Prescription of non-steroidal anti-inflammatory drugs for patients with inflammatory arthritis decreases with the initiation of tumour necrosis factor inhibitor therapy: results from the ICEBIO registry.

OBJECTIVE: To study the impact of tumour necrosis factor-α inhibitor (TNFi) therapy on the use of non-steroidal anti inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) in Iceland. METHOD: This registry cohort study used data from the nationwide database on biologics in Iceland (ICEBIO) and the Icelandic Prescription Medicines Register on disease activity, and filled prescriptions for NSAIDs, to study the period from 2 years before to 2 years after initiation of a first TNFi. Five randomly selected individuals from the general population matched on age, sex, and calendar time for each patient served as comparators. RESULTS: Data from 940 patients and 4700 comparators were included. Patients with arthritis were prescribed 6.7 times more defined daily doses of NSAIDs than comparators (149 vs 22 per year). After TNFi initiation, NSAID use decreased to a mean of 85 DDD per year, or by 42% in RA, 43% in PsA, and 48% in axSpA. At TNFi initiation, the quintile of axSpA patients who used most NSAIDs reported significantly worse pain (mean ± sd 66 ± 21 vs 60 ± 23 mm), global health (70 ± 20 vs 64 ± 23 mm), and Health Assessment Questionnaire score (1.21 ± 0.66 vs 1.02 ± 0.66) than the other patients, whereas no significant differences were observed in the groups with peripheral arthritis. CONCLUSION: Patients with inflammatory arthritides requiring TNFi therapy use more NSAIDs than matched comparators, and consumption decreased following TNF initiation. Patient-reported measures are not associated with high NSAID use in patients with peripheral arthritis.

Persistent pain and its predictors after starting anti-tumour necrosis factor therapy in psoriatic arthritis: what is the role of inflammation control?

OBJECTIVE: While considerable focus has been placed on pain due to inflammation in psoriatic arthritis (PsA), less is reported on pain despite inflammation control. Here, we aimed to investigate the occurrence/predictors of persistent pain, including non-inflammatory components, after starting anti-tumour necrosis factor (anti-TNF) therapy. METHOD: Bionaïve PsA patients starting a first anti-TNF therapy 2004-2010 were identified (South Swedish Arthritis Treatment Group register; N = 351). Outcomes included unacceptable pain [visual analogue scale (VAS) pain > 40 mm], and unacceptable pain despite inflammation control (refractory pain; VAS pain > 40 mm + C-reactive protein < 10 mg/L + ≤ 1 swollen joint of 28), assessed at 0, 3, 6, and 12 months. Baseline predictors were estimated by logistic regression. RESULTS: Upon starting anti-TNF therapy, 85% of patients reported unacceptable pain, falling to 43% at 3 months and then remaining stable. After 12 months, refractory pain constituted 63% of all unacceptable pain. Higher baseline VAS pain/global, worse physical function and lower health-related quality-of-life were associated with a higher risk of unacceptable/refractory pain at 12 months. More swollen joints and higher evaluator's global assessment were associated with a lower risk of 12-month refractory pain. CONCLUSIONS: A substantial proportion of PsA patients reported unacceptable pain throughout the first anti-TNF treatment year. At 12 months, refractory pain constituted about two-thirds of this remaining pain load. More objective signs of inflammation at anti-TNF initiation were associated with less future refractory pain. This highlights insufficient effect of biologics in patients with inflammation-independent pain, warranting alternative treatments.

Validity of clinical psoriatic arthritis diagnoses made by rheumatologists in the Swedish National Patient Register.

