Body composition is associated with tacrolimus pharmacokinetics in kidney transplant recipients.

PURPOSE: A population pharmacokinetic (popPK) model may be used to improve tacrolimus dosing and minimize under- and overexposure in kidney transplant recipients. It is unknown how body composition parameters relate to tacrolimus pharmacokinetics and which parameter correlates best with tacrolimus exposure. The aims of this study were to investigate which body composition parameter has the best association with the pharmacokinetics of tacrolimus and to describe this relationship in a popPK model. METHODS: Body composition was assessed using bio-impedance spectroscopy (BIS). Pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM). Lean tissue mass, adipose tissue mass, over-hydration, and phase angle were measured with BIS and then evaluated as covariates. The final popPK model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis. RESULTS: In 46 kidney transplant recipients, 284 tacrolimus concentrations were measured. The base model without body composition parameters included age, plasma albumin, plasma creatinine, CYP3A4 and CYP3A5 genotypes, and hematocrit as covariates. After full forward inclusion and backward elimination, only the effect of the phase angle on clearance (dOFV = - 13.406; p < 0.01) was included in the final model. Phase angle was positively correlated with tacrolimus clearance. The inter-individual variability decreased from 41.7% in the base model to 34.2% in the final model. The model was successfully validated. CONCLUSION: The phase angle is the bio-impedance spectroscopic parameter that correlates best with tacrolimus pharmacokinetics. Incorporation of the phase angle in a popPK model can improve the prediction of an individual's tacrolimus dose requirement after transplantation.

The association between executive functioning, coping styles and depressive symptoms in patients with Multiple Sclerosis.

OBJECTIVES: To investigate the direct, mediated and moderated relationships between executive functioning, coping and depressive symptoms in patients with multiple sclerosis (MS). METHODS: Cross-sectional cohort study of routine follow-up visits, including a standardized (neuro)psychological evaluation of 68 MS patients. Coping was measured with the Coping Inventory for Stressful Situations; Depressive symptoms with the subscale depression of the Hospital Anxiety and Depression Scale. Cognitive tests were reduced to a single 'executive function' factor by means of confirmatory factor analysis. Path analyses tested mediating and moderating effects of coping on the relation between executive functioning and depressive symptoms. RESULTS: Consistently, the executive functioning factor was not related to task-oriented and emotion-oriented coping. Better executive functioning, however, and less reliance on avoidance coping, was related to more depressive symptoms. Testing of the mediating path showed that executive dysfunctioning was indeed significantly related to more depressive symptoms by less reliance on avoidance coping. There was no additional direct effect of executive functioning on depressive symptoms and also no moderating effect of any coping style on the association between cognition and depressive symptoms. CONCLUSION: Our findings suggest that task-oriented and emotion-oriented coping do not influence the relationship between executive functioning and depression in MS patients, but their mental health might benefit from more reliance on avoidance coping.

Repercusión de un sistema de reconocimiento del habla integrado en un PACS/RIS con respecto al tiempo invertido en elaborar y poner a disposición los informes radiológicos / Impact of a PACS/RIS-integrated speech recognition system on the time expenditure in completing and making available radiology reports

Purpose: Quantification of the impact of a PACS/RIS-integrated speech recognition system (SRS) on the time expenditure for radiology reporting and on hospital-wide report availability (RA) in a university institution. Material and methods: In a prospective pilot study, the following parameters were assessed for 669 radiographic examinations (CR): 1. time requirement per report dictation (TED: dictation time (s)/number of images (examination) x number of words (report)) with either a combination of PACS/ tape-based dictation (TD: analog dictation device/ minicassette/transcription) or PACS/RIS/speech recognition system(RR: remote recognition/transcription and OR: online recognition/self-correction by radiologist), respectively, and 2. the ReportTur-naround Time (RTT) as the time interval from the entry of the first image into the PACS to the available RIS/HIS report. Two equal time periods were chosen retrospectively from the RIS database: 11/2002-2/2003 (only TD) and 11/2003-2/2004 (only RR or OR with speech recognition system (SRS)). The midterm (> 24 h, 24 h intervals) and short-term (< 24 h, 1 h intervals) RA after examination completion were calculated for all modalities and for CR, CT, MR and XA/DS separately. The relative increase in the mid-term RA (RIMRA: related to total number of examinations in each time period) and increase in the short-term RA (ISRA: ratio of available reports during the 1st to 24th hour) were calculated. Results: Prospectively there was a significant difference between TD/RR/OR (n = 151/257/261) regarding mean TED (0.44/0.54/0.62 s (per word and image)) and mean RTT.

