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This paper provides an overview of the usability engineering process and relevant standards informing the development of medical devices, together with adaptations to accommodate situations such as global pandemics where use of traditional face-to-face methods is restricted. To highlight some of those adaptations, a case study of a project developing a novel electronic rehabilitation device is referenced, which commenced in November 2020 amidst the COVID-19 pandemic. The Sheffield Adaptive Patterned Electrical Stimulation (SHAPES) project, led by Sheffield Teaching Hospitals NHS Foundation Trust (STH), aimed to design, manufacture and trial an intervention for use to treat upper arm spasticity after stroke. Presented is an outline and discussion of the challenges experienced in developing the SHAPES health technology intended for at-home use by stroke survivors and in implementing usability engineering approaches. Also highlighted, are the benefits that arose, which can offer easier involvement of vulnerable users and add flexibility in the ways that user feedback is sought. Challenges included: restricted travel; access to usual prototyping facilities; social distancing; infection prevention and control; availability of components; and changing work pressures and demands. Whereas benefits include: less travel; less time commitment; and greater scope for participants with restricted mobility to participate in the process. The paper advocates a more flexible approach to usability engineering and outlines the onward path for development and trialling of the SHAPES technology.

Functional electrical stimulation has been shown to be a safe and effective means of correcting foot drop of central neurological origin. Current surface-based devices typically consist of a single channel stimulator, a sensor for determining gait phase and a cuff, within which is housed the anode and cathode. The cuff-mounted electrode design reduces the likelihood of large errors in electrode placement, but the user is still fully responsible for selecting the correct stimulation level each time the system is donned. Researchers have investigated different approaches to automating aspects of setup and/or use, including recent promising work based on iterative learning techniques. This paper reports on the design and clinical evaluation of an electrode array-based FES system for the correction of drop foot, ShefStim. The paper reviews the design process from proof of concept lab-based study, through modelling of the array geometry and interface layer to array search algorithm development. Finally, the paper summarises two clinical studies involving patients with drop foot. The results suggest that the ShefStim system with automated setup produces results which are comparable with clinician setup of conventional systems. Further, the final study demonstrated that patients can use the system without clinical supervision. When used unsupervised, setup time was 14min (9min for automated search plus 5min for donning the equipment), although this figure could be reduced significantly with relatively minor changes to the design., (Copyright © 2016 IPEM. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the feasibility of using a novel form of multichannel electrical stimulation, termed Sensory Barrage Stimulation (SBS) for the treatment of spasticity affecting the elbow flexor muscles and to compare this with conventional single-channel TENS stimulation., Materials and Methods: Altogether ten participants with spasticity of the flexor muscles of the elbow of Grade 2 or above on the Modified Ashworth Scale (MAS) were recruited to this crossover double blind randomized trial. The participants received two intervention sessions (SBS and TENS), one week apart in a randomized order. Both interventions were applied over the triceps brachii on the affected arm for a duration of 60 minutes. Spasticity was measured using the MAS. Secondary outcome measures were self-reported change in spasticity, measured on a visual analog scale (VAS, 0-100), and therapist-rated strength of elbow extension and strength of elbow flexion. Measurements were taken immediately before each intervention was applied, immediately after the intervention, and one hour after the intervention., Results: Immediately after stimulation spasticity showed a significant reduction for both TENS and SBS groups assessed by MAS -0.9 ± 0.2 vs. -1.1 ± 0.2 and by VAS -15 ± 3 vs. -31 ± 8. For SBS this improvement in MAS was still present at one hour after the stimulation, but not for TENS. Altogether seven SBS responders and four TENS responders were identified., Conclusions: This study demonstrates the feasibility and practicality of applying the new concept of SBS. Promising results indicate it causes a reduction in spasticity., (© 2015 International Neuromodulation Society.)

