Experience with low-dose methotrexate: toxicity, tolerability and effect on conventional patterns of drug therapy for inflammatory arthritis.
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Adult↗
Biomedical subjects
L Carlisle
Publications and source records attributed to L Carlisle.
Methotrexate and sulphasalazine as combination therapy in rheumatoid arthritis.
Sulphasalazine (SASP) and methotrexate (MTX) are well-established treatments for RA but the use of these drugs in combination has been avoided as both have antifolate activity. In this paper we report our experience with 32 patients treated with the combination MTX/SASP and compare the toxicity and tolerability of the combination with 63 patients treated with MTX alone. The median duration of exposure to the combination was 23 months. Nineteen patients have continued this regime for over 18 months. Five patients on MTX/SASP combination discontinued MTX, in four cases due to toxicity and in one because MTX/SASP was ineffective. In 17 patients on MTX alone, the drug was withdrawn permanently. In seven cases the cause was toxicity including two patients with severe reactions. In patients known to tolerate SASP alone, the combination of MTX/SASP is also well tolerated. In our experience of 48 patient-years of such combination therapy, there is no increase in toxicity compared to therapy with MTX alone in RA.
Adult↗
Recent advances in the treatment of childhood obesity.
The multidisciplinary, four-phase approach, which includes PSMF, BEM, and MPE is successful in treating mild, moderate, and severe degrees of childhood and adolescent obesity. The MPE program is appropriate for use with PSMF and BEM due to its progressive nature, variety of options, and moderate intensity level. In addition, the MPE program is of sufficient intensity, duration, and frequency to promote a significant increase in estimated aerobic capacity (VO2max) and to promote the maintenance of lean body mass and resting energy expenditure. The short-term intervention of PSMF, BEM, and MPE also results in an improvement in body composition, lipid profiles, and IGF-1 and T3 levels. The 1200-calorie balanced diet, MPE, and BEM also provide a successful method of weight maintenance in children and adolescents, as indicated by further improvement in body composition at the 26-week measure. Additional studies are needed to assess the contribution of exercise to the maintenance of lean body mass and resting energy expenditure in obese children and adolescents. In addition, it will be important to assess long-term weight maintenance in obese adolescents who effectively lose weight in this multidisciplinary program.
Adolescent↗
An effective multidisciplinary approach to weight reduction in youth.
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Adolescent↗
Endocochlear potential generation is associated with intercellular communication in the stria vascularis: structural analysis in the viable dominant spotting mouse mutant.
Deafness in the viable dominant spotting mouse mutant is due to a primary defect of the stria vascularis which results in absence of the positive endocochlear potential in scala media. Endocochlear potentials were measured and the structure of stria vascularis of mutants with potentials close to zero was compared with that in normal littermate controls by use of morphometric methods. The stria vascularis was significantly thinner in mutants. Marginal cells were not significantly different from controls in terms of volume density or intramembrane particle density but the network density of tight junctions was significantly reduced in the mutants. A virtual absence of gap junctions between basal cells and marginal or intermediate cells was observed, but intramembrane particle density and junctional complexes between adjacent basal cells were not different from controls. The volume density of basal cells was significantly greater in mutants. Intermediate cells accounted for a significantly smaller volume density of the stria vascularis in mutants and had a lower density of intramembrane particles than controls. Melanocytes were not identified in the stria vascularis of mutants. These results suggest that communication between marginal, intermediate and basal cells might be important to the normal function of the stria vascularis.
Animals↗
Auditory dysfunction and cochlear vascular injury following trimethyltin exposure in the guinea pig.
