Silicone encapsulation of thin-film SiOx, SiOxNyand SiC for modern electronic medical implants: a comparative long-term ageing study.

Objective.Ensuring the longevity of implantable devices is critical for their clinical usefulness. This is commonly achieved by hermetically sealing the sensitive electronics in a water impermeable housing, however, this method limits miniaturisation. Alternatively, silicone encapsulation has demonstrated long-term protection of implanted thick-film electronic devices. However, much of the current conformal packaging research is focused on more rigid coatings, such as parylene, liquid crystal polymers and novel inorganic layers. Here, we consider the potential of silicone to protect implants using thin-film technology with features 33 times smaller than thick-film counterparts.Approach.Aluminium interdigitated comb structures under plasma-enhanced chemical vapour deposited passivation (SiOx, SiOxNy, SiOxNy+ SiC) were encapsulated in medical grade silicones, with a total of six passivation/silicone combinations. Samples were aged in phosphate-buffered saline at 67 ∘C for up to 694 days under a continuous ±5 V biphasic waveform. Periodic electrochemical impedance spectroscopy measurements monitored for leakage currents and degradation of the metal traces. Fourier-transform infrared spectroscopy, x-ray photoelectron spectroscopy, focused-ion-beam and scanning-electron- microscopy were employed to determine any encapsulation material changes.Main results.No silicone delamination, passivation dissolution, or metal corrosion was observed during ageing. Impedances greater than 100 GΩ were maintained between the aluminium tracks for silicone encapsulation over SiOxNyand SiC passivations. For these samples the only observed failure mode was open-circuit wire bonds. In contrast, progressive hydration of the SiOxcaused its resistance to decrease by an order of magnitude.Significance.These results demonstrate silicone encapsulation offers excellent protection to thin-film conducting tracks when combined with appropriate inorganic thin films. This conclusion corresponds to previous reliability studies of silicone encapsulation in aqueous environments, but with a larger sample size. Therefore, we believe silicone encapsulation to be a realistic means of providing long-term protection for the circuits of implanted electronic medical devices.

Apparatus to investigate the insulation impedance and accelerated life-testing of neural interfaces.

OBJECTIVE: Neural interfaces and other implantable micro-devices that use polymer-encapsulated integrated circuits will only be allowed in medical devices when their lifetimes can be estimated from experimental data. An apparatus has been developed and tested that allows hundreds of insulated samples (interdigitated combs) to be aged under accelerated conditions of high temperature and voltage stress. Occasionally, aging is paused while the sample's impedance is measured; the impedance spectrogram may show degradation as it progresses before failure. APPROACH: The design was based on practical considerations which are reviewed. A Solartron Modulab provides the frequency response analyser and the femtoammeter. The apparatus can accommodate batches of samples at several temperatures and with different aging voltage waveforms. It is important to understand features of the spectra that are not due to comb-comb leakage, but come from other places (for example substrate-solution leakage); some have been observed and investigated using SPICE. MAIN RESULTS: The design is described in detail and test results show that it is capable of making measurements over long periods, at least up to 67 °C. Despite the size of the apparatus, background capacitance is about 1 pF and comb-comb capacitances of about 30 pF can be measured down to 10 mHz, an impedance of about 100 GΩ. An important discovery was the advantage of grounding the bathing solution, primarily in that it raises the measurement ceiling. Observation and SPICE simulation shows that leakage from the substrate to the bathing solution can give phase lags >90°, in contrast to comb-comb leakage which reduces phase lag to <90°. SIGNIFICANCE: The value of this paper is that it will facilitate research into the endurance of small implanted devices because, given a description of a proven apparatus, researchers can start building their own apparatus relatively quickly and with confidence.

A chronic disease management programme can reduce days in hospital for patients with chronic obstructive pulmonary disease.

