New look at the metabolism of nonsteroidal anti-inflammatory drugs: influence on human serum albumin antioxidant activity.

Body's homeostasis is dependent on many factors, such as maintaining balance between free radicals formation and degradation. Human serum albumin (HSA) also plays an important role in homeostasis. The aim of this study was thermodynamic analysis of the interaction between ketoprofen (KET), naproxen (NPX), diclofenac (DIC) and HSA, as well as the effect of drug-albumin binding on HSA antioxidant activity using calorimetric and spectrophotometric techniques. Based on the calorimetric analysis it has been shown that accompanied by hydrophobic interaction drugs-albumin binding is an exoenergetic reaction. All analyzed drugs and HSA showed the ability to react with free radicals such as a radical cation, formed as a result of the reaction between 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) and potassium persulfate (K2S2O8). Using ABTS assay a synergistic effect of ketoprofen (KET) and naproxen (NPX) on HSA antioxidant activity was observed while the effect of diclofenac (DIC) binding with albumin was probably additive. Because some medications including KET, NPX and DIC belong to over the counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs), it is necessary to understand their influence on HSA antioxidant activity.Communicated by Ramaswamy H. Sarma.

Landing limb posture in volleyball athletes with patellar tendinopathy: a pilot study.

The aims of this pilot study were to investigate how a novel sagittal plane kinematic measurement - the lower extremity contact angle (LECA) - relates to the landing dynamics of elite male volleyball athletes with and without patellar tendinopathy. The LECA was defined as the angle between the ground and the line connecting the center of pressure to the L5S1 marker. 18 athletes (9 with patellar tendinopathy and 9 with asymptomatic tendons) completed simulated spike jumps while instrumented for kinetic and kinematic analysis using a force platform and 3D motion analysis system. The patellar tendinopathic group demonstrated a significantly more acute LECA compared to the asymptomatic group (65.3°±2.2° vs. 69.1°±4.5°) and was the only kinematic or kinetic variable measured to discriminate between the 2 groups. The LECA further demonstrated less variability between trials than sagittal plane hip, knee, and ankle kinematics. Additionally, the LECA's - and not individual joints' - high correlation with the braking impulse ensures its predictive value for landing dynamics (r=- 0.890). The LECA has the potential to be a valuable tool to help assess jumping athletes in both injury prevention screening and as a variable that, if modified, could help alter the maladaptive behavior observed in symptomatic athletes.

GABA system as a target for new drugs.

4-Aminobutyric acid is an inhibitory neurotransmitter involved in the control of neuronal activity in the mammalian central nervous system. There is considerable direct and indirect evidence that impaired activity of GABAmediated inhibitory synapses may be an important causative factor in experimental and clinical seizure disorders. This review is focused on the recent development of compounds which can influence GABA neurotransmission by affecting the GABA receptors, the plasma-membrane GABA transporters (GATs) and catabolic enzyme GABA-transaminase (GABAT). These compounds have been primarily investigated in relation to epilepsy, but it has also been found that a decrease in GABA neurotransmission appears to be involved in the aetiology of several neurological disorders such as insomnia, spasticity, neuropathic pain, anxiety and other mental disorders.

Patellar tendon morphology in volleyball athletes with and without patellar tendinopathy.

Appropriate management of patellar tendinopathy requires distinguishing between inflammatory and degenerative conditions, often difficult because tendon thickening can be a normal or pathological adaptation, and micromorphology is not observable on clinical imaging. The purpose of this study was to quantitatively examine patellar tendon micro- and macromorphology in volleyball athletes and relate those findings to reported symptoms. Longitudinal ultrasound images of proximal and distal patellar tendons were acquired from 84 male elite volleyball athletes (44 symptomatic, 40 asymptomatic) and 10 asymptomatic nonathlete controls. Micromorphology was determined using two-dimensional Fast Fourier Transform analysis providing a discriminating peak spatial frequency parameter (PSF). Macromorphology (patellar tendon thickness) was measured using Image J software. All athletes regardless of symptoms had thicker proximal tendons compared to nonathletes, suggesting a normal adaptation to training loads. However, symptomatic athletes demonstrated lower PSF than asymptomatic athletes and nonathletes at the proximal tendon, suggesting greater collagen disorganization, and tendon degeneration rather than inflammation. Only symptomatic athletes had thicker distal tendons than nonathletes, but there was no difference in PSF distally. Diagnostic ultrasound enhances the understanding of the micromorphology of patellar tendons, supporting the rationale for management that remodels the degenerated tendon instead of treating inflammation.

