The value of an evaluation framework for telehealth initiatives.

Healthcare managers and policy makers will, in the immediate and near future, make major decisions about the allocation of scarce healthcare resources for telehealth 'solutions'. In our haste to capitalize on what technology can do we may be obscuring discussion and research about what technology should do. For example, currently much attention is being paid to standardization for technological aspects of telehealth. In contrast few efforts have been made to seek standardization in regards to a broad evaluation framework for telehealth. A body of opinion believes that missing in our rush into the on-line world is a systematic approach to research into the human, social, cultural, economic, and political factors associated with healthcare. As a result we lack the tools and experience necessary to assess the true value and implications of telehealth 'solutions'. Developing general guidelines for an evaluation framework, from needs assessment through integrated research to post-study assessment, would greatly enhance the quality of decision making by healthcare managers and policy makers. We propose a model--the Telehealth Integrated Research Model (TIRM)--as the first step in encouraging discussion and development of an internationally accepted standardized telehealth evaluation framework.

Mercuric chloride induces a stress response in cultured astrocytes characterized by mitochondrial uptake of iron.

Mercury exerts a variety of toxic effects on both neurons and glia. Mercury induces aberrations in microtubules, ion channels and mitochondria presumably by binding to sulfhydryl groups. Indirect evidence further suggests that mercury targeted to mitochondria may induce iron-catalyzed oxygen radical production. We have previously shown that the mitochondria of astrocytes subjected to oxidative stress accumulate redox active transition metals that may catalyze the formation of cytotoxic oxygen free radicals. In the present study we have investigated the effect of mercuric chloride on astrocytes in monolayer culture in order to determine whether mercury accumulates in astrocytic mitochondria and whether mercury exposure triggers a stress response-associated uptake of iron. Our results indicate that mercuric chloride exposure initiates the constellation of changes in mitochondrial structure that typifies the response of these cells to oxidative stress. Energy dispersive Xray microspectroscopy demonstrates that these altered mitochondria concentrate both mercury and iron. Concurrent with these changes, mercuric chloride treatment activates transcription of the heme oxygenase-1 (HO-1) gene in a dose dependent manner, further indicating an oxidative stress response. Thus, mercury-induced stress may transform innocuous astrocytes into potentially lethal sources of cytotoxic oxygen free radicals.

Colocalization of somatostatin receptors and growth hormone-releasing factor immunoreactivity in neurons of the rat arcuate nucleus.

Recent studies from our group have demonstrated an association of [125I]-labeled somatostatin (SRIF)-binding sites with a subpopulation of arcuate (ARC) neurons. The distribution of these cells was similar to that of growth hormone-releasing factor (GRF)-immunoreactive neurons, which led us to propose that at least some SRIF receptors may be directly localized to GRF-containing cells. To test this hypothesis, we have visualized radiolabeled SRIF-binding sites and GRF immunoreactivity (ir) in adjacent sections of the hypothalamus, by combined radioautography and immunohistochemistry. Adult male rats were sacrificed by decapitation and the brains were rapidly frozen and serially sectioned on a cryostat. Fifteen pairs of adjacent 6-microns-thick sections, taken at 100-microns intervals through the rostrocaudal extent of the ARC nucleus, were alternately processed for [125I]-SRIF radioautography and GRF immunohistochemistry. GRF-ir and [125I]-SRIF-labeled cells were mapped at each level and quantified with the aid of a camera lucida. The maps were subsequently superimposed to determine the extent of [125I]-SRIF/GRF-ir colocalization. GRF-ir perikarya [13.2 +/- 4.4 (mean +/- SE) cells per section] were mainly localized in the ventrolateral portion of the ARC nucleus and predominated within the caudal-most tier. [125I]-SRIF-labeled cells (35.6 +/- 6.5 cells per section) were more numerous, more evenly distributed, and extended further rostrally and caudally than GRF-ir cells. Superimposition of the camera lucida maps indicated that, overall, 33.5 +/- 10.8% of the GRF-ir cells were labeled with [125I]-SRIF in adjacent sections.(ABSTRACT TRUNCATED AT 250 WORDS)

Cysteamine-induced enhancement of growth hormone-releasing factor (GRF) immunoreactivity in arcuate neurons: morphological evidence for putative somatostatin/GRF interactions within hypothalamus.

