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1.
Ocul Surf ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32422285

RESUMO

PURPOSE: To evaluate the effects of topical castor oil application to the eyelids on ocular surface and tear film parameters in patients with blepharitis. METHODS: Twenty-six participants (14 females, 12 males; mean ±â€¯SD age, 38 ±â€¯21 years) with clinical signs of blepharitis were enrolled in a prospective, investigator-masked, randomized, paired-eye trial. A 100% cold pressed castor oil formulation (Lotus Garden Botanicals, Biddeford, ME, USA) was applied to the eyelids of one eye (randomized), twice daily for 4 weeks. Ocular surface characteristics, symptoms, and tear film parameters were assessed at baseline and day 28. RESULTS: Baseline measurements did not differ between treated and control eyes (all p > 0.05). A significant reduction in OSDI symptomology score was observed following the four-week treatment period (p = 0.001). Clinical improvements in eyelid margin thickening, telangiectasia, eyelash matting, madarosis, cylindrical dandruff, and lid wiper epitheliopathy were limited to treated eyes (all p < 0.01), while greater decreases in staphylococcal and seborrheic eyelash crusting were observed in treated than control eyes (both p < 0.05). No adverse events were reported during the treatment period. CONCLUSION: Topical castor oil application effected significant improvements in ocular surface signs and symptoms in patients with blepharitis. The favourable therapeutic profile would suggest that castor oil demonstrates promise as a potential treatment for blepharitis, and support further efficacy trials with longer follow up. TRIAL REGISTRATION NUMBER: ACTRN12618000856213.

2.
Eur J Heart Fail ; 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32353205

RESUMO

AIMS: Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of 'health deficits' across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Using a cumulative deficits approach, we constructed a 42-item frailty index (FI) and applied it to identify frail patients enrolled in two HFrEF trials (PARADIGM-HF and ATMOSPHERE). In keeping with previous studies, patients with FI ≤0.210 were classified as non-frail and those with higher scores were divided into two categories using score increments of 0.100. Clinical outcomes were examined, adjusting for prognostic variables. Among 13 625 participants, mean (± standard deviation) FI was 0.250 (0.10) and 8383 patients (63%) were frail (FI >0.210). The frailest patients were older and had more symptoms and signs of heart failure. Women were frailer than men. All outcomes were worse in the frailest, with high rates of all-cause death or all-cause hospitalization: 40.7 (39.1-42.4) vs. 22.1 (21.2-23.0) per 100 person-years in the non-frail; adjusted hazard ratio 1.63 (1.53-1.75) (P < 0.001). The rate of all-cause hospitalizations, taking account of recurrences, was 61.5 (59.8-63.1) vs. 31.2 (30.3-32.2) per 100 person-years (incidence rate ratio 1.76; 1.62-1.90; P < 0.001). CONCLUSION: Frailty is highly prevalent in HFrEF and associated with greater deterioration in quality of life and higher risk of hospitalization and death. Strategies to prevent and treat frailty are needed in HFrEF.

4.
JACC Heart Fail ; 8(3): 188-198, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31926854

RESUMO

OBJECTIVES: The purpose of this study was to investigate the effects of mineralocorticoid receptor antagonists (MRAs) on systolic blood pressure (SBP) and outcomes according to baseline SBP in patients with heart failure with reduced ejection fraction (HFrEF). BACKGROUND: MRAs are greatly underused in patients with HFrEF, often because of fear of adverse events. Concern about hypotension has been raised by the demonstration that MRAs are particularly effective treatment for resistant hypertension. METHODS: The effect of MRA therapy was studied in 4,396 patients with HFrEF randomized in the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. RESULTS: Mean SBP change from baseline to 6 months was +1.4 ± 18.1 mm Hg in the placebo group and -1.2 ± 17.9 mm Hg in the MRA group. The between-treatment difference was 2.6 mm Hg (95% confidence interval [CI]: 1.5 to 3.6; p < 0.001). All outcomes were reduced by MRA therapy overall, with consistent effects across SBP categories (e.g., all-cause mortality, overall hazard ratio [HR] of 0.72; 95% CI: 0.64 to 0.82; p < 0.001; SBP ≤105 mm Hg; HR: 0.72; 95% CI: 0.56 to 0.94; SBP >105 to ≤115 mm Hg; HR: 0.78; 95% CI: 0.60 to 1.02; SBP >115 to ≤125 mm Hg; HR: 0.71; 95% CI: 0.53 to 0.94; SBP >125 to ≤135 mm Hg; HR: 0.79; 95% CI: 0.57 to 1.10; and SBP > 135 mm Hg; HR: 0.67; 95% CI: 0.50 to 0.90; p for interaction = 0.95). Hypotension was infrequent and not more common with MRA therapy than with placebo, overall (4.6% vs. 3.9%; p = 0.25) or in any SBP category. CONCLUSIONS: MRA treatment had little effect on SBP in patients with HFrEF, and the clinical benefits were not modified by baseline SBP. MRA treatment infrequently caused hypotension, even when the baseline SBP was low. The treatment discontinuation rates between MRA and placebo therapy were similar. Low SBP is not a reason to withhold MRA therapy in patients with HFrEF.

