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1.
Cells Tissues Organs ; : 1-12, 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33333518

RESUMO

Owing to their neural crest origin, dental pulp stem cells (DPSCs) are increasingly gaining prominence in treating nervous system disease conditions. However, as per the regulatory bodies [European-Medicines Agency (EMA), Indian-Council of Medical-Research (ICMR)], their biodistribution after transplantation needs to be evaluated for them to be considered for cell-based therapy for clinical trials. There are yet no studies describing the dynamic distribution of human origin DPSCs (hDPSCs) after transplantation in an immunocompetent, physiologically healthy animal model. Here, using near-infrared (NIR)-based whole animal and ex vivo tissue imaging, we assessed the biodistribution of intramuscularly transplanted hDPSCs in immunocompetent healthy Wistar rats. Further validation was done by quantifying gene expression of the human Alu gene in rat tissues. After 24 h of transplantation, an increase in signal intensity and area of signal was observed in the muscle of administration compared to 30 min and 6 h. At hour 24, neither increase in human Alu nor human Ki67 gene expression was seen in the rat muscle, thus confirming that the increase in signal area and intensity at hour 24 was not due to proliferation of the transplanted cells. Rather at hour 24, the NIR-signal intensity in bone marrow increased, suggesting that the NIR-tagged DPSCs have started entering into the blood vessels adjacent to the muscle, and the blood vessels being placed just beneath the subcutaneous layer might be responsible for an increase in signal intensity. Signal intensity increased distinctly in all organs at this timepoint, confirming that the cells entered the bloodstream by hour 24. Lung entrapment of DPSCs was not observed, since signal intensity was least in lungs as compared to the site of injection. Cells were retained for up to 28 days at the site of injection. These findings lay the basis to design the dosage for intramuscular delivery of hDPSCs for degenerative disease models and for future clinical trials.

2.
Br J Anaesth ; 125(5): 779-801, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32798067

RESUMO

BACKGROUND: Despite common use, the benefit of adding steroids to local anaesthetics (SLA) for chronic non-cancer pain (CNCP) injections is uncertain. We performed a systematic review and meta-analysis of English-language RCTs to assess the benefit and safety of adding steroids to local anaesthetics (LA) for CNCP. METHODS: We searched MEDLINE, EMBASE, and CENTRAL databases from inception to May 2019. Trial selection and data extraction were performed in duplicate. Outcomes were guided by the Initiative in Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT) statement with pain improvement as the primary outcome and pooled using random effects model and reported as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CIs). RESULTS: Among 5097 abstracts, 73 trials were eligible. Although SLA increased the rate of success (42 trials, 3592 patients; RR=1.14; 95% CI, 1.03-1.25; number needed to treat [NNT], 13), the effect size decreased by nearly 50% (NNT, 22) with the removal of two intrathecal injection studies. The differences in pain scores with SLA were not clinically meaningful (54 trials, 4416 patients, MD=0.44 units; 95% CI, 0.24-0.65). No differences were observed in other outcomes or adverse events. No subgroup effects were detected based on clinical categories. Meta-regression showed no significant association with steroid dose or length of follow-up and pain relief. CONCLUSIONS: Addition of cortico steroids to local anaesthetic has only small benefits and a potential for harm. Injection of local anaesthetic alone could be therapeutic, beyond being diagnostic. A shared decision based on patient preferences should be considered. If used, one must avoid high doses and series of steroid injections. CLINICAL TRIAL REGISTRATION: PROSPERO #: CRD42015020614.


Assuntos
Corticosteroides/uso terapêutico , Anestésicos Locais/uso terapêutico , Dor Crônica/tratamento farmacológico , Manejo da Dor/métodos , Corticosteroides/efeitos adversos , Anestésicos Locais/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
3.
Naunyn Schmiedebergs Arch Pharmacol ; 393(2): 147-165, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31468077

RESUMO

Besides the effects on the striatum, the impairment of visceral organs including liver functions has been reported in Parkinson's disease (PD) patients. However, it is yet unclear if liver functions are affected in the early stage of the disease before the motor phase has appeared. The aim of our present study was thus to assess the effect of intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in different doses on striatum and liver functions. Deterioration of non-motor activities appeared on single exposure to MPTP along with rise in striatum oxidative stress and decline in antioxidant levels. Decreases in dopamine, noradrenaline, and GABA and increase in serotonin were detected in striatum. Motor coordination was impaired with a single dose of MPTP, and with repeated MPTP exposure, there was further significant impairment. Locomotor activity was affected from second exposure of MPTP, and the impairment increased with third MPTP exposure. Impairment of liver function through increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels was observed after first MPTP insult, and it worsened with second and third administrations. First administration of MPTP triggered systemic inflammation showing significant increase in inflammatory markers in the liver. Our data shows for the first time that an intranasal route of entry of MPTP affects liver from the non-motor phase of PD itself, occurring concomitantly with the reduction of striatal dopamine. It also suggests that a single dose is not enough to bring about progression of the disease from non-motor to locomotor deficiency, and a repeated dose is needed to establish the motor severity phase in the rat intranasal MPTP model.