BACKGROUND: A steady increase in chronic obstructive pulmonary disease (COPD) admissions was addressed by enhancing primary care to provide intensive chronic disease management. AIM: To compare the effect of a disease management programme, including a COPD management guideline, a patient-specific care plan and collaboration between patients, general practitioners, practice nurses, hospital physicians and nurse specialists with conventional care, on hospital admissions and quality of life. METHODS: One hundred and thirty-five patients with a clinical diagnosis of moderate to severe COPD were identified from hospital admission data and general practice records. General practices were randomized to either conventional care (CON), or the intervention (INT). Pre- and post-study assessment included spirometry, Shuttle Walk Test, Short Form-36, and the Chronic Respiratory Questionnaire (CRQ). Admission data were compared for 12 months prior to and during the trial. RESULTS: For respiratory conditions, mean hospital bed days per patient per year for the INT group were reduced from 2.8 to 1.1, whereas those for the CON group increased from 3.5 to 4.0 (group difference, P = 0.030) The INT group also showed an improvement for two dimensions of the CRQ, fatigue (P = 0.010) and mastery (P = 0.007). CONCLUSIONS: A chronic disease management programme for COPD patients that incorporated a variety of interventions, including pulmonary rehabilitation and implemented by primary care, reduced admissions and hospital bed days. Key elements were patient participation and information sharing among healthcare providers.

Circular dichroism in core level photoemission from an adsorbed chiral molecule.

The results of experimental measurements and theoretical simulations of circular dichroism in the angular dependence (CDAD) of photoemission from atomic core levels of each of the enantiomers of a chiral molecule, alanine, adsorbed on Cu(110) are presented. Measurements in, and out of, substrate mirror planes distinguish CDAD due to the chirality of the sample and the experimental geometry. The effect due to sample chirality is relatively weak, so such measurements may not provide a routine spectral fingerprint of adsorbate chirality.

Bond lengths and bond strengths in weak and strong chemisorption: N2, CO, and CO/H on nickel surfaces.

New chemical-state-specific scanned-energy mode photoelectron diffraction experiments and density functional theory calculations, applied to CO, CO/H, and N2 adsorption on Ni(100), show that chemisorption bond length changes associated with large changes in bond strength are small, but those associated with changes in bond order are much larger, and are similar to those found in molecular systems. Specifically, halving the bond strength of atop CO to Ni increases the Ni-C distance by 0.06 A, but halving the bond order (atop to bridge site) at fixed bond strength causes an increase of 0.16 A.

Molecular adsorption bond lengths at metal oxide surfaces: failure of current theoretical methods.

New experimental structure determinations for molecular adsorbates on NiO(100) reveal much shorter Ni-C and Ni-N bond lengths for adsorbed CO and NH3 as well as NO (2.07, 1.88, 2.07 A) than previously computed theoretical values, with discrepancies up to 0.79 A, highlighting a major weakness of current theoretical descriptions of oxide-molecule bonding. Comparisons with experimentally determined bond lengths of the same species adsorbed atop Ni on metallic Ni(111) show values on the oxide surface that are consistently larger (0.1-0.3 A) than on the metal, indicating somewhat weaker bonding.

Adrenergic stimulation of rat resistance arteries affects Ca(2+) sparks, Ca(2+) waves, and Ca(2+) oscillations.

Confocal laser scanning microscopy and fluo 4 were used to visualize local and whole cell Ca(2+) transients within individual smooth muscle cells (SMC) of intact, pressurized rat mesenteric small arteries during activation of alpha1-adrenoceptors. A method was developed to record the Ca(2+) transients within individual SMC during the changes in arterial diameter. Three distinct types of "Ca(2+) signals" were influenced by adrenergic activation (agonist: phenylephrine). First, asynchronous Ca(2+) transients were elicited by low levels of adrenergic stimulation. These propagated from a point of origin and then filled the cell. Second, synchronous, spatially uniform Ca(2+) transients, not reported previously, occurred at higher levels of adrenergic stimulation and continued for long periods during oscillatory vasomotion. Finally, Ca(2+) sparks slowly decreased in frequency of occurrence during exposure to adrenergic agonists. Thus adrenergic activation causes a decrease in the frequency of Ca(2+) sparks and an increase in the frequency of asynchronous wavelike Ca(2+) transients, both of which should tend to decrease arterial diameter. Oscillatory vasomotion is associated with spatially uniform synchronous oscillations of cellular [Ca(2+)] and may have a different mechanism than the asynchronous, propagating Ca(2+) transients.