Behavior of poly(glycerol sebacate) plugs in chronic tympanic membrane perforations.

The tympanic membrane (TM), separating the external and middle ear, consists of fibrous connective tissue sandwiched between epithelial layers. To treat chronic ear infections, tympanostomy drainage tubes are placed in surgically created holes in TMs which can become chronic perforations upon extrusion. Perforations are repaired using a variety of techniques, but are limited by morbidity, unsatisfactory closure rates, or minimal regeneration of the connective tissue. A more effective, minimally-invasive therapy is necessary to enhance the perforation closure rate. Current research utilizing decellularized or alignate materials moderately enhance closure but the native TM architecture is not restored. Poly(glycerol sebacate) (PGS) is a biocompatible elastomer which supports cell migration and enzymatically degrades in contact with vascularized tissue. PGS spool-shaped plugs were manufactured using a novel process. Using minimally invasive procedures, these elastomeric plugs were inserted into chronic chinchilla TM perforations. As previously reported, effective perforation closure occurred as both flange surfaces were covered by confluent cell layers; >90% of perforations were closed at 6-week postimplantation. This unique in vivo environment has little vascularized tissue. Consequently, PGS degradation was minimal over 16-week implantation, hindering regeneration of the TM fibrous connective tissue. PGS degradation must be enhanced to promote complete TM regeneration.

Tendinopathy discrimination by use of spatial frequency parameters in ultrasound B-mode images.

The structural characteristics of a healthy tendon are related to the anisotropic speckle patterns observed in ultrasonic images. This speckle orientation is disrupted upon damage to the tendon structure as observed in patients with tendinopathy. Quantification of the structural appearance of tendon shows promise in creating a tool for diagnosing, prognosing, or measuring changes in tendon organization over time. The current work describes a first step taken towards this goal-classification of Achilles tendon images into tendinopathy and control categories. Eight spatial frequency parameters were extracted from regions of interest on tendon images, filtered and classified using linear discriminant analysis. Resulting algorithms had better than 80% accuracy in categorizing tendon image kernels as tendinopathy or control. Tendon images categorized wrongly provided for an interesting clinical association between incorrect classification of tendinopathy kernels as control and the symptom and clinical time history based inclusion criteria. To assess intersession reliability of image acquisition, the first 10 subjects were imaged twice during separate sessions. Test-retest of repeated measures was excellent (tau = 0.996, ICC = (2, 1) = 0.73 with one outlier) indicating a general consistency in imaging techniques.

Influence of the absolute configuration on pharmacological activity of antihypertensive and antiarrhythmic drugs.

Chirality is a fundamental property of biological systems and reflects the underlying asymmetry of matter. Interactions of drugs with receptors, enzymes or binding sites have long been known to be stereoselective, and it is increasingly recognized that both pharmacodynamic and pharmacokinetic events contribute to the overall clinically observed stereoselectivity. The pharmacological activity may reside only in one enantiomer, while the second one may be inactive or have desirable or undesirable activity. Two isomers may be nearly identical both in qualitative and quantitative aspects of pharmacological activity. The activity of particular enantiomers may differ only at the quantitative level. It is also possible that a particular enantiomer displays qualitatively different mode of action than the second one. This review describes the influence of the absolute configuration on pharmacological activity of the selected currently used or being under investigation drugs acting on cardiovascular system, especially as the antihypertensive and antiarrhythmic agents.

Position paper: gastric lavage.