OBJECTIVES: : Knowledge of the correspondence between clinical ICD diagnoses and classification criteria fulfilment is crucial to interpret studies identifying cases via ICD codes. We assessed the degree to which patients registered with ICD-10 diagnoses of psoriatic arthritis (PsA) in the Swedish National Patient Register (NPR) fulfil established PsA classification criteria. METHOD: Four hundred patients with at least one outpatient visit to one of five rheumatology or internal medicine departments (three university/two county departments across Sweden) in 2013-2015, with a main ICD-10 diagnosis of PsA (L40.5, M07.0-M07.3), were randomly selected (80 cases/site). Through a structured medical record review, positive predictive values (PPVs) for fulfilment of the following classification criteria were assessed: CASPAR, Moll and Wright, Vasey and Espinoza, and modified ESSG criteria for PsA. A subset analysis regarding CASPAR fulfilment was also performed among cases with available rheumatoid factor and peripheral X-ray status (central CASPAR items; n = 227). RESULTS: Of the 400 patients with a main ICD-10 diagnosis of PsA, 343 (86%) fulfilled at least one of the four PsA classification criteria. PPVs for the different criteria were: CASPAR 69% (82% in the subset analysis), Moll and Wright 51%, Vasey and Espinoza 76%, and modified ESSG 64%. Overall, only 6.5% of the 400 PsA diagnoses were judged as clearly incorrect by the medical record reviewers. CONCLUSION: The validity of rheumatologist-made, clinical ICD-10 diagnoses for PsA in the Swedish NPR is good, with PPVs of 69-82% for CASPAR fulfilment and 86% for meeting any established PsA classification criteria.

Association of female sex and positive rheumatoid factor with low serum infliximab and anti-drug antibodies, related to treatment failure in early rheumatoid arthritis: results from the SWEFOT trial population.

Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX < 0.2 µg/mL and ADA development in a randomized setting. Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX > 0.2 µg/mL]. The primary and secondary outcome measures were low disease activity [LDA = 28-joint Disease Activity Score (DAS28) ≤ 3.2] and remission (DAS28 < 2.6). Baseline characteristics were assessed as potential predictors of sIFX < 0.2 µg/mL or ADA positivity, using logistic regression. Results: Categorization of sIFX levels into < 0.2, 0.2-2.9, 3.0-7.0, and > 7.0 µg/mL showed a dose-response association with LDA (30%, 64%, 67%, and 79%, respectively, p = 0.008) and remission (10%, 45%, 39%, and 66%, p = 0.004) at trial cessation (21 months). Female patients had sIFX < 0.2 µg/mL more often than males (35% vs 7%, p = 0.006), with a similar trend for rheumatoid factor (RF)-positive vs RF-negative patients (34% vs 16%, p = 0.059). ADA positivity showed similar patterns, also after adjustment for potential confounders (female sex: p = 0.050; RF positivity: p = 0.067). PandA captured four highly ADA-reactive patients with sIFX > 0.2 µg/mL, of whom three were ADA positive at other time-points, all with high DAS28 at follow-up. Conclusion: In early RA patients receiving IFX as a second-line agent, sIFX < 0.2 µg/mL and ADA development were associated with treatment failure and were more common in females, with a similar trend for RF positivity. Our findings support the use of therapeutic drug monitoring, and PandA in ADA-negative non-responders. Trial registration: SWEFOT NCT00764725 ( https://clinicaltrials.gov/ct2/show/NCT00764725 ).

What PASSes for good? Experience-based Swedish and hypothetical British EuroQol 5-Dimensions preference sets yield markedly different point estimates and patient acceptable symptom state cut-off values in chronic arthritis patients on TNF blockade.

OBJECTIVES: Health utilities derived from answers to generic health-related quality of life (HRQoL) questionnaires such as the EuroQol 5-Dimensions (EQ-5D) are often used in cost-utility analyses (CUAs) of new and expensive treatments. Different preference sets (tariffs) used in the computation of utility values and quality-adjusted life-years (QALYs) from questionnaire responses (health states) yield varying results, potentially affecting decisions of resource allocation. The objective of the present study was to compare British (UK), hypothetical, and Swedish (SE), experience-based, EQ-5D utilities using data from clinical practice. METHOD: UK and SE EQ-5D utilities were computed in an observational cohort of patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA) treated with tumour necrosis factor (TNF) blockers, comparing point estimates and patient acceptable symptom state (PASS) cut-off levels. RESULTS: SE utilities were found to be consistently higher than UK utilities, and PASS cut-offs were essentially stable over time. CONCLUSIONS: With higher baseline utilities, there may be less room for improvement after an intervention and thus less accumulation of QALYs in CUAs applying the SE, as opposed to the UK, EQ-5D tariff.

