The impact of self-reported arthritis and diabetes on response to a home-based physical activity counselling intervention.

OBJECTIVES: Physical activity (PA) has the potential to improve outcomes in both arthritis and diabetes, but these conditions are rarely examined together. Our objective was to explore whether persons with arthritis alone or those with both arthritis and diabetes could improve amounts of PA with a home-based counselling intervention. METHODS: As part of the Veterans LIFE (Learning to Improve Fitness and Function in Elders) Study, veterans aged 70-92 were randomized to usual care or a 12-month PA counselling programme. Arthritis and diabetes were assessed by self-report. Mixed models were used to compare trajectories for minutes of endurance and strength training PA for persons with no arthritis (n = 85), arthritis (n = 178), and arthritis plus diabetes (n = 84). RESULTS: Recipients of PA counselling increased minutes of PA per week independent of disease status (treatment arm by time interaction p < 0.05 for both; endurance training time p = 0.0006 and strength training time p < 0.0001). Although PA was lower at each wave among persons with arthritis, and even more so among persons with arthritis plus diabetes, the presence of these conditions did not significantly influence response to the intervention (arthritis/diabetes group x time interactions p > 0.05 for both outcomes) as each group experienced a nearly twofold or greater increase in PA. CONCLUSIONS: A home-based PA intervention was effective in increasing minutes of weekly moderate intensity endurance and strength training PA in older veterans, even among those with arthritis or arthritis plus diabetes. This programme may serve as a useful model to improve outcomes in older persons with these pervasive diseases.

Is diabetes associated with poorer self-efficacy and motivation for physical activity in older adults with arthritis?

OBJECTIVES: The primary aim was to explore whether arthritis is associated with poorer self-efficacy and motivation for, and participation in, two specific types of physical activity (PA): endurance training (ET) and strength training (ST). A further objective was to determine whether the added burden of diabetes contributes to a further reduction in these PA determinants and types. METHODS: Self-efficacy and motivation for exercise and minutes per week of ET and ST were measured in 347 older veterans enrolled in a home-based PA counselling intervention. Regression analyses were used to compare high versus low self-efficacy and motivation and PA minutes in persons without arthritis, with arthritis alone, and with arthritis plus diabetes. RESULTS: Persons with arthritis alone reported lower self-efficacy for ET and ST than those without arthritis [odds ratio (OR)ET 0.71, 95% confidence interval (CI) 0.39­1.20; ORST 0.69, 95% CI 0.39­1.20]. A further reduction in self-efficacy for these two types of PA was observed for those with both arthritis and diabetes (ORET 0.65, 95% CI 0.44­0.92; ORST 0.64, 95% CI 0.44­0.93; trend p < 0.001). There was no trend towards a reduction in motivation for PA in those with arthritis alone or with arthritis and diabetes. Persons with arthritis exhibited higher motivation for ET than those without arthritis (ORET 1.85, 95% CI 1.12­3.33). There were no significant differences between the three groups in minutes of ET (p = 0.93), but persons with arthritis plus diabetes reported significantly less ST compared to individuals with arthritis only (p = 0.03). CONCLUSIONS: Despite reduced self-efficacy for ET and ST and less ST in older persons with arthritis, motivation for both PA types remains high, even in the presence of diabetes.

Body mass index associations between mother and offspring from birth to age 18: the Fels Longitudinal Study.

BACKGROUND: Parental obesity is a known determinant of childhood obesity. Previous research has shown a strong maternal influence on body mass index (BMI) during infancy and early childhood. OBJECTIVES: The purpose of this research was to investigate the BMI associations between mother and offspring from birth to age 18 years. METHODS: Participants were selected from the Fels Longitudinal Study. The current study sample includes 427 (215 mother/son and 212 mother/daughter) mother/child pairs. These pairs are repeatedly measured at multiple age groups in children, resulting in a total of 6,263 (3,215 mother/son, 3,048 mother/daughter) observations for data analysis. Inclusion criteria were children with measured height and weight for BMI collected at ages 0 to 18 years and their mother with BMI data. Maternal influences of BMI on offspring BMI from birth to early adulthood were analyzed by Spearman correlations and linear regression analyses. RESULTS: Mother/son BMI correlations became statistically significant (p ≤ 0.05) at age 5-6 years and were significant through puberty and into early adulthood at age 18 years. Mother/daughter correlations became significant at age 1.5 years and also continued through adolescence, puberty and early adulthood at age 18 years. Associations persisted after the study sample was grouped into life stages and adjusted for decade of birth and parity. CONCLUSIONS: The mother/daughter relationship was more strongly correlated than the mother/son relationship and also became statistically significant at an earlier age than boys.