Objetivo: Cuantificar la repercusión de un sistema de reconocimiento del habla integrado en un PACS/RIS en el tiempo invertido en los informes radiológicos y su disponibilidad en una Clínica Universitaria. Material y métodos: Estudio piloto prospectivo; en 669 radiografías se registró el tiempo invertido por dictado con cinta y sistemas PACS/RIS de reconocimiento (dictado por lotes o dictado en línea) y el Report Turnaround Time, intervalo de tiempo desde la introducción de imagen en PACS hasta tener informe disponible en RIS/CIS. En análisis retrospectivo de base de datos de RIS se estudió 11/2002-02/2003 y 11/2003-02/2004. Se calculó la media y el aumento relativo de la disponibilidad de informes a mediano y corto plazo tras la finalización del estudio. Resultados: Se observaron importantes diferencias en el tiempo invertido para cada modalidad (0,44/0,54/0,62 s por palabra e imagen) y del RTT medio (10,47/6,65/1,27 h). Se evaluaron retrospectivamente 37.898/39.680 informes de los períodos mencionados. En CR/TC, se observó un aumento medio del 20 por ciento en la disponibilidad de informes a corto plazo y en todas las modalidades fue más del triple en las primeras 24 h. En el caso de CR/TC/RM, el primer día hubo un aumento máximo de la disponibilidad a mediano plazo (factor 3,1/5,8/4,0) y en el caso de XA/DS, en el segundo día (factor 2,0). Conclusión: Cuando se utiliza un sistema de reconocimiento del habla se modifica el flujo de trabajo y se invierte inicialmente más tiempo para la elaboración de informes. Los sistemas de reconocimiento integrados en PACS/RIS mejoran considerablemente la disponibilidad de los informes a corto y mediano plazo, redundando en la calidad de la atención de los pacientes.

[Impact of a PACS/RIS-integrated speech recognition system on radiology reporting time and report availability]. / Einfluss eines PACS-/RIS-integrierten Spracherkennungssystems auf den Zeitaufwand der Erstellung und die Verfügbarkeit radiologischer Befunde.

PURPOSE: Quantification of the impact of a PACS/RIS-integrated speech recognition system (SRS) on the time expenditure for radiology reporting and on hospital-wide report availability (RA) in a university institution. MATERIAL AND METHODS: In a prospective pilot study, the following parameters were assessed for 669 radiographic examinations (CR): 1. time requirement per report dictation (TED: dictation time (s)/number of images [examination] x number of words [report]) with either a combination of PACS/tape-based dictation (TD: analog dictation device/mini-cassette/transcription) or PACS/RIS/speech recognition system (RR: remote recognition/transcription and OR: online recognition/self-correction by radiologist), respectively, and 2. the Report Turnaround Time (RTT) as the time interval from the entry of the first image into the PACS to the available RIS/HIS report. Two equal time periods were chosen retrospectively from the RIS database: 11/2002 - 2/2003 (only TD) and 11/2003 - 2/2004 (only RR or OR with speech recognition system [SRS]). The mid-term (> or = 24 h, 24 h intervals) and short-term (< 24 h, 1 h intervals) RA after examination completion were calculated for all modalities and for CR, CT, MR and XA/DS separately. The relative increase in the mid-term RA (RIMRA: related to total number of examinations in each time period) and increase in the short-term RA (ISRA: ratio of available reports during the 1st to 24th hour) were calculated. RESULTS: Prospectively, there was a significant difference between TD/RR/OR (n = 151/257/261) regarding mean TED (0.44/0.54/0.62 s [per word and image]) and mean RTT (10.47/6.65/1.27 h), respectively. Retrospectively, 37 898/39 680 reports were computed from the RIS database for the time periods of 11/2002 - 2/2003 and 11/2003 - 2/2004. For CR/CT there was a shift of the short-term RA to the first 6 hours after examination completion (mean cumulative RA 20 % higher) with a more than three-fold increase in the total number of available reports within 24 hours (all modalities). The RIMRA for CR/CT/MR was 3.1/5.8/4.0 in the first 24 hours, and 2.0 for XA/DS in the second 24-hour interval. CONCLUSION: In comparison to tape-based dictation, an SRS results in a significantly higher primary time expenditure and a modified report dictation workflow. In a university institution, a PACS/RIS-integrated SRS achieves a marked improvement in both short- and mid-term RA which eventually results in an improvement in patient care.