Extreme myopia produced by modest change in early visual experience.

Chicks whose vision was restricted to the frontal visual field became extremely myopic (mean, -10 diopters; maximum, -24 diopters) and had eyes of increased axial length. Animals restricted to lateral field vision did not differ from normal animals. Monocular deprivation of form vision also produced myopia and eye enlargement and, in addition, produced increased anterior chamber depth.

Local retinal regions control local eye growth and myopia.

In chicks, visual deprivation leads to myopia and enlargement of the vitreous chamber of the eye. When chicks were raised with white translucent occluders over their eyes so that either the nasal half, the temporal half, or all of the retina was visually deprived, the resulting myopia (median = -15 diopters) was limited to the deprived part of the retina, regardless of which half of the retina was visually deprived; the nondeprived part remained nearly emmetropic. Correspondingly, the vitreous chamber was elongated only in the region of the visual deprivation, resulting in eyes with different asymmetric shapes depending on which retinal region was deprived. These results argue for a local regulation of ocular growth that is dependent on vision and suggest a hypothesis to explain the epidemiological association of myopia in humans with large amounts of reading. Because most nonfoveal retinal neurons have large receptive fields, they cannot resolve the individual letters on the printed page; this may lead to their activity being less during reading than during most other forms of visual stimulation. Thus, the impoverished stimulus situation of reading may lead to myopia, as do other types of visual form deprivation.

Covalent disulfide binding of human IL-1 beta to alpha 2-macroglobulin: inhibition by D-penicillamine.

Secreted human IL-1 beta is known to have two free SH groups due to unpaired cysteines (positions 8 and 71). Alpha 2-Macroglobulin (alpha 2-M) has internal thioester bonds between cysteine and glutamate residues. Free SH groups may be generated at these alpha 2M residues through the action of proteinases, amines such as methylamine, or at a slow rate, by H2O ("aging" of alpha 2M). Thus, the possibility that IL-1 beta forms a disulfide bond with alpha 2M was investigated. 125I-labeled human rIL-1 beta (15 kDa) was incubated with fresh normal human serum or with purified alpha 2M, treated or not with methylamine. The mixtures were submitted to nondenaturing and denaturing polyacrylamide gel electrophoresis (PAGE) followed by autoradiography. IL-1 beta bound to commercially purified "aged" alpha 2M and to alpha 2M in methylamine-treated serum but not to native serum alpha 2M. It did not bind detectably to any other serum proteins. The addition of D-penicillamine (D-pen) during the reaction of [125I]rIL-1 beta with serum or purified alpha 2M blocked the covalent binding of rIL-1 beta to alpha 2M. [125I]rIL-1 beta was removed from alpha 2M by 2-mercaptoethanol in SDS. Thus, disulfide bonds were formed between the free SH groups on [125I]rIL-1 beta and those resulting from the cleavage of the internal thioester bonds of alpha 2M. "Cold" rIL-1 beta and a Cys71----Ser71 rIL-1 beta mutant effectively competed with [125I]rIL.1 beta for binding sites on alpha 2M. When complexes of rIL-1 beta or the mutant rIL-1 beta and alpha 2M were subjected to nonreducing SDS-PAGE and subsequent Western blot analysis, the rIL-1 beta molecules were found to be present in the alpha 2M bands in a dose-dependent manner. rIL-1 beta attached to alpha 2M in the presence or absence of D-pen showed similar biological activity in the mouse thymocyte-assay. Thus, rIL-1 beta attached noncovalently to alpha 2M is biologically active. The lack of inhibition of rIL-1 beta activity by binding to methylamine-treated alpha 2M in the absence of D-pen suggests, but does not prove, that the covalently bound rIL-1 beta is also active. We concluded that human rIL-1 beta binds to alpha 2M through the Cys at position 8 and that D-pen inhibits this binding. We speculate that this inhibitory effect may contribute to the therapeutic benefits of D-pen in patients with rheumatoid arthritis.