A direct demonstration of cortical LTP in humans: a combined TMS/EEG study.

Repetitive transcranial magnetic stimulation (rTMS) is increasingly being used to promote cortical reorganization, under the assumption that it can induce long-term potentiation (LTP) of neural responses. This assumption is supported by several lines of indirect evidence. For example, rTMS of motor cortex can induce a potentiation of muscle motor evoked potentials that outlasts the stimulation by several minutes. In animal models, a direct demonstration of LTP is typically obtained by high-frequency electrical stimulation coupled with local field recordings of population responses. In this study, we exploited a new approach based on combined rTMS/high-density electroencephalography (hd-EEG) to obtain direct, noninvasive evidence for LTP in humans. Cortical responses to single TMS pulses were measured with hd-EEG before and after applying rTMS to motor cortex (5Hz, 1500 pulses). The results demonstrate that, after rTMS, EEG responses at latencies of 15-55ms were significantly potentiated. A topographic analysis revealed that this potentiation was significant at EEG electrodes located bilaterally over premotor cortex. Thus, these findings provide a direct demonstration in humans of LTP induced by rTMS.

Effects of oral temazepam on slow waves during non-rapid eye movement sleep in healthy young adults: A high-density EEG investigation.

Slow waves are characteristic waveforms that occur during non-rapid eye movement (NREM) sleep that play an integral role in sleep quality and brain plasticity. Benzodiazepines are commonly used medications that alter slow waves, however, their effects may depend on the time of night and measure used to characterize slow waves. Prior investigations have utilized minimal scalp derivations to evaluate the effects of benzodiazepines on slow waves, and thus the topography of changes to slow waves induced by benzodiazepines has yet to be fully elucidated. This study used high-density electroencephalography (hdEEG) to evaluate the effects of oral temazepam on slow wave activity, incidence, and morphology during NREM sleep in 18 healthy adults relative to placebo. Temazepam was associated with significant decreases in slow wave activity and incidence, which were most prominent in the latter portions of the sleep period. However, temazepam was also associated with a decrease in the magnitude of high-amplitude slow waves and their slopes in the first NREM sleep episode, which was most prominent in frontal derivations. These findings suggest that benzodiazepines produce changes in slow waves throughout the night that vary depending on cortical topography and measures used to characterize slow waves. Further research that explores the relationships between benzodiazepine-induced changes to slow waves and the functional effects of these waveforms is indicated.

Red blood cell sorbitol as an indicator of polyol pathway activity. Inhibition by sorbinil in insulin-dependent diabetic subjects.

In a double-blind crossover study of 15 diabetic patients, elevated red blood cell (RBC) sorbitol levels were reduced by oral doses of the potent aldose reductase inhibitor, sorbinil (250 mg o.d.), to near-normal ranges. In diabetic rats with severe hyperglycemia, oral sorbinil (5 mg/kg) dramatically reduced (80-90%) sorbitol levels in tissues without affecting blood glucose; the RBC dose-response curve was similar to that in lens and sciatic nerve. In streptozotocin-treated rats with varying degrees of diabetes sorbitol levels in the lens, sciatic nerve, and RBC were elevated in proportion to the degree of hyperglycemia. RBC sorbitol levels in these animals were positively correlated with the levels in lens and sciatic nerve. These results establish that orally administered sorbinil is effective in lowering elevated sorbitol levels, and strongly suggest that the reduction seen in RBC sorbitol levels in human diabetic subjects is likely to reflect comparable effects of the drug in less accessible tissues associated with the long-term complications of diabetes.

Evaluation of Fall Recovery and Gait Adaptation to Medial and Lateral Gait Perturbations.