Objective: To investigate the feasibility of unsupervised community use of an array-based automated setup functional electrical stimulator for current foot-drop functional electrical stimulation (FES) users., Design: Feasibility study., Setting: Gait laboratory and community use., Participants: Participants (N=7) with diagnosis of unilateral foot-drop of central neurologic origin (>6mo) who were regular users of a foot-drop FES system (>3mo)., Intervention: Array-based automated setup FES system for foot-drop (ShefStim)., Main Outcome Measures: Logged usage, logged automated setup times for the array-based automated setup FES system and diary recording of problems experienced, all collected in the community environment. Walking speed, ankle angles at initial contact, foot clearance during swing, and the Quebec User Evaluation of Satisfaction with Assistive Technology version 2.0 (QUEST version 2.0) questionnaire, all collected in the gait laboratory., Results: All participants were able to use the array-based automated setup FES system. Total setup time took longer than participants' own FES systems, and automated setup time was longer than in a previous study of a similar system. Some problems were experienced, but overall, participants were as satisfied with this system as their own FES system. The increase in walking speed (N=7) relative to no stimulation was comparable between both systems, and appropriate ankle angles at initial contact (N=7) and foot clearance during swing (n=5) were greater with the array-based automated setup FES system., Conclusions: This study demonstrates that an array-based automated setup FES system for foot-drop can be successfully used unsupervised. Despite setup's taking longer and some problems, users are satisfied with the system and it would appear as effective, if not better, at addressing the foot-drop impairment. Further product development of this unique system, followed by a larger-scale and longer-term study, is required before firm conclusions about its efficacy can be reached., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Functional electrical stimulation is commonly used to correct drop foot following stroke or multiple sclerosis. This technique is successful for many patients, but previous studies have shown that a significant minority have difficulty identifying correct sites to place the electrodes in order to produce acceptable foot movement. Recently there has been some interest in the use of 'virtual electrodes', the process of stimulating a subset of electrodes chosen from an array, thus allowing the site of stimulation to be moved electronically rather than physically. We have developed an algorithm for automatically determining the best site of stimulation and tested it on a computer linked to a small, battery-powered prototype stimulator with 64 individual output channels. Stimulation was delivered via an 8×8 array adhered to the leg by high-resistivity self-adhesive hydrogel. Ten participants with stroke (ages 53-71 years) and 11 with MS (ages 40-80 years) were recruited onto the study and performed two walks of 10 m for each of the following conditions: own setup (PS), clinician setup (CS), automated setup (AS) and no stimulation (NS). The PS and CS conditions used the participant's own stimulator with two conventional electrodes; the AS condition used the new stimulator and algorithm. Outcome measures were walking speed, foot angle at initial contact and the Borg Rating of Perceived Exertion. Mean walking speed with no stimulation was 0.61 m/s; all FES setups significantly increased speed relative to this (AS p<0.05, PS p<0.01, CS p<0.01). Speed for PS (0.72 m/s) was faster than both AS (0.65 m/s, p<0.01) and CS (0.68 m/s, p<0.05). Frontal plane foot orientation at heel-strike was more neutral for AS (0.3° everted) than in the NS (11.2° inverted, p<0.01), PS (4.5° inverted, p<0.05) and CS (3.1° inverted, p<0.05) conditions. Dorsiflexion angles for AS (4.2°) were larger than NS (-3.0°, p<0.01), not different to PS (4.3°, p>0.05) and less dorsiflexed than CS (6.0°, p<0.05). This proof of principle study has demonstrated that automated setup of an array stimulator produces results broadly comparable to clinician setup. Slower walking speed for automated and clinician setups compared to the participants' own setup may be due to the participants' lack of familiarity with responses different to their usual setups. Automated setup using the method described here seems sufficiently reliable for future longer-term investigation outside the laboratory and may lead to FES becoming more viable for patients who, at present, have difficulty setting up conventional stimulators., (Copyright © 2012 IPEM. Published by Elsevier Ltd. All rights reserved.)

Functional electrical stimulation (FES) applied to the common peroneal nerve is commonly prescribed to correct both equinus and excessive foot inversion in swing and initial contact. This paper presents the development of a simple shoe model, to allow quantification of 3-D shoe (foot and footwear) kinematics in clinical situations when footwear is required, e.g. with FES systems requiring footswitches. To preliminarily validate the shoe model, barefoot 'normal' adult data (n=11) processed using validated 3-D foot models, were reprocessed with the shoe model. Outputs were compared through calculation of waveform similarity and correlation. Clinical utility of the shoe model is demonstrated through the presentation of 3-D shoe kinematics, calculated from a cohort of existing unilateral common peroneal FES users (n=16), both with and without FES. A trend of reduced inversion at mid-swing and initial contact was seen, although this was not found to be statistically significant (p≤0.0125). The shoe model was found to be practical to use in a clinical environment, and has potential to contribute to the evidence base for interventions such as common peroneal FES., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