[Speech recognition: impact on workflow and report availability]. / Spracherkennung: Auswirkung auf Workflow und Befundverfügbarkeit.

With ongoing technical refinements speech recognition systems (SRS) are becoming an increasingly attractive alternative to traditional methods of preparing and transcribing medical reports. The two main components of any SRS are the acoustic model and the language model. Features of modern SRS with continuous speech recognition are macros with individually definable texts and report templates as well as the option to navigate in a text or to control SRS or RIS functions by speech recognition. The best benefit from SRS can be obtained if it is integrated into a RIS/RIS-PACS installation. Report availability and time efficiency of the reporting process (related to recognition rate, time expenditure for editing and correcting a report) are the principal determinants of the clinical performance of any SRS. For practical purposes the recognition rate is estimated by the error rate (unit "word"). Error rates range from 4 to 28%. Roughly 20% of them are errors in the vocabulary which may result in clinically relevant misinterpretation. It is thus mandatory to thoroughly correct any transcribed text as well as to continuously train and adapt the SRS vocabulary. The implementation of SRS dramatically improves report availability. This is most pronounced for CT and CR. However, the individual time expenditure for (SRS-based) reporting increased by 20-25% (CR) and according to literature data there is an increase by 30% for CT and MRI. The extent to which the transcription staff profits from SRS depends largely on its qualification. Online dictation implies a workload shift from the transcription staff to the reporting radiologist.

Experimental dispase-induced retinopathy causes up-regulation of P2Y receptor-mediated calcium responses in Müller glial cells.

During proliferative vitreoretinopathy (PVR) Müller glial cells show an up-regulation of their responsiveness to extracellular adenosine 5'-triphosphate (ATP). In the present study, we investigated if such a glial cell response is also a feature for other retinopathies besides PVR. To this aim, the proteolytic enzyme, dispase (0.1 U), was injected into the vitreous of rabbit eyes. After 3 weeks, a distinct retinopathy had developed which showed no signs of PVR. The retinopathy was characterized by strong alterations of the retinal vasculature in the medullary rays, by photoreceptor degeneration, retinal atrophy, and activation of microglial cells. Müller cells became reactive, as indicated by up-regulation of glial fibrillary acidic protein immunoreactivity and by hypertrophy involving subretinal fibrosis. Müller cell reactivity was also evidenced electrophysiologically by a down-regulation of their inwardly rectifying potassium currents and by an up-regulation of their responsiveness to extracellular ATP. Significantly more Müller cells from dispase-treated eyes showed ATP-evoked calcium (83%) and current responses (69%) when compared with cells from control eyes (13 and 9%, respectively). The results indicate that increased responsiveness to extracellular ATP may be a more general feature of Müller cell gliosis, and is also observed in retinopathies besides PVR.

[Improving productivity by implementing RIS and PACS throughout the clinic: a case study]. / Produktivitätsverbesserung durch klinikweite RIS und PACS: eine Fallstudie.