The aim of this study was to develop an active gait perturbation system and to evaluate its efficacy in evaluating fall recovery and gait adaptation. We hypothesized that a translating perturbation during the single stance phase would alter gait adaptations, in terms of gait parameters and muscle co-contractions, during recovery to maintain dynamic stability for continued walking. A customized miniature treadmill, built on a large force plate and embedded perpendicular to the walkway, was used to translate the loaded stance foot medially and laterally to interrupt swing foot trajectory. The perturbation was activated when the stepping foot was placed entirely on the belt to ensure the foot would remain on the belt when translated. The translating floor surface was applied to 10 young, healthy adult subjects (5 males, 5 females; aged <35y) during normal walking at their preferred speed. Step length, step width, step duration, and muscle co-contraction at the ankle of the stance limb was examined before, during, and after both the medial and lateral translations. Shorter step length, wider step width, faster step duration, and higher muscle co-contraction at the ankle joint were observed strategies for fall recovery and regaining body stability.

Effects of oral temazepam on sleep spindles during non-rapid eye movement sleep: A high-density EEG investigation.

Benzodiazepines are commonly used medications that alter sleep spindles during non-rapid eye movement (NREM) sleep, however the topographic changes to these functionally significant waveforms have yet to be fully elucidated. This study utilized high-density electroencephalography (hdEEG) to investigate topographic changes in sleep spindles and spindle-range activity caused by temazepam during NREM sleep in 18 healthy adults. After an accommodation night, sleep for all participants was recorded on two separate nights after taking either placebo or oral temazepam 15 mg. Sleep was monitored using 256-channel hdEEG. Spectral analysis and spindle waveform detection of sleep EEG data were performed for each participant night. Global and topographic data were subsequently compared between temazepam and placebo conditions. Temazepam was associated with significant increases in spectral power from 10.33 to 13.83 Hz. Within this frequency band, temazepam broadly increased sleep spindle duration, and topographically increased spindle amplitude and density in frontal and central-posterior regions, respectively. Higher frequency sleep spindles demonstrated increased spindle amplitude and a paradoxical decrease in spindle density in frontal and centroparietal regions. Further analysis demonstrated temazepam both slowed the average frequency of spindle waveforms and increased the relative proportion of spindles at peak frequencies in frontal and centroparietal regions. These findings suggest that benzodiazepines have diverse effects on sleep spindles that vary by frequency and cortical topography. Further research that explores the relationships between topographic and frequency-dependent changes in pharmacologically-induced sleep spindles and the functional effects of these waveforms is indicated.

Human myeloid zinc finger gene MZF produces multiple transcripts and encodes a SCAN box protein.

The myeloid zinc finger gene 1 (MZF1) encodes a C(2)H(2) zinc finger transcription factor that regulates granulopoiesis and may have a regulatory role in cellular proliferation and oncogenesis. The MZF1 gene has been previously reported to be 3kb and without introns. However, at least three transcripts of approximately 3, 7.5, and 9kb are detected by MZF1-specific probes in northern blot analysis and the identity of the transcripts has not been addressed. We screened a K562 cDNA library and identified novel transcripts, MZF1B and MZF1C. The 2.9kb MZF1B cDNA encodes a putative 734 aa protein and MZF1C maintains an identical open reading frame with 320 nucleotides deleted in the 5'-untranslated region. The MZF1B/1C protein contains all but the first eight amino acids of MZF1. Thus, MZF protein isoforms share 100 aa, as well as the bipartite 13 zinc finger DNA binding domain. In addition, MZF1B/1C encodes a unique 257 aa MZF1B/C amino terminus containing a SCAN box, or leucine-rich domain, which has recently been demonstrated to facilitate protein interactions. Sequence analysis reveals that the MZF gene contains six exons and spans 11kb and may be the most telomeric gene on chromosome 19q13. Exons 1-6 produce MZF1B/C cDNA, whereas MZF1 cDNA initiates within intron 5 and continues through exon 6. The 7.5 and 9kb transcripts are incompletely processed and contain intron sequences. These studies are the first description of the complete human MZF gene and of the composition of the multiple transcripts that are detected by northern blot analysis.

Determinants of retinopathy progression in type 1 diabetes mellitus.