It has been hypothesized that high concentrations of tissue iron may enhance carcinogenesis induced by free radical mechanisms. Wy-14,643 is a peroxisome proliferator that is hepatocarcinogenic in rats. Tumor induction may result in part from excessive production of reactive oxygen species, particularly H(2)O(2). The purpose of this study was to examine the effect of iron status on oxidative stress and NF-kappaB activation in livers of rats treated with Wy-14,643. Forty-eight male Sprague-Dawley rats were fed one of four diets (20, 45, 650, 1500 mg Fe/kg diet) for 28 d. At the time of tissue collection, liver iron ranged from 1.4 to 9.9 micro mol/g wet tissue in the diet groups. Wy-14,643 (0 or 0.1 g/100 g diet) was added to the diet for the final 10 d of the study. Wy-14,643 doubled the liver weight/body weight ratio (P = 0.0001), which was also increased by iron supplementation (P < 0.01). Iron supplementation increased thiobarbituric acid reactive substances and/or conjugated dienes, but there was no synergism between Wy 14,643 and iron on lipid peroxidation measures. The hepatic DNA binding activity of NF-kappaB was increased in rats administered Wy-14,643. However, differences in liver iron concentration did not alter activation of NF-kappaB in untreated rats or in those treated with Wy-14,643. DNA double-strand breakage was not affected by iron or Wy-14,643. In summary, although moderate changes in iron status altered liver lipid peroxidation, iron did not significantly increase oxidative stress induced by a hepatocarcinogenic peroxisome proliferator.

Clonal populations of lineage-uncommitted pluripotent mesenchymal stem cells have been identified in prenatal avians and rodents. These cells reside in the connective tissue matrices of many organs and tissues. They demonstrate extended capabilities for self-renewal and the ability to differentiate into multiple separate tissues within the mesodermal germ line. This study was designed to determine whether such cells are present in the connective tissues of postnatal mammals. This report describes a cell clone derived by isolation from postnatal rat connective tissues, cryopreservation, extended propagation, and serial dilution clonogenic analysis. In the undifferentiated state, this clone demonstrates a high nuclear-to-cytoplasmic ratio and extended capacity for self-renewal. Subsequent morphological, histochemical, and immunochemical analysis after the induction of differentiation revealed phenotypic markers characteristic of multiple cell types of mesodermal origin, such as skeletal muscle, smooth muscle, fat cells, cartilage, and bone. These results indicate that this clone consists of pluripotent mesenchymal stem cells. This report demonstrates that clonal populations of reserve stem cells are present in mammals after birth. Potential roles for such cells in the maintenance, repair, and regeneration of mesodermal tissues are discussed., (Copyright 2001 Wiley-Liss, Inc.)

In the present study phosphodiesterase (PDE) isozymes in human airway smooth muscle were isolated, identified and characterized, and the functional roles of these isozymes in intact bronchi were evaluated by using isozyme-selective PDE inhibitors. PDE isozymes in human trachealis were isolated by using a combination of DEAE-Sepharose and calmodulin-Sepharose affinity chromatography, and were identified based upon their kinetic characteristics as well as their sensitivity to allosteric modulators and isozyme-selective PDE inhibitors. By using this approach, six distinct isozymes were identified: two calmodulin-stimulated PDEs (PDE I alpha and PDE I beta), cyclic GMP (cGMP)-stimulated PDE (PDE II), cGMP-inhibited PDE (PDE III), cyclic AMP (cAMP)-specific PDE (PDE IV) and cGMP-specific PDE (PDE V). PDEs III and IV were the major cAMP-hydrolyzing enzymes present, whereas PDEs I alpha, I beta and V accounted for most of the cGMP-hydrolytic activity. In carbachol-precontracted small (< 0.5-2 mm diameter) or large (4-15 mm diameter) human bronchus, zaprinast (10 nM-30 microM), the selective PDE V inhibitor, was without marked relaxant activity (< 13%), whereas rolipram (30 microM), the selective PDE IV inhibitor, produced approximately 25% relaxation in both preparations. Siguazodan was a significantly more effective relaxant than zaprinast or rolipram in large bronchus, producing a maximum relaxation of 77 +/- 15% at a concentration of 30 microM, whereas in small bronchus 30 microM siguazodan elicited 20 +/- 6% relaxation. Similar results were obtained in large bronchi contracted with leukotriene (LT) D4 (0.1 microM). The ability of isozyme-selective PDE inhibitors to potentiate agonist-induced relaxation was studied in LTD4-contracted large bronchi. Siguazodan (10 microM), but not rolipram (10 microM) or zaprinast (10 microM), potentiated the relaxant response in LTD4-contracted large bronchus to isoproterenol, a beta adrenoceptor agonist thought to induce relaxation via a cAMP-mediated mechanism. In contrast, zaprinast (10 microM), but not siguazodan (10 microM), potentiated relaxation induced by sodium nitroprusside, a nitrovasodilator that relaxes airway smooth muscle via a cGMP-mediated mechanism. The most striking observation from functional studies was that the combination of rolipram and siguazodan produced a much greater relaxation of small or large human bronchi than either agent alone, indicating an interaction between PDE III and PDE IV inhibitors that was at least additive and, in some cases, synergistic.(ABSTRACT TRUNCATED AT 400 WORDS)

