Modelling and Control of a 2-DOF Robot Arm with Elastic Joints for Safe Human-Robot Interaction.

Collaborative robots (or cobots) are robots that can safely work together or interact with humans in a common space. They gradually become noticeable nowadays. Compliant actuators are very relevant for the design of cobots. This type of actuation scheme mitigates the damage caused by unexpected collision. Therefore, elastic joints are considered to outperform rigid joints when operating in a dynamic environment. However, most of the available elastic robots are relatively costly or difficult to construct. To give researchers a solution that is inexpensive, easily customisable, and fast to fabricate, a newly-designed low-cost, and open-source design of an elastic joint is presented in this work. Based on the newly design elastic joint, a highly-compliant multi-purpose 2-DOF robot arm for safe human-robot interaction is also introduced. The mechanical design of the robot and a position control algorithm are presented. The mechanical prototype is 3D-printed. The control algorithm is a two loops control scheme. In particular, the inner control loop is designed as a model reference adaptive controller (MRAC) to deal with uncertainties in the system parameters, while the outer control loop utilises a fuzzy proportional-integral controller to reduce the effect of external disturbances on the load. The control algorithm is first validated in simulation. Then the effectiveness of the controller is also proven by experiments on the mechanical prototype.

Patient creates filtering bleb: hypotony following traumatic rupture of an old scleral incision for intracapsular cataract surgery.

An 86-year-old woman presented with symptomatic hypotony on the left eye since a few weeks, blurry vision and a very sensitive eye. She had a history of bilateral intracapsular cataract extraction (ICCE) in 1982 and secondary intraocular lens implantation in 1988. The patient mentioned a fall on the left side of the head 6 months earlier. The diagnosis of a superior scleral fistula was made, confirmed by gonioscopy and anterior segment optical coherence tomography. Direct surgical repair of the fistula led to a favourable outcome. This case demonstrates the occurrence of symptomatic hypotony due to the traumatic creation of a scleral fistula with an inadvertent filtering bleb many years after ICCE, and the resolution of signs and symptoms after surgical repair. Conventional as well as contemporary modalities can be valuable in the assessment of such fistulae. Management depends on the clinical course and the mechanism and extent of fistulation.

Pralatrexate in relapsed/refractory T-cell lymphoma: a retrospective multicenter study.

We present a retrospective multicenter study of pralatrexate treatment outcomes in an Australian practice setting for patients with relapsed/refractory T-cell lymphoma who had failed 1+ systemic therapies, treated via a compassionate access program. Endpoints assessed included response rates, toxicities, and subsequent therapies. Progression-free survival (PFS), time to next treatment (TTNT), event-free survival (EFS), overall survival (OS), and time to best response, were assessed by Kaplan-Meier analysis. The study included 31 patients, with median age 69 years. We demonstrated ORR of 35.5% (n = 11), including 4 complete responses (13%) and 7 partial responses (23%). The predicted median OS was 10 months, with EFS of 9 months, and PFS of 9 months. Median TTNT was 8 months. Mucositis was the most commonly observed toxicity. This study - the second largest real-world cohort reported to date - underscores the importance of pralatrexate in relapsed/refractory T-cell lymphoma, as well as its acceptable toxicity profile.

Fifteen years of IOL exchange: indications, outcomes, and complications.

PURPOSE: To report the indications, frequency, and outcomes regarding intraocular lens (IOL) exchange in 2 university hospital tertiary referral settings over a period of 15 years. SETTING: Ophthalmology departments of the University Hospital Antwerp and the University Hospital Leuven, Belgium. DESIGN: Retrospective cross-sectional study. METHODS: In this retrospective study, included were patients who underwent an IOL exchange between 2002 and 2017. Patient demographics, surgical indication, comorbidities, visual outcomes, and complications were reported. Patients who underwent IOL repositioning or add-on IOL implantation or extraction, and patients who were left aphakic, were excluded. RESULTS: Included in the study were 492 eyes. The mean age was 66.0 ± 13.3 years (range 19-91 years). The mean time between primary surgery and IOL exchange was 54.61 ± 67.07 months (range 0-343 months). Primary indication for explantation was IOL opacification, and the most common ophthalmic comorbidity was a previous history of vitreoretinal surgery. Preoperatively, the mean uncorrected visual acuity (UCVA) and corrected distance visual acuity (CDVA) were 0.47 ± 0.27 (range 0-1) and 0.61 ± 0.32 (range 0-1.2), respectively. Postoperative UCVA and CDVA was 0.7 ± 0.3 (range 0-1.2) and 0.8 ± 0.28 (range 0.05-1.6), respectively. The increase in both CDVA and UCVA was statistically significant (P < .001, paired t test). The most common complication perioperatively was vitreous prolapse, which occurred in 61 eyes (16%). CONCLUSIONS: IOL exchange is a challenging yet valuable treatment option for a wide spectrum of problematic IOL outcomes. The most common indication remains IOL opacification, although IOL dislocation and patient dissatisfaction are increasing as indications.

