider the definition of shortage being used.

The effect of passing an "anti-immigrant" ballot proposition on the use of prenatal care by foreign-born mothers in California.

This study examines whether the passage of California's Proposition 187, a proposition designed to restrict undocumented immigrants from using public services, had a negative effect on the use of prenatal care and birth outcomes. Comparisons of prenatal care use and birth outcomes before and after the passage of the proposition are made between low-education foreign-born and U.S.-born mothers using California's Birth Public Use files. Multivariate linear and logistic regressions were used to control for regional and maternal characteristics. We find a significant but small decline in the use of prenatal care by low-education foreign-born women after Proposition 187 passed; however, there was no detectable deterioration of birth outcomes. Whether future reductions in the availability of prenatal care would damage the health of children is unclear.

The effects of managed care and prospective payment on the demand for hospital nurses: evidence from California.

OBJECTIVE: To examine the effects of managed care and the prospective payment system on the hospital employment of registered nurses (RNs), licensed practical nurses (LPNs), and aides. DATA SOURCES: Hospital-level data from California's Office of Statewide Health Planning and Development (OSHPD) Hospital Disclosure Reports from 1976/1977 through 1994/1995. Additional information is extracted from OSHPD Patient Discharge Data. STUDY DESIGN: Multivariate regression equations are used to estimate demand for nurses as a function of wages, hospital output, technology level, and ownership. Separate equations are estimated for RNs, LPNs, and aides for all daily services and for medical-surgical units. Instrumental variables are used to correct for the endogeneity of wages, and fixed effects are included to control for unobserved differences across hospitals. PRINCIPAL FINDINGS: HMOs are associated with a lower use of LPNs and aides, and HMOs do not have a statistically significant effect on the demand for RNs. Managed care has a smaller effect on nurse staffing in medical-surgical units than in daily service units as a whole. The prospective payment system does not have a statistically significant effect on nurse staffing. CONCLUSIONS: HMOs have affected nursing employment both because HMOs have reduced the number of discharges and because of a direct relationship between HMO penetration and the demand for LPNs and aides. Contrary to press reports, LPNs and aides have been affected more by HMOs than have registered nurses.

Maintaining an adequate supply of RNs in California.

PURPOSE: Over the past 2 years, concerns have arisen about the adequacy of the supply of RNs in California and the rest of the United States. Nurse leaders have called upon the California State Legislature to respond to concerns by increasing funding for RN education at public colleges and universities. DESIGN: Descriptive--to ascertain whether California faces a shortage of RNs and whether greater state government funding of RN educational programs is necessary to alleviate such a shortage. Secondary data from several sources were analyzed. METHODS: Cross-sectional analysis of data from the 1996 National Sample Survey of Registered Nurses concerning California RNs' demographic characteristics and employment patterns was conducted. Longitudinal analysis of data was examined for trends in California's population, utilization of RNs, and graduations from RN education programs. FINDINGS: Approximately 230,000 RNs lived in and were licensed to practice in California; 77% of California RNs were employed in nursing (70% working full-time; 30% part-time). Only a small number of California RNs were not currently working in nursing but were likely to enter the labor market. Most RNs who were not working were older retired women. CONCLUSIONS: A large increase in the RN workforce is needed to keep pace with the rapid growth of California's population. For California to maintain a stable ratio of RNs to population, we estimated an additional 43,000 RNs will be needed by 2010, and an additional 74,000 will be needed by 2020. Educators, employers, and state policymakers should implement concerted and coordinated efforts to avert a shortage. The magnitude of the impending shortage of RNs in California is too large for the RN labor market to resolve. State government should provide additional resources for basic RN education programs.

Hospital employment of nursing personnel. Has there really been a decline?

There was a steady increase in the number of hours worked by nursing personnel in California hospitals from 1977 through 1996, mostly due to an increase in the number of hours worked by registered nurses (RNs). The hours worked by nursing personnel and RNs per case-mix adjusted discharge and per adjusted patient day also have increased. Possible explanations for the discrepancy between perceptions of declining nursing staffing and the data are discussed.

A human SP-C promoter fragment targets alpha 1-proteinase inhibitor gene expression to lung alveolar type II cells in transgenic mice.

A 1.277 kb promoter fragment of the gene encoding one of the lung surfactant proteins, SP-C, was cloned from a human genomic library and characterized using the human alpha 1-proteinase inhibitor (alpha 1PI) gene as reporter. Messenger RNA for human alpha 1PI isolated from a single transgenic mouse line was detected solely in lung tissue. Using immunogold electron microscopy, accumulation of human alpha 1PI was shown unambiguously to occur only in type II pulmonary cells and, in discrete amounts, in the alveolar lining fluid. The protein was secreted and glycosylated showing a molecular weight close to that of plasma-derived human alpha 1PI.

Suppressive effects of dehydroepiandrosterone and 3-beta-methylandrost-5-en-17-one on attack towards lactating female intruders by castrated male mice.