Gastric lavage should not be employed routinely, if ever, in the management of poisoned patients. In experimental studies, the amount of marker removed by gastric lavage was highly variable and diminished with time. The results of clinical outcome studies in overdose patients are weighed heavily on the side of showing a lack of beneficial effect. Serious risks of the procedure include hypoxia, dysrhythmias, laryngospasm, perforation of the GI tract or pharynx, fluid and electrolyte abnormalities, and aspiration pneumonitis. Contraindications include loss of protective airway reflexes (unless the patient is first intubated tracheally), ingestion of a strong acid or alkali, ingestion of a hydrocarbon with a high aspiration potential, or risk of GI hemorrhage due to an underlying medical or surgical condition. A review of the 1997 Gastric Lavage Position Statement revealed no new evidence that would require a revision of the conclusions of the Statement.

The effect of level of spinal cord injury on shoulder joint kinetics during manual wheelchair propulsion.

OBJECTIVE: The effects of spinal cord injury level on shoulder kinetics during manual wheelchair propulsion were studied. DESIGN: Single session data collection in a laboratory environment. METHODS: Male subjects were divided into four groups: low level paraplegia (n=17), high level paraplegia (n=19), C7 tetraplegia (C7, n=16) and C6 tetraplegia (C6, n=17). Measurements were recorded using a six-camera VICON motion analysis system, a strain gauge instrumented wheel, and wheelchair ergometer. Shoulder joint forces and moments were calculated using the inverse dynamics approach. RESULTS: Mean self-selected propulsion velocity was higher in the paraplegic (low paraplegia=90.7 m/min; high paraplegia=83.4 m/min) than tetraplegic (C7=66.5 m/min; C6=47.0 m/min) groups. After covarying for velocity, no significant differences in shoulder joint moments were identified. However, superior push force in subjects with tetraplegia (C7=21.4 N; C6=9.3 N) was significantly higher than in those with high paraplegia (7.3 N), after covarying velocity. CONCLUSIONS: The superior push force in the tetraplegic groups coupled with weakness of thoraco-humeral depressors increases susceptibility of the subacromial structures to compression. RELEVANCE: Increased vertical force at the shoulder joint, coupled with reduced shoulder depressor strength, may contribute to shoulder problems in subjects with tetraplegia. Wheelchair design modifications, combined with strength and endurance retention, should be considered to prevent shoulder pain development.

Peptide loading of nascent MHC class I molecules.

A critical molecular interaction during assembly of the major histocompatibility complex (MHC) class I molecules takes place between the heavy chain and the transporter-associated with antigen-processing (TAP) complex. The recent mapping of regions of the heavy chain involved in the binding to TAP suggests a complex molecular interaction essential for the cell surface expression of the MHC class I. The advances made in understanding the TAP-MHC class I interaction are reviewed and discussed here.

The effects of eccentric velocity on activation of elbow flexors: evaluation by magnetic resonance imaging.

PURPOSE: To compare magnetic resonance imaging (MRI) signal intensity changes in the primary elbow flexors during two isotonic exercise protocols varying in eccentric velocity and the ratio of eccentric to concentric activity. METHODS: Twelve men performed two exercise protocols. The right and left arms were randomly assigned to one of two protocols that had the same workload (60% 1RM) and same total time of exercise (144 s) but differed in the velocity and ratio of eccentric to concentric activity (1:1 and 5:1 for the fast and slow protocols, respectively). MRI signal intensity changes were quantified pre- and post-exercises using an inversion recovery sequence with a 1.5T MRI system (TR = 2500 ms, TE = 90 ms, TI = 140 ms). Percent change in MRI signal intensity, rate of perceived exertion (RPE), and delayed onset muscle soreness (DOMS) were recorded and analyzed. RESULTS: The biceps brachii was found to be preferentially recruited during the fast protocol compared with the brachialis, whereas the brachialis was found to be preferentially recruited during the slow protocol (P < 0.05). The fast exercise protocol was perceived as being more strenuous (RPE = 8.3 +/- 2.1) than the slow (RPE = 5.4 +/- 1.5, P < 0.05) and produced DOMS in 58% of the tested subjects. CONCLUSIONS: These results suggest that agonists respond to various loading conditions nonhomogeneously. These findings may have implications with respect to exercise prescriptions for specific muscles.

