Nanoelectronic primary thermometry below 4 mK.

Cooling nanoelectronic structures to millikelvin temperatures presents extreme challenges in maintaining thermal contact between the electrons in the device and an external cold bath. It is typically found that when nanoscale devices are cooled to ∼ 10 mK the electrons are significantly overheated. Here we report the cooling of electrons in nanoelectronic Coulomb blockade thermometers below 4 mK. The low operating temperature is attributed to an optimized design that incorporates cooling fins with a high electron-phonon coupling and on-chip electronic filters, combined with low-noise electronic measurements. By immersing a Coulomb blockade thermometer in the (3)He/(4)He refrigerant of a dilution refrigerator, we measure a lowest electron temperature of 3.7 mK and a trend to a saturated electron temperature approaching 3 mK. This work demonstrates how nanoelectronic samples can be cooled further into the low-millikelvin range.

Mesopic background lights enhance dark-adapted cone ERG flash responses in the intact mouse retina: a possible role for gap junctional decoupling.

The cone-driven flash responses of mouse electroretinogram (ERG) increase as much as twofold over the course of several minutes during adaptation to a rod-compressing background light. The origins of this phenomenon were investigated in the present work by recording preflash-isolated (M-)cone flash responses ex vivo in darkness and during application of various steady background lights. In this protocol, the cone stimulating flash was preceded by a preflash that maintains rods under saturation (hyperpolarized) to allow selective stimulation of the cones at varying background light levels. The light-induced growth was found to represent true enhancement of cone flash responses with respect to their dark-adapted state. It developed within minutes, and its overall magnitude was a graded function of the background light intensity. The threshold intensity of cone response growth was observed with lights in the low mesopic luminance region, at which rod responses are partly compressed. Maximal effect was reached at intensities sufficient to suppress ∼ 90% of the rod responses. Light-induced enhancement of the cone photoresponses was not sensitive to antagonists and agonists of glutamatergic transmission. However, applying gap junction blockers to the dark-adapted retina produced qualitatively similar changes in the cone flash responses as did background light and prevented further growth during subsequent light-adaptation. These results are consistent with the idea that cone ERG photoresponses are suppressed in the dark-adapted mouse retina by gap junctional coupling between rods and cones. This coupling would then be gradually and reversibly removed by mesopic background lights, allowing larger functional range for the cone light responses.

Temperature dependence of dark-adapted sensitivity and light-adaptation in photoreceptors with A1 visual pigments: a comparison of frog L-cones and rods.

Flash responses of L-cones and rods were recorded as ERG mass potentials in the frog retina at different temperatures (2-25 degrees C). The purpose was to elucidate factors that make cones faster and less sensitive than rods, particularly the possible role of thermal activation of L-cone visual pigment in maintaining a "light-adapted" state even in darkness. Up to ca. 15 degrees C, cones and rods were desensitized roughly equally by warming (Q(10) approximately 2.2-2.7), retaining a 5-fold sensitivity difference. In this range, the cone/rod difference must depend on factors other than thermal activation of the visual pigment. Above 15 degrees C, cones showed an additional component of desensitization compared with rods, coupled to accelerated response shut-off. This behavior is consistent with light-adaptation from temperature-dependent intrinsic activity (dark light). The apparent dark light as measured by the minimum background intensities needed to affect sensitivity and/or kinetics increased by ca. 10-fold between 15 and 25 degrees C, whereas reported increases in visual-pigment activation rates over this range are less than 5-fold. We conclude that the dark state of frog L-cones above 15 degrees C may be largely set by thermal activation of the phototransduction machinery, but only part of the experimentally determined dark light can be ascribed to the visual pigment.

Mouse cone photoresponses obtained with electroretinogram from the isolated retina.