Three experiments were performed. In Experiment I, triads of adult castrated male mice were chronically administered with either oil-vehicle or 80 micrograms/day of dehydroepiandrosterone (D) or 3-beta-methylandrost-5-en-17-one (D-CH3). They were subsequently tested for their attack on a lactating intruder female introduced for 15 min in their home-cage, 2 hr after their last injection. Both D and D-CH3 significantly reduced male aggressive responses (cf. oil-injected category). In Experiment II the effects of D-CH3 dosed at 20, 40 or 80 micrograms/day were measured in the same testing situation. D-CH3 dose-dependently reduced the mice attack probability on lactating intruders with the highest dose being the most effective. Finally, to test in Experiment III that D-CH3 was not demonstrably androgenic, castrated males received daily injections of 20, 40 or 80 micrograms of this synthetic steroid for 4, 8, 16 or 32 days before tissue sampling. At all doses and whatever treatment duration, D-CH3 did not significantly increase the weights of the accessory sex organs.

[The role of dehydroepiandrosterone and pregnenolone in the expression of stress behavior towards lactating females in mice]. / Rôle de la déhydroépiandrostérone et de la prégnénolone dans l'expression du comportement d'agression vis-à-vis de femelles allaitantes chez la souris.

Triads of castrated male mice were chronically administered with either oil vehicle or 280 nmol of dehydroepiandrosterone (D) or pregnenolone (P). They were tested for their attack on a lactating intruder female introduced in their home-cage 2, 24 or 47 hr after their last injection. D significantly reduced male aggressive behavior for at least 24 hr. Other groups of castrated males were daily treated with vehicle or 280 nmol of D, dehydroepiandrosterone sulfate (DS) or androstenediol (ADIOL), a D metabolite with clear-cut oestrogenic properties. D, but neither DS nor ADIOL, significantly reduced their aggressive responses to lactating intruders. Finally, neural levels of D, DS and testosterone (T) were measured in intact and castrated males injected with either vehicle or D. Measurable amounts of D and DS were detected, with DS being the predominant chemical form. D and DS concentrations were unchanged by castration but neural D was increased more than twenty fold in castrates treated with D, whereas DS was unchanged. The concentration of T in the brain of the intact (sham-operated) mouse approached 3 ng/g but fell close to the detection limit after gonadectomy. D treatment caused a slight but significant increase in brain T concentration in castrated mice, although T remained far below the level measured in intact males.

Effects of gender, gonadectomy and social status on attack directed towards female intruders by resident mice.

Small unisexed groups (triads) of either male of female Swiss strain mice attack lactating intruders introduced into their home-cages. Female residents are, however, generally much more aggressive towards such intruders than are males. Ovariectomy of female residents (on day 15 or day 50 of life) has little effect on such responses, but castration of male residents significantly increases their attack on lactating intruders to a level resembling that of females. The introduction of the lactating female into the home-cage of sham-operated or gonadectomized male or female residents also enhances intragroup fighting with males (irrespective of their endocrine status) being the more aggressive. Finally, the social status of the male alters the response towards lactating females. Dominants generally show higher levels of attack, an effect that can be augmented by castration.

Effects of naloxone administration on attack by castrated male mice on lactating intruders.

The effect of the narcotic antagonist naloxone (a mu blocker at low doses) on the attack displayed by castrated male mice towards lactating intruders was investigated. Naloxone at doses of 1 mg and 2 mg/kg decreased attacks an effect which was also evident to a lesser extent at 0.75 mg/kg. These findings suggest a role for endogenous opiates in the expression of this form of aggression although one must warn that naloxone at some of the higher doses used here can influence kappa and delta receptors as well as gabaergic activity. The interrelationships between endogenous opioids, gabaergic neurotransmission and gonadal hormones in the regulation of this attack response are discussed.

Studies on the effects of dehydroepiandrosterone and its metabolites on attack by castrated mice on lactating intruders.

Triads of castrated male mice (residents) were injected each day for 2 weeks with oil vehicle or 280 nmol of dehydroepiandrosterone (D). They were tested for their attack on a lactating female (intruder) introduced in their home-cage 2,24 or 48 hr after their last injection. D significantly reduced male aggressive behavior for at least 24 hr. Other groups of castrated males were injected each day with vehicle or 280 nmol of D, dehydroepiandrosterone sulfate (DS) or androstenediol (ADIOL). D, but neither DS nor ADIOL, significantly reduced their aggressive responses to intruders. Neural levels of D, DS and testosterone (T) were measured in intact males injected with vehicle or D. The concentration of D in brain was unchanged by castration and was increased about 20 fold in D injected males. The concentration of neural T was 10 nmol/g of tissue in intact males, was almost undetectable in castrated males, and was slightly increased in D injected males. Further work will be needed to identify the steroid molecule(s) responsible for this behavioral effect of D.