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.

High affinity binding of TAR RNA by the human immunodeficiency virus type-1 tat protein requires base-pairs in the RNA stem and amino acid residues flanking the basic region.

The binding site for tat protein on TAR RNA has been defined in quantitative terms using an extensive series of mutations. The relative dissociation constants for the mutant TAR RNAs were measured using a dual-label competition filter binding assay in which 35S-labelled wild-type TAR RNA (K1) was competed against 3H-labelled mutant TAR RNA (K2). The error in the self-competition experiment was usually less than 10% (e.g. K2/K1 = 1.07 +/- 0.05, n = 19) and the experimental data accurately matched theoretical curves calculated with fitted dissociation constants. Mutations in U23, a critical residue in the U-rich "bulge" sequence, or in either of the two base-pairs immediately above the "bulge", G26.C39 and A27.U38 reduced that affinity by 8- to 20-fold. Significant contributions to tat binding affinity were also made by the base-pairs located immediately below the bulge. For example, mutation of A22.U40 to U.A reduced tat affinity 5-fold, and mutation of G21.C41 to C.G reduced tat affinity 4-fold. The binding of a series of peptides spanning the basic "arginine-rich" sequence of tat was examined using both filter-binding and gel mobility shift assays. Each of the peptides showed significantly reduced affinities for wild-type TAR RNA compared to the tat protein. The ADP-2 (residues 43 to 72), ADP-3 (residues 48 to 72) and ADP-5 (residues 49 to 86) peptides were unable to discriminate between wild-type TAR RNA and TAR RNA mutants with the same fidelity as the tat protein. For example, these peptides showed no more than 3-fold reductions in affinity relative to wild-type TAR RNA for the U23-->C mutation in the bulge, or G26.G39-->C.G mutation in the stem of TAR RNA. By contrast, the ADP-I (residues 37 to 72), ADP-4 (residues 32 to 62) and ADP-6 (residues 32 to 72) peptides, which each carry amino acid residues from the "core" region of the tat protein have binding specificities that more closely resemble the protein. The ADP-4 and ADP-6 peptides showed between 4- and 7-fold reductions in affinity for the U23-->C or G26.C39-->C.G mutations. The ADP-1 peptide most closely resembles the protein in its binding specificity and showed 9-fold and 14-fold reductions in affinity for the two mutants, respectively. Chemical-modification interference assays using diethylpyrocarbonate (DEPC) and ethylnitrosourea (ENU) were also used to compare the binding properties of the tat protein and the tat-derived peptides.(ABSTRACT TRUNCATED AT 400 WORDS)

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 outcome of hospitalization for acute illness in the elderly.

The use of acute-care hospitals by the elderly is rising rapidly, particularly in the age group 75 and older. Any changes that will reduce the length of stay could result in considerable savings in health care costs. It is imperative to look at present policies and explore possible changes that could reduce costs by reducing the total hospital days. A study was conducted in a 290-bed county-founded community hospital in California that serves the majority of disadvantaged and poor elderly residing in an area with a population of approximately 300,000 persons. The objective was to determine what demographic, medical, and sociologic characteristics of elderly patients recorded at admission would be of value in predicting those most likely to change their functional status. It was found that the most important predictors of deterioration of function are (1) older age, especially 85+, and (2) abnormal mental status. Patients admitted from nursing homes had a longer than average length of stay, and those who survived (80 per cent) returned to a nursing home. It was concluded that routine assessment of elderly patients admitted for acute illness or injury could facilitate discharge planning by an early prediction of the level of care that will be required after discharge. This assessment should include preadmission mental and functional status; identification of causes for, and correction of, acute confusional states; and an assessment of the impact of the present illness or injury on future level of function following rehabilitation. This could result in a reduced length of average hospital stay.

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.

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.

Glue-sniffing as a cause of a positive radio-isotope brain scan.

Convulsions are a known complication of the acute intoxicant effects of solvent abuse. A radio-isotope brain scan done 9 months following status epilepticus secondary to toluene inhalation, in a previously normal school-boy, demonstrated several wedge-shaped areas of increased uptake, in both cerebral hemispheres, consistent with infarcts. It is worth remembering that a positive brain scan in a young person, with recent onset of epilepsy, may be due to glue-sniffing.

Calcium sensitizing action of carnosine and other endogenous imidazoles in chemically skinned striated muscle.

1. The imidazole-containing compounds carnosine and homocarnosine, endogenous to skeletal and cardiac muscle, have been tested for effect on the contractile behaviour of chemically skinned (saponin or Triton X-100) skeletal and cardiac muscle. 2. Carnosine, at millimolar concentrations which are near physiological for many skeletal fibres, and in a concentration-dependent fashion, shifts the curve relating [Ca2+] to steady-state tension to lower [Ca2+] in both skeletal (frog but not crab) and cardiac (rat) muscle preparations. 3. Of other imidazoles endogenous to heart, homocarnosine is somewhat more effective, while N-acetyl L-histidine is much less so. 4. The maximum level of Ca(2+)-activated force is increased significantly by homocarnosine in cardiac trabeculae. 5. We propose that the cellular imidazoles related to carnosine are natural 'Ca2+ sensitizers' in striated muscle. Alterations in their levels as a result of disease or training, and between different fibre types, may contribute to differences in contractile performance of the intact tissues.