We characterize the dark-adapted photoresponses from mouse cones intact in the isolated retina, their virtually natural environment, by isolating pharmacologically the photoreceptor light responses from the electroretinogram (ERG). Due to the different photoresponse kinetics and sensitivity of rods and cones, the cone responses were readily attained by using a rod-saturating preflash. The stimulus wavelength (544 nm) was chosen to selectively stimulate the green sensitive ("M"-)pigment. Obtained responses were monophasic, showing fast kinetics (mean t(p)=51 ms) and low sensitivity (fractional single-photon response ca. 0.23%). The amplification coefficient of cones (4.6 s(-2)) was very close to that of rods (5.6 s(-2)), while the dominant time constant of recovery was clearly smaller for cones (33 ms) than for rods (160 ms).

Patient satisfaction with switching to Stalevo: an open-label evaluation in PD patients experiencing wearing-off (Simcom Study).

OBJECTIVES AND METHODS: This study investigated the ease with which 52 Parkinson's disease patients already receiving adjunct entacapone to traditional levodopa were switched to Stalevo (levodopa/carbidopa/entacapone). RESULTS: The switch to Stalevo was straightforward for most patients taking standard-release levodopa with 86% of these patients being able to replace their entire regimen without having to change the amount of levodopa taken. The majority of patients (54%, P = 0.162) preferred Stalevo; 31% preferred their prior treatment regimen; 15% had no preference. Patients found Stalevo more simple to dose (94%), more convenient to use (84%), easier to handle (84%), easier to remember (67%) and easier to swallow (59%), compared with their previous medication. CONCLUSIONS: Stalevo was well tolerated, with a low incidence of adverse events. The study shows that Stalevo is an effective, preferred and well-tolerated means of delivering levodopa/carbidopa/entacapone in one easy-to-use tablet.

Light responses and light adaptation in rat retinal rods at different temperatures.

Rod responses to brief pulses of light were recorded as electroretinogram (ERG) mass potentials across isolated, aspartate-superfused rat retinas at different temperatures and intensities of steady background light. The objective was to clarify to what extent differences in sensitivity, response kinetics and light adaptation between mammalian and amphibian rods can be explained by temperature and outer-segment size without assuming functional differences in the phototransduction molecules. Corresponding information for amphibian rods from the literature was supplemented by new recordings from toad retina. All light intensities were expressed as photoisomerizations per rod (Rh*). In the rat retina, an estimated 34% of incident photons at the wavelength of peak sensitivity caused isomerizations in rods, as the (hexagonally packed) outer segments measured 1.7 microm x 22 microm and had specific absorbance of 0.016 microm(-1) on average. Fractional sensitivity (S) in darkness increased with cooling in a similar manner in rat and toad rods, but the rat function as a whole was displaced to a ca 0.7 log unit higher sensitivity level. This difference can be fully explained by the smaller dimensions of rat rod outer segments, since the same rate of phosphodiesterase (PDE) activation by activated rhodopsin will produce a faster drop in cGMP concentration, hence a larger response in rat than in toad. In the range 15-25 degrees C, the waveform and absolute time scale of dark-adapted dim-flash photoresponses at any given temperature were similar in rat and toad, although the overall temperature dependence of the time to peak (t(p)) was somewhat steeper in rat (Q(10) approximately 4 versus 2-3). Light adaptation was similar in rat and amphibian rods when measured at the same temperature. The mean background intensity that depressed S by 1 log unit at 12 degrees C was in the range 20-50 Rh* s(-1) in both, compared with ca 4500 Rh* s(-1) in rat rods at 36 degrees C. We conclude that it is not necessary to assume major differences in the functional properties of the phototransduction molecules to account for the differences in response properties of mammalian and amphibian rods.

The effects of different repeated doses of entacapone on the pharmacokinetics of L-Dopa and on the clinical response to L-Dopa in Parkinson's disease.