The episodic secretion of GH is regulated through the reciprocal release into the hypophyseal portal circulation of two hypothalamic peptides, SRIF and GRF. Recent physiological evidence suggests that, in addition to exerting their well documented opposite actions at the level of the anterior pituitary, SRIF and GRF may interact within the central nervous system to modulate GH secretion. The aim of the present study was to provide morphological evidence to support the concept that SRIF exerts an influence on the GRF-containing neuronal system within the hypothalamus. To accomplish this, we used the thiol agent cysteamine (CSH; 300 mg/kg sc) to manipulate endogenous hypothalamic SRIF and examined its effects on the immunoreactivity and mRNA content of GRF-containing arcuate (ARC) neurons, using immunohistochemistry and semi-quantitative in situ hybridization, respectively. Hypothalamic SRIF content and pulsatile GH secretion were also monitored. CSH treatment reduced hypothalamic immunoreactive SRIF concentrations (to 60% of vehicle-injected control values) and severely suppressed the spontaneous surges of GH release (mean GH peak amplitude: 24.2 +/- 2.7 vs. 168.0 +/- 27.8 ng/ml in H2O-injected controls; P less than 0.001). CSH treatment also resulted in a striking increase in the number and labeling density of GRF-immunoreactive cells detected in the ARC nucleus. Cell counts revealed an overall 126% increase, over controls, in the mean number of detectable GRF-positive ARC neurons. This increase (P less than 0.01) was apparent over all rostrocaudal levels of the ARC nucleus, but was most pronounced within the caudal tier. Administration of CSH also produced a massive qualitative increase in the intensity and extent of staining of GRF-positive terminal elements in the external zone of the median eminence. Conversely, CSH treatment resulted in a decline in GRF mRNA-associated signal in cells of the ARC nucleus, with this decline being most evident in the caudal third of the nucleus. The finding of an increase in GRF immunoreactivity in ARC neurons in association with a decrease in plasma GH, as well as with a decline in relative GRF mRNA content, suggests that CSH leads to an overall decrease in GRF release from the median eminence. These results provide morphological evidence to support the concept of a SRIF-mediated central influence on the GRF-containing ARC neuronal system. Such central regulation of GRF by SRIF may be an important mechanism in the physiological control of pulsatile GH secretion.

Induction of Stein-Leventhal-like polycystic ovaries (PCO) in the rat: a new model for cystic ovarian disease.

An injection of estradiol valerate (EV) in the rat produces an anovulatory polycystic ovarian (PCO) condition. Chronic estrogen exposure, produced by subcutaneously implanted, estradiol (E2)-containing chronic release capsules, results in acyclicity and in hypothalamic changes similar to those seen in the EV-injected rat. We, therefore, examined the ovarian histology and plasma gonadotropin patterns in the E2-implanted rat and found that this model exhibits a polycystic ovarian condition and a plasma gonadotropin pattern very different from those in the EV-treated model. The plasma patterns of LH and FSH are bimodal consisting of small frequent pulses as well as less frequent large episodes of long duration. The ovaries contain multiple small cysts, characterized by an extensively hypertrophied theca interna, and vast chords of hypertrophied secondary interstitial cells. In contrast, cystic follicles in EV-treated rats are fewer in number, but much larger than those in the E2-implanted animals. The cystic theca and the secondary interstitial cell clusters are also far less extensive in the EV-induced polycystic ovary. These and other differences between the two types of PCO indicate that they are produced by fundamentally different morphogenic mechanisms. The cystic ovary produced by the E2 implants is similar in appearance to that seen in the human Stein-Leventhal condition, and thus provides a new model for the study of cystic ovarian disease.

Remission of the polycystic ovarian condition (PCO) in the rat following hemiovariectomy.

The estradiol valerate-induced polycystic ovarian condition in the rat represents a normal ovarian response to aberrant endocrine stimuli. Although we have shown that removal of one polycystic ovary (hemiovariectomy) results in restoration of cyclicity and normal morphology in the remaining ovary by 1 week, nothing is known about the process of recovery or about the role of the hypothalamo-pituitary unit in initiating recovery. We have therefore examined ovaries at 3, 12, 24, 48, and 120 hours following removal of the contralateral polycystic ovaries. The ovarian content and size distribution of healthy and atretic follicles was determined, as well as the occurrence of follicular cysts, type III large follicular structures, and corpora lutea. The plasma LH pattern was also examined at a short postoperative interval. At 3 hours, there was a significant increase in mean ovarian weight that coincided with the emergence of healthy large secondary follicles. By 12 hours, there was a significant sustained diminution in the number of atretic follicles of all sizes, but the total number of healthy follicles did not increase significantly until 120 hours. The cystic follicles had all but disappeared by 120 hours because of mechanical compression by newly developing ovarian tissue. Ovarian recovery is, therefore, biphasic, consisting of a very early diminution in atresia coincident with, and perhaps caused by, a major alteration in the plasma LH pattern. The second phase is characterized by a wave of follicular recruitment and development.