Donor-Related Nontuberculous Mycobacterial Interface Infection After Descemet Membrane Endothelial Keratoplasty.

PURPOSE: To describe the first reported case of Mycobacterium chelonae-related interface keratitis after Descemet membrane endothelial keratoplasty (DMEK), successfully treated with DMEK exchange. METHODS: A case of donor-related DMEK interface keratitis, treated with medical therapy and DMEK exchange, was studied retrospectively. RESULTS: A patient with Fuchs endothelial dystrophy developed infectious interface keratitis after DMEK. In cultures of the donor cornea transport medium, M. chelonae was isolated. Subsequent clinical investigation showed early signs of infectious keratitis with multiple infiltrates at the donor-graft interface. Cultures at the cornea bank of origin also showed M. chelonae, indicating a donor-related infection. Because of unsuccessful medical therapy, the DMEK graft was exchanged 4.5 months after initial DMEK. After 2 weeks, some interface precipitates appeared. These precipitates regressed over the following months with continued medical therapy. Antibiotic therapy was successfully ended 5 months after DMEK exchange. CONCLUSION: This case highlights the importance of early diagnosis and intensive treatment of nontuberculous mycobacterial interface keratitis. If intensive medical therapy is able to contain infection but fails to eradicate interface keratitis, DMEK exchange is a possible treatment option.

The role of the vitreous body in effective IOL positioning.

PURPOSE: To compare the effective lens position (ELP) after phaco surgery alone and after combined phacovitrectomy surgery. METHODS: Twenty patients who were scheduled for elective surgery in both eyes were included. In one eye, phacovitrectomy surgery was performed (without any tamponade), and in the fellow eye, only phaco surgery was performed using the same IOL type. Pre- and postoperative biometric measurements were performed using laser interference biometry. The postoperative anterior chamber depth (ACD) was measured to determine the ELP. The primary outcome measure was the difference in the postoperative ACD between both eyes. RESULTS: The postoperative ACD following phacovitrectomy showed a statistically significant increase compared with that following phaco surgery alone, indicating a more posterior position of the IOL. CONCLUSIONS: An adjusted ELP parameter to optimize IOL calculation may be useful in eyes undergoing combined phacovitrectomy sugergy.

Clinical Practice: A Proposed Standardized Ophthalmological Assessment for Patients with Cystinosis.

Cystinosis is a rare autosomal recessive disease with an incidence of approximately 1 case per 100,000-200,000 live births. Over the years, gaining in-depth knowledge of the disease has led to vast improvement in patient life expectancy. However, debilitating, extra-renal manifestations such as eye disease, in particular corneal crystal deposition and its associated photophobia, still occur frequently, regardless of patient age and notwithstanding the increased implementation of systemic therapy. Ophthalmological assessment has not yet been standardized. The aim of this article was to provide clear recommendations for ophthalmological assessment during follow-up of patients with cystinosis to improve quality and regularity of ophthalmological care and thereby minimize ophthalmological complications. A literature search was performed to assess previous and current recommendations on examinations to conduct during follow-up of patients with cystinosis. Multidisciplinary cystinosis clinics were set up in collaboration with the Department of Ophthalmology and the Department of Pediatric Nephrology to allow patients to be seen by a nephrologist, an ophthalmologist and other specialists on the same day. Based on the results of these multidisciplinary clinics the standardized clinical ophthalmological assessment was drafted. This is a protocol for follow-up, describing the approach taken regarding ophthalmological follow-up of patients with cystinosis, considering the different types of the disease and the time since diagnosis. Standard examination includes history, visual acuity, tonometry and slit-lamp examination, with fundus photography performed at diagnosis and annually thereafter. Confocal microscopy is the imaging modality of choice, while anterior segment optical coherence tomography (OCT) is a good alternative. Finally, posterior segment OCT for imaging of the macular region and optic nerve should be conducted on an annual basis.