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.

Radiology in Idiopathic chronic ulcerative enteritis.

Two patients with idiopathic chronic ulcerative enteritis (ICUE) having malabsorption, subtotal villous atrophy and non-specific small intestinal ulceration are presented with emphasis on the radiological features. No improvement was shown morphologically following gluten withdrawal. The literature on this condition is reviewed. Obstruction, perforation and melaena are serious complications and the prognosis is poor; only 11 out of 31 reported cases survived. Differentiation from coeliac disease, Crohn's disease and primary intestinal lymphoma is discussed.

Hysteresis and the length dependence of calcium sensitivity in chemically skinned rat cardiac muscle.

1. The relationship between pCa (-log10[Ca2+]) and steady-state isometric tension has been investigated in saponin- or Triton-treated (chemically 'skinned') cardiac muscle of rat. 2. Hysteresis exists in the relationship such that the muscle is less sensitive to Ca2+ during increasing activation (as [Ca2+] is stepped upward) than during reducing activation (as [Ca2+] is stepped downward). 3. The extent of the hysteresis is insensitive to interventions that increase overall calcium sensitivity by chemical means, such as caffeine, carnosine or increased pH. 4. The extent of the hysteresis is sensitive to sarcomere length. The phenomenon is virtually absent above sarcomere lengths of about 2.2-2.3 microns but becomes progressively greater at shorter sarcomere lengths. 5. The effect of sarcomere length on calcium sensitivity is restricted to the upward-going (increasing activation) part of the pCa-tension loop below 2.2 microns. The downward-going (decreasing activation) part of the hysteretic relationship is virtually unaffected by sarcomere length up to 2.2 microns. 6. Significant alterations in sarcomere length do not occur during tension development in the experiments described here: the phenomenon is not attributable to experimental artifacts of this kind. 7. Hysteresis develops sufficiently rapidly to be consistent with a physiological relevance during the normal heart beat. 8. The effects of sarcomere length show that the phenomenon is not due to force per se since, for example, greater peak force produces less hysteresis as sarcomere length is increased towards 2.2 microns. 9. Tonicity increase (by high-molecular-weight dextran), which shrinks the myofilament lattice, increases calcium sensitivity but reduces the effect of sarcomere length on calcium sensitivity. 10. The results suggest that lattice shrinkage is the mechanism which accounts for hysteresis in, and the sarcomere length dependence of, calcium sensitivity in cardiac muscle.

Role of the sarcolemma in triggered propagated contractions in rat cardiac trabeculae.

We have recently described that after contractions propagate through multicellular cardiac muscle preparations. These propagating contractions are triggered in damaged regions of rat right ventricular trabeculae during relaxation of electrically stimulated twitches. Propagation of triggered contractions has been attributed to calcium ions that diffuse along the preparation, causing calcium-induced calcium release from the sarcoplasmic reticulum in adjacent cells. In the present study we have investigated a possible role of the sarcolemma and delayed afterdepolarizations (DADs) in the initiation and propagation of triggered propagated contractions (TPCs) in multicellular preparations. We studied whether 1) TPCs are accompanied by delayed sarcolemmal depolarizations, 2) such depolarizations mediate local contraction, and 3) an intact sarcolemma is required for propagation of contractions. TPCs that remained stable for prolonged periods of time could be induced by trains of 15 stimuli (2 Hz, 15-second intervals) at lowered temperature (19-21 degrees C) of the superfusing Krebs-Henseleit medium and a [Ca(2+)]o of 1.0-1.5 mM. Although TPCs could be induced at 38 degrees C and a [Ca2+]o of 3.0-4.0 mM, they disappeared within 10 minutes. Force was measured with a silicon strain gauge; length and shortening of sarcomeres were measured at two sites of the muscle using laser diffraction techniques. Membrane potential was measured with flexible microelectrodes. Saponin was used to selectively render the sarcolemma permeable to small ions and molecules. Propagation velocity of TPCs in intact trabeculae varied from 1.7 to 13.4 mm/sec at 19-21 degrees C. TPCs were accompanied by DADs that could reach threshold and induce triggered arrhythmias. Changes in latency, duration, and force of TPCs, induced by changing [Ca(2+)]o or the number of conditioning stimuli, were closely matched by changes in latency, duration, and amplitude of DADs; DADs consistently preceded TPCs, on average by 60 msec. Local heating of the muscle, by applying a current through an insulated platinum wire (diameter 100 microns) that touched the muscle, interrupted propagation of TPCs reversibly. DADs were, in the absence of a local contraction, still recorded distal to the heated site. In muscles that were treated with saponin and exposed to solutions approximating the intracellular milieu, spontaneously occurring local contractions that propagated in both directions (at velocities of 70-200 microns/sec) were elicited at a bathing calcium concentration of approximately 0.6 microM. Below this threshold, propagated contractions could be triggered by pressure ejection of a calcium-containing solution from a microelectrode positioned close to the trabecula.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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.