5.
Catheter Cardiovasc Interv ; 95(2): 232-241, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31264314

RESUMO

AIM: Evaluate sex differences in procedural net adverse clinical events and long-term outcomes following rotational atherectomy (RA). METHODS AND RESULTS: From August 2010 to 2016, 765 consecutive patients undergoing RA PCI were followed up for a median of 4.7 years. 285 (37%) of subjects were female. Women were older (mean 76 years vs. 72 years; p < .001) and had more urgent procedures (64.6 vs. 47.3%; p < .001). Females received fewer radial procedures (75.1 vs. 85.1%; p < .001) and less intravascular imaging guidance (16.8 vs. 25.0%; p = .008). After propensity score adjustment, the primary endpoint of net adverse cardiac events (net adverse clinical events: all-cause death, myocardial infarction, stroke, target vessel revascularization plus any procedural complication) occurred more often in female patients (15.1 vs. 9.0%; adjusted OR 1.81 95% CI 1.04-3.13; p = .037). This was driven by an increased risk of procedural complications rather than procedural major adverse cardiac events (MACE). Specifically, women were more likely to experience coronary dissection (4.6 vs. 1.3%; p = .008), cardiac tamponade (2.1 vs. 0.4%; p = .046) and significant bleeding (BARC ≥2: 5.3 vs. 2.3). Despite this, overall MACE-free survival was similar between males and females (adjusted HR 1.03; 95% CI 0.80-1.34; p = .81). Procedural complications during RA were associated with almost double the incidence of MACE at long-term follow-up (HR 1.92; 95% CI 1.34-2.77; p < .001). CONCLUSION: Women may be at greater risk of procedural complications following rotational atherectomy. These include periprocedural bleeding episodes and coronary perforation leading to cardiac tamponade. Despite this, the adjusted overall long-term survival free of major adverse cardiac events was similar between males and females.

6.
Circulation ; 141(5): 338-351, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31736337

RESUMO

BACKGROUND: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men. METHODS: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. RESULTS: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men. CONCLUSIONS: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

7.
Eur J Heart Fail ; 21(12): 1532-1533, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31815336
8.
Surg Obes Relat Dis ; 15(9): 1554-1562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31375443

RESUMO

BACKGROUND: Use of liposomal bupivacaine (LB) in surgery is reported with decreased postoperative opioid requirements. The efficacy of LB versus standard bupivacaine injections at laparoscopic port sites during bariatric surgery is unknown. OBJECTIVES: To determine whether there was a difference in postoperative hospital opioid requirements after port site injections of LB versus standard bupivacaine during laparoscopic bariatric surgeries. Primary endpoint was total in hospital opioid use expressed as morphine-equivalent use. Secondary endpoints included home opioid use, pain scores, hospital length of stay, and adverse events. SETTING: Academic-affiliated private practice. METHODS: A 2-group randomized, double-blinded trial from November 2017 to August 2018 with patients randomly assigned to receive either LB or bupivacaine alone at trocar site injections during laparoscopic Roux-en-Y gastric bypass (LRYGB) or vertical sleeve gastrectomy (VSG). All patients underwent enhanced recovery after bariatric surgery protocols. RESULTS: All patients undergoing LRYGB or VSG assessed for eligibility. Of 682 patients undergoing LRYGB or VSG, 231 met inclusion criteria, 52 patients excluded intraoperatively. Among 231 patients (mean age, 39.2 years; 79% women; mean body mass index 45.0), 179 patients (77%) completed the trial. Patients randomly assigned to receive either LB (n = 89) or bupivacaine alone (n = 90) at trocar site injection during LRYGB or VSG. Postoperative morphine-equivalent use were similar (LB 8.3 [standard deviation 4.0-13.9] versus bupivacaine group 7.5 [standard deviation 3.6-13.1] P = .94) with highest requirement in first 4 hours after surgery. There was no significant difference in length of stay, pain scores, or complications. There were more patients in the bupivacaine group that did not take pain medications on postoperative days 2 to 4 (P = .032, P = .23, P = .005, respectively). There were more patients in the bupivacaine group 48.1% (n = 39) compared with the LB group 34.2% (n = 27) that did not consume any narcotic tablets at home but this not found to be statistically significant (P value = .07). CONCLUSIONS: Among patients undergoing primary bariatric surgery under enhanced recovery after bariatric surgery protocol, there was no significant difference in postoperative hospital opioid use in those receiving LB compared with standard bupivacaine. A greater percentage of patients in the standard bupivacaine group did not require any narcotics at home, which was significant on postoperative days 2 to 4. To become completely opioid free after bariatric surgery, resources should be focused on multimodal approaches instead of reliance on type of anesthetic medication used.