PURPOSE: To determine the risk factors for retinopathy progression in type 1 (insulin-dependent) diabetes mellitus in a prospective cohort study. SUBJECTS AND METHODS: Subjects were 485 participants in the Sorbinil Retinopathy Trial, a randomized trial of aldose reductase inhibition among patients aged 18 to 56 years with type 1 diabetes mellitus (duration of 1 to 15 years) and no or only mild retinopathy. Retinopathy progression, assessed by seven-field stereoscopic fundus photography, was defined as worsening by two or more levels on a standardized grading scale at the end of follow-up (median, 41 months). RESULTS: The relative risks for retinopathy progression according to successively greater quintiles of total glycosylated hemoglobin level at baseline, after adjusting for age, diabetes duration, sorbinil assignment, and other variables, were 1.0, 2.0, 1.6, 3.7, and 4.4 (P trend <0.0001). Risk increased with greater baseline diastolic blood pressure: 1.0 for <70 mm Hg, 1.2 for 70 to 79 mm Hg, and 1.8 for > or =80 mm Hg (P for trend = 0.04). Diastolic blood pressure was a significant risk factor for progression in participants with mild baseline retinopathy (P for trend <0.02) but not in those without retinopathy at entry. Systolic blood pressure, by comparison, was not associated with progression. Baseline total cholesterol level was a marginally significant predictor of retinopathy progression when examined as a categorical variable (relative risks for increasing quartiles; 1.0, 1.6, 1.8, 1.9; P for trend = 0.03) but not when it was examined as a continuous variable or when hypercholesterolemic patients were compared with those with normal levels. Furthermore, when cholesterol levels were updated in subsequent visits, it was not a significant predictor of progression, and low density lipoprotein (LDL) cholesterol levels did not predict progression no matter how analyzed. Smoking was not associated with progression of retinopathy. CONCLUSIONS: Levels of hyperglycemia and diastolic blood pressure predicted progression of retinopathy in type 1 diabetes mellitus. We found only a suggestion of an association between total cholesterol level (but not of LDL cholesterol level) and progression of retinopathy; resolution of this issue will require additional studies with larger sample sizes and longer follow-up.

Spiro oxazolidinedione aldose reductase inhibitors.

Spiro oxazolidinediones (2) derived from five- and six-membered ring aralkyl ketones are potent aldose reductase inhibitors in vitro and in vivo. Their novel and general synthesis has been devised with alpha-hydroxyimidates (5) and 4-alkoxy-2-oxo-3-oxazolines (6) as key intermediates, since traditional synthetic routes through alpha-hydroxy amides (8) usually led to alpha, beta-unsaturated amides (9). Resolution with cinchonidine afforded optically active spiro oxazolidinediones. Optimum biological activity resided in (4S)-6-chlorospiro [4H-2,3-dihydrobenzopyran-4,5'-oxazolidine]-2',4'-dione (21) and its 6,8-dichloro congener (23).

Spiro hydantoin aldose reductase inhibitors.

Sorbitol formation from glucose, catalyzed by the enzyme aldose reductase, is believed to play a role in the development of certain chronic complications of diabetes mellitus. Spiro hydantoins derived from five- and six-membered ketones fused to an aromatic ring or ring system inhibit aldose reductase isolated from calf lens. In vivo these compounds are potent inhibitors of sorbitol formation in sciatic nerves of streptozotocinized rats. Optimum in vivo activity is reached in spiro hydantoins derived from 6-halogenated 2,3-dihydro-4H-1-benzopyran-4-ones (4-chromanones). In 2,4-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5 '-dione, the activity resides exclusively in the 4S isomer, compound 115 (CP-45,634, USAN: sorbinil). This compound is currently being used to test, in humans, the value of aldose reductase inhibitors in the therapy of diabetic complications.

Synthesis, absolute configuration, and conformation of the aldose reductase inhibitor sorbinil.

The aldose reductase inhibitor 2,3-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5 '-dione was resolved into its enantiomers. Sorbinil, the S isomer, was found to be a better inhibitor of the enzyme in vitro and in vivo than the corresponding R isomer. X-ray data on sorbinil, which were used to determine its absolute configuration, are presented. NMR studies of sorbinil in solution indicate the existence of two conformers with a low energy barrier for interconversion.

Aldose reductase inhibitors in clinical practice. Preliminary studies on diabetic neuropathy and retinopathy.