Soluble and particulate fractions from extracts of rat epididymal fat cells were shown to exhibit a number of different phosphodiesterase activities, as determined by substrate specificity and sensitivity to activators and inhibitors. These activities were then further characterized following separation by MonoQ fast protein liquid chromatography (FPLC). A cyclic AMP-specific activity, unaffected by the presence of calcium and calmodulin and inhibited by rolipram, was the major soluble phosphodiesterase. This fraction also contained distinct calcium and calmodulin- and cyclic-GMP-stimulated activities. Over 80% of the phosphodiesterase activity in the particulate fraction could be accounted for by an insulin-activated cyclic AMP and cyclic GMP-hydrolysing enzyme, which was sensitive to inhibition by cyclic GMP, SKF 94120, SKF 95654 and cilostamide, and eluted as a single peak during MonoQ chromatography. At 1 microM cyclic AMP, the phosphodiesterase activity in the soluble fraction was about eight times greater than in the particulate fraction. Specific inhibitors to the particulate phosphodiesterase (cilostamide and SKF 95654) were added to incubations of isolated fat cells, and were able to potentiate sub-maximal concentrations of isoproterenol in the stimulation of lipolysis. These inhibitors were also able to reverse the antilipolytic effect of insulin, demonstrating the importance of the particulate phosphodiesterase in insulin action, despite the fact that its activity represents only a small proportion of the total phosphodiesterase activity in fat cells. Inhibitors of the major soluble phosphodiesterase had no effect on lipolysis.

Selective inhibitors of the cyclic nucleotide phosphodiesterase (PDE) isoenzymes have been studied to assess the potential for such agents in the treatment of asthma. A novel selective PDE V inhibitor, SK&F 96231, reversed the bronchoconstriction induced in anaesthetised guinea pigs by histamine, a thromboxane-mimetic or by ovalbumin challenge. There was no effect of SK&F 96231 on heart rate or blood pressure in conscious dogs. Siguazodan (SK&F 94836, a selective PDE III inhibitor) caused bronchodilation but also had cardiovascular effects in conscious dogs. Studies on the PDE profile of various inflammatory cells have indicated that inhibition of PDE IV would be beneficial in the treatment of the inflammatory aspects of asthma and this is briefly reviewed.

1,4-Bis(3-oxo-2,3-dihydropyridazin-6-yl)benzene and a series of related bis(azinone) compounds were synthesized. These novel compounds were evaluated for inhibition of the low Km, cAMP-selective, cGMP-inhibited phosphodiesterase (PDE III) derived from cat heart and hemodynamic activity in the ganglion- and beta-blocked anesthetized cat. The most potent PDE III inhibitor of the series was 6-[4-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-phenyl]p yridazin- 3(2H)-one (IC50 = 0.07 microM), which also retained the greatest inotrope and vasodilator (inodilator) potency (ED50 for first derivative of left ventricular pressure (dLVP/dt(max)) = 0.02 mumol/kg, ED15 for 15% fall in perfusion pressure = 0.01 mumol/kg). The structure-activity relationships observed within the bis(azinone) series were consistent with those reported for formally analogous 6-(4-substituted-phenyl)pyridazin-3(2H)-one-based PDE III-inhibiting inodilators with less-extended phenyl substituents (see e.g. Sircar et al. J. Med. Chem. 1987, 30, 1955, Moos et al. J. Med. Chem. 1987, 30, 1963). PDE III inhibitory potency is associated with overall planar topology of the phenylpyridazinone moiety and the presence of two critically separated electronegative centers. A methyl group at the 5-position of a dihydropyridazinone ring leads to enhanced potency. However, the generally higher levels of PDE III inhibitory potency shown by compounds in the bis(azinone) series relative to earlier 6-(4-substituted-phenyl)pyridazin-3(2H)-one derivatives appears to derive from a closer to optimal separation of two interacting points in the inhibitor molecule achieved through the more extended bis(azinone) structure. Correlation between the pharmacological and PDE III inhibitory activities of compounds in the bis(azinone) series provides additional evidence for PDE III being an important mediator of inodilator action.