Trimethyltin chloride (TMT) produces an auditory impairment in the rat due, presumably, to cochlear injury. The loss is unusual in that it persists for several weeks, but ultimately resolves at least at low to middle frequencies. Recovery of high frequency auditory loss is less predictable. Given this pattern of injury and recovery plus the known ability of TMT to impair oxidative phosphorylation, it was hypothesized that TMT would damage the stria vascularis which is the most metabolically active area and a structure containing one of the primary vascular networks in the cochlea. Trimethyltin chloride ototoxicity was evaluated in guinea pigs treated with the toxicant and then subjected to weekly tests of the auditory brainstem response evoked by tonal stimuli. A high frequency impairment was found which tended to improve within the first 2 weeks after exposure. Subjects were euthanized 6 weeks after TMT for histopathological study of the cochlea. At that time point most subjects showed full functional recovery. Subjects showed significant changes both in the number of outer hair cells and in the condition of the stria vascularis. Outer hair cell loss was observed in a restricted portion of the most basal turn of the cochlea which is responsible for encoding high frequency sound despite recovery of function in some animals. A very marked increase in the diameter of the vessels of the stria vascularis was observed along with signs of atrophy in the stria vascularis. Enlarged vessel diameters were particularly apparent in the apical and middle turns of the cochlea, which did not show significant hair cell loss. The data confirm that TMT does produce both hair cell damage and vascular pathology in the cochlea.
Animals↗
Neural basis for regulation of cochlear blood flow: peptidergic and adrenergic innervation of the spiral modiolar artery of the guinea pig.
The spiral modiolar artery is the terminal artery in the cochlea, and as such is expected to play a major role in the control of cochlear blood flow. In this study, we examined the distribution of adrenergic and peptidergic nerve fibres on the spiral modiolar artery of the guinea pig using histofluorescence and immunofluorescence techniques. The spiral modiolar artery was dissected from the modiolus so that the entire length of the vessel and its branches, could be observed. Noradrenaline was identified using the glyoxylic acid histofluorescence technique. The presence of the vasoactive peptides substance P, calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP), was investigated using antibodies against these peptides. Each putative transmitter tested yielded labelled nerve fibres throughout the length of the spiral modiolar artery and its branches. Double-labelling experiments confirmed that CGRP and substance P are contained in the same fibres but that VIP and substance P appear to be contained in different populations of fibres. These results establish that nerve fibres containing vasoactive peptides and noradrenaline supply the spiral modiolar artery and suggest that they are involved in the regulation of cochlear blood flow.
Animals↗
Mission statements.
With the move towards a far more business-oriented NHS, Lynne Carlisle looks at a private company whose efforts at staff communication could provide a useful lesson to health service managers.
Documentation↗
NHS joins battle to woo women back to work.
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England↗
The vessels of the stria vascularis: quantitative comparison of three rodent species.
The stria vascularis (SV) was quantitatively compared in three species commonly used in auditory research: guinea pig, mouse and gerbil. Measurements were obtained for surface area, cross-sectional area, length, width and thickness of SV. Surface area and length were proportional to the overall size of the cochlea in each species, but there was no significant difference between species in mean cross-sectional area. In guinea pig and mouse, there was no significant difference in thickness (endolymphatic surface to spiral ligament) and a similar pattern was observed for width (Reissner's membrane to spiral prominence): the width of SV increased from the apical end to a point 80% of the distance from the apex, then decreased to the basal end of SV. The thickness of gerbil SV was significantly less (P less than 0.001) and there was less of a gradient in width as compared to guinea pig and mouse. The vessels of SV were compared in terms of vascular density (vessels per unit area), rbc density (red blood cells per unit area), R/V (rbc density/vascular density), inter-vessel spacing and vessel diameter. Highly significant (P less than 0.001) differences between species were found in vascular density, RBC density and vessel diameter, but there were no differences between species for R/V or inter-vessel spacing. The results of this study may reflect differences in the metabolic requirements of SV among different species.
Animals↗
Potentiation of noise induced threshold shifts and hair cell loss by carbon monoxide.