Fracture types and risk factors in men with prostate cancer on androgen deprivation therapy: a matched cohort study of 19,079 men.

PURPOSE: Accumulating evidence shows that androgen deprivation therapy is associated with osteoporosis and fragility fractures of the spine, hip and wrist. One study suggested that androgen deprivation therapy may also be associated with nonfragility fractures in older men. Whether other clinical risk factors independently increase the risk of fractures is not certain. MATERIALS AND METHODS: Using linked administrative databases in Ontario, Canada, we matched 19,079 men 66 years old or older with prostate cancer with at least 6 months of continuous androgen deprivation therapy or bilateral orchiectomy with men with prostate cancer who had never received androgen deprivation. Matching variables were age, prior cancer treatment, diagnosis year, comorbidity, medication, prior fractures and socioeconomic variables. Primary outcomes were a typical fragility fracture of the spine, hip or wrist and any fracture. Independent predictors of fracture outcomes were assessed with Cox proportional hazards models. RESULTS: At a mean 6.47-year followup androgen deprivation therapy was associated with an increased risk of fragility fracture (HR 1.65, 95% CI 1.53-1.78) and any fracture (HR 1.46, 95% CI 1.39-1.54). Independent predictors of fragility and any fracture were increasing age, prior bone thinning medications, chronic kidney disease, prior dementia, prior fragility fracture and prior osteoporosis diagnosis or treatment (p <0.05). CONCLUSIONS: Continuous androgen deprivation therapy for at least 6 months is associated with an increased risk of fracture. Increasing age, prior osteoporotic fracture and dementia are important clinical factors that may warrant greater consideration of anti-osteoporotic therapy in these men.

Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study.

OBJECTIVE: To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen's effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6). DESIGN: Population based cohort study. PARTICIPANTS: Women living in Ontario aged 66 years or older treated with tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI. MAIN OUTCOME MEASURES: Risk of death from breast cancer after completion of tamoxifen treatment, as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed. RESULTS: Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P<0.05 for each comparison). By contrast, no such risk was seen with other antidepressants. We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) patients so treated; the risk with more extensive overlap would be greater. CONCLUSION: Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.

Impact of androgen deprivation therapy on cardiovascular disease and diabetes.

PURPOSE Use of androgen deprivation therapy (ADT) may be associated with an increased risk of diabetes mellitus but the risk of both acute myocardial infarction (AMI) and cardiovascular mortality remain controversial because few outcomes and conflicting findings have been reported. We sought to clarify whether ADT is associated with these outcomes in a large, representative cohort. METHODS Using linked administrative databases in Ontario, Canada, men age 66 years or older with prostate cancer given continuous ADT for at least 6 months or who underwent bilateral orchiectomy (n = 19,079) were matched with men with prostate cancer who had never received ADT. Treated and untreated groups were matched 1:1 (ie, hard-matched) on age, prior cancer treatment, and year of diagnosis and propensity-matched on comorbidities, medications, cardiovascular risk factors, prior fractures, and socioeconomic variables. Primary outcomes were development of AMI, sudden cardiac death, and diabetes. Fragility fracture was also examined. Results The cohort was observed for a mean of 6.47 years. In time-to-event analyses, ADT use was associated with an increased risk of diabetes (hazard ratio [HR], 1.16; 95% CI, 1.11 to 1.21) and fragility fracture (HR, 1.65; 95% CI, 1.53 to 1.77) but not with AMI (HR, 0.91; 95% CI, 0.84 to 1.00) or sudden cardiac death (HR, 0.96; 95% CI, 0.83 to 1.10). Increasing duration of ADT was associated with an excess risk of fragility fractures and diabetes but not cardiac outcomes. CONCLUSION Continuous ADT use for at least 6 months in older men is associated with an increased risk of diabetes and fragility fracture but not AMI or sudden cardiac death.