PROBLEM: How are improvements in productivity in connection with RIS/PACS to be defined? What do they cost? To limit the problem to the relevant topics, we first describe the objectives of a radiology department and the identified bottlenecks in the workflow. How to define and assess the improvements is discussed. METHODS: The case in question for this study is the RIS/PACS project at the "Klinikum der Universität München, Campus Grosshadern". The goals of the project and its present status are reviewed. The project is not yet completed, so this is a "midterm" report. RESULTS AND DISCUSSION: We describe the status of the achieved and not yet achieved goals and of the eliminated bottlenecks. On the plus side, for example, nearly 100% of all digitally generated images (except mammogramms) are digitally archived. They are accessible to the same percentage in radiology via PACS and in the hospital via the webbased intranet image distribution system when needed. In some radiology areas, such as multislice CT, already the reporting can no longer be performed without softcopy image interpretation. However, the full elimination of hardcopy images is still not reality, since the distribution to DICOM viewers for selected requesters with demands for almost reporting quality, high cost image displays is still in the testphase. To reduce film costs, images are being printed on a high resolution paper printer in addition to the intranet distribution during this transition period. On the negative side, due to a lack of job positions in the transcription rooms, about 40% of the reports are still being handwritten by radiologists. Furthermore, the dictated and transcribed reports are usually still not available early enough in the RIS and thereby in the intranet report distribution of the hospital. Here only a speech recognition system can remedy the situation. As soon as this problem is solved and the image distribution to the DICOM viewers works routinely, the reports and the images will be accessible within minutes to maximally within some hours after the examination. CONCLUSION: The goals reached so far suffered delays due to unforeseen problems and pitfalls. Altogether, a quieter operation and workflow in radiology has already been achieved, due to less inquiries from the requestors for unfinished examinations, images and/or image copies.

Retinal pigment epithelium melanin granules are phagocytozed by Müller glial cells in experimental retinal detachment.

The ability of retinal Müller glial cells to perform phagocytosis in vivo is studied in a rabbit model of experimental retinal detachment where pigment epithelial cells are occasionally detached together with the neural retina. While macrophages and/or microglial cells phagocytoze most of the cellular debris at the sclerad surface of the detached retinae, some Müller cells accumulate melanin granules. The granules are virtually intact at the ultrastructural level, and are surrounded by a membrane. They are often located close to the sclerad end of the cells, but some are distributed throughout the outer stem process up to the soma. It is concluded that rabbit Müller cells in vivo are capable of phagocytosis and of transporting the phagocytozed material within their cytoplasm.

Electrophysiology of rabbit Müller (glial) cells in experimental retinal detachment and PVR.

PURPOSE: To determine the electrophysiological properties of Müller (glial) cells from experimentally detached rabbit retinas. METHODS: A stable local retinal detachment was induced by subretinal injection of a sodium hyaluronate solution. Müller cells were acutely dissociated and studied by the whole-cell voltage-clamp technique. RESULTS: The cell membranes of Müller cells from normal retinas were dominated by a large inwardly rectifying potassium ion (K+) conductance that caused a low-input resistance (<100 M(Omega)) and a high resting membrane potential (-82 +/- 6 mV). During the first week after detachment, the Müller cells became reactive as shown by glial fibrillary acidic protein (GFAP) immunoreactivity, and their inward currents were markedly reduced, accompanied by an increased input resistance (>200 M(Omega)). After 3 weeks of detachment, the input resistance increased further (>300 M(Omega)), and some cells displayed significantly depolarized membrane potentials (mean -69 +/- 18 mV). When PVR developed (in 20% of the cases) the inward K+ currents were virtually completely eliminated. The input resistance increased dramatically (>1000 MOmega), and almost all cells displayed strongly depolarized membrane potentials (-44 +/- 16 mV). CONCLUSIONS: Reactive Müller cells are characterized by a severe reduction of their K+ inward conductance, accompanied by depolarized membrane potentials. These changes must impair physiological glial functions, such as neurotransmitter recycling and K+ ion clearance. Furthermore, the open probability of certain types of voltage-dependent ion channels (e.g., Ca2+-dependent K+ maxi channels) increases that may be a precondition for Müller cell proliferation, particularly in PVR when a dramatic downregulation of both inward current density and resting membrane potential occurs.

Experimental retinal detachment causes widespread and multilayered degeneration in rabbit retina.

