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.     

The ordered transmission disequilibrium test: detection of modifier genes

We consider the problem of detection of modifier genes that lead to variations in a disease‐related continuous variable (DRCV), such as the age of onset or a measure of disease severity, in a strategy of candidate genes. We propose a novel method, the ordered transmission disequilibrium test (OTDT), to test for a relation between the clinical heterogeneity expressed by a DRCV and marker genotypes of a candidate gene. The OTDT applies to trio families with one patients and his parents, all three genotyped at a bi‐allelic marker M. The OTDT aims to find a critical value of the DRCV which separates the sample of families in two subsamples in which the transmission rates are significantly different. We investigate the power of the method by simulations under various genetic models and covariate distributions and compare it with a linear regression analysis. Genet. Epidemiol. 2008. ©2008 Wiley‐Liss, Inc.     

Characteristics of apathy in Parkinson's disease.

The objective of this study was to use the Lille Apathy Rating Scale to assess apathy in a large population of Parkinson's disease (PD) patients and identify several different apathy profiles. One hundred fifty-nine patients with probable PD and 58 healthy controls participated in the study. Apathy was assessed using the Lille Apathy Rating Scale. Motor, cognitive, and depressive symptoms were rated on standardized scales. Data were analyzed using linear regression and multivariate analyses of variance. Thirty-two percent of the PD patients were classified as apathetic. Apathy was more frequent in patients with dementia. The four apathy dimensions contributed differently to the overall severity of the apathetic condition. Action initiation and intellectual curiosity had a marked influence. Linear regression analysis revealed that the apathy level was mainly determined by cognitive impairment, not associated with the severity of motor symptoms, and only associated with the apathy subcomponent of the Montgomery and Asberg Depression Rating Scale. Apathy is highly prevalent in PD patients. Apathy profiles vary according to the clinical presentation of PD. The high prevalence of apathy in PD suggests the involvement of frontal-subcortical circuits. Although the neurochemical substrate of apathy remains poorly characterized, the strong link between apathy and cognitive impairment observed in several studies suggests the participation of nondopaminergic circuits.     

Thyroid disease and pregnancy: degrees of knowledge.

OBJECTIVE: The literature on the impact of thyroid abnormalities on pregnancy and the postpartum has expanded rapidly over the last two decades. The objective of the present study was to determine the level of knowledge of endocrinologists, obstetrician/gynecologists, internists, and family physicians in regard to thyroid disease and pregnancy. DESIGN: A 16-item questionnaire on issues related to thyroid disease and pregnancy was developed. Endocrinologists (n = 116), obstetrician/gynecologists (n = 81), internists (n = 109), and family physicians (n = 99) were asked to complete the questionnaire. Physician self-report of confidence regarding degree of knowledge was obtained through completion of a seven-point Likert scale. MAIN OUTCOME: The percentage of questions answered correctly by all physicians was 63%. Endocrinologists had the highest correct response rate (77%), followed by obstetrician/gynecologists. Hierarchical regression analysis revealed that medical specialty, years of training, confidence level, and whether or not the physician treated pregnant women were significantly related to the overall score. CONCLUSIONS: The present study demonstrates a suboptimal level of knowledge regarding thyroid disease and pregnancy among physicians in four specialties. A comprehensive physician education program is needed.     

Propriospinal myoclonus: utility of magnetic resonance diffusion tensor imaging and fiber tracking.

Propriospinal myoclonus (PSM) is a rare movement disorder characterized by involuntary spinal-generated muscular jerks that spread rostrally and caudally to other spinally innervated muscles. Most patients have no clear etiology, and conventional MRI of the spinal cord is generally normal. Here we report the use of magnetic resonance diffusion tensor imaging (DTI) and fiber tracking to detect tract-specific abnormalities in a patient with propriospinal myoclonus. As the patient had the fragile-X premutation and antithyroid antibodies, spinal cord DTI abnormalities may be related to these conditions. Tract-specific analysis may provide new insights into the pathophysiology of propriospinal myoclonus.     

Experiences of pain and distress in hip fracture patients

The aims were to investigate: (1) experiences of physical pain in elderly patients with hip fracture; (2) if background variables, confusion, experiences of pain and distress and interventions aimed at reducing pain and distress, functional ability, pain in the ambulance, and type of fracture varied between patients with more intense physical pain and patients with less intense physical pain. The sample included 49 patients, 70 years or older, with hip fracture. Structured instruments were used to interview and observe the patients on four occasions during the hospital stay. The patients’ experiences of physical pain decreased during the hospital stay. Physical pain at rest was lower than pain with movement. Patients who scored physical pain as more intense (group B) during the visit to the hospital had significantly more unfavourable experiences in the sensory, emotional, and existential dimensions the day before discharge from the hospital compared with the patients who scored pain as less intense (group A). The patients in group B perceived the interventions as less favourable than group A. Furthermore, group B had more intense physical pain in the ambulance than the patients in the other group. More patients in group B than in group A had additional health problems.     

The role of gastric pH testing with small-bore feeding tubes: in the intensive care unit.

In this observational study, we sought to assess the usefulness of pH values from residuals in intensive care unit (ICU) patients with small-bore feeding tubes. A review of the literature demonstrated that most critically ill patients were excluded in previous studies on gastric pH testing, suggesting that pH testing in critical care is not warranted. Our results demonstrated that 21% of intestinal testing and 64% of gastric testing yielded potential misinformation to the bedside nurse with regards to possible tube location. In conclusion, pH testing for small-bore tube placement and maintenance was not deemed meaningful in our critical care unit.