Prescription and nonprescription drug use among at-risk community-dwelling seniors in Ottawa-Carleton.

BACKGROUND: The Council on Aging Ottawa-Carleton conducted an evaluation study aimed at reducing the inappropriate use of medication by community-dwelling seniors. During a 17-month period from 1990 to 1992, 278 of 415 seniors consented to participate. All were new referrals to home care, all were 65 years of age or older and all were taking a minimum of six prescription medications. OBJECTIVE: To describe the patterns of prescription and nonprescription drug use among high risk elderly people living in the Ottawa-Carleton region. ANALYSIS: Descriptive statistics and logistic regression were used to explore relationships between the numbers of drugs (prescription and nonprescription), drug classes and drug subclasses, and sex, age and number of prescribing physicians. RESULTS: The top 10 prescription or nonprescription drugs taken by study participants were consistent among diseases and health problems most commonly found among the elderly. Comparisons by rank for subclasses of drugs indicated that eye, ear, nose and throat (EENT), and respiratory drugs were considerably more prevalent among males than females, while women took more hormones and anxiolytics, sedatives and hypnotics. Age also appeared to have an effect; the proportions of respiratory drugs and hormones decreased with age. In contrast, vitamins and EENT drugs were most prevalent among the oldest seniors. These findings were supported by the results of multivariate analyses. Having three or more prescribing doctors was positively associated with the use of laxatives. Findings from multivariate analyses indicated that for prescription drugs, the youngest age group was about four times more likely than the oldest age group to be taking at least eight drugs. For nonprescription drugs, the only statistically significant finding was that those with three or more doctors were twice as likely as those with one or two doctors to take at least one nonprescription drug.

Intercellular Ca2+ waves in rat heart muscle.

1. Confocal laser scanning microscopy was used to visualize intercellular transmission of Ca2+ waves in intact rat ventricular trabeculae micro-injected with the calcium indicator fluo-3. 2. Ca2+ waves usually failed to be transmitted from cell to cell. At identified individual end-to-end cell contacts, successful transmission interspersed with failure, which sometimes occurred despite an apparent small spritz of Ca2+ between cells. The probability of cell to cell transmission (Ptran) was 0.13. 3. Ca2+ waves arose preferentially near junctions of connected cells, where connexin-43 was found, but randomly in enzymatically disconnected heart cells. 4. beta-Adrenergic stimulation significantly increased Ptran (to 0.22) and heptanol, an uncoupler of gap junction channels, significantly decreased it (to 0.045). 5. In regions of high [Ca2+]i due to damage, wave frequency decreased markedly with each cell-cell junction passed. 6. The Ca2+ permeability of cardiac gap junctions may be regulated, and the low ability of cardiac gap junctions to transmit Ca2+ may help control the spread of Ca2+ from damaged regions.

Intracellular Na+ measurements in smooth muscle using SBFI--changes in [Na+], Ca2+ and force in normal and Na(+)-loaded ureter.