Frosted branch angiitis with undiagnosed Hodgkin lymphoma.

PURPOSE: To report the case of a patient with bilateral frosted branch angiitis and undiagnosed Hodgkin lymphoma. METHODS: Review of clinical history, laboratory findings, histology of supraclavicular lymph node biopsy, and follow-up. RESULTS: A 22-year-old man presented with a sudden, bilateral visual loss. Fundus examination and fluorescein angiography disclosed a bilateral frosted branch angiitis that was dramatically responsive to systemic corticosteroid therapy. Laboratory tests were unremarkable but radiologic studies showed extensive mediastinal and supraclavicular lymphadenopathy. A supraclavicular lymph node biopsy led to the diagnosis of nodular sclerosis Hodgkin lymphoma. CONCLUSIONS: The occurrence of frosted branch angiitis in combination with classical Hodgkin lymphoma, although possibly coincidental, raises the possibility of a paraneoplastic syndrome. Thus, we suggest that, for patients with frosted branch angiitis, Hodgkin lymphoma should be considered in the diagnostic workup.

Angiotensin inhibition in renovascular disease: a population-based cohort study.

BACKGROUND: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers effectively reduce blood pressure in patients with renovascular disease (RVD); yet, randomized cardiovascular prevention trials of these drugs typically exclude individuals with this condition. PATIENTS AND METHODS: We studied the association of renin-angiotensin system inhibition with prognosis in a population-based cohort comprising 3,570 patients with RVD in Ontario, Canada; slightly more than half (n = 1,857, 53%) were prescribed angiotensin inhibitors. The primary outcome was the composite of death, myocardial infarction, or stroke. Secondary outcomes included individual cardiovascular and renal events. RESULTS: Patients receiving angiotensin inhibitors had a significantly lower risk for the primary outcome during follow-up (10.0 vs 13.0 events per 100 patient-years at risk, multivariable adjusted hazard ratio [HR] 0.70, 95% CI 0.59-0.82). In addition, hospitalization for congestive heart failure (HR 0.69, 95% CI 0.53-0.90), chronic dialysis initiation (HR 0.62, 95% CI 0.42-0.92), and mortality (HR 0.56, 95% CI 0.47-0.68) was lower in treated patients. Conversely, patients receiving angiotensin inhibitors were significantly more likely to be hospitalized for acute renal failure during follow-up (HR 1.87, 95% CI 1.05-3.33; 1.2 vs 0.6 events per 100 patient-years at risk). CONCLUSIONS: These data emphasize the high vascular risk of RVD and suggest that angiotensin inhibitors may improve prognosis in this setting at the expense of acute renal toxicity. If the latter are selected in the management of RVD, renal function parameters should be assiduously followed.

Pergolide associated cardiac valvulopathy based on Ontario administrative data.

INTRODUCTION: Pergolide is an ergot derived dopamine agonist that is widely used for the treatment of Parkinson's disease. Studies have found an association between pergolide and valvular heart abnormalities although there is still much to be learned about the clinical significance of the valvular changes, who is at risk, and whether there is duration of exposure effect. OBJECTIVE: To assess the long term risk of hospital admissions for valvular heart disease (VHD) or congestive heart failure (CHF, a clinically overt outcome of VHD) in new users of pergolide compared to new users of levodopa. The secondary objective was to assess whether there are any characteristics that can predict who is at higher risk of developing this outcome. DESIGN: Retrospective, population-based cohort study. SETTING: Ontario, Canada. SUBJECTS: Ontario residents aged 66 and older, newly started on treatment with either pergolide or levodopa. OUTCOMES: Admission to hospital with the most responsible diagnosis of congestive heart failure or valvular heart disease. RESULTS: The risk for admission for valvular heart disease or congestive heart failure were higher in those with 1-4 years exposure to pergolide compared with no exposure to pergolide (VHD: hazard ratio 2.4, p = 0.04; CHF: hazard ratio 1.6, p = 0.02). No such pattern was found with exposure to levodopa. CONCLUSION: Our study demonstrates that treatment with pergolide is associated with a higher risk of hospital admission for valvular heart disease or congestive heart failure and that this risk is greater in those with 1-4 years exposure than in those with less exposure. We did not find an increased risk beyond four years.