Fomepizole for the treatment of methanol poisoning.

BACKGROUND: Methanol poisoning may result in metabolic acidosis, blindness, and death. The inhibition of alcohol dehydrogenase is fundamental to the treatment of methanol poisoning. We performed a multicenter study to evaluate fomepizole, an inhibitor of alcohol dehydrogenase, in the treatment of patients with methanol poisoning. METHODS: We administered intravenous fomepizole to 11 consecutive patients who presented with methanol poisoning at a participating center. Serial clinical and laboratory studies, including measurements of plasma formic acid and fomepizole, were performed. The outcomes measured were the preservation of visual acuity, the resolution of metabolic acidosis, the inhibition of formic acid production, the achievment of therapeutic plasma concentrations of fomepizole with the dosing regimen, residual illness or disability, and death. RESULTS: Plasma formic acid concentrations were detectable in eight patients, and these concentrations were closely correlated with the initial arterial pH values (r=0.92, P<0.001). In response to fomepizole, plasma formic acid concentrations fell and metabolic abnormalities resolved in all patients. Nine patients survived. Seven patients initially had visual abnormalities, but at the end of the trial no surviving patient had any detectable visual deficits related to methanol poisoning. Fomepizole had few adverse effects. The two patients who died had anoxic brain injury that was present at the time of enrollment. During treatment, methanol had an elimination half-life of 54 hours. CONCLUSIONS: Fomepizole appears to be safe and effective in the treatment of methanol poisoning.

Management of foot pain associated with accessory bones of the foot: two clinical case reports.

STUDY DESIGN: Case study. OBJECTIVES: To discuss the differential diagnosis, the nonsurgical and postoperative management of common accessory bones of the foot. BACKGROUND: Accessory bones of the foot that are formed during abnormal ossification are commonly found in asymptomatic feet. Two of the most common accessory bones are the accessory navicular and the os peroneum. Their painful presence must be considered in the differential diagnosis of any acute or chronic foot pain. The optimal treatment for the conservative and postoperative management of painful os peroneum and accessory navicular bones remains undefined. METHODS AND MEASURES: Therapeutic management of the fractured os peroneum included bracing, taping, and foot orthotics to allow healing of involved tissues, and stretching. The focus of the postoperative management of the accessory navicular was joint mobilization and progressive strengthening. Dependent variables included level of pain with provocation and alleviation tests of joint and soft tissue; girth and sensory tests of the foot and ankle; goniometric measures of foot and ankle; strength of ankle and hip muscles; functional tests; and patient's self-reported pain status. RESULTS: The patient with the fractured os peroneum was treated in 13 visits for 10 weeks. At discharge from physical therapy, the patient had the following outcomes relative to the noninvolved side: 100% return of normal sensation tested by light touch and vibration; pain decreased from 6/10 to 1/10; 100% reduction of swelling with ankle girth to normal; 100% range of motion of ankle and subtalar joints. Strength in plantar flexion and eversion remained 20% impaired (80% return to normal) secondary to pain. Upon discharge, he still reported mild pain when walking but was able to return to previous leisure activities. The second patient with the accessory navicular was treated in 18 visits over 9 weeks. Relative to the uninvolved side, she was discharged with the following: 70% return of range of motion in the foot and ankle, 100% of strength in hip and ankle, and 100% return of balance. She could squat and jump without pain and she returned to full premorbid activity level. CONCLUSIONS: Rehabilitative management of both cases addressed specific impairments and was successful in improving the patients' activity limitation. Clinicians should be aware that these accessory bones are possible sources of disability, secondary to foot pain.

Effect of 10%, 30%, and 60% body weight traction on the straight leg raise test of symptomatic patients with low back pain.