Our understanding of the control and effects of intracellular [Na+] ([Na+]i) in intact smooth muscle is limited by the lack of data concerning [Na+]i. The initial aim of this work was therefore to investigate the suitability of using the Na+-sensitive fluorophore SBFI in intact smooth muscle. We find this to be a good method for measuring [Na+]i in ureteric smooth muscle. Resting [Na+]i was found to be around 10 mM and rose to 25 mM when the Na+-K+-ATPase was inhibited by ouabain. This relatively low [Na+]i in the absence of Na+-K+-ATPase suggests that other cellular processes, such as Na+-Ca2+ exchange, play a role in maintaining [Na+]i under these conditions. Simultaneous measurements of [Na+]i or [Ca2+] i and force showed that Na+-Ca2+ exchange can play a functional role in ureteric smooth muscle. We found that the greater the driving force for Na+ exit and hence Ca2+ entry, the larger the contraction. In addition the Na+-Ca2+ exchanger activity under these conditions was found to be pH sensitive: acidification reduced the contraction and concomitant changes in [Ca2+] and [Na+]i. We conclude that SBFI is a useful method for monitoring [Na] in smooth muscle and that Na+-Ca2+ exchange may play a functional role in the ureter.

Radioprotection of bone marrow stem cell subsets by interleukin-1 and kit-ligand: implications for CFU-S as the responsible target cell population.

Various cytokines have been reported to have radioprotective effects on the bone marrow. Of these, c-kit-ligand (KL) and interleukin-1 (IL-1) have the most dramatic effect when given prior to total body irradiation (TBI). Given simultaneously, KL and IL-1 demonstrated a strong effect on increasing the LD50/30 of mice. In this case the LD50/30 of C57BL/6 mice was 1.25 (1.14-1.38) times higher (10.08 Gy [confidence interval (c.i.): 9.62-10.56] vs. 8.05 Gy [c.i.: 7.64-8.42]) when KL (120 micrograms/kg) and IL-1 (40 micrograms/kg) were injected subcutaneously at 20 hours before TBI. It was also investigated whether the combined effects of KL and IL-1 resulted in changes in the intrinsic radiation sensitivity of different bone marrow subsets. Therefore, mice were irradiated and the survival of bone marrow subsets was determined at 4-6 hours after TBI by using the CFU-S assay and the competitive repopulation assay. The CFU-S subset displayed an increased Dzero value in KL and IL-1-treated mice (0.88 Gy vs. 0.72 Gy) and the protection factor was 1.22, close to the factor found for the hemopoietic syndrome (LD50/30). It may therefore be concluded that CFU-S are the target cell population involved in hemopoietic death. Additional protection of the more primitive stem cell subset with long-term repopulation ability (LTRA) could not be shown from the data we obtained with the competitive repopulation assay. Both Dzero and the extrapolation number (n) were increased, but not significantly. These data suggest that radioprotection by cytokines is caused mainly by the decreased radiation sensitivity of the CFU-S subset, although earlier subsets may also be protected (but to a lesser extent).

The sarcolemmal mechanisms involved in the control of diastolic intracellular calcium in isolated rat cardiac trabeculae.

We performed experiments using the calcium indicator Indo-1 to determine the relative roles of the sarcolemmal mechanisms involved in the regulation of diastolic intracellular calcium concentration ([Ca2+]i) in trabeculae from the rat heart. Ryanodine was used to eliminate sarcoplasmic reticulum (SR) function. In the functional absence of the SR, 76.8 +/- 3.9% of the calcium was extruded by the Na-Ca exchange carrier in the [Ca2+]i range of diastolic concentration +/- 200-400 nM. This was assessed by measuring the recovery of [Ca2+]i from small perturbations in the presence and absence of extracellular sodium. The steady-state relationship between [Ca2+]o and [Ca2+]i was linear over the range of 1-40 mM, a 20-fold increase of [Ca2+]o produced a 1.97-fold +/- 0.13-fold increase in [Ca2+]i (n = 5). In the absence of extracellular sodium raising [Ca2+]o had a variable effect. In some preparations there was little change of [Ca2+]i while in others the response was almost as large as in control conditions. We conclude that the Na-Ca exchanger contributes approximately 77% of sarcolemmal calcium extrusion following small perturbations in [Ca2+]i and that this fraction does not diminish as the [Ca2+]i declines. In addition we have shown a sodium-independent entry of calcium into quiescent cardiac muscle under resting conditions.