Covalent binding to alpha-macroglobulins of a protein with free SH groups produced by activated B cells: blocking by D-penicillamine and gold compounds.

alpha 2-Macroglobulin (alpha 2M) complexed with proteinases or modified by the action of amines has been shown to affect immune responses in vitro, though as yet the mechanisms are poorly understood. Supernates from rabbit lymphoid cells cultured in medium with normal rabbit serum and 35S-methionine (or 14C-leucine) were found to contain intensely radiolabeled alpha-macroglobulins (alpha M) (alpha 1 and alpha 2) on electrophoresis. When human alpha 2 M, instead of rabbit serum, was added to cultures, it also appeared radiolabeled, suggesting that lymphocyte-produced proteins (LyP) formed complexes with serum alpha M. These alpha M-associated LyP were produced in greater quantity when lymphocytes were cultured in the presence of mitogens; they were not produced by cells cultured in the presence of cycloheximide; they were produced primarily by B cells rather than T cells or macrophages. Pretreatment of serum or alpha M with methylamine, enhanced rather than inhibited the formation of LyP-alpha M complexes, a finding which is contrary to that expected if the LyP were a proteinase. Since this methylamine treatment of alpha M also results in the generation of free SH groups from the internal thioester bonds of alpha M, the formation of disulfide bonds between LyP and alpha M was considered. Indeed, (a) the LyP-alpha M complex formation was inhibited by N-ethylmaleimide, aurothiomalate, sodium aurothioglucose or D-penicillamine; (b) blocking the SH groups with NEM, of either culture fluid supernates or serum, had an inhibitory effect on the formation of these complexes; (c) the LyP-alpha M complexes were dissociated by sodium dodecyl sulfate (SDS) only after their reduction with 2-mercaptoethanol (2-ME). Thus, a disulfide bond was formed between alpha M and LyP with free SH groups (SH-LyP). Molecular sieving by high performance liquid chromatography (HPLC) of the serum-free radiolabeled supernates indicated that SH-LyP eluted at a position corresponding to a polypeptide of mol. wt of about 22,000. However, SDS-PAGE of the 22,000 mol. wt HPLC fraction showed that the major protein was approximately mol. wt 11,000 under both reducing and non-reducing conditions. In addition, the SH-LyP reduced by 2-ME from its binding site on alpha 2M had a mol. wt of about 11,000 in SDS-PAGE, suggesting that it was a non-covalent homodimer of mol. wt 11,000 polypeptides. We suggest that alpha 2M as well as SH-LyP may affect the immune system by functioning as SH-reactive agents.

Growth of the two layers of the chick sclera is modulated reciprocally by visual conditions.

PURPOSE: Although visual deprivation causes increased ocular elongation and myopia in both birds and mammals, changes in sclera appear to be in opposite directions. Because avian sclera has a cartilaginous layer as well as the fibrous layer found in mammals, we examined whether the scleral responses to various visual manipulations differ between the two layers. METHODS: To produce increases in ocular elongation and myopia, monocular diffusers or negative lenses were fitted to eyes. Conversely, to produce decreases in ocular elongation, diffusers were removed (restoring normal vision) or monocular positive lenses were fitted. Scleral layers were then dissected apart, and incorporation of labeled precursors into glycosaminoglycans (GAGs), DNA, and protein was assessed. Tissue coculture experiments were used to assess humoral interactions between scleral layers and with the choroid. RESULTS: In the cartilaginous layers, the incorporation of label into proteoglycans and DNA was significantly higher in eyes elongating faster than normal because of wearing diffusers or negative lenses and significantly lower than normal in eyes elongating slower than normal because of removal of the diffuser or wearing positive lenses. In the fibrous layers, the reverse was the case. Coculturing cartilaginous sclera from normal eyes with fibrous sclera from myopic or recovering eyes produced the same increase or decrease in sulfate incorporation into GAGs in the cartilaginous layer as though the tissue measured was from the animal providing the conditioning tissue. Coculturing with choroid, especially from recovering eyes, also inhibited cartilaginous sclera. CONCLUSIONS: The fibrous layer of the avian sclera shows changes in sulfate incorporation into GAGs during deprivation and recovery from deprivation in the same direction as does the mammalian sclera, whereas the cartilaginous layer changes in the opposite direction. The responses of the cartilaginous layer may be controlled by the fibrous layer, although they are influenced by the choroid as well.