1. The cyclic AMP-dependent protein kinase activity-ratio assay was investigated by comparing histone and a synthetic peptide, malantide [Malencik & Anderson (1983) Anal. Biochem. 132, 32-40], as substrates. 2. In several tissues the activity ratio was higher when assayed with histone as the substrate; this result was obtained in control tissues and also in those incubated with agents known to increase cyclic AMP. The effect of these agents to increase the activity ratio was more clearly demonstrated with malantide. 3. The higher activity ratios observed with histone are due to: (a) measurement of phosphorylation not catalysed by cyclic AMP-dependent protein kinase; (b) activation of cyclic AMP-dependent protein kinase by histone during the assay. 4. When tissues were homogenized in buffers without NACl, lower activity ratios were found, owing to the catalytic subunit being artifactually removed from the supernatant. 5. We conclude that the measured activity ratio more faithfully reflects that in the tissue when NaCl is included in the homogenization buffer and malantide is used in the assay. This was confirmed in experiments where cyclic AMP-dependent protein kinase was added to the tissue before homogenization, and no dissociation of the exogenous enzyme was observed.

1. The effects of siguazodan (SK&F 94836) a selective phosphodiesterase (PDE) inhibitor with inotropic and vasodilator activity, were studied on human platelets. 2. Siguazodan selectively inhibited the major cyclic AMP-hydrolysing PDE in human platelet supernatants. The inhibited enzyme has been variously termed cyclic GMP-inhibited PDE or PDE-III. 3. In platelet-rich plasma (PRP), siguazodan inhibited U46619-induced aggregation more potently than that induced by ADP and collagen. Treatment of the PRP with aspirin had no effect on the potency of siguazodan. 4. In washed platelets, siguazodan increased cyclic AMP levels and reduced cytoplasmic free calcium [( Ca2+]i). ADP decreased the ability of siguazodan to raise cyclic AMP and this may explain its lower potency in inhibiting responses to ADP. 5. Siguazodan has anti-platelet actions over the same concentration range that it is an inotrope and vasodilator.

The roles of cyclic AMP, cyclic AMP-dependent protein kinase and the phosphorylation of specific proteins in the regulation of cardiac contractility are briefly reviewed. Criteria for determining whether changes in cyclic AMP and protein phosphorylation are involved in a physiological response are discussed. Although cyclic AMP-dependent phosphorylation of the voltage-operated Ca2+ channel, phospholamban, troponin-I and C-protein have all been implicated in the response of the heart to inotropic agents which elevate cyclic AMP, none of these phosphorylations satisfy all of the criteria completely. Evidence is presented that there are compartments of cyclic AMP in heart which are coupled to different functional responses.

We studied the psychological effects of a program of intensification of glycemic control, using three different insulin regimens: (1) twice-daily regular and lente insulin; (2) multiple preprandial doses of regular insulin coupled with long-acting ultralente insulin; and (3) continuous subcutaneous insulin infusion (CSII). Ten patients used each of the regimens for periods of 2 mo. Patients monitored blood glucose 4-7 times daily. Using the Hopkins Symptom Checklist, there were significant reductions in depression, interpersonal sensitivity, and anxiety during all three treatment programs. Self-concept scores were more positive following CSII therapy. Positive self-concept ratings were correlated with positive attitudes about diabetes, medical care, persons with diabetes, and current diabetes regimens. After all subjects had experienced CSII, self-concept was positively related to attitudes regarding the insulin pump. Patients reporting more positive attitudes toward their current diabetes regimens had lower glycosylated hemoglobin levels. Thus, there were no adverse psychological effects of blood glucose monitoring, intensification of therapy, or use of infusion pumps by the parameters measured.