Previous studies have determined that severe systemic hypoxia disrupts cochlear function acutely, but have suggested that augmentation of cochlear perfusion may successfully protect cochlear function under all but the most profound hypoxic treatments. In the current study we report on the chronic effects of simultaneous exposures to noise and carbon monoxide on pure tone thresholds and hair cell survival in rats. Following initial threshold determination, rats received acute exposure to carbon monoxide, noise, or both agents concurrently. Thresholds were evaluated 2-4 and 6-8 weeks later. The data show that carbon monoxide alone does not affect either auditory thresholds or compromise hair cells at the light microscopic level. The noise exposure alone produced variable, but quite limited permanent threshold shifts which were related to the power spectrum of the broad band noise that was employed. Hair cell loss was restricted to the basal turn of the cochlea. Simultaneous exposure to carbon monoxide and noise induced large threshold shifts at all frequencies studied, but the effect was greatest at the highest test frequency; an effect not consistent with the noise power spectrum. Widespread hair cell loss persisted over fully half of the basilar membrane in the most severely affected rat. Outer hair cells appear to be particularly vulnerable. Carbon monoxide plus noise did not appear to preferentially disrupt a particular row of outer hair cells. These data complement existing evidence that hyperoxia can mitigate against noise induced injury and reinforce the view that some types of noise induced damage may result from metabolic insufficiencies.
Acoustic Stimulation↗
Species differences in the distribution of infracuticular F-actin in outer hair cells of the cochlea.
The distribution of filamentous actin (F-actin) in outer hair cells has been examined in several mammalian species using tetramethylrhodamine phalloidin, a specific marker for F-actin. The stereocilia and cuticular plates of the OHC in all species examined (pigmented guinea pig, hooded rat, chinchilla and squirrel monkey) contained F-actin; however, an infracuticular network of F-actin was present in OHC of the apical turns of the guinea pig cochlea but could not be identified in any other species examined.
Actins↗
Differences in the distribution of F-actin in outer hair cells along the organ of Corti.
There is evidence of differences in the structure, innervation and physiological responses between outer hair cells (OHCs) of the basal and apical turns of the mammalian cochlea. In this study we have used rhodamine-labelled phalloidin to investigate the differential distribution of F-actin in OHCs along the organ of Corti of the guinea pig. Isolated OHCs and surface preparations and cryosections of the organ of Corti were studied. F-actin was observed in stereocilia and the cuticular plate of all OHCs. In addition, some OHCs had a network of F-actin extending from the cuticular plate towards the nucleus. This infracuticular network was observed in most OHCs of the apical cochlear turns but was not seen in any OHCs of the basal turn. These microstructural differences between OHCs of the base and apex could be related to differences in OHC function between the apical and basal portions of the cochlea.
Actins↗
Hydroxyethyl starch versus albumin in cardiopulmonary bypass prime solutions.
To compare hydroxyethyl starch (HES) with 25% albumin, 20 patients undergoing aortocoronary bypass were randomized into two groups: 10 received 1,000 ml of HES and 10 received 200 ml of 25% albumin in a bloodless priming solution for cardiopulmonary bypass (CPB). Platelet aggregation, antithrombin III, reptilase time, fibrinogen, plasminogen, fluid requirements, and hemodynamics were monitored. Platelet aggregation was abnormal in both groups, being relatively poorer in the albumin group. Both groups exhibited below normal antithrombin III and plasminogen levels, with significantly lower antithrombin III levels noted in the HES group postoperatively (41.9 +/- 11.8% versus 56.6 +/- 9.9%; p = 0.006). Compared with the albumin group, the HES group had slightly, but not significantly, elevated liver function test results, total volume replacement (9,173 +/- 2,046 ml versus 8,522 +/- 1,192 ml; p = 0.057), packed red blood cell usage (227 +/- 284 ml versus 75 +/- 168 ml; p = 0.066), and chest tube drainage (599 +/- 253 ml versus 454 +/- 174 ml; p = 0.144). In the HES group, 5% albumin requirement was greater (386 +/- 466 ml versus 50 +/- 158 ml; p = 0.002) and percent increase of body weight was higher (5.2 +/- 0.8% versus 2.3 +/- 0.6%; p = 0.05) postoperatively. Postoperative weight increase and colloid requirements plus trends toward larger blood loss and blood transfusions indicate possible further evaluation. However, results suggest that HES is a safe additive to priming solutions. Compared with albumin, HES has comparable changes in coagulation variables and slightly less severe derangements in platelet aggregation.
