TetraGrip - a four channel upper limb FES device for people with C5/C6 tetraplegia: device design and clinical outcome.

The TetraGrip is an inertial measurement unit-controlled surface upper limb FES device developed for improving hand functions of people with tetraplegia. The reliability of the control system and the repeatability and reproducibility of the device were assessed by analysing the results obtained when 14 able-bodied volunteers used the device. These volunteers were able to generate the control signals effectively once they had sufficient training. The two tetraplegic volunteers participated in a 12-week long clinical study (exercise, 4 weeks; functional tasks, 8 weeks), where they used the device to perform functional tasks. Outcome measures used were the grasp release test, the grip strength test, and the box and block test. Both tetraplegic volunteers showed improvement in performing the tasks specified in all outcome measures. The TetraGrip performed as intended when the able-bodied volunteers used it, and it improved the hand functions of both volunteers with tetraplegia. However, a larger clinical study is necessary to assess the performance of the device with a wider range of people with tetraplegia such as those with C5 complete/incomplete.

Upper limb functional electrical stimulation devices and their man-machine interfaces.

Functional Electrical Stimulation (FES) is a technique that uses electricity to activate the nerves of a muscle that is paralysed due to hemiplegia, multiple sclerosis, Parkinson's disease or spinal cord injury (SCI). FES has been widely used to restore upper limb functions in people with hemiplegia and C5-C7 tetraplegia and has improved their ability to perform their activities of daily living (ADL). At the time of writing, a detailed literature review of the existing upper limb FES devices and their man-machine interfaces (MMI) showed that only the NESS H200 was commercially available. However, the rigid arm splint doesn't fit everyone and prevents the use of a tenodesis grip. Hence, a robust and versatile upper limb FES device that can be used by a wider group of people is required.

Evaluation of a pilot Pressure Ulcer Prevention Initiative (PUPI) for patients with traumatic spinal cord injury.

OBJECTIVE: The purpose of this study was to determine whether implementation of a Pressure Ulcer Prevention Initiative (PUPI) changed the assessment and treatment of patients with a traumatic spinal cord injury (SCI) in an acute care setting, and improved patient outcomes. METHOD: The success of implementation was evaluated by examining the percentage of patients with completed occupational therapist (OT) skin care assessments and prescriptions for therapeutic support surfaces (TSS; i.e., mattresses) before implementation (historical, cohort 1) and after implementation (experimental, cohort 2). Patient outcomes were evaluated by examining changes in PU incidence, severity, timing and recurrence, as well as PU prevalence and satisfaction with life in the community. RESULTS: Final analysis included 70 patients in cohort 1 and 73 in cohort 2. OT skin care assessment documentation (31% to 60%; p<0.001) and TSS prescriptions (31% to 60%; p=0.02) significantly increased following the implementation. The PU incidence based on patient charts (both nursing and OT assessments) did not increase significantly (26% to 36%; p=0.2). However, documented PU incidence according to OT assessments showed a substantial increase (14% to 33%; p=0.002). No effect of the PUPI was seen on immediate or long-term patient outcomes during the study period. CONCLUSION: PUPI was successful in changing clinical practice in PU prevention but no statistically significant improvements in PU-related patient outcomes were demonstrated. Results from this study identified facilitators and barriers to implementation and highlighted the complexity and difficulty of instituting effective preventative or therapeutic interventions for this population in an acute care setting. This information will assist with refinements of the PUPI and inform similar future initiatives.

Thermography and thermometry in the assessment of diabetic neuropathic foot: a case for furthering the role of thermal techniques.

There are currently 3 established techniques employed routinely to determine the risk of foot ulceration in the patient with diabetes mellitus. These are the assessment of circulation, neuropathy, and foot pressure. These assessments are widely used clinically as well as in the research domain with an aim to prevent the onset of foot ulceration. Routine neuropathic evaluation includes the assessment of sensory loss in the plantar skin of the foot using both the Semmes Weinstein monofilament and the biothesiometer. Thermological measurements of the foot to assess responses to thermal stimuli and cutaneous thermal discrimination threshold are relatively uncommon. Indeed, there remains uncertainty regarding the importance of thermal changes in the development of foot ulcers. Applications of thermography and thermometry in lower extremity wounds, vascular complications, and neuropathic complications have progressed as a result of improved imaging software and transducer technology. However, the uncertainty associated with the specific thermal modality, the costs, and processing times render its adaptation to the clinic. Therefore, wider adoption of thermological measurements has been limited. This article reviews thermal measurement techniques specific to diabetic foot such as electrical contact thermometry, cutaneous thermal discrimination thresholds, infrared thermography, and liquid crystal thermography.

In-shoe measurement of plantar blood flow in diabetic subjects: results of a preliminary clinical evaluation.

The findings of clinical pilot study (n = 9 subjects) using a new laser Doppler sensor for assessing blood flux in plantar skin tissue are described. Cutaneous blood perfusion was recorded under the first metatarsal head (right foot) in standing and walking. The sensor was located in a measurement shoe custom made for each test subject. The test group comprised diabetic patients (type II) with vascular (n = 3) or neuropathic (n = 3) complications and three controls. All subjects were Caucasian males and in the age range considered particularly at risk of diabetic foot problems (mean 61 years, 51-72 years). Following static loading for 2, 3 and 4 min the blood.flux response increased rapidly in the control (mean = 10 s) and neuropathic (mean = 18 s) groups to a well-defined, peak blood flow. For the vascular group. the blood flux response was typically a slower rise (mean = 30 s) to a poorly defined peak blood flow value. Due to movement artifact a reliable signal could only be obtained for the swing phase of gait during which blood flux was observed to increase linearly. This was interpreted as reperfusion of the tissue following unloading. The rates of reperfusion expressed in arbitrary units (of blood flux) per millisecond (au ms(-1)) were 6.1-7.9 au ms(-1) for the control, 4-6.2 au ms- for the vascular and 2.3-4.5 au ms(-1) for the neuropathic groups. The feasibility of assessing the microcirculation of the plantar skin under conditions of static and dynamic loading, with the foot in-shoe, has been demonstrated for the first time. The results suggest that abnormal responses may be obtained from asymptomatic feet of diabetic patients with vascular and/or neuropathic complications. This method of assessment could be of use in predicting the occurrence of ulceration in the diabetic foot.

