Differential gene expression in cultured osteoblasts and bone marrow stromal cells from patients with Paget's disease of bone.

Paget's disease is a focal condition of bone. To study changes in cells within pagetic lesions, we cultured osteoblasts and stromal cells from 22 patients and compared gene expression in these cells to cells from healthy bone. We identified several differentially regulated genes, and we suggest that these changes could lead to the formation of the lesions. INTRODUCTION: Paget's disease is a focal condition of bone of unknown cause. Although it is regarded as primarily an osteoclast disorder, the tight coupling of the activity of osteoclasts and osteoblasts suggests that the osteoblast could play a key role in its pathogenesis. The aim of the study was to identify possible changes in pagetic osteoblasts and stromal cells that might contribute to the development of pagetic lesions. MATERIALS AND METHODS: Candidate genes were identified based on known bone cell regulators, supplemented with microarray analysis. Gene expression was determined by real-time PCR in primary cultures of osteoblasts and bone marrow stromal cells from pagetic patients and control subjects. Concentrations of secreted proteins were determined by ELISA. RESULTS: Dickkopf1 mRNA and protein levels were increased in both pagetic osteoblast and stromal cell cultures, and interleukin (IL)-1 and IL-6 were overexpressed in pagetic osteoblasts. These changes parallel recent findings in myeloma bone disease, which shares some clinical similarities with Paget's disease. Alkaline phosphatase was overexpressed, and bone sialoprotein and osteocalcin were underexpressed in pagetic osteoblasts, consistent with their circulating levels in pagetic patients. It is hypothesized that overexpression of Dickkopf1, IL-1, and IL-6 would result in stimulation of osteoclast proliferation and inhibition of osteoblast growth, leading to the development of the characteristic lytic bone lesions. By stimulating osteoblast differentiation, Dickkopf1 and IL-6 may also promote mineralization, leading to the conversion of lytic lesions to sclerotic. CONCLUSIONS: These findings suggest that dysregulated gene expression in pagetic osteoblasts could cause the changes in bone cell number and function characteristic of Paget's disease.     

ON BEING THERE, ON STRUGGLING TO BE THERE AND ON BEING ORDINARY

ABSTRACT It is my view that healing takes place in a situation of intimacy around a vulnerable and damaged area and that, in order to have access to that area, the therapist must conduct himself as an ordinary and decent human being. He must have the capacity to 'be there'. This paper discusses what it means to 'be there' and examines why it is of such central importance in bringing about change. Included in this is the struggle to 'be there', that is, the intimate struggle between the therapist and patient, as well as the separate and private struggle that both therapist and patient have intrapersonally. A clinical example is given in illustration.     

Flavor preference conditioning by oral self-administration of ethanol

 Oral self-administration and operant tasks have been used successfully to confirm ethanol′s positive reinforcing effects in rats. However, in flavor conditioning tasks, ethanol is typically found to have aversive effects. The present studies explored this apparent paradox by examining the change in value of a flavor paired with orally self-administered ethanol in two different limited-access procedures. Rats were food-deprived and trained to drink (experiment 1) or to barpress for (experiment 2) 10% (v/v) ethanol during daily 30-min sessions using prandial initiation techniques. All rats were then exposed to a differential flavor conditioning procedure in which banana or almond extract was added to the drinking solution. One flavor (counterbalanced) was always mixed with ethanol (CS+), whereas the other flavor was mixed with water (CS–). By the end of conditioning, rats in both experiments drank more flavored ethanol than flavored water, confirming ethanol’s efficacy as a reinforcer. Moreover, barpress rates for CS+ exceeded those for CS– in the operant task. Ethanol doses self-administered in final sessions averaged about 1 g/kg. The effect of the flavor-ethanol contingency was assessed in preference tests that offered a choice between the two flavor solutions without ethanol. In both experiments, subjects developed a preference for the flavor that had been paired with ethanol. Thus, the outcome of flavor conditioning was consistent with that of the oral self-administration tasks in providing evidence of ethanol’s rewarding effects. These experiments confirm and extend previous studies showing that flavor aversion is not the inevitable result of flavor-ethanol association in rats. It seems likely that ethanol’s nutrient and pharmacological effects both contributed to the development of conditioned flavor preference. Received: 15 February 1997 / Final version: 11 June 1997     

MOBILITY AIDS FOR CHILDREN WITH HIGH-LEVEL MYELOMENINGOCELE: PARAPODIUM VERSUS WHEELCHAIR

The optimal method for providing mobility for children with myelomeningocele remains controversial. 39 children using a parapodium were compared with 29 children in wheelchairs. There were no significant differences between the two groups for medical complications, use of health-care services or activities of daily living, although there were differences in the patterns of complications. Children using the parapodium were more likely to develop lesions of the lower extremities, to have dislocated hips, to be more obese and to watch more television; children using wheelchairs were more likely to develop lesions of the gluteal region, to have knee-flexion contractures and to have fewer fecal accidents. The parapodium was judged by families to be less effective as a mobility aid; however, the upright posture it allows was considered extremely advantageous. A combined approach allowing upright posture and wheeled mobility would appear to be optimal.     

Marchiafava-Bignami Disease

Marchiafava-Bignami disease is a rare demyelinating disease involving the corpus callosum and other central white matter tracts. In the patient described here, the disease produced extensive demyelination of the corpus callosum and deep cerebral white matter. This widespread demyelination, confirmed pathologically, was associated with a fulminant fatal course. The magnetic resonance imaging appearance is quite suggestive of Marchiafava-Bignami disease and plays an important role in the premortem diagnosis.     

Spiral laminar flow in the abdominal aorta: a predictor of renal impairment deterioration in patients with renal artery stenosis?

BACKGROUND: Spiral or helical arterial blood flow patterns have been widely observed in both animals and humans. The absence of spiral flow has been associated with carotid arterial disease. The aim of this study was to detect the presence of aortic spiral flow using magnetic resonance imaging (MRI) and to evaluate the relationship of the presence of spiral aortic flow with renal arterial disease and renal function in the follow-up of patients with suspected renal atheromatous disease. METHODS: Prospective study of 100 patients with suspected renal arterial disease and 44 patient controls. Using a 1.5 T MRI unit (Siemens Symphony), phase contrast flow quantification and three-dimensional contrast enhanced MR angiography of the abdominal aorta were performed. Renal arterial stenoses (RAS) were classified minimal, moderate or severe. Renal function was followed at 3 months before and 6 months after MRI. RESULTS: Non-spiral flow was more prevalent in patients with more severe RAS. Renal impairment progressed significantly in severe RAS without spiral flow (P = 0.0065), but did not progress significantly in severe RAS with spiral flow (P = 0.12). In minimal or moderate RAS with or without spiral flow there was no significant progression (P = 0.16, 0.13, 0.47, 0.092, respectively). CONCLUSIONS: Aortic spiral blood flow can be assessed with MRI. Lack of aortic spiral blood flow in patients with severe RAS is associated with significant short-term renal function deterioration. Determination of blood flow patterns may be a useful indicator of renal impairment progression in patients with suspected renal artery stenosis.