Extensive animal data now exist to indicate potential benefit of sorbinil in the treatment of the major complications of diabetes mellitus. A clinical programme has been constructed to explore this therapeutic potential and encouraging evidence of drug effect has already been observed in patients with neuropathy and retinopathy. Two small preliminary studies in patients with painful neuropathy have shown that clinically significant reduction of pain was more frequently achieved with sorbinil than with placebo. A 6-month study of patients with retinopathy, using vitreous fluorophotometry as the criterion of retinal damage, showed significant (p = 0.03) benefit for the sorbinil group compared with the placebo group. Drug evaluation in these areas is complex and difficult but it is anticipated that the accumulation of additional data will further substantiate the efficacy suggested by these early findings. The only clinically important adverse effect of sorbinil is the hypersensitivity reaction. This usually occurs during the initial weeks of therapy and is similar to that seen with phenytoin. The long term use of sorbinil is without significant adverse effects.

Sorbinil: a member of the novel class of spirohydantoin aldose reductase inhibitors.

A decade ago, we discovered that spirohydantoins are a novel class of aldose reductase inhibitors characterized by very potent in vivo activity. This important discovery resulted from a systematic screening effort for in vitro activity against aldose reductase isolated from bovine lens and subsequent testing of active compounds for in vivo activity in a streptozotocin-diabetic rat model, measuring inhibition of sorbitol formation in sciatic nerve. In this in vivo model, spirohydantoins were clearly more potent than all known carboxylic acid-type aldose reductase inhibitors. Structure-activity studies in the spirohydantoin class demonstrated that potent in vitro and in vivo activity were obtained when the spiro junction was adjacent to an aromatic ring and when this junction was part of a 5- or 6-membered ring system fused to the aromatic ring. Excellent in vitro and in vivo activity was achieved in 6-halogenated chromane derivatives with the spirohydantoin group attached in the 4-position. In this series, biologic activity is highly stereospecific and associated with the S configuration. Sorbinil, the S isomer of the 6-fluoro derivative in this series, is one such example: it is 30 times more potent than its R isomer in vitro (IC50 0.15 v 4.4 mumol/L) and 100 times more potent in vivo (ED50 0.25 mg/kg po v 25 mg/kg po).

CP-45,634: a novel aldose reductase inhibitor that inhibits polyol pathway activity in diabetic and galactosemic rats.

In some tissues containing aldose reductase, increased flux through the polyol pathway has been implicated as being causative in diabetic complications (e.g., cataracts, peripheral neuropathy). We have found CP-45,634 (d-6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione) to be a highly potent, structurally novel, uncompetitive inhibitor of calf lens aldose reductase (IC50 approximately 5 X 10(-7)M). In a system in which sorbitol accumulation in isolated rat sciatic nerves was monitored in the presence of high (50 mM) glucose concentrations, CP-45,634 produced inhibition of polyol accumulation at levels as low as 1 X 10(-6)M. To determine if in vitro activity would translate to in vivo models, sorbitol accumulation in rat sciatic nerves was measured 27 hr after induction of diabetes with streptozotocin. Orally administered CP-45,634 was effective at dose levels as low as 0.25 mg/kg, t.i.d., and at 0.75 mg/kg produced an 85% inhibition of sorbitol accumulation. Two weeks after induction of diabetes by streptozotocin, sorbitol levels in rat lens and the sciatic nerve rose to 21,203 nmole/gm and 1,161 nmole/gm, respectively. Subsequent oral administration of CP-45,634 (2.5 mg/kg, b.i.d.) for 1 wk reduced these levels by 92% in nerves and 90% in lenses. In galactosemic rats, CP-45,634 inhibited the rise in lens galactitol and effectively delayed cataract formation at oral doses as low as 5 mg/kg/day. These high levels of in vivo activity suggest that CP-45,634 has potential for assessing the role of the polyol pathway in diabetic complications.

Applicability of red blood cell sorbitol measurements to monitor the clinical activity of sorbinil.