Polytherapy with two or more antihypertensive drugs to lower blood pressure in elderly Ontarians. Room for improvement.

BACKGROUND: Although guidelines now recommend polytherapy to achieve blood pressure targets, little is know about which antihypertensive drugs are combined in clinical practice. OBJECTIVE: To examine current practices for the coprescribing of antihypertensive agents. METHODS: A population-based cohort study was performed using linked administrative databases on all Ontario residents 66 years of age or older who were newly treated for hypertension between July 1, 1994, and March 31, 2002, and did not have diabetes or other relevant comorbidities. All patients were followed for two years to determine which antihypertensives were prescribed concurrently. RESULTS: Of the 166,018 patients in the described cohort, 1819 (1%) were prescribed a combination therapy tablet as their first-line therapy. The number of patients prescribed antihypertensive polytherapy within the first two years of diagnosis increased from 2071 (21%) of the 9825 hypertensive patients starting treatment in the second half of 1994 to 2578 (37%) of the 6988 hypertensive patients beginning treatment in the first quarter of 2002 (P<0.0001). Overall, 11,003 (27%) of polytherapy prescriptions were for drugs without additive hypotensive effects when combined and this proportion did not change over time. CONCLUSIONS: Although there has been an increase in the use of polytherapy in elderly hypertensive patients without comorbidities in Ontario over the past decade, more than one-quarter of the two drugs prescribed together have not been proven to have additive hypotensive effects. Because this likely contributes to suboptimal blood pressure control rates, future guidelines and educational programs should devote increased attention to the choice of optimal polytherapy combinations.

Antihypertensive medication prescribing in 27,822 elderly Canadians with diabetes over the past decade.

OBJECTIVE: The purpose of this study was to examine whether prescribing practices for elderly individuals with diabetes and hypertension changed over the past decade. RESEARCH DESIGN AND METHODS: We linked the Ontario Diabetes Database and four administrative databases in Ontario, Canada, to identify 27,822 patients >65 years of age who had diabetes and were newly treated for hypertension between 1 January 1995 and 31 December 2001. All patients were followed for 2 years after their initial antihypertensive medication prescription. RESULTS: The 27,822 patients in this study (mean age 72 years, 51% men) were treated with oral hypoglycemic agents alone (n = 17,128 patients, 62%), insulin alone (n = 2,346, 8%), both oral hypoglycemic agents and insulin (n = 2,205, 8%), or diet alone (n = 6,143, 22%). Management within the first 2 years of hypertension diagnosis consisted of antihypertensive monotherapy in 20,183 patients (73%), two antihypertensive drugs in 6,207 (22%), and three or more drugs in 1,432 (5%); the most frequently chosen antihypertensive drugs were ACE inhibitors (68%), thiazides (15%), and calcium channel blockers (9%). Between 1995 and 2001, physician prescribing practices changed: the population-adjusted rates of antihypertensive drug prescribing increased by 46% (95% CI 33-55%), the proportion of initial antihypertensive prescriptions for ACE inhibitors increased from 54 to 76% (P < 0.0001), and the use of multiple antihypertensive agents within the first 2 years of diagnosis increased from 21 to 32% (P < 0.0001). CONCLUSIONS: Antihypertensive prescribing patterns in elderly individuals with diabetes changed over the past decade in Ontario in directions consistent with the evolving evidence base.

The impact of the Canadian Hypertension Education Program on antihypertensive prescribing trends.