We performed a double-blind, placebo-controlled, randomized, crossover, multiple-dose study on entacapone in 25 patients with Parkinson's disease with levodopa (L-Dopa) treatment-related fluctuations. A run-in period was followed by four 2-week treatment periods during which the patients took 4 to 6 daily doses of L-Dopa concomitantly with 100, 200, or 400 mg of entacapone or with placebo. The effects were assessed at the end of each period; the inhibition of soluble catechol-O-methyltransferase (S-COMT) activity in red blood cells and the plasma concentrations of entacapone, L-Dopa, and 3-O-methyldopa (3-OMD) were measured and clinical effects assessed on an 18-hour home diary. Twenty-one patients completed the study. Entacapone decreased the COMT activity from predose level: 100 mg by 25%, 200 mg by 33%, and 400 mg by 32% (p < 0.001 vs. placebo for each dose). Correspondingly, the 3-OMD concentrations decreased by 39%, 54%, and 66% with 100-, 200-, and 400-mg doses, respectively. The elimination half-life of L-Dopa was prolonged by 23% (p < 0.05), 26% (p < 0.001), and 48% (p < 0.001), and the area under the curve of L-Dopa increased by 17% (p < 0.05), 27% (p < 0.001), and 37% (p < 0.001) with the increasing doses. Despite a significant decrease in the daily dose of L-Dopa, entacapone decreased the proportion of daily "off" time: 100 mg by 11%, 200 mg by 18%, and 400 mg by 20% compared with placebo. However, this decrease was not statistically significant for any of the doses in this small patient population. The dyskinetic "on" time did not increase with different doses of entacapone. All doses were well tolerated, and no severe adverse events were reported. The study showed that repeated dosing of entacapone inhibits the COMT activity in a dose-dependent manner and thereby reduces the loss of L-Dopa to 3-OMD. Therefore, the area under the curve of L-Dopa is increased and the patient's clinical condition improved.

Pharmacokinetics of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, in man. A study using a stable isotope techique.

OBJECTIVE: This study investigated the pharmacokinetics of the catechol-O-methyltransferase (COMT) inhibitor entacapone by giving simultaneously stable non-radioactive isotope 13C-entacapone intravenously (i.v.) and unlabelled entacapone orally. In comparison with a crossover design, the simultaneous i.v. and oral administration made it possible to minimise intra-individual variation, sample size and the duration of the study and still obtain accurate pharmacokinetic data. METHODS: Eight healthy male volunteers were enrolled in this study. They were given a 20-mg i.v. dose of 13C-entacapone as a 1-mg/ml infusion at a constant rate of 5 mg/min over 4 min and a 100-mg dose of unlabelled entacapone orally immediately after the infusion. Blood samples were drawn at -5 (before onset of infusion), 0 (upon termination of infusion), 2, 5, 10, 20, 30 and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h after the tablet ingestion. Urine during the 48 h after dosing was collected in fractions. Concentrations of 13C-entacapone and entacapone in plasma samples and urine fractions were determined using gas chromatography-mass spectrometry. RESULTS: The decay of i.v. 13C-entacapone in plasma was tri-exponential and its pharmacokinetics were described using an open three-compartment model. The volume of the central compartment (Vc) and the volume of distribution at steady state (Vss) were 0.08+/-0.03 l/kg and 0.27+/-0.10 l/kg, respectively. Total plasma clearance (Cltot) averaged 11.7+/-1.9 ml/min kg(-1). The half-lives for the distribution phase and for the rapid and terminal elimination phases (t1/2alpha, t1/2beta and t1/2gamma) were 0.05+/-0.01 h, 0.38+/-0.16 h and 2.40+/-1.70 h, respectively. The terminal elimination phase accounted for only 9% of the total area under the plasma concentration-time curve (AUC), which was 409 +/- 98 ng h/ml after the i.v. dose. Oral entacapone was absorbed rapidly with a time to reach the peak concentration (tmax) of 0.9+/-0.4 h, a maximum concentration (Cmax) of 457+/-334 ng/ml and an AUC of 497+/-118 ng h/ml. During the 48 h after dosing, the recovery of free and conjugated unchanged 13C-entacapone in urine was 38.1+/-7.2% of the i.v. dose and the recovery of free and conjugated unchanged entacapone 13.3+/-3.9% of the oral dose. The bioavailability of oral entacapone was 25% based on the AUC values and 35% based on urinary excretion. CONCLUSION: The results of the present study using stable isotope technique indicate that entacapone is rapidly absorbed, distributed to a small volume and rapidly eliminated by mainly non-renal routes. The pharmacokinetic profile of entacapone provides the rationale for a concomitant and frequently repeated simultaneous dosing of entacapone with levodopa and dopa decarboxylase inhibitors in the treatment of Parkinson's disease. This study confirmed the previously published data and fully support the validity of the technique used.