10.
Surg Endosc ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31342260

RESUMO

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been extensively proven in lower gastrointestinal surgery to decrease postoperative physiologic stress and length of stay (LOS). ERAS in bariatric surgery (ERABS) varies immensely from each program with inconsistent results with a predominant goal of reducing LOS. Our focus in implementing enhanced recovery after bariatric surgery (ERABS) protocols is aimed at reducing postoperative pain and opioid use. METHODS: This is a retrospective review of patients who underwent laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (VSG) at a single high-volume center from June 2016 to October 2017. Patients on previous standard protocol were categorized into "Pre-Liposomal Bupivacaine (LB) group." After routine use of Exparel™, patients were grouped into "LB group." After ERABS protocol was initiated, patients were categorized into "ERABS/LB group." Postoperative opioids were converted to morphine equivalents units (MEU); pain scores, LOS, and 30-day outcomes were analyzed using combination of t test and Mann-Whitney U. RESULTS: A total of 1340 patients were included in the study: 304 patients in pre-LB group; 754 patients in LB group, and 282 patients in ERABS/LB group. Total hospital opioid use was 58.6 MEU in pre-LB, 40.8 MEU in LB, and 23.8 MEU in ERABS/LB (p = 0.01). ERABS/LB group found a 59.5% decline in MEU requirements compared to pre-LB (p < 0.001) and 44.9% of patients did not require any additional narcotics on the floor compared to 0% in pre-LB group (p < 0.001). ERABS/LB LOS was an average of 1.48 days compared to 1.54 days in pre-LB group (p = 0.03) with an overall decrease of 3.74% in readmission rates (p = 0.03). CONCLUSIONS: Implementation of ERABS significantly reduced postoperative opioid use, LOS, and readmissions. With ERABS, a more profound effect was observed than simply adding Exparel™ to preexisting protocols. Almost half of these patients did not require narcotics while recovering on the surgical floor. More studies are required to assess the true effect of ERABS without use of Exparel™.

11.
Ann Thorac Surg ; 108(5): 1369-1375, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31255616

RESUMO

BACKGROUND: We introduced a new algorithm utilizing a patient's own platelet rich plasma and factor concentrates to better manage coagulopathy in aortic surgery under circulatory arrest. This study compares the outcomes of the patients treated with a new algorithm with those of patients managed with our traditional approach. METHODS: The data of 247 consecutive patients who had aortic surgery were analyzed. The 158 patients (group 1) who were managed with our usual algorithm were compared with the 89 patients (group 2) who were treated with the novel algorithm consisting of utilization of the patient's own platelet rich plasma, fibrinogen, and prothrombin cell concentrates. Differences in transfusion and intensive care unit stay were analyzed. Univariate and multivariable robust regression analyses were performed. RESULTS: In comparison with group 1, patients in group 2 had significantly reduced need for transfusion of red cells (7.9 ± 8.6 vs 3.5 ± 3.8 units, P < .001). Postoperative intubation time was reduced from a mean of 42 hours to a mean of 12 hours (P < .001). The time to medical discharge from the intensive care unit was reduced from a mean of 7 days to a mean of 5 days (P < .001), favoring the new algorithm. After adjustment for demographics and comorbidities, the novel algorithm remained significantly associated with a reduction in units of red blood cells transfused (robust parameter estimate, -1.14; P = .027) and blood products transfused (robust parameter estimate, -5.11; P < .001). CONCLUSIONS: Using autologous plasma and factor concentrates to reverse coagulopathy in aortic surgery significantly reduces blood product transfusion.