STUDY DESIGN: Single group test-retest repeated measures. OBJECTIVES: To determine the effects of lumbar traction with 3 different amounts of force (10%, 30% and 60% body weight) on pain-free mobility of the lower extremity as measured by the straight leg raise (SLR) test. BACKGROUND: There are several recommendations on how lumbar traction should be performed, but the duration, frequency, force, and type of technique to be applied differ among the sources. METHODS AND MEASURES: Ten subjects with subjective complaints of low back pain or radicular symptoms with a positive unilateral SLR test below 45 degrees participated in this study. The pain-free mobility of the lower extremity in the SLR test position was measured prior to and immediately following 5 minutes of static traction in the supine position. Random assignment in the order of the amount of applied traction was implemented. RESULTS: The straight leg raise measurements were found to be significantly greater immediately following 30% and 60% of body weight traction as compared to pretraction and 10% of body weight traction. The mean (SD) SLR measurements were pretraction (24.1 degrees +/- 13.0), 10% of body weight traction (27.4 degrees +/- 14.5), 30% of body weight traction (34.0 degrees +/- 14.3), 60% of body weight traction (36.5 degrees +/- 15.8). CONCLUSIONS: The results of this study indicate that traction in this group of patients improved the mobility of the lower extremity during the SLR test. Both 30% and 60% of body weight tractions were shown to be effective for increasing motion beyond pretraction levels.

Thoracic spine dysfunction in upper extremity complex regional pain syndrome type I.

STUDY DESIGN: Case study. OBJECTIVE: To demonstrate the importance of assessment and treatment of the thoracic spine in the management of a patient with signs and symptoms of upper extremity Complex Regional Pain Syndrome Type I (CRPS-I). BACKGROUND: The patient was a 38-year-old woman who suffered a traumatic injury to her left hand. Five months after injury, she presented with severe pain, immobility of the left arm, and associated dystrophic changes. She was unable to work and needed help in some activities of daily living. METHODS AND MEASURES: The patient was treated for 3 months in 36 visits. Initial treatment consisted of cutaneous desensitization, edema management, and gentle therapeutic exercises. However, further examination indicated hypomobility and hypersensitivity of the upper thoracic spine. Joint manipulation of the T3 and T4 segments was implemented. The patient's status was monitored and range of motion, strength, temperature, and skin moisture were measured. RESULTS: Immediately after the vertebral manipulation, there was a significant increase in the left hand's skin temperature and a decrease in hyperhydrosis as measured by palpation. Shoulder range of motion increased from 135-175 degrees and the patient reported reduced pain from 6/10 to 3/10 on a scale from 0 to 10, where 0 represents no pain. The decrease in the patient's dystrophic and allodynic symptoms permitted further progress in functional re-education. The patient was discharged with full return to independence and initiation of a vocational retraining program. CONCLUSION: Assessment and treatment of the thoracic spine should be considered in patients with upper extremity CRPS-I.

Soluble polymer supported synthesis of alpha-amino acid derivatives.

A Schiff base activated glycine supported on a soluble polymer (poly(ethylene glycol) (PEG)) was readily alkylated with a wide variety of electrophiles in the presence of a carbonate base in acetonitrile. The presence of the polymer provided a phase-transfer catalysis environment which accelerated the reaction. Effects of various carbonate bases and leaving groups have been also studied. Completion of the PEG-supported reaction was obtained without using a large excess of reagents or an extra phase-transfer catalyst, even in the case of unreactive or hindered electrophiles. After cleavage from the polymer, alpha-amino esters are obtained in good yields.

CD8(+) T cell cytolytic activity independent of mitogen-activated protein kinase / extracellular regulatory kinase signaling (MAP kinase / ERK).