[Day case surgery in Kuopio]. / Päiväkirurgisen potilaan hoito ja toipuminen leikkauksesta.

In day case surgery nursing the nurse must have multidisciplinary basic knowledge and skills and strong experience in nursing practice in order to be able to prepare a patient for an operation, to treat him during the operation and postoperatively and to give the patient guidance about care at home so that he understands it. A questionnaire which was completed by the patients in a day case surgery unit exposed that they were generally satisfied with their care. Some patients asked for more specific information about the physical activity they can have and what they may or may not do after the operation. Varicose veins patients asked for more guidance about bandaging, and phimosis patients wanted more information on how to take care of the wound during the healing process.

Transvaginal salpingosonography for the assessment of tubal patency in infertile women: methodological and clinical experiences.

OBJECTIVE: To evaluate the advantages and accuracy of transvaginal salpingosonography in the assessment of tubal patency with regards to laparoscopic chromopertubation. SETTING: Infertility policlinic of the hospital. DESIGN: Thirty-one women suffering from infertility were examined with transvaginal salpingosonography using air and saline as a contrast medium. The results were compared with those obtained with laparoscopic chromopertubation. RESULTS: Altogether 61 fallopian tubes were examined with both transvaginal salpingosonography and laparoscopic chromopertubation. Concordance was 85%. Of the tubes investigated by transvaginal salpingosonography, 45 were found to be patent and 16 were found to be occluded. In chromopertubation, 50 of 61 tubes were patent and 11 were occluded. Bilateral tubal patency was found by transvaginal salpingosonography in 17 cases and by laparoscopy in 22 cases. Unilateral tubal patency was found in 11 and 6 cases, respectively. Bilateral occlusion was found in three cases using either technique. CONCLUSION: Transvaginal salpingosonography with the combination of air and saline is a low-cost, reliable, safe, and comfortable examination method. It can be used for the primary investigation of infertility on an outpatient basis.

Diazepam loading in alcohol withdrawal: clinical pharmacokinetics.

The pharmacokinetics of diazepam and its major active metabolite, desmethyl-diazepam, following a loading dose of diazepam (fixed oral doses of 20 mg) were studied in 16 patients on alcohol withdrawal. No toxic drug levels were measured irrespective of the amount of diazepam needed on the loading (83 +/- 27 mg on average). The mean elimination half-life of diazepam fell within the range observed in healthy persons after the ingestion of therapeutic doses (5), or it was only moderately prolonged (t1/2 49.7 h). The ageing process was associated with a slightly prolonged half-life of diazepam. Standard liver function tests could not predict the length of the elimination half-life of diazepam. Active drug concentrations remained high during the first 48 h of treatment, followed by a steady decline. On the basis of this study, it seems that diazepam can be safely and effectively used in loading doses in the treatment of alcohol withdrawal.

Determination of cyclic 3'-5'-adenosine monophosphate in plasma by RIA methods in the presence of EDTA.