12.
Eur J Heart Fail ; 21(7): 827-843, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31243866

RESUMO

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the months following delivery in women without another known cause of heart failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism, myocardial infarction, hypertensive heart disease during pregnancy, and pre-existing heart disease. A genetic contribution is present in up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high probability of partial and often full recovery. Use of guideline-directed pharmacological therapy for HFrEF is recommended in all patients respecting contraindications during pregnancy/lactation. The oxidative stress-mediated cleavage of the hormone prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological blockade of prolactin release using bromocriptine as a disease-specific therapy in addition to standard therapy for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable cardioverter-defibrillators, cardiac resynchronization therapy and implanted long-term ventricular assist devices) are higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and counselling around contraception and future pregnancies is emphasised.

13.
Eur J Heart Fail ; 20(6): 951-962, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29578284

RESUMO

Peripartum cardiomyopathy is an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause for heart failure is identified. Outcome varies from full recovery to residual left ventricular systolic dysfunction and even death. Many women return to their physician to acquire information on their long-term prognosis, to seek medical advice regarding contraception, or when planning a subsequent pregnancy. This position paper summarizes current evidence for long-term outcome, risk stratification of further pregnancies and overall management. Based on the best available evidence, as well as the clinical experience of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy members, a consensus on pre- and postpartum management algorithms for women undergoing a subsequent pregnancy is presented.


Assuntos
Cardiologia , Cardiomiopatias , Gerenciamento Clínico , Insuficiência Cardíaca , Período Periparto , Guias de Prática Clínica como Assunto , Sociedades Médicas , Cardiomiopatias/complicações , Cardiomiopatias/fisiopatologia , Cardiomiopatias/terapia , Anticoncepção , Europa (Continente) , Feminino , Previsões , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Morbidade/tendências , Gravidez
15.
Eur J Neurosci ; 46(1): 1663-1672, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28493650

RESUMO

Retinitis pigmentosa (RP) is a group of hereditary retinal diseases, characterised by photoreceptor cell loss. Despite a substantial understanding of the mechanisms leading to cell death, an effective therapeutic strategy is sought. Our laboratory has previously demonstrated the neuroprotective properties of Norgestrel, a progesterone analogue, in the degenerating retina, mediated in part by the neurotrophic factor basic fibroblast growth factor (bFGF). In other retinal studies, we have also presented a pro-survival role for reactive oxygen species (ROS), downstream of bFGF. Thus, we hypothesized that Norgestrel utilises bFGF-driven ROS production to promote photoreceptor survival. Using the 661W photoreceptor-like cell line, we now show that Norgestrel, working through progesterone receptor membrane complex 1 (PGRMC1); generates an early burst of pro-survival bFGF-induced ROS. Using the rd10 mouse model of RP, we confirm that Norgestrel induces a similar early pro-survival increase in retinal ROS. Norgestrel-driven protection in the rd10 retina was attenuated in the presence of antioxidants. This study therefore presents an essential role for ROS signalling in Norgestrel-mediated neuroprotection in vitro and demonstrates that Norgestrel employs a similar pro-survival mechanism in the degenerating retina.


Assuntos
Fármacos Neuroprotetores/farmacologia , Norgestrel/farmacologia , Células Fotorreceptoras/metabolismo , Progesterona/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Retinite Pigmentosa/metabolismo , Animais , Linhagem Celular , Feminino , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Fotorreceptoras/efeitos dos fármacos , Receptores de Progesterona/metabolismo , Transdução de Sinais
16.
Sci Rep ; 7: 43067, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-28216676