Cytotoxicity is a major effector function of CD8(+) T cells. Although mitogen-activated protein kinase (MAP kinase) / extracellular regulatory kinase (ERK) activity is indispensable for cytotoxic activity of most CD8(+) T cells a portion of CD8(+) T cells appears resistant to MEK inhibition as cytotoxicity of bulk cultures was partially preserved in the presence of a MEK inhibitor. We have also identified a long-term CD8(+) T cell line with unaltered cytolytic activity after prevention of ERK activation. Antigen-induced microtubule organizing center (MTOC) reorientation was not prevented in this CD8(+) cell line by MEK inhibition, in sharp contrast to the MTOC reorientation prevention in a CD8(+) T cell clone with MEK inhibition-sensitive cytolytic activity. These findings suggest that resistance of lysis to MEK inhibition may be due to a lack of ERK control over MTOC reorientation in some CD8(+) T cells. Thus, there appears to be a heterogeneity of ERK-regulated cytolytic activity in CD8(+) T cells, most likely resulting from a differential control of ERK over MTOC motility.

Synthesis, physicochemical properties, anticonvulsant activities, and GABA-ergic and voltage-sensitive calcium channel receptor affinities of alpha-substituted N-benzylamides of gamma-hydroxybutyric acid. Part 4: Search for new anticonvulsant compounds.

In a search for new anticonvulsant compounds, two series of N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (series A) and alpha-(2-phenylethylamino)-gamma-hydroxybutyric acid (series B), were investigated in maximal electroshock (MES), subcutaneous metrazole, and rotorod toxicity assays. The most potent anticonvulsant compounds were alpha-(benzylamino)-gamma-hydroxybutyric acid N-benzylamide (3) and N-(2-chlorobenzylamide (4) with median effective (ED50) doses 63.0 mg/kg and 54.0 mg/kg, respectively. alpha-(4-Phenylpiperazinyl)-gamma-hydroxybutyric acid N-(4-methylbenzyl)amide (17) and alpha-(benzylpiperazinyl-gamma-hydroxy-butyric acid N-(4-methylbenzyl)amide (18) were also tested for their ability to potentiate [3H]-muscimol binding and to inhibit [35S]-TBPS binding (as indices of GABA-A receptor potentiation). Amide 17 exhibited activity at the GABA-A complex which may be the mechanism by which the anticonvulsant effect of this compound is mediated. The N-benzylamides of alpha-(benzylamino)-gamma-hydroxybutyric acid (3-9) were also evaluated for their ability to displace [3H]-nitrendipine from voltage-sensitive calcium channel (VSCC) receptors isolated from rat cortex.

Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group.

BACKGROUND: Ethylene glycol poisoning causes metabolic acidosis and renal failure and may cause death. The standard treatment is inhibition of alcohol dehydrogenase with ethanol, given in intoxicating doses, and adjunctive hemodialysis. We studied the efficacy of fomepizole, a new inhibitor of alcohol dehydrogenase, in the treatment of ethylene glycol poisoning. METHODS: We administered intravenous fomepizole to 19 patients with ethylene glycol poisoning (plasma ethylene glycol concentration, > or =20 mg per deciliter [3.2 mmol per liter]). Patients who met specific criteria also underwent hemodialysis. Treatment was continued until plasma ethylene glycol concentrations were less than 20 mg per deciliter. Acid-base status, renal function, the kinetics of fomepizole, and ethylene glycol metabolism were assessed at predetermined intervals. RESULTS: Fifteen of the patients initially had acidosis (mean serum bicarbonate concentration, 12.9 mmol per liter). Acid-base status tended to normalize within hours after the initiation of treatment with fomepizole. One patient with extreme acidosis died. In nine patients, renal function decreased during therapy; at enrollment, all nine had high serum creatinine concentrations and markedly elevated plasma glycolate concentrations (> or =97.7 mg per deciliter [12.9 mmol per liter]). None of the 10 patients with normal serum creatinine concentrations at enrollment had renal injury during treatment; all 10 had plasma glycolate concentrations at or below 76.8 mg per deciliter (10.1 mmol per liter). Renal injury was independent of the initial plasma ethylene glycol concentration. The plasma concentration of glycolate and the urinary excretion of oxalate, the major metabolites of ethylene glycol, uniformly fell after the initiation of fomepizole therapy. Few adverse effects were attributable to fomepizole. CONCLUSIONS: In patients with ethylene glycol poisoning, fomepizole administered early in the course of intoxication prevents renal injury by inhibiting the formation of toxic metabolites.