Plasma gonadotropin patterns characterizing the development of polycystic ovaries in the estradiol valerate treated rat.

Polycystic ovaries (PCO) develop in female rats within 4 weeks of an injection of estradiol valerate (EV). The final morphological transition from a noncystic to a cystic state occurs in the presence of estrous (control) mean serum gonadotropin concentrations, suggesting that gonadotropin patterns rather than mean concentrations are causal to PCO. We have examined plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) patterns in female rats at estrus and on days 5, 11, 16, and 21 following EV treatment. Estrous animals displayed large amplitude LH pulses of short duration, interspersed among frequent, low amplitude pulses of similar duration, and infrequent, broad-based LH episodes. Following EV treatment, there was a progressive decline in the frequency and magnitude of the large amplitude LH pulses, such that by day 16, they ceased altogether. Conversely, the frequency of the low amplitude pulses increased such that the total pulse frequency remained constant. The onset of this pattern coincides with the wave of atresia that precedes the emergence of cystic follicles. The pulsatile plasma pattern of FSH seen at estrus remained unaltered at all time intervals examined after EV treatment. We conclude that there is a specific LH pattern responsible for the generation and maintenance of the PCO condition.

Radioautographic evidence for slow astrocyte turnover and modest oligodendrocyte production in the corpus callosum of adult mice infused with 3H-thymidine.

To find out whether glial cells proliferate in the corpus callosum of adult mice, two series of experiments were carried out. The first one made use of 9-month-old "aged" male mice. Some of them were given 3H-thymidine as a 2-hour pulse to examine which cells became labeled and, therefore, had the ability to divide. Others were sacrificed after a continuous infusion of 3H-thymidine for 30 days to examine whether the label would then appear in different cells. In other aged animals, the 30-day infusion was followed by 60 or 180 days without 3H-thymidine to determine whether cells retained or lost their label with time. A second series of experiments was carried out in 4-month old "young adult" male mice to seek confirmation of the main conclusions. Following the 3H-thymidine pulse given to aged mice, only immature glial cells were labeled. After a 30-day infusion, 12.1% astrocytes and 1.1% oligodendrocytes were labeled, so that the net daily addition rate of astrocytes averaged 0.4% and of oligodendrocytes, 0.04%. In young adult mice, the rate after a 7-day infusion averaged 0.9% for astrocytes and 0.08% for oligodendrocytes. However, when the 30-day infusion into aged mice was followed by 60 and 180 days without 3H-thymidine, the labeled astrocytes decreased to 5.3% and 0%, respectively, whereas the number of labeled oligodendrocytes did not change significantly. The interpretation of the results is that the immature cells present in the corpus callosum of mice continue dividing throughout life and their progeny give rise to astrocytes and oligodendrocytes. In the case of astrocytes, the production of new cells occurs in parallel with a loss, so that the astrocyte population turns over. In the case of oligodendrocytes, there is a small production of new, apparently stable cells.

Plasma patterns of LH, FSH and prolactin in rats with a polycystic ovarian condition induced by oestradiol valerate.

The patterns of plasma LH, FSH and prolactin concentrations were investigated in rats with a polycystic ovary condition (PCO). The condition was induced by treatment with oestradiol valerate 9 weeks before blood sampling. Serial blood samples were taken at 10-min intervals for 4 h from ten rats with PCO. All samples were assayed for LH, those from five animals for FSH and those from the remaining five animals for prolactin. In addition, five control animals with normal oestrous cycles were sampled during oestrus and the samples assayed for LH. Mean concentrations of LH, FSH and prolactin in rats with PCO were 140 ng/l, 76 micrograms/l and 7.6 micrograms/l respectively. All three hormones exhibited an episodic pattern. The mean peak amplitudes of LH, FSH and prolactin were 120 ng/l, 25 micrograms/l and 3.5 micrograms/l respectively. All three hormones exhibited a similar mean frequency of four or five episodes per 4 h. The LH and FSH patterns were closely synchronized; nearly all FSH peaks coincided with LH peaks. The prolactin pattern did not, however, correlate with that of the gonadotrophins. Despite the persistent oestrous condition of the animals with PCO, it was clear that their pattern of LH did not resemble that of cyclic animals in normal oestrus; in the normally cyclic animals in oestrus the pulse period was nearly twice as long and the pulse amplitude was more than sixfold greater than those in animals with PCO. We conclude that the unique episodic patterns of gonadotrophins are more important than mean blood concentrations of these hormones in establishing and maintaining the polycystic ovary syndrome.