RESUMO

Retinitis pigmentosa (RP) encompasses a group of retinal diseases resulting in photoreceptor loss and blindness. We have previously shown in the rd10 mouse model of RP, that rd10 microglia drive degeneration of viable neurons. Norgestrel, a progesterone analogue, primes viable neurons against potential microglial damage. In the current study we wished to investigate this neuroprotective effect further. We were particularly interested in the role of fractalkine-CX3CR1 signaling, previously shown to mediate photoreceptor-microglia crosstalk and promote survival in the rd10 retina. Norgestrel upregulates fractalkine-CX3CR1 signaling in the rd10 retina, coinciding with photoreceptor survival. We show that Norgestrel-treated photoreceptor-like cells, 661Ws, and C57 explants modulate rd10 microglial activity in co-culture, resulting in increased photoreceptor survival. Assessment of Norgestrel's neuroprotective effects when fractalkine was knocked-down in 661 W cells and release of fractalkine was reduced in rd10 explants confirms a crucial role for fractalkine-CX3CR1 signaling in Norgestrel-mediated neuroprotection. To further understand the role of fractalkine in neuroprotection, we assessed the release of 40 cytokines in fractalkine-treated rd10 microglia and explants. In both cases, treatment with fractalkine reduced a variety of pro-inflammatory cytokines. These findings further our understanding of Norgestrel's neuroprotective properties, capable of modulating harmful microglial activity indirectly through photoreceptors, leading to increased neuroprotection.


Assuntos
Receptor 1 de Quimiocina CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Neuroproteção , Norgestrel/farmacologia , Retina/metabolismo , Transdução de Sinais , Animais , Células Cultivadas , Citocinas , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras/fisiologia , Progesterona/farmacologia , Retina/efeitos dos fármacos , Retina/fisiologia
17.
PLoS One ; 11(11): e0165197, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27814376

RESUMO

Retinitis pigmentosa (RP) is a degenerative disease leading to photoreceptor cell loss. Mouse models of RP, such as the rd10 mouse (B6.CXBl-Pde6brd10/J), have enhanced our understanding of the disease, allowing for development of potential therapeutics. In 2011, our group first demonstrated that the synthetic progesterone analogue 'Norgestrel' is neuroprotective in two mouse models of retinal degeneration, including the rd10 mouse. We have since elucidated several mechanisms by which Norgestrel protects stressed photoreceptors, such as upregulating growth factors. This study consequently aimed to further characterize Norgestrel's neuroprotective effects. Specifically, we sought to investigate the role that microglia might play; for microglial-derived inflammation has been shown to potentiate neurodegeneration. Dams of post-natal day (P) 10 rd10 pups were given a Norgestrel-supplemented diet (80mg/kg). Upon weaning, pups remained on Norgestrel. Tissue was harvested from P15-P50 rd10 mice on control or Norgestrel-supplemented diet. Norgestrel-diet administration provided significant retinal protection out to P40 in rd10 mice. Alterations in microglial activity coincided with significant protection, implicating microglial changes in Norgestrel-induced neuroprotection. Utilizing primary cultures of retinal microglia and 661W photoreceptor-like cells, we show that rd10 microglia drive neuronal cell death. We reveal a novel role of Norgestrel, acting directly on microglia to reduce pro-inflammatory activation and prevent neuronal cell death. Norgestrel effectively suppresses cytokine, chemokine and danger-associated molecular pattern molecule (DAMP) expression in the rd10 retina. Remarkably, Norgestrel upregulates fractalkine-CX3CR1 signaling 1 000-fold at the RNA level, in the rd10 mouse. Fractalkine-CX3CR1 signaling has been shown to protect neurons by regulating retinal microglial activation and migration. Ultimately, these results present Norgestrel as a promising treatment for RP, with dual actions as a neuroprotective and anti-inflammatory agent in the retina.


Assuntos
Quimiocina CX3CL1/metabolismo , Microglia/metabolismo , Fármacos Neuroprotetores/metabolismo , Progesterona/metabolismo , Receptores de Quimiocinas/metabolismo , Degeneração Retiniana/metabolismo , Transdução de Sinais/fisiologia , Animais , Receptor 1 de Quimiocina CX3C , Linhagem Celular , Estimulantes do Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Norgestrel/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/metabolismo , Retinite Pigmentosa/metabolismo
18.
Eur J Neurosci ; 44(12): 3067-3079, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27763693