Calcium ions definitively increase the ability of cyclic 3',5'-adenosine monophosphate (cAMP) to bind to its antibody. In contrast, ethylenedinitrolotetra-acetic acid as its disodium salt (EDTA) shows a dose-dependent inhibition of the binding of cAMP to its antibody. The less sensitive protein binding methods are not affected by EDTA. This is inconvenient, because the EDTA-plasmas can be stored frozen without breakdown of cAMP, but are unsuitable for sensitive radioimmunoassays. The aim of this investigation was to determine how calcium ions and EDTA affect the binding of cAMP to its antibody. Based on these results, we describe an alternative procedure for commercial RIA methods for the determination of cAMP in EDTA-plasma. The almost complete inhibition of the hapten-antibody reaction by EDTA can be abolished by adding an equivalent concentration of calcium ions to the reaction medium together with trichloroacetic acid. Thus a simple and rapid procedure was found for the storage of plasma and for the determination of plasma cAMP.

Droperidol, alizapride and metoclopramide in the prevention and treatment of post-operative emetic sequelae.

Women (182) undergoing elective orthopaedic surgery under general anaesthesia received 100 or 200 mg alizapride, 1.25 mg droperidol, 20 mg metoclopramide or a saline placebo intravenously 5-10 min before the end of anaesthesia in a double-blind random fashion to prevent post-operative nausea and vomiting. Administration of the same anti-emetic was repeated during 24 h post-operatively if the patient complained of nausea or retched or vomited. Significantly fewer patients given any of the anti-emetics prophylactically were nauseated or vomited in comparison with patients given saline. The incidence of nausea and vomiting in the saline group was 83%, while in those patients who received an anti-emetic it was as follows: droperidol 35% (P less than 0.001 vs. saline), alizapride, 100 mg 46% (P less than 0.01), alizapride 200 mg 53% (P less than 0.05) and metoclopramide 58% (P less than 0.05). The number of patients needing an additional dose of the same substance in the post-operative period was significantly higher in the saline group (67%) than in the groups which had received droperidol (32%, P less than 0.01) and alizapride 100 mg (37%, P less than 0.05) or 200 mg (33%, P less than 0.05). The patients who received metoclopramide, however, did not differ statistically from the saline group in the treatment of nausea and vomiting. It is concluded that droperidol was the most effective, and metoclopramide the least effective, anti-emetic in this study.

Virulence plasmid-associated autoagglutination in Yersinia spp.

The autoagglutination of Yersinia enterocolitica was dependent on the presence of the virulence plasmid and on the active growth of bacteria in tissue culture media at 37 degrees C. Cultures with a high initial concentration of bacteria failed to autoagglutinate , indicating that synthesis of new virulence plasmid-associated surface factors was essential for autoagglutination. The synthesis of a plasmid-encoded polypeptide (molecular weight, 240,000), designated P1, that could be dissociated under strongly reducing conditions into subunits of 52,500 daltons was found to be correlated with autoagglutination. Further, a strain of Yersinia pseudotuberculosis [ YPIII ( PIB102 )], which has Tn5 inserted within the structural gene of P1 that prevents the synthesis of P1, failed to autoagglutinate , in contrast to the wild-type strain, strongly indicating that P1 is involved in this phenomenon. It was also found by immunoblotting that in addition to the common response to temperature, the P1 proteins of Y. enterocolitica and Y. pseudotuberculosis were immunologically related.

Prevention of diazepam-induced thrombophlebitis with cremophor as a solvent.

In 104 patients undergoing anaesthesia of short duration, two different solvents, propylene glycol and cremophor, were compared in a double-blind trial. Diazepam 10 mg in a coded solution was injected into a superficial vein of the hand using a small-gauge needle. The vein was examined after 14 days. The frequency of thrombophlebitis with propylene glycol was 62.2% and with cremophor 3.4% (P less than 0.001). The frequency of pain on injection was also in favour of the new solvent (P less than 0.001). The possibility of anaphylactic reactions accredited to cremophor, however, restricts the use of the new injection.