Two general routes to 1,4-disubstituted-2,3,4,5-tetrahydro- 1H-3-benzazepines.

[structure] Two general routes to 1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepines are described. Both routes utilize an appropriately functionalized phenethylamino alcohol as the penultimate intermediate: the first route makes use of the reductive amination of a benzyl alkyl ketone with alpha-(aminomethyl)benzyl alcohol, while the second route utilizes the addition of a Grignard reagent to the oxazolidine derived from a substitued phenylacetaldehyde and alpha-(methylaminomethyl)benzyl alcohol. In all cases studied, the cis-1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepine was obtained as the major product.

A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat.

The discovery that peroxisome proliferator-activated receptor (PPAR)-gamma was the molecular target of the thiazolidinedione class of antidiabetic agents suggested a key role for PPAR-gamma in the regulation of carbohydrate and lipid metabolism. Through the use of high-throughput biochemical assays, GW1929, a novel N-aryl tyrosine activator of human PPAR-gamma, was identified. Chronic oral administration of GW1929 or troglitazone to Zucker diabetic fatty (ZDF) rats resulted in dose-dependent decreases in daily glucose, free fatty acid, and triglyceride exposure compared with pretreatment values, as well as significant decreases in glycosylated hemoglobin. Whole body insulin sensitivity, as determined by the euglycemic-hyperinsulinemic clamp technique, was significantly increased in treated animals. Comparison of the magnitude of glucose lowering as a function of serum drug concentrations showed that GW1929 was 2 orders of magnitude more potent than troglitazone in vivo. These data were consistent with the relative in vitro potencies of GW1929 and troglitazone. Isolated perfused pancreas studies performed at the end of the study confirmed that pancreata from vehicle-treated rats showed no increase in insulin secretion in response to a step change in glucose from 3 to 10 mmol/l. In contrast, pancreata from animals treated with GW1929 showed a first- and second-phase insulin secretion pattern. Consistent with the functional data from the perfusion experiments, animals treated with the PPAR-gamma agonist had more normal islet architecture with preserved insulin staining compared with vehicle-treated ZDF rats. This is the first demonstration of in vivo efficacy of a novel nonthiazolidinedione identified as a high-affinity ligand for human PPAR-gamma. The increased potency of GW1929 compared with troglitazone both in vitro and in vivo may translate into improved clinical efficacy when used as monotherapy in type 2 diabetic patients. In addition, the significant improvement in daily meal tolerance may impact cardiovascular risk factor management in these patients.

A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.

The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARgamma subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2, 4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPARgamma ligand that was a weak partial agonist of PPARgamma transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents.

We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified as a structurally novel PPARgamma agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chemically labile enaminone moiety in compound 2, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid (9). Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARgamma, affording a series of potent and selective PPARgamma agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(methylpyridin-2-ylamino+ ++)ethoxy ]phenyl¿propionic acid (18), 3-¿4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (20). Compounds 18 and 20 show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addition, these analogues are readily prepared in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARgamma agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety.

We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (2) (PPARgamma pKi = 8.94, PPARgamma pEC50 = 9.47) as a potent and selective PPARgamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARgamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-pyridin-4-yloxazol+ ++- 4-yl)ethoxy]phenyl¿propionic acid (16) (PPARgamma pKi = 8.85, PPARgamma pEC50 = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-¿2-[5-methyl-2-(4-methylpiperazin+ ++- 1-yl)thiazol-4-yl]ethoxy¿phenyl)propionic acid (24) (PPARgamma pKi = 8.66, PPARgamma pEC50 = 8.89) provided two potent and selective PPARgamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARgamma ligands (PPARgamma pKi's 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPARgamma binding, functional activity, selectivity, and aqueous solubility.

N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent.

3-¿4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-¿4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl¿ ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.

Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma.

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent transcription factor that is important in adipocyte differentiation and glucose homeostasis and which depends on interactions with co-activators, including steroid receptor co-activating factor-1 (SRC-1). Here we present the X-ray crystal structure of the human apo-PPAR-gamma ligand-binding domain (LBD), at 2.2 A resolution; this structure reveals a large binding pocket, which may explain the diversity of ligands for PPAR-gamma. We also describe the ternary complex containing the PPAR-gamma LBD, the antidiabetic ligand rosiglitazone (BRL49653), and 88 amino acids of human SRC-1 at 2.3 A resolution. Glutamate and lysine residues that are highly conserved in LBDs of nuclear receptors form a 'charge clamp' that contacts backbone atoms of the LXXLL helices of SRC-1. These results, together with the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-gamma homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators.

Mercury in a commercial preparation of rat amylin.

The biological activity of amylin is reported to vary widely depending on the source and purity of the material. Three commercial samples of rat amylin were compared for structural differences. The samples were nearly identical using most of the available analytical measures--amino acid analysis, HPLC retention, even Edman sequencing data. When the samples were compared by ion spray ionization mass spectrometry, the molecular mass of one sample was 200 daltons higher than anticipated. Careful analysis of the sample, including atomic emission spectrometry, revealed that a mercury atom was associated with the polypeptide. The mercury presumably resulted from a deprotection step in the synthesis, involving the removal of an acetamidomethyl group from cysteine.