Type I insulin-dependent diabetic patients have an increased risk of atherosclerotic vascular disease that may be determined in part by their tendency to develop circulating lipid and lipoprotein abnormalities. The occurrence of such findings in asymptomatic ambulant Type I patients with mild or moderate hyperglycemia might suggest that conventional methods of insulin treatment are as inefficient at normalizing lipid abnormalities as they are in achieving euglycemia. It would then be important to ascertain whether intensive methods of insulin treatment effectively normalized lipid levels. Ten insulin-dependent young adult diabetic patients were studied on a conventional insulin treatment regimen and then at two-monthly intervals for a six-month period during which they were managed by three different intensified insulin treatment regimens. Plasma glucose levels improved substantially (p less than 0.001) after two months of intensified therapy (106 +/- 4 mg/dl) and did not change significantly thereafter for the remaining four months of intensified insulin treatment. Apart from a short-lived decrease in total-, LDL- and HDL-cholesterol after two months of intensified treatment (baseline total triglyceride 116 +/- 13 mg/dl, total cholesterol 174 +/- 16 mg/dl, HDL-cholesterol 46 +/- 3 mg/dl). There were no persistent changes in serum lipids, lipoprotein cholesterol or in levels of their major apoproteins A-I, A-II and B. These findings support the contention that, despite moderate hyperglycemia, conventional insulin treatment may be adequate to maintain normal lipid levels. In such circumstances achievement of euglycemia by intensified insulin therapy leads to little change in circulating lipid and lipoprotein values.

We compared glycemic control achieved on an outpatient basic with three insulin regimens in 10 patients with insulin-dependent diabetes mellitus. The regimens studied included: (1) intensified conventional therapy with twice-daily regular and lente insulin; (2) intensified conventional therapy with long-acting ultralente insulin plus multiple preprandial injections of regular insulin; (3) continuous subcutaneous insulin infusion. Each treatment period was two months long. At the beginning of the study and the close of each study period, patients were hospitalized for a 48-hour evaluation of glycemic control. Each new insulin regimen was begun after discharge, with the dosage adjusted using preplanned algorithms, patient self-monitoring of blood glucose and defined blood glucose targets. Glycemic control markedly improved on all three treatment regimens, to a comparable degree, as assessed by mean plasma glucose level, mean amplitude of glycemic excursions, M value (an index of glycemic lability), urinary glucose excretion and glycosylated hemoglobin level.

Glycemic control in 10 ambulatory patients with insulin-dependent diabetes mellitus was compared on three intensive treatment regimens: (1) twice-daily regular and lente insulin; (2) multiple preprandial injections of regular insulin accompanied by long-acting ultralente insulin; and (3) continuous subcutaneous insulin infusion with a portable infusion pump. All regimens included (1) careful attention to diet, exercise, and insulin; (2) patient self-monitoring of blood glucose; and (3) the use of algorithms for the attainment of improved control. Treatment periods were 2 mo in duration. All parameters of glycemic control evaluated (including inpatient mean plasma glucose, mean amplitude of glycemic excursions, M-value, urinary glucose excretion; glycosylated hemoglobin; and outpatient blood glucose values) showed marked improvement from baseline, yet no difference when the intensive regimens were compared with each other. All elements of the treatment system appeared to be important in achieving improved glycemic control.

The use of portable devices for the subcutaneous infusion of insulin may facilitate the attainment of improved glycemic control in selected patients with insulin-dependent diabetes mellitus. Successful use of a program of continuous subcutaneous insulin infusion requires patient cooperation and motivation, routine monitoring of glycemia, and attention to food intake and activity. This article describes an approach by which patients may optimize glycemic control utilizing a set of algorithms based on patient-determined blood glucose measurements. The algorithms permit programming the insulin infusion device to achieve the desired control.

The effects of near-normal glucose control on nerve conduction results were studied in 10 patients with insulin-dependent diabetes mellitus who underwent a six-month program of intensification of therapy. The most striking electrophysiologic abnormality was the medial plantar sensory nerve conduction response. A sensory nerve action potential could not be elicited in seven of the 10 patients at the baseline evaluation. Over the six-month period of near-normal glucose control, there was a return of sensory nerve action potential in all 10 patients. Medial plantar sensory nerve conduction responses appear to be a sensitive and early electrophysiologic indicator of peripheral nerve dysfunction in patients with diabetes mellitus. Near-normalization of plasma glucose levels by intensification of diabetes management may be accompanied by correction of this early abnormality.

