Peroxisome Proliferator-Activated Receptor beta/delta in the Brain: Facts and Hypothesis.

peroxisome proliferator-activated receptors (PPARs) are nuclear receptors acting as lipid sensors. Besides its metabolic activity in peripheral organs, the PPAR beta/delta isotype is highly expressed in the brain and its deletion in mice induces a brain developmental defect. Nevertheless, exploration of PPARbeta action in the central nervous system remains sketchy. The lipid content alteration observed in PPARbeta null brains and the positive action of PPARbeta agonists on oligodendrocyte differentiation, a process characterized by lipid accumulation, suggest that PPARbeta acts on the fatty acids and/or cholesterol metabolisms in the brain. PPARbeta could also regulate central inflammation and antioxidant mechanisms in the damaged brain. Even if not fully understood, the neuroprotective effect of PPARbeta agonists highlights their potential benefit to treat various acute or chronic neurological disorders. In this perspective, we need to better understand the basic function of PPARbeta in the brain. This review proposes different leads for future researches.

Characterization of textured NiO films for application as buffer layers in high temperature superconducting tapes.

Textured NiO films have been grown, by thermal oxidation, on biaxially textured Ni substrates. The films have been characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and electron backscatter diffraction (EBSD). The XRD results showed two texture components, cube texture (001)[100] and (111) with out of plane orientation only. SEM showed much inhomogeneity of grain size on the sample surface. Analysis by EBSD revealed that coarse grained regions were cube textured and fine grained regions were <111> fibre textured. The ability to correlate textural and microstructural data is crucial to the optimization of textured NiO films for use in coated conductor technology.

Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers.

AIMS: NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. METHODS: A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. RESULTS: Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg x kg(-1) body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (+/- s.d.) AUC(0,infinity) (capsule 602 +/- 154 vs solution 602 +/- 146 microg x ml(-1) h) or t1/2 (capsule 55 +/- 13 vs solution 54 +/- 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,infinity) and Cmax increased linearly with dose. Following administration of 1 mg NTBC x kg(-1) in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol x ml(-1). Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol x ml(-1) following a dose of 4 mg x kg(-1) body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione x kg(-1), but returned to background levels during the following 24 h period. CONCLUSIONS: NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use.

A randomized comparison of driver reaction time after open and endoscopic tension-free inguinal hernia repair.

BACKGROUND: The aim of this study was to assess whether prosthetic tension-free inguinal hernia repair would cause less impairment of reaction times, thus allowing an earlier return to driving than previously recommended after conventional hernia repair. METHODS: Driver reaction times were measured in 64 patients randomized to open tension-free repair or totally extraperitoneal endoscopic inguinal hernia repair. Measurements were made preoperatively and on postoperation days 1, 3, and 6. RESULTS: In the endoscopic group, there was a gradual improvement in hand and foot reaction times over the days tested. In the open group, there was a slowing in both hand and foot reaction times on postoperation days 1 and 3. The difference in foot reaction times between the open and endoscopic groups was significant on these days (p = 0.01 and 0.003, respectively). By day 6, the foot reaction times in the open group were slightly faster than before surgery. CONCLUSIONS: After prosthetic tension-free inguinal hernia repair, patients can return to driving 1 week after the operation.

Quality framework for force plate testing.

Following work done in C.E.C. project AIM 2002 CAMARC II, a framework of the relevant standards for testing equipment used in laboratories analysing human movement is presented. In particular, gait analysis laboratories may provide a service for a clinical team considering treatment such as surgical intervention or provision of orthoses. In this case the analysis and equipment used in the analysis must have assured quality so that the correct clinical interpretation of the results is possible. The operation of a gait analysis laboratory may be described in quality standards terminology as the operation of a 'special process'. The operation of a special process requires that particular attention be paid to procedures including confirmation of the equipment and regular testing to ensure correct operation of the equipment. In general this is difficult to achieve since equipment manufacturers still have to address this technical requirement. Although difficult, these procedures must be accomplished in the operation of a special process. Passages of the most pertinent standards are presented and a methodology of a periodic confirmation and regular spot checking of equipment suggested to ensure its correct operation. Although force plates are specifically addressed, the framework could be applied to other dynamometers and measurement equipment.

Static in situ calibration of force plates.

An in situ calibration protocol for ground-to-foot force measuring platforms is described. The methodology allows verification of the function of the force plate and allows accurate calibration for three force and moment channels. The effect of cross-sensitivity on recorded data is discussed along with the need for improvements in methodology to quantify this property.

The effect of the hypermobility syndrome on knee joint proprioception.

Proprioceptive sensory feedback is utilized by the central nervous system for conscious appreciation of the position and movement of the body and limbs. In patients with the hypermobility syndrome (HMS), it has been suggested that there is alteration of proprioceptive acuity. Proprioceptive performance of the knee joint was investigated in 10 female subjects who suffered from HMS using a threshold detection paradigm (accurate determination of the onset and direction of knee joint displacement at constant angular velocity). Compared to age- and sex-matched controls, HMS subjects showed significantly higher detection levels at starting knee flexion angles of 30 degrees P < 0.001) and 5 degrees (P < 0.001). Control subjects showed no significant difference in threshold acuity between the sexes (at 5 degrees P = 0.63, at 30 degrees P = 0.48). The increased acuity in proprioception observed towards full extension in the control population (P < 0.001) was absent in the HMS subjects (P = 0.596). Findings reported here suggest that HMS subjects have poorer proprioceptive feedback than controls. Reduced sensory feedback may lead to biomechanically unsound limb positions being adopted. Such a mechanism may allow acceleration of degenerative joint conditions, and may account for the increased prevalence of such conditions seen with HMS subjects.