Aged↗
A histone programme during the life cycle of the sea urchin.
The histone complement of chromatin from early gastrula, late gastrula and from fully differentiated gut cells of the sea urchin Parechinus angulosus has been fractionated by molecular sieve and ion-exchange chromatography. Several of the subfractions thus isolated have been characterized by amino acid composition and partial amino acid sequences as a series of variants of the histones H1, H2A and H2B. Specific histone variants are present in chromatin at specific stages of differentiation.
Amino Acid Sequence↗
Brainstem auditory pathway degeneration associated with chronic cochlear implants in the monkey.
The form and pattern of first-order and transsynaptic degeneration in the central auditory pathway was studied in monkeys following inner ear stimulation by a cochlear implant. Multielectrode, scala tympani, and modiolar systems were implanted; in some cases, neomycin was perfused into the cochlea to destroy the organ of Corti at the time of implantation. The monkeys were maintained chronically for 5 to 120 weeks, then the cochleas and brainstems were examined histologically. The extent of spiral ganglion cell loss across animals showed variability, reflecting the different procedures and devices used. The degree and distribution of spiral ganglion cell loss was related to the degree and distribution of neural degeneration seen in the cochlear nucleus in all cases. Peripheral damage progressed toward the cochlear apex as survival time increased, and this progression was reflected in the cochlear nucleus by a ventrolateral shift in the locus of degeneration over time. In addition, evidence for transneuronal degeneration was seen at the superior olive, the lateral lemniscus and the inferior colliculus. Our findings indicate that several factors inherent in the use of a cochlear prosthesis, i.e., insertion trauma, host reaction, and/or electrical stimulation, may be associated with a long-term, continuing process of central degeneration visible at several levels of the auditory system.
Animals↗
Experimental cochleo-vestibular deafferentation with NaCl.
An animal experiment was performed to evaluate structural and ultrastructural changes in the inner ear as a result of placing 10-12 crystals of reagent grade sodium chloride (NaCl) in the vestibule. Chinchillas were sacrificed 8 and 24 hours after treatment and the cochlear and vestibular tissues were examined by light microscopy and scanning electron microscopy. Inner ear pathology consisted of extensive degenerative changes in morphology of all sensory structures of the inner ear. The extent of these pathological changes supports the idea of eventual total deafferentation of the inner ear.
Afferent Pathways↗
Chemical labyrinthectomy with NaCl. Menière's disease treatment with deposition of NaCl in the vestibule.
Thirteen individuals with unilateral Menière's disease were chosen for experimental chemical labyrinthectomy. All subjects suffered from frequent attacks of disabling vertigo and had mean pure-tone thresholds greater than 50 dB in the affected ear. The surgical procedure was similar to stapedectomy; after removal of the stapes, several crystals of NaCl were placed in the vestibule which was then covered with a vein graft. Postoperative recovery was rapid, allowing patients to be discharged 4-6 days after surgery. Of the 13 subjects, all reported complete relief from vertigo. Tinnitus was cured in 7 subjects, greatly improved in 4 and unchanged in 2. Most patients complaining of aural fullness preoperatively reported relief from this symptom following surgery. To date (up to 4 years post-surgery) none of the subjects has shown any significant alteration in audiologic or vestibular function in the contralateral ear. The ease and safety of this procedure make it an attractive method when cochleovestibular deafferentation is indicated.
Adult↗