Evidence that increased scleral growth underlies visual deprivation myopia in chicks.

The authors evaluated three measures of scleral growth in chicks that were visually deprived with the use of translucent occluders. The authors sought to determine whether the ocular elongation and myopia that results from this deprivation is associated with increased growth of the sclera. The authors found that the dry weight of the sclera of deprived eyes increased 65% faster than that of nondeprived eyes. Furthermore, the uptake of labeled methionine and thymidine was significantly increased by visual deprivation, whether expressed as incorporation per sclera, per milligram of sclera, per milligram of protein, or per milligram of DNA. In addition, the amount of DNA and soluble protein was significantly greater in the scleras of deprived eyes than in those of nondeprived eyes. Finally, the degree of hydration of the scleras from deprived eyes was greater relative to their weight than that of the scleras from nondeprived eyes. These results suggest that visual deprivation causes increased cellular proliferation and increased protein synthesis in the sclera of chicks.

Differences in time course and visual requirements of ocular responses to lenses and diffusers.

PURPOSE: Myopia can be induced in chickens by having them wear either negative lenses (lens-compensation myopia [LCM]) or diffusers (form-deprivation myopia [FDM]), whereas positive lenses cause lens-compensation hyperopia (LCH). These three conditions were compared with respect to (i) their early time course and (ii) the effect of two manipulations of the lighting. METHODS: Longitudinal changes in ocular dimensions and refractive error were measured in chicks maintained under three different conditions: (i) wearing either -15 D lenses or diffusers in a normal light/dark cycle; (ii) wearing either +15 D lenses, -15 D lenses, or diffusers with brief periods of stroboscopic lights at the beginning and end of the dark period; (iii) wearing either +6 D lenses, -6 D lenses, or diffusers with the nights interrupted by brief periods of white light. In addition, scleral and choroidal proteoglycan synthesis was measured in eyes that wore positive lenses, negative lenses, or diffusers for 3 hours followed by different periods of darkness. RESULTS: (i) The time course of the changes in axial length over the first 72 hours was significantly faster in LCM than in FDM. Indeed, the diffusers did not begin to significantly affect the total length of the globe for 3 days, although the vitreous chamber had deepened after 9 hours, because the choroid thinned extremely rapidly (within 1 hour) with either diffusers or negative lenses. (ii) Scleral proteoglycan synthesis was higher in eyes with negative lenses than in those with diffusers at 11 hours, but the reverse was true at 27 hours. (iii) Brief periods of stroboscopic light attenuated FDM more than LCM. (iv) In contrast, interruption of the nights by brief periods of light attenuated LCM more than FDM. (v) Neither lighting manipulation affected LCH. (vi) Choroidal proteoglycan synthesis decreased similarly with 3 hours of wearing either diffusers or negative lenses. CONCLUSIONS: Although both negative lenses and diffusers cause similar increases in the rate of ocular elongation, the responses differ in time course and in the effect of manipulations of the daily lighting. The responses to positive lenses differ from both of these.

Vision-dependent changes in the choroidal thickness of macaque monkeys.