Trinitrotoluene: assessment of occupational absorption during manufacture of explosives.

Trinitrotoluene (TNT) absorption was assessed in groups of workers at two explosives factories by measuring the urinary concentrations of dinitroaminotoluene (DNAT) metabolites. DNAT was detected in most of the urine samples analysed and for postshift samples the mean (SD) concentration was 9.7 (7.9) mg/l (range 0.1-44 mg/l (n = 219)). Individual workers showed substantial day to day variations in DNAT concentrations in postshift urine samples, but on a group basis the concentrations remained fairly constant throughout the working week. Preshift urine samples taken at the beginning of a working week showed low concentrations of DNAT which initially suggested that the elimination of TNT metabolites is fairly rapid. A survey carried out of preshift and postshift urine samples collected from a group of workers for a full working week showed wide variations in the rate of clearance of TNT metabolites from the body and in some cases higher concentrations of metabolites were seen in the samples taken the morning after exposure. When urine samples were collected from the same group of workers after 17 days away from the workplace DNAT was still detectable in samples from eight of the nine subjects, indicating that a proportion of TNT or its metabolites is slowly excreted. When five subjects were monitored more intensively during two workshifts TNT was shown to be absorbed rapidly during the exposure period. In most cases the highest concentrations were seen in the postshift urine samples but significant proportions were still present in samples taken the morning after exposure. Atmospheric levels of TNT were found to be too low to account for the observed excretion of DNAT and dermal uptake rather than inhalation appears to be the major route of absorption.

Autograft frontoplasty. A simple technique for correction of post-osteoplastic flap defects.

A rare but distressing complication of frontal embossment was managed after osteoplastic flap surgery. The technique is relatively simple and predictable, consisting of frontal bone autografts, bone paté, and Silastic sheeting. This technique may have potential application to other posttraumatic defects that require frontal contour restoration.

Dinitrotoluene: an assessment of occupational absorption during the manufacture of blasting explosives.

Two biological monitoring studies were carried out among workers in an explosives factory who were exposed to technical grade dinitrotoluene (DNT). In the first study urine samples from 28 workers were analysed for the metabolite 2,4-dinitrobenzoic acid (2,4-DNBA). Metabolite concentrations in urine were extremely low or non-detectable, prior to starting work at the beginning of the working week, but post-shift urine samples contained a mean 2,4-DNBA level of 17 mg/l. There were wide variations in the concentrations excreted in urine by different workers and by individual workers on consecutive days. Atmospheric levels of DNT (determined by personal monitoring) were found to be well below the recommended limit and therefore could not account for the observed excretion of 2,4-DNBA. It is suggested that skin may be the major route of absorption of DNT during this process. A second study was carried out to investigate the kinetics of absorption and excretion of DNT. Intensive urine sampling was carried out on five individuals over a 2-day period with additional samples over the subsequent 2 non-working days. Analysis for 2,4-DNBA showed that uptake of DNT is rapid and that the highest levels were normally seen in the end-of-shift specimens. Urine samples were analysed for other known metabolites of DNT which have been found in animal studies and it was shown that 2,4-DNBA is the major known metabolite which is excreted in human urine. Unchanged DNT was detected in blood samples taken during a single workshift at levels up to 250 ng/ml. It is concluded that there is a measurable uptake of DNT by the group of workers studied. The measurement of 2,4 DNBA in end-of-shift urine samples is an appropriate way of assessing the effectiveness of measures taken to reduce the absorption of DNT.

Ultraviolet-B damages corneal endothelium.

Direct in vivo observation of acute ultraviolet (UV)-induced corneal endothelial damage is not possible due to the more severe damage produced in the epithelium. In order to quantify damage and evaluate endothelial recovery an indirect method was used. Eyes of pigmented rabbits were irradiated with UV-B (290 to 320 nm) isolated from the output of a high-pressure 1000 W reflectorized Xenon arc lamp by a grating monochromator and appropriate filters. The peak wavelength of the radiation used was 305 nm, with a 18 nm bandwidth at half-maximum. Corneal thickness variations measured with a modified Zeiss (Oberkochen) pachometer were used to follow alterations in epithelial and endothelial function. Epithelial damage alone resulted in a maximum thickness increase of 13.5% within 24 hr with recovery within a further 24 hr. Greater increases in corneal thickness, in the absence of anterior uveal involvement, were taken to indicate endothelial damage, and reached maximum at 2 days, with recovery occurring in 7 days. The threshold for endothelial damage sufficient to disturb corneal deturgescence was 0.12 J X cm-2.

General immune reactivity in keloid patients.

Serum immunoglobulin levels (IgM, IgG, IgA), complement levels (C3 and C4), and the response of peripheral blood lymphocytes to mitogens [phytohemagglutinin (PHA), concanavalin A (Con-A), and pokeweed mitogen (PWM)] were investigated in healthy patients clinically diagnosed as keloid formers and in nonkeloid volunteers in good health. Serum IgM and serum C3 were significantly higher in keloid patients than in nonkeloid patients both at P less than 0.001, while serum IgA and serum C4 levels were higher in nonkeloid patients than in keloid patients at P less than 0.01 and P less than 0.001, respectively. Serum IgG levels were essentially unchanged in the keloid and the control groups in this study. Mitogenic stimulation was significantly lower in the keloid population in this investigation at P less than 0.001 for both PHA and Con-A. However, major differences were not observed with PWM stimulation in both keloid and control groups.