Although previous studies have shown that hypertension management has improved in Canada during the past decade, this study was designed to determine whether these changes were temporally related to initiation of the Canadian Hypertension Education Program in 1999. Antihypertensive prescription rates in Ontario were compared using time series analyses before and after 1999 in 2 Ontario cohorts: all hypertensives prescribed therapy (using the Intercontinental Medical Statistics CompuScript Database) and all elderly hypertensives without diabetes prescribed therapy (using linked administrative databases including the Ontario Drug Benefit Database). Between January 1998 and December 2003, &280 million prescriptions for antihypertensive agents were filled in Ontario, and total antihypertensive prescriptions increased by 58% annually; time series analyses confirmed that the prescribing rates for total antihypertensives, thiazide diuretics, beta-blockers, and calcium channel blockers increased significantly after 1999, even after adjustment for the temporal trends in the pre-1999 data. In the 166,018 nondiabetic individuals over age 65 who were newly treated for hypertension in Ontario between July 1994 and March 2002, changes in prescription rates for total antihypertensive drugs, angiotensin-converting enzyme inhibitors, beta blockers, and calcium channel blockers occurred in directions that were consistent with guideline recommendations and were statistically significantly related to the initiation of the Canadian Hypertension Education Program. The substantial changes in prescription rates for guideline-recommended antihypertensive drug classes in elderly Ontarians without diabetes and the general Ontario population seen in the past decade are temporally related to the initiation of the Canadian Hypertension Education Program.

Hypertension management in the elderly has improved: Ontario prescribing trends, 1994 to 2002.

To examine whether the treatment of elderly hypertensives had become more aggressive over the past decade, we evaluated: (1) the frequency of new prescriptions for hypertension treatment, adjusted by age and gender; (2) the frequency with which multiple antihypertensives were prescribed concurrently within 2 years of initial diagnosis; and (3) discontinuation rates for antihypertensive therapy. We linked 4 administrative databases and a province-wide clinical database in Ontario, Canada, to derive a cohort of patients > or =66 years of age who were newly started on an antihypertensive agent between July 1, 1994, and March 31, 2002, without another indication for the agent (all patients were followed for 2 years after their initial antihypertensive prescription). Our cohort consisted of 196 451 people newly started on antihypertensive therapy, 30 433 of whom also had diabetes mellitus. The population-adjusted rate of new antihypertensive prescriptions increased by 30% between 1994 and 2002. Whereas 21% of patients newly diagnosed with hypertension in 1994 were prescribed multiple antihypertensives concurrently within 2 years of diagnosis, this proportion had increased to 40% by 2002 (P<0.0001). In the cohort of patients first prescribed an antihypertensive in 1994, 36% were not taking any antihypertensive within 2 years; only 21% of patients first prescribed an antihypertensive in 2002 had discontinued all therapy within 2 years (P<0.0001). Our data provide evidence that the physician management of hypertension in elderly Canadians became more aggressive between 1994 and 2002.

Lack of estrogen increases pain in the trigeminal formalin model: a behavioural and immunocytochemical study of transgenic ArKO mice.

In order to examine the effect of estrogen on facial pain, we first compared the face-rubbing evoked by a formalin injection in the lip of aromatase-knockout (ArKO) mice, lacking endogenous estrogen production, 17 beta-estradiol-treated ArKO mice (ArKO-E2) and wild-type (WT) littermates. During the 'acute' phase of pain the time spent rubbing was similar in the three groups, whereas during the following 'interphase' and the second phase of pain, grooming was increased in ArKO mice. Estradiol-treatment restored a behaviour similar to WT group. To better understand estrogens modulation on pain processes, we examined changes in 5-HT and CGRP innervations of trigeminal nucleus caudalis (TNC) in ArKO, ArKO-E2 and WT groups sacrificed during the interphase. Whereas serotonin and CGRP immunoreactivities were comparable in WT and ArKO non-injected control groups, our data showed that 9 min after formalin injection, the density of serotoninergic terminals increased significantly in WT, but not in ArKO mice, while that of CGRP-immunoreactive fibers was lower in WT than in ArKO mice on the injected side. Estradiol-treatment only partially reversed these changes in ArKO-E2 mice. We conclude that estrogen deprivation in ArKO mice can be responsible for increased nociceptive response and that it is accompanied by transmitter changes favouring pro- over anti-nociceptive mechanisms in TNC during interphase of the formalin model. That estradiol-treatment completely reverses the behavioural abnormality suggests that estrogens absence produces chiefly functional activation-dependent changes. However, the fact that the immunohistochemical abnormalities were not totally normalized by estradiol-treatment suggested that some permanent developmental alterations may occur in ArKO mice.