Retinal detachment remains one of the most frequent causes of visual impairment in humans, even after ophthalmoscopically successful retinal reattachment. This study was aimed at monitoring (ultra-) structural alterations of retinae of rabbits after experimental detachment. A surgical procedure was used to produce local retinal detachments in rabbit eyes similar to the typical lesions in human patients. At various periods after detachment, the detached retinal area as well as neighbouring attached regions were studied by light and electron microscopy. In addition to the well-known degeneration of photoreceptor cells in the detached retina, the following progressive alterations were observed, (i) in both the detached and the attached regions, an incomplete but severe loss of ganglion cell axons occurs; (ii) there is considerable ganglion cell death, particularly in the detached area; (iii) even in the attached retina distant from the detachment, small adherent groups of photoreceptor cells degenerate; (iv) these photoreceptor cells degenerate in an atypical sequence, with severely destructed somata and inner segments but well-maintained outer segments; and (v) the severe loss of retinal neurons is not accompanied by any significant loss of Müller (glial) cells. It is noteworthy that the described progressive (and probably irreparable) retinal destructions occur also in the attached retina, and may account for visual impairment in strikingly large areas of the visual field, even after retinal reattachment.

Patch-clamp study of neurons and glial cells in isolated myenteric ganglia.

Most of the physiological information on the enteric nervous system has been obtained from studies on preparations of the myenteric ganglia attached to the longitudinal muscle layer. This preparation has a number of disadvantages, e.g., the inability to make patch-clamp recordings and the occurrence of muscle movements. To overcome these limitations we used isolated myenteric ganglia from the guinea pig small intestine. In this preparation movement was eliminated because muscle was completely absent, gigaseals were obtained, and whole cell recordings were made from neurons and glial cells. The morphological identity of cells was verified by injecting a fluorescent dye by micropipette. Neurons displayed voltage-gated inactivating inward Na(+) and Ca(2+) currents as well as delayed-rectifier K(+) currents. Immunohistochemical staining confirmed that most neurons have Na(+) channels. Neurons responded to GABA, indicating that membrane receptors were retained. Glial cells displayed hyperpolarization-induced K(+) inward currents and depolarization-induced K(+) outward currents. Glia showed large "passive" currents that were suppressed by octanol, consistent with coupling by gap junctions among these cells. These results demonstrate the advantages of isolated ganglia for studying myenteric neurons and glial cells.

Alterations of sensory retinal explants exposed to choroidal melanoma cells ex vivo.

BACKGROUND: Cultures of retinal explants have been established as a useful tool to investigate effects of pathogenic agents in vitro. We used such cultures as a model to study the effects of choroidal melanoma on retinal organisation and function. METHODS: Rabbit retinal explants were co-cultured with human choroidal melanoma cells, or exposed to supernatants from choroidal melanoma cell cultures, for various periods from 1 day to 10 days. The retinal explants were then studied by histology and immunocytochemistry for glial fibrillary acidic protein (GFAP) and vimentin. The release of the pro-inflammatory interleukins IL-6 and IL-8 into the media was measured by enzyme-linked immunosorbent assay. RESULTS: Both in the co-cultures and after treatment with choroidal melanoma cell supernatants for more than 1 week, the layered structure of the retinae became disorganised. Retinal glial (Müller) cells displayed gliosis as indicated by increased GFAP immunoreactivity and decreased immunoreactivity for vimentin. Additionally, the secretion of cytokines, particularly of IL-8, was significantly modulated. The retinal explants produced much less IL-8 than the melanoma cells in separate cultures but increased their IL-8 release significantly after a few days' exposure to melanoma cell-conditioned medium. CONCLUSION: The results show that in cases of choroidal melanoma, the well-known morphological and inflammatory alterations of the retina are accompanied by glial cell reactivity and up-regulated retinal cytokine secretion, and may be caused by soluble factors secreted and induced by the melanoma.

Role of glial K(+) channels in ontogeny and gliosis: a hypothesis based upon studies on Müller cells.

