Internalization of sst2, sst3, and sst5 receptors: effects of somatostatin agonists and antagonists.

The uptake of radiolabeled somatostatin analogs by tumor cells through receptor-mediated internalization is a critical process for the in vivo targeting of tumoral somatostatin receptors. In the present study, the somatostatin receptor internalization induced by a variety of somatostatin analogs was measured with new immunocytochemical methods that allow characterization of trafficking of the somatostatin receptor subtype 2 (sst2), somatostatin receptor subtype 3 (sst3), and somatostatin receptor subtype 5 (sst5) in vitro at the protein level. METHODS: Human embryonic kidney 293 (HEK293) cells expressing the sst2, sst3, or the sst5 were used in a morphologic immunocytochemical internalization assay using specific sst2, sst3 and sst5 antibodies to qualitatively and quantitatively determine the capability of somatostatin agonists or antagonists to induce somatostatin receptor internalization. In addition, the internalization properties of a selection of these agonists have been compared and quantified in sst2-expressing CHO-K1 cells using an ELISA. RESULTS: Agonists with a high sst2-binding affinity were able to induce sst2 internalization in the HEK293 and CHO-K1 cell lines. New sst2 agonists, such as Y-DOTA-TATE, Y-DOTA-NOC, Lu-DOTA-BOC-ATE (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; TATE is [Tyr3, Thr8]-octreotide; NOC is [1-NaI3]-octreotide; and BOC-ATE is [BzThi3, Thr8]-octreotide), iodinated sugar-containing octreotide analogs, or BIM-23244 were considerably more potent in internalizing sst2 than was DTPA-octreotide (where DTPA is diethylenetriaminepentaacetic acid). Similarly, compounds with high sst3 affinity such as KE108 were able to induce sst3 internalization. In sst2- or sst3-expressing cell lines, agonist-induced receptor internalization was efficiently abolished by sst2- or sst3-selective antagonists, respectively. Antagonists alone had no effect on sst2 or sst3 internalization. We also showed that somatostatin-28 and somatostatin-14 can induce sst5 internalization. Unexpectedly, however, potent sst5 agonists such as KE108, BIM-23244, and L-817,818 were not able to induce sst5 internalization under the same conditions. CONCLUSION: Using sensitive and reproducible immunocytochemical methods, the ability of various somatostatin analogs to induce sst2, sst3, and sst5 internalization has been qualitatively and quantitatively determined. Whereas all agonists triggered sst2 and sst3 internalization, sst5 internalization was induced by natural somatostatin peptides but not by synthetic high-affinity sst5 agonists. Such assays will be of considerable help for the future characterization of ligands foreseen for nuclear medicine applications.     

Thermal injury in pregnancy--the neglected tragedy

Thermal injury sustained during pregnancy presents special management problems for the gravid woman and her unborn child. Because of the reported high morbidity and mortality and lack of available data in South Africa, a multicentre retrospective review was undertaken by five burn centres. Thirty-three patients (average age 25,7 years) with mean 30% (range 1-80%) total body surface area burn were assessed. A review of the clinical material led to the following observations and conclusions. Pregnancy does not influence maternal outcome after thermal injury and maternal survival is usually accompanied by fetal survival in the absence of significant maternal complications. Maternal survival is less likely if the burn wound exceeds 50% total body surface area. Thermal injury does increase the risk of spontaneous abortion and premature labour, and fetal survival depends on fetal maturity. Early obstetric intervention is only indicated in the gravely ill patient where complications (hypoxia, hypotension, sepsis) jeopardize the life of a viable fetus. The mode of delivery should be determined by obstetric considerations.     