Four cyclic nucleotide phosphodiesterase (PDE) activities were separated from low-speed supernatants of homogenates of human cardiac ventricle by DEAE-Sepharose chromatography, and designated PDE I-PDE IV in order of elution with an increasing salt gradient. PDE I was a Ca2+/calmodulin-stimulated activity, and PDE II was an activity with a high Km for cyclic AMP which was stimulated by low concentrations of cyclic GMP. Human ventricle PDE III had Km values of 0.14 microM (cyclic AMP) and 4 microM (cyclic GMP), and showed simple Michaelis-Menten kinetics with both substrates. PDE IV is a previously unrecognized activity in cardiac muscle, the human enzyme having Km values of 2 microM (cyclic AMP) and 50 microM (cyclic GMP). PDE III and PDE IV were not activated by cyclic nucleotides or calmodulin. Four PDE activities were also isolated from guinea-pig ventricle, and had very similar kinetic properties. By gel filtration, the Mr of PDE III was 60,000, and that of PDE IV 45,000. The drug SK&F 94120 selectively and competitively inhibited PDE III with a Ki value of 0.8 microM (human), showing simple hyperbolic inhibition kinetics. Rolipram (Schering ZK 62711) and Ro 20-1724 (Roche), which have previously been reported to inhibit PDE III-like activities strongly, were shown to be weak inhibitors of human and guinea-pig PDE III enzymes (Ki values greater than 25 microM), but potent inhibitors of PDE IV [Ki values 2.4 microM (Rolipram) and 3.1 microM (Ro 20-1724) with human PDE IV]. The inhibition in all cases demonstrated simple hyperbolic competition. These observations suggest that the previously reported complex inhibition of PDE III-type activities from cardiac muscle was caused by incomplete separation of the PDE III from other enzymes, particularly PDE IV.

Elevation of cyclic AMP concentrations in platelets inhibits agonist-induced responses. Pharmacological interventions which could increase the levels of platelet cyclic AMP include activation of the synthesis of cyclic AMP or inhibition of its breakdown. In this study we have investigated the effects of SK&F 94120 on human platelet phosphodiesterase (PDE) activities separated by ion-exchange chromatography, and studied the effects of this agent on platelet responses caused by the agonists collagen, U44069 and ADP. Four PDE activities were identified from human platelet preparations. The PDE activities found comprised a cyclic GMP selective PDE, a Ca2+/calmodulin stimulated PDE, a cyclic GMP stimulated PDE and a "low Km" PDE activity called PDE III by analogy with activities described in other tissues. SK&F 94120 was found selectively to inhibit the "low Km" PDE III activity with an IC50 of 10.8 microM, which is consistent with the effects of this compound on cardiac ventricle PDE activities. Exposure of human platelets to SK&F 94120 produced concentration dependent increases in cyclic AMP, showing that inhibition of PDE III activity alone can cause an increase in the level of platelet cyclic AMP. SK&F 94120 also caused an inhibition of platelet responses to collagen, U44069 and ADP. However, SK&F 94120 was much less effective as an inhibitor of aggregation induced by ADP (IC50 greater than 100 microM) than by collagen (IC50 = 24.1 microM) or by U44069 (IC50 = 1.7 microM). Isobutylmethylxanthine (IBMX), a non-selective PDE inhibitor, was less effective than SK&F 94120 as an inhibitor of platelet responses for the same measured increase in cyclic AMP levels. M&B 22948 and rolipram, inhibitors of PDE I and PDE IV respectively, had no significant effect on platelet responses. These data suggest that selective inhibition of PDE III is the primary mechanism of action of SK&F 94120 as an inhibitor of agonist-induced platelet responses, and that increased cyclic AMP in the pool controlled by PDE III has important consequences on platelet responses. Moreover, these data suggest that some form of compartmentalization of cyclic AMP and/or PDE activity exists in human platelets.

Ten patients with insulin-dependent diabetes mellitus underwent a program of intensification of therapy that resulted in marked improvement in glycemic control. C-peptide secretion in response to a test meal and to an intravenous glucagon challenge was used to assess pancreatic B-cell function in terms of residual endogenous insulin secretion. Patients, who had diabetes for a mean (+/- SEM) of 8.4 +/- 1.9 yr, had minimal or no C-peptide response at baseline evaluation. C-peptide responses remained unchanged when reassessed after 2, 4, and 6 mo of improved glycemic control.