The electrophysiological properties of Müller cells, the principal glial cells of the retina, are determined by several types of K(+) conductances. Both the absolute and the relative activities of the individual types of K(+) channels undergo important changes in the course of ontogenetic development and during gliosis. Although immature Müller cells express inwardly rectifying K(+) (K(IR)) currents at a very low density, the membrane of normal mature Müller cells is predominated by the K(IR) conductance. The K(IR) channels mediate spatial buffering K(+) currents and maintain a stable hyperpolarized membrane potential necessary for various glial-neuronal interactions. During "conservative" (i.e., non-proliferative) reactive gliosis, the K(IR) conductance of Müller cells is moderately reduced and the cell membrane is slightly depolarized; however, when gliotic Müller cells become proliferative, their K(IR) conductances are dramatically down-regulated; this is accompanied by an increased activity of Ca(2+)-activated K(+) channels and by a conspicuous unstability of their membrane potential. The resultant variations of the membrane potential may increase the activity of depolarization-activated K(+), Na(+) and Ca(2+) channels. It is concluded that in respect to their K(+) current pattern, mature Müller cells pass through a process of dedifferentiation before proliferative activity is initiated.

Human Müller glial cells: altered potassium channel activity in proliferative vitreoretinopathy.

PURPOSE: To determine differences of K+ channel activity between Müller glial cells obtained from retinas of healthy human donors and of patients with retinal detachment and proliferative vitreoretinopathy. METHODS: Müller cells were enzymatically isolated from retinas of healthy donors and from excised retinal pieces of patients. The whole-cell and the cell-attached configurations of the patch-clamp technique were used to characterize the current densities of different K+ channel types and the activity of single Ca2+ -activated K+ channels of big conductance (BK). RESULTS: Cells from patients displayed a less negative mean membrane potential (-52.8 mV) than cells from healthy donors (-80.6 mV). However, the membrane potentials in cells from patients scattered largely between -6 and -99 mV. The inwardly rectifying K+ permeability in cells from patients was strongly reduced (0.3 pA/pF) when compared with cells from healthy donors (6.0 pA/pF). At the resting membrane potential, single BK channels displayed a higher mean activity (open probability, Po, and channel current amplitude) in cells from patients (Po, 0.30) than in cells from healthy donors (Po: 0.03). The variations of BK current amplitudes were correlated with the variations of the membrane potential. CONCLUSIONS: The dominant expression of inwardly rectifying channels in cells from healthy donors is thought to support important glial cell functions such as the spatial buffering of extracellular K+. The downregulation of these channels and the less negative mean membrane potential in cells from patients should impair spatial buffering currents and neurotransmitter clearance. The increased activity of BK channels may support the proliferative activity of gliotic cells via feedback regulation of Ca2+ entry and membrane potential.

Renal metastasis from prostatic adenocarcinoma: a potential diagnostic pitfall.

We report a case of renal metastases from prostate cancer to show that the possibility of tumor metastasis, although rare, should always be considered in the differential diagnosis of renal mass.

Isolated necrotizing arteritis of the female genital tract: a clinicopathologic and immunohistochemical study of 11 cases.

Isolated necrotizing arteritis (INA) of the polyarteritis-nodosa type localized to the female genital tract is rare. Approximately 30 case reports have been published to date. Eleven additional patients are described here, all with a favorable follow-up. INA is usually localized in the uterine cervix, but, when multifocal lesions are present, the latter is almost always involved. Patients most frequently report menorrhagia or postmenopausal bleeding. With immunohistochemical studies, immune-complex deposits (IgM, IgG, and C'3) in 7 of 11 patients with INA of the female genital tract were demonstrated for the first time. The inflammatory cells were composed mainly of T-lymphocytes with macrophages and scarce B-lymphocytes also present. These results suggest that INA is primarily an immune complex-mediated disease, implicating humoral and cellular mediator systems. Possible pathogenetic factors of INA are immune complex-mediated hypersensitivity reactions to drugs, foreign materials (after cone biopsy or curettage), and cancers, or an autoimmune reaction against constituents of the vessel walls caused by tissue injury after local surgical intervention through in situ immune-complex formation.

Loss of inwardly rectifying potassium currents by human retinal glial cells in diseases of the eye.