PURPOSE: To determine whether changes in the eye's effective refractive state produce changes in the thickness of the choroid in infant monkeys. METHODS: Normal developmental changes in choroidal thickness were studied in 10 normal rhesus monkeys. Hyperopia or myopia was induced by rearing 26 infant monkeys with either spectacle or diffuser lenses secured in front of one or both eyes. The treatment lenses were worn continuously beginning at approximately 3 weeks of age for an average of 120 days. Refractive status and ocular axial dimensions, including choroidal thickness, were measured by retinoscopy and high-frequency A-scan ultrasonography, respectively. RESULTS: Three lines of evidence indicate that the normal increase in choroidal thickness that occurs during early maturation can be altered by the eye's refractive state. First, in monkeys experiencing form deprivation or those in the process of compensating for imposed optical errors, choroidal thickness and refractive error were significantly correlated with eyes developing myopia having thinner choroids than those developing hyperopia. Second, the choroids in eyes recovering from binocularly induced myopia increased in thickness at a faster rate than the choroids in recovering hyperopic eyes. Third, monkeys recovering from induced anisometropias showed interocular alterations in choroidal thickness that were always in the appropriate direction to compensate for the anisometropia. These changes in choroidal thickness, which were on the order of 50 microm, occurred quickly and preceded significant changes in overall eye size. CONCLUSIONS: Changes in the eye's effective refractive state produce rapid compensating changes in choroidal thickness. Although these choroidal changes are small relative to the eye's refractive error, they may play an important role in the visual regulation of axial growth associated with emmetropization.

The eyes of young chickens grow toward emmetropia.

The distribution of refractive errors was followed in chicks from hatching to 8 weeks of age. A dramatic progressive decrease in the variability of refractions was observed over this period. In addition, there appeared to be a parallel decline in hyperopia, even when the artifactual hyperopia of retinoscopy was taken into account. These results are evidence for a postnatal development regulatory mechanisms, most likely dependent on vision, which directs growth of the eye toward emmetropia.

Different visual deprivations produce different ametropias and different eye shapes.

To compare the effects on the postnatal development of the eye of both total and partial form deprivation in diurnally reared chicks and of dark-rearing, chicks were reared with occluders covering one eye from hatching for up to 6 weeks. In diurnally reared birds, both total and partial form deprivation resulted in severe axial myopia and increased eye size. These effects were greatest for the eyes of chicks raised with total form deprivation; they had highly curved corneas and very deep anterior and vitreous chambers. In addition, the amount of myopia produced in eyes with total form deprivation was the same at 2 and 6 weeks, whereas eyes with partial form deprivation showed substantial remission even with the occluders left on. The partially deprived eyes developed a striking shape asymmetry: the posterior globe only became enlarged in the deprived region of the retina. The eyes of dark-reared chicks, regardless of whether or not an occluder was worn, also were enlarged but were hyperopic owing to a severe flattening of the cornea. This hyperopia was slow to develop compared to the myopia produced in the diurnally reared visually restricted eyes. Finally, the shape of the posterior globe of these hyperopic eyes was no different from that of normal eyes.

Muscarinic acetylcholine receptor antagonists inhibit chick scleral chondrocytes.

PURPOSE: Muscarinic acetylcholine receptors (mAChRs) have been implicated in the control of myopia in humans and in animal models. This study was conducted to determine whether mAChRs influence the growth of the chick sclera and, if so, which mAChR subtypes are involved. METHODS: Sclera and scleral chondrocytes from normal and form-deprived eyes of 10- to 14-day-old chicks were treated with a total of seven ligands: two agonists, carbachol (nonselective) and McN-A-343 (selective for the M1 mAChR subtype); and five antagonists, atropine (nonselective), pirenzepine and telenzepine (M1), gallamine (M2), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; M1 and M3). Incorporation of sulfate into glycosaminoglycans and of thymidine into DNA were quantified and normalized to sample DNA content. Possible toxicity of ligands at high doses was examined by analysis of cell number (by cell counting), viability (by trypan blue exclusion), and cellular metabolic activity (by dehydrogenase activity). RESULTS: Cellular proliferation and extracellular matrix production were inhibited by atropine in whole sclera and in its cartilaginous layer. Sulfate incorporation by chondrocytes from normal and form-deprived eyes was inhibited by mAChR antagonists with a rank order of potency (atropine > pirenzepine = 4-DAMP >> gallamine) consistent with regulation by M1, rather than M3 or M2 mAChR subtypes. Pirenzepine inhibited sulfate incorporation by chondrocytes from form-deprived eyes more effectively than those from normal eyes. Chondrocyte cultures were not viable when grown in high doses of any of the ligands used except gallamine. CONCLUSIONS: In chick scleral chondrocytes, synthesis of DNA and glycosaminoglycans was inhibited by mAChR antagonists. This inhibition was probably mediated by the M1 subtype mAChR. Therefore in vivo the sclera may be a site of action for the mAChR antagonists previously used to influence myopia. Although at high concentrations mAChR antagonists tested seemed to be toxic to chondrocytes, at lower doses inhibition occurred without toxic effects.