RESUMO

Retinitis pigmentosa (RP) is a degenerative retinal disease leading to photoreceptor cell loss. In 2011, our group identified the synthetic progesterone 'Norgestrel' as a potential treatment for RP. Subsequent research showed Norgestrel to work through progesterone receptor membrane component 1 (PGRMC1) activation and upregulation of neuroprotective basic fibroblast growth factor (bFGF). Using trophic factor deprivation of 661W photoreceptor-like cells, we aimed to further elucidate the mechanism leading to Norgestrel-induced neuroprotection. In the present manuscript, we show by flow cytometry and live-cell immunofluorescence that Norgestrel induces an increase in cytosolic calcium in both healthy and stressed 661Ws over 24 h. Specific PGRMC1 inhibition by AG205 (1 µm) showed this rise to be PGRMC1-dependent, primarily utilizing calcium from extracellular sources, for blockade of L-type calcium channels by verapamil (50 µm) prevented a Norgestrel-induced calcium influx in stressed cells. Calcium influx was also shown to be bFGF-dependent, for siRNA knock down of bFGF prevented Norgestrel-PGRMC1 induced changes in cytosolic calcium. Notably, we demonstrate PGRMC1-activation is necessary for Norgestrel-induced bFGF upregulation. We propose that Norgestrel protects through the following pathway: binding to and activating PGRMC1 expressed on the surface of photoreceptor cells, PGRMC1 activation drives bFGF upregulation and subsequent calcium influx. Importantly, raised intracellular calcium is critical to Norgestrel's protective efficacy, for extracellular calcium chelation by EGTA abrogates the protective effects of Norgestrel on stressed 661W cells in vitro.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Norgestrel/administração & dosagem , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/metabolismo , Progesterona/análogos & derivados , Estresse Fisiológico/efeitos dos fármacos , Animais , Linhagem Celular , Proteínas de Membrana/metabolismo , Camundongos , Progesterona/administração & dosagem , Receptores de Progesterona/metabolismo
19.
Redox Biol ; 10: 128-139, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27744118

RESUMO

Retinitis pigmentosa (RP) is one of the most common retinal degenerative conditions affecting people worldwide, and is currently incurable. It is characterized by the progressive loss of photoreceptors, in which the death of rod cells leads to the secondary death of cone cells; the cause of eventual blindness. As rod cells die, retinal-oxygen metabolism becomes perturbed, leading to increased levels of reactive oxygen species (ROS) and thus oxidative stress; a key factor in the secondary death of cones. In this study, norgestrel, an FDA-approved synthetic analog of progesterone, was found to be a powerful neuroprotective antioxidant, preventing light-induced ROS in photoreceptor cells, and subsequent cell death. Norgestrel also prevented light-induced photoreceptor morphological changes that were associated with ROS production, and that are characteristic of RP. Further investigation showed that norgestrel acts via post-translational modulation of the major antioxidant transcription factor Nrf2; bringing about its phosphorylation, subsequent nuclear translocation, and increased levels of its effector protein superoxide dismutase 2 (SOD2). In summary, these results demonstrate significant protection of photoreceptor cells from oxidative stress, and underscore the potential of norgestrel as a therapeutic option for RP.


Assuntos
Antioxidantes/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Norgestrel/administração & dosagem , Degeneração Retiniana/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Camundongos , Fator 2 Relacionado a NF-E2/genética , Norgestrel/farmacologia , Fosforilação , Degeneração Retiniana/etiologia , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Regulação para Cima
20.
Int J Dev Biol ; 60(4-6): 127-39, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27160072

RESUMO

Mouse models of retinitis pigmentosa (RP) are essential tools in the pursuit to understand fully what cell types and processes underlie the degeneration observed in RP. Knowledge of these processes is required if we are to develop successful therapies to treat this currently incurable disease. We have used the rd10 mouse model of RP to study retinal morphology prior to photoreceptor loss, using immunohistochemistry and confocal microscopy on cryosections, since little is known about how the mutation affects the retina during this period. We report novel findings that the mutation in the rd10 mouse results in retinal abnormalities earlier than was previously thought. Defects in rod and cone outer segments, bipolar cells, amacrine cells and photoreceptor synapses were apparent in the retina during early stages of postnatal retinal development and prior to the loss of photoreceptors. Additionally, we observed a dramatic response of glial cells during this period. Microglia responded as early as postnatal day (P) 5; ?13 days before any photoreceptor loss is detected with Müller glia and astrocytes exhibiting changes from P10 and P15 respectively. Overall, these findings present pathological aspects to the postnatal development of the rd10 retina, contributing significantly to our understanding of disease onset and progression in the rd10 mouse and provide a valuable resource for the study of retinal dystrophies.


Assuntos
Células Fotorreceptoras de Vertebrados/patologia , Retina/patologia , Retinite Pigmentosa/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Camundongos
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