Increased flux of glucose through the polyol pathway with resultant resultant accumulation of tissue sorbitol is implicated in the pathogenesis of the chronic complications of diabetes. Sorbinil is a potent inhibitor of aldose reductase (the first enzyme in the polyol pathway) and has been shown to normalize sorbitol levels in relevant tissues (eg, nerve, kidney, lens) of experimentally-induced diabetic animals. The purpose of this study was to identify a relatively noninvasive method of monitoring the intrinsic (or biochemical) efficacy of sorbinil in diabetic man. Specifically, the objective was to identify a readily accessible tissue that would be reflective of polyol pathway activity and the activity of sorbinil in clinically relevant but less accessible tissues. Based on several previous studies, which demonstrated that sorbitol accumulation in human red blood cells (RBCs) was a function of ambient glucose concentrations, either in vitro or in vivo, our investigations were conducted to determine if RBC sorbitol accumulation would correlate with sorbitol accumulation in lens and nerve tissue of diabetic rats; the effect of sorbinil in reducing sorbitol levels in lens and nerve tissue of diabetic rats would be reflected by changes in RBC sorbitol; and sorbinil would reduce RBC sorbitol in diabetic man.

Clinical experience with sorbinil--an aldose reductase inhibitor.

A considerable volume of animal pharmacologic data support the view that increased flux through the polyol pathway provides a unifying hypothesis for the major complications of diabetes. An extensive clinical program has been established to verify the extrapolation of the animal pharmacologic findings to man. Clinical data accumulated to date confirm the biochemical and electrophysiologic effects, and encouraging evidence of a drug effect in diabetic neuropathy and retinopathy has already been observed. In the large, controlled safety data base already available, the long-term clinical use of sorbinil is devoid of significant adverse effects in terms of both subjective side effects and laboratory parameters. The only clinically important adverse reaction reported to date has been a hypersensitivity reaction in the early weeks of therapy, which is similar to that seen with other hydantoins.

Pharmacokinetics of the aldose reductase inhibitor, zopolrestat, in humans.

The pharmacokinetics of zopolrestat, an aldose reductase inhibitor that may be useful for the treatment of complications of diabetes, have been investigated using oral doses ranging from 50 to 1200 mg administered to healthy male volunteers. In a single-dose study, Cmax, AUC(0-48), and urinary elimination of zopolrestat increased linearly with increasing dose. The amount of zopolrestat excreted unchanged in the urine within 48 hours ranged from 34 to 45% of the administered dose. Renal clearance ranged from 2.6 to 5.6 mL/min, and appeared to decrease as the dose was increased. In a 2-week multiple dose study, the mean steady-state minimum and maximum plasma concentrations, Cmin and Cmax, were 91.5 and 196 micrograms/mL for subjects administered 800 mg/day, and 131 and 281 micrograms/mL for subjects administered 1200 mg/day. Steady-state AUC(0-24) was also dose proportional. The mean steady state half life of about 30.3 hours was consistent with the observed 2.2-fold accumulation in plasma. Apparent oral clearance (Clpo) was 5.2 mL/min, and apparent volume of distribution (Vdss/F) was 12 L. Mean renal clearance was 2.2 mL/min, and approximately 45% of the administered dose was excreted into the urine at steady state. There was no effect of food consumption during dosing on the extent of absorption of zopolrestat. In in vitro studies, extensive, concentration-dependent binding of zopolrestat to plasma proteins was observed. These data indicate that once-daily dosing of zopolrestat will provide suitable exposure in the treatment of diabetic complications.

Imagery paradigms: how vulnerable are they to experimenters' expectations?

The effects of experimenters' expectations on subjects' responses in imagery paradigms were investigated by leading some experimenters to believe that performance based on the use of imagery would be superior to performance based on perception. Other experimenters were led to expect perceptual superiority. Three paradigms are tested. Experiment 1 considered imaginal and perceptual acuity as functions of the size and relative brightness of the stimulus patterns; Experiment 2 compared imaginal and perceptual scanning of maps; and Experiments 3 and 4 studied the identification of rotated hands after imaginal or perceptual priming. In all the experiments, subjects' performances varied with the experimenters' beliefs, suggesting that these paradigms are sensitive to subtle influences from experimenters' tacit, unintentional cues. Experiment 4 probed the ability of observers to identify both tacit cues and the experimenters' expectations. The observers accurately assigned the experimenters' beliefs but were unable to systematically detect distinguishing and differential characteristics of the experimenters' presentations of the instructions. Analysis of taped transcriptions yielded some differences in temporal phrasing. Implications of these results are discussed.