We compared the inward K+ currents of Müller glial cells from healthy and pathologically changed human retinas. To this purpose, the whole-cell voltage-clamp technique was performed on noncultured Müller cells acutely isolated from human retinas. Cells originated from retinas of four healthy organ donors and of 24 patients suffering from different vitreoretinal and chorioretinal diseases. Müller cells from organ donors displayed inward K+ currents in the whole-cell mode similar to those found in other species. In contrast, this pattern was clearly changed in the Müller cells from patient retinas. In whole-cell recordings many Müller cells had strongly decreased inward K+ current amplitudes or lost these currents completely. Thus, the mean input resistance of Müller cells from patients was significantly increased to 1,129 +/- 812 M omega, compared to 279 +/- 174 M omega in Müller cells from healthy organ donor retinas. Accordingly, since the membrane potential is mainly determined by the K+ inward conductance in healthy Müller cells, a large amount of Müller cells from patient retinas had a membrane potential which was significantly lower than that of Müller cells from control eyes. The mean membrane potentials were -37 +/- 24 mV and -63 +/- 25 mV for patient and donor Müller cells, respectively. The newly described membrane characteristic changes of Müller cells from patient eyes are assumed to interfere severely with normal retinal function: (1) the retinal K+ homeostasis, which is partly regulated by the Müller cell-mediated spatial buffering, should be disturbed, and (2) the diminished membrane potential should influence voltage-dependent transporter systems of the Müller cells, e.g., the Na(+)-dependent glutamate uptake.

Comparative studies on mammalian Müller (retinal glial) cells.

Müller cells from 22 mammalian species were subjected to morphological and electrophysiological studies. In the 'midperiphery' of retinae immunocytochemically labeled for vimentin, estimates of Müller cell densities per unit retinal surface area, and of neuron-to-(Müller) glia indices were performed. Müller cell densities were strikingly similar among the species studied (around 8000-11,000 mm-2) with the extremes of the horse (< or = 5000 mm-2) and the tree shrew (> or = 20,000 mm-2). By contrast, the number of neurons per Müller cell varied widely, being clustered at 6-8 (in retinae with many cones), at about 16, and at up to more than 30 (in strongly rod-dominated retinae). Isolated Müller cell volumes were estimated morphometrically, and cell surface areas were calculated from membrane capacities. Müller cells isolated from thick vascularized retinae (carnivores, rats, mice, ungulates) were longer and thinner, and had smaller volumes but higher surface-to-volume ratios than cells from thin paurangiotic (i.e. with blood vessels only near the optic disc) or avascular retinae (rabbits, guinea pigs, horses, zebras). In whole-cell voltage-clamp studies, Müller cells from all mammals studied displayed two dominant K+ conductances, inwardly rectifying currents and delayed rectifier currents. TTX-sensitive Na+ currents were recorded only in some species. Based on these data, the following hypotheses are presented, (a) neuron-to-(Müller) glia indices are determined by precursor cell proliferation rather than by metabolic demands; (b) Müller cell volumes depend on available space rather than on the number of supported neurons; and (c) it follows that, the specific metabolic activities of Müller cells must differ greatly between species, a difference that may contribute to distinct patterns of retinal vascularization.

Insulinoma associated with a case of multiple endocrine neoplasia type I: Functional somatostatin receptors and abnormal glucose-induced insulin secretion.

A sporadic case of multiple endocrine neoplasia type I with coexisting insulinoma and hyperparathyroidism was investigated in vivo and in vitro. The insulinoma was localized by somatostatin receptor scintigraphy and these receptors were functionally active. Octreotide administration decreased the basal insulin and glucagon secretion by 90 and 46%, respectively. Immunocytochemistry of the insulinoma tissue was positive for insulin, chromogranin A and neuropeptide Y. The insulinoma cells were also isolated and cultured in vitro. Incubation experiments revealed that a low glucose concentration (1 mmol/l) was sufficient to increase cytosolic free calcium and to produce a maximal glucose-induced insulin release. Northern blot analysis of RNA obtained from the tumor showed a high abundance of the low Km glucose transporter GLUT1 but no transcript for the high Km glucose transporter GLUT2. The abnormal distribution of glucose transporters probably relates to the abnormal glucose sensing of insulinoma cells, and explains their sustained insulin secretion at low glucose concentrations. Whether these abnormalities share a pathogenetic link with the presence of functionally active somatostatin receptors remains to be elucidated.