An adjusted version of Kohlberg's moral theory: discussion of its validity for research in nursing ethics

Critics of Kohlberg's moral theory today focus on the content of his theory and more specifically on its justice-orientated moral concept. This has led to the well-known 'justice-care debate'. The purpose of this article is to critically examine the validity of Kohlberg's moral theory for research in nursing ethics from a caring perspective (referring to the content) as well as from a cognitive-structural perspective (referring to the basic assumptions of the model). The analysis points to the usefulness and value of the cognitive-structural model to empirically study nurses' ethical behaviour; the content of Kohlberg's model, however, needs to be adapted by adding a caring perspective as well as some personal and situational variables. An adjusted version of Kohlberg's model is proposed and discussed.     

Distribution of α-integrin subunits in fetal polycystic kidney diseases

An alteration in cell/matrix interactions is one of the suggested mechanisms leading to cyst formation in polycystic kidney diseases. Most of these interactions are mediated by β1-integrins, a subfamily of integrin receptors, formed by the association of the β1-chain with different α-subunits. To date, no study on α-integrin subunit distribution during the early stages of cyst development has been reported. Using immunofluorescence, we analyzed the distribution of α-integrin subunits (α1, α2, α3, α5, and α6) and basement membrane proteins in kidneys of fetuses with autosomal dominant (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). The distribution was compared with that observed in normal fetal and post-natal kidneys, and in fetal cystic dysplasia and Meckel syndrome. Marked increase in α1-integrin staining was observed in normal and cystic collecting duct cells of both polycystic diseases (PKD), compared with normal and cystic controls. The distribution of integrin subunits α2, α3, and α6 was irregular in cyst epithelial cells of PKD and cystic controls. The increased expression of the α1-subunit specifically observed in PKD collecting duct cells may be an early consequence of the genetic defect in ARPKD. In ADPKD it parallels the reported expression of polycystin, the protein product of PKD1. The irregular expression of α2, α3, and α6 integrin subunits observed in all types of cysts suggests that cell/matrix interactions are altered early and may participate in the development of cysts, perhaps by contributing to the deregulation of cell survival in cystic diseases. Received May 28, 1996; received in revised form October 2, 1996; accepted October 25, 1996     

Safety Concerns Affecting Delivery of Home Health Care

Abstract Factors influencing the remarkable growth of home health care include increased elderly population, decreased average length of hospital stay, and technological advancements that reduce the need for hospitalization. Societal changes have prompted increasing concern about personal risk to home care providers. The purpose of this pilot study was to: 1) ascertain factors related to perception of risk by home health care administrators and staff and to identify strategies used by home health care administrators to reduce risk to staff; and 2) determine whether quality of care is affected when home-visit situations present risk. A convenience sample of 36 home health care administrators and 62 staff was surveyed about risks and measures provided by the home health care agency to minimize risk. Factors associated with risk are geographic location, high incidence of crime, inappropriate patient or caregiver behavior, infectious diseases, and evening assignments. Strategies used to minimize risk include safety programs, preplanning of visits, personal protective equipment, escorts, and buddy systems. Perceived ability to refuse high-risk assignments, however, is questionable, as 66% of the staff stated that they leave a situation "as soon as possible." These findings will be used to strengthen inservice programs and to provide a basis for future studies.     

Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior

The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.     

Natural rhythm: evidence for occult 40 Hz gamma oscillation in resting motor cortex

Fast gamma oscillations, often at 40 Hz, have been demonstrated throughout the brain including the thalamus, auditory, visual and motor cortices. The function of gamma rhythms is elusive, but several authors have hypothesized that they contribute to the "binding" of diverse information into a single coherent percept, and to the synchronization of movement. In skeletal muscle a "Piper rhythm" around 40 Hz is commonly observed during maximal voluntary contraction, and has been shown to correlate with activity of similar frequency in a limited area of contralateral motor cortex. Gamma rhythms are detected primarily during complex cortical activity, and are seldom recorded at rest or coherently over wide areas. Here we use bihemispheric transcranial magnetic stimulation (TMS) to study time-dependent correlations between evoked motor potentials from non-homologous muscles in opposite limbs of normal volunteers. The results suggest the presence of an occult, synchronous 40 Hz rhythm across broad areas of resting motor cortex in both hemispheres.