Food consumption and individual lifespan of adults of the blowfly, Calliphora stygia: a test of the 'rate of living' theory of aging.

Following eclosion, adult Calliphora stygia were individually housed (at 22 degrees C and 73% RH) in 125 ml plastic vials and provided with ad libitum access to either 0.125 or 0.2M sucrose as a food source and daily food consumption measured throughout their adult life. All blowflies were weighed daily and food consumed is determined by weighing individual food dishes. Blowflies provided with 0.125 M sucrose (N=59) consumed daily a significantly greater amount of the sucrose solution than those provided with 0.2M sucrose (n=55) such that the average rates of sucrose consumption were, respectively, 1.72 and 1.96 mg sucrose day(-1). There was no significant difference in the survival curves of the two populations with respective average (+/-SEM) lifespans being 25.4 (+/-1.2) and 26.5 (+/-1.2) days. The respective ranges of individual lifespans were 4-53 and 5-50 days. There was no statistically significant relationship between mass-specific rate of sucrose consumption and lifespan in either population but there were highly significant (P<0.0001) correlations between lifetime sucrose consumption and lifespan in both groups of blowflies. These findings contradict the predictions of the 'rate of living' theory of aging. In both populations of blowflies, body mass and the rate of food consumption were relatively constant through the adult life of blowflies, except that a few days before death both sucrose consumption and body mass showed a dramatic decline.

Antinociceptive effects of vaginal stimulation in rats: neurophysiological and behavioral studies.

The present studies extend previous findings that probing the vaginal cervix of rats blocks withdrawal reflexes and induces immobilization44. In the present studies, we report that this effect is apparently not due to an action on the final motor pathway, for limb or facial movement induced by electrical stimulation of the pyramidal tract was not suppressed by the probing. In contrast, the sensory response of neurons in the ventrobasal complex of the thalamus to noxious pinch stimulation was markedly attenuated by probing the vaginal cervix. However, the response of these neurons to gentle tactile stimulation was not attenuated, indicating a selective antinociceptive effect of the probing. The antinociceptive effect was not necessarily related to changes in arousal. These findings were supported by behavioral studies in which probing the vaginal cervix blocked vocalization in response to tail shock, and elevated the current threshold for eliciting vocalization in response to tail shock. Furthermore, during the probing, the rats were found to be capable of vocalizing in response to presumably non-noxious (lifting) stimulation, even though their vocalization response to noxious tail shock was suppresed. These studies suggest that probing the vaginal cervix rats exerts an analgesic action.

Expression of the Fos protein reveals functional subdivisions of the avian ventral lateral geniculate nucleus.

The Fos protein was immunocytochemically detected in the chick ventral lateral geniculate nucleus after novel stationary and optokinetic stimulation. Fos-positive nuclei were mainly detected in the internal part of the ventral geniculate when the animals were submitted to stationary visual stimulation. On the other hand, Fos-positive nuclei were mainly seen in the external part of the nucleus when optokinetic stimuli were used. These data reveal functional subdivisions of the avian ventral geniculate, and support the hypothesis that this nucleus is involved in several aspects of the visual function.