B7-1 is superior to B7-2 costimulation in the induction and maintenance of T cell-mediated antileukemia immunity. Further evidence that B7-1 and B7-2 are functionally distinct.

Although intact, viable tumor cells rarely induce a clinically significant immune response in vivo, immunogenicity can be elicited by irradiated tumor cells that protect against subsequent challenge with wild-type intact viable tumor cells. Genetic modification of murine tumor cells, by transfection of cDNAs encoding either cytokines, MHC molecules, or costimulatory molecules, has been capable of inducing antitumor immunity. We and others have previously demonstrated that expression of the B7-1 costimulatory molecule, in either immunogenic or nonimmunogenic tumors, can protect against subsequent challenge with wild-type tumor cells. In this work, using a murine model of acute myeloid leukemia, we demonstrate that the B7-1 costimulatory molecule is superior to the B7-2 molecule in its capacity to protect against wild-type tumor challenge and eradicate minimal residual disease. These results provide compelling evidence that the B7-1 and B7-2 costimulatory signals are functionally distinct, thus resulting in clinically significant differences in the induction of antitumor immunity in vivo.

Hematopoietic stem cells in the blood after stem cell factor and interleukin-11 administration: evidence for different mechanisms of mobilization.

Peripheral blood stem cells and progenitor cells, collected during recovery from exposure to cytotoxic agents or after cytokine administration, are being increasingly used in clinical bone marrow transplantation. To determine factors important for mobilization of both primitive stem cells and progenitor cells to the blood, we studied the blood and splenic and marrow compartments of intact and splenectomized mice after administration of recombinant human interleukin-11 (rhlL-11), recombinant rat stem cell factor (rrSCF), and IL-11 + SCF. IL-11 administration increased the number of spleen colony-forming units (CFU-S) in both the spleen and blood, but did not increase blood long-term marrow-repopulating ability (LTRA) in intact or splenectomized mice. SCF administration increased the number of CFU-S in both the spleen and blood and did not increase the blood or splenic LTRA of intact mice, but did increase blood LTRA to normal marrow levels in splenectomized mice. The combination of lL-11 + SCF syngeristically enhanced mobilization of long-term marrow-repopulating cells from the marrow to the spleen of intact mice and from the marrow to the blood of splenectomized mice. These data, combined with those of prior studies showing granulocyte colony-stimulating factor mobilization of long-term marrow repopulating cells from the marrow to the blood of mice with intact spleens, suggest different cytokine-induced pathways for mobilization of primitive stem cells.

Role of B7-1 in mediating an immune response to myeloid leukemia cells.

A costimulatory signal from B7-1 (CD80) to its counter-receptor CD28 is required for T-cell activation. Many tumors, including most human leukemias, lack expression of B7-1, and this has been suggested to contribute to the failure of immune recognition of these diseases. A murine leukemia model system was developed to assess the potential role of B7-1 in the induction immunity to leukemia cells. The nonleukemic 32Dc13 myeloid cell line was transformed by transfection of the BCR/ABL gene, generating a subline (32Dp210/clone 26) that was leukemic and rapidly lethal to syngeneic, immunocompetent C3H/HeJ mice or T-cell-deficient nude mice. B7-1-modified leukemic cells remained lethal in nude mice, but caused only a transient, nonlethal leukemia in C3H/HeJ mice. After a single exposure to live, nonirradiated B7-1-modified leukemic cells, C3H/HeJ mice developed protective immunity against subsequent challenge with B7-1(-) leukemic cells. Further, hyperimmunization with B7-1(+) leukemic cells prolonged the survival of mice previously injected with a lethal number of B7-1(-) leukemic cells. These results indicate that myeloid leukemic cells may be attractive candidates for B7-1 gene transfer.