4.
Neurotox Res ; 35(3): 621-634, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30729451

RESUMO

Alzheimer's disease (AD) is the most common cause of progressive decline of memory function in aged humans. To study about a disease mechanism and progression, animal models for the specific disease are needed. For AD, although highly valid animal models exist, none of the existing models recapitulates all aspects of human AD. The pathogenic mechanisms involved in AD are diverse and thus it is difficult to recapitulate human AD in model organisms. Intracerebroventricular (ICV) injection of okadaic acid (OKA), a protein phosphatase 2A (PP2A) inhibitor, in rats causes neurotoxicity associated with neurofibrillary degeneration. However, this model lacks amyloid pathology as observed in AD. We aimed at combining two different treatments and hence producing a better animal model of AD which may mimic most of the neuropathological, neurobehavioral, and neurochemical changes observed in AD. For this, OKA (200 ng) was microinjected bilaterally into the hippocampus of male Wistar rats followed by exposure of same rats to hypoxic conditions (10%) for 3 days. The result of which, the combination model exhibited tau hyperphosphorylation along with Aß upregulation as evident by western blotting and immunohistochemistry. The observed changes were accompanied with dysfunction of neurotransmitter system, i.e., decreased acetylcholine activity and expression. This combinatorial model also exhibited cognitive deficiency which was assessed by Morris water maze and avoidance tests along with enhanced oxidative stress which is thought to be a major player in AD pathogenesis. Taken together, we established an easily reproducible and reliable rat model for sporadic dementia of Alzheimer's type in rats which allows effective testing of new therapeutic strategies.


Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Aprendizagem da Esquiva , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Hipóxia , Masculino , Aprendizagem em Labirinto , Microinjeções , Neurônios/metabolismo , Neurônios/patologia , Ácido Okadáico , Estresse Oxidativo/fisiologia , Ratos Wistar , Técnicas Estereotáxicas
5.
JAMA ; 320(23): 2448-2460, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30561481

RESUMO

Importance: Harms and benefits of opioids for chronic noncancer pain remain unclear. Objective: To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain. Data Sources and Study Selection: The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control. Data Extraction and Synthesis: Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence. Main Outcomes and Measures: The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference [MID] is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score [SF-36 PCS]; higher is better and the MID is 5 points), and incidence of vomiting. Results: Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years [interquartile range, 51-61 years]) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference [WMD], -0.69 cm [95% CI, -0.82 to -0.56 cm] on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% [95% CI, 9.7% to 14.1%]), improved physical functioning (WMD, 2.04 points [95% CI, 1.41 to 2.68 points] on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% [95% CI, 5.9% to 11.2%]), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low- to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, -0.60 cm [95% CI, -1.54 to 0.34 cm]; physical functioning: WMD, -0.90 points [95% CI, -2.69 to 0.89 points]), tricyclic antidepressants (pain: WMD, -0.13 cm [95% CI, -0.99 to 0.74 cm]; physical functioning: WMD, -5.31 points [95% CI, -13.77 to 3.14 points]), and anticonvulsants (pain: WMD, -0.90 cm [95% CI, -1.65 to -0.14 cm]; physical functioning: WMD, 0.45 points [95% CI, -5.77 to 6.66 points]). Conclusions and Relevance: In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.


Assuntos
Analgésicos Opioides/uso terapêutico , Dor Crônica/tratamento farmacológico , Adulto , Analgésicos Opioides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticonvulsivantes/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Canabinoides/uso terapêutico , Dor Crônica/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Ensaios Clínicos Controlados Aleatórios como Assunto , Vômito/induzido quimicamente
6.
Can J Anaesth ; 65(11): 1180-1195, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30094613

RESUMO

PURPOSE: Pilot trials inform the design and conduct of larger scale trials. Using the Consolidated Standards of Reporting Trials (CONSORT) pilot extension guidelines, we assessed reporting quality in five high-impact anesthesia journals and explored factors associated with reporting quality. METHODS: The five highest-impact anesthesia journals were screened for randomized-controlled trials published as pilot or feasibility trials between 2006 and 2016. A pair of reviewers independently screened citations, extracted data, and assessed reporting quality using the CONSORT pilot trial extension checklists for abstracts and full texts. We reported the percentage adherence for each item, along with the median [interquartile range (IQR)] or mean (standard deviation [SD]) for all items. The factors considered to influence reporting were: 1) trial registration, 2) industry funding, 3) trial identification as a pilot or feasibility in the title or abstract, 4) primary objective as "feasibility", and 5) the specific journal. The association was estimated using generalized estimating equations and reported as incidence rate ratios with 99% confidence intervals. RESULTS: Of 364 citations, 58 articles were eligible. The median [IQR] number of CONSORT abstract items reported was 5 [4-7], and the mean (SD) number of full text items reported was 13 (5). Significantly poor reporting was associated with "not registering the trial" (both abstracts and full texts), "trial not identified as a pilot" (abstracts), and "using clinical hypothesis as the primary objective" (full texts). CONCLUSION: The reporting quality of pilot trials published in leading anesthesia journals is poor. Journal editorial boards can encourage improved reporting by supporting adherence to the CONSORT extension for pilot trials.


Assuntos
Anestesiologia , Publicações Periódicas como Assunto/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Lista de Checagem , Estudos Transversais , Estudos de Viabilidade , Humanos , Fator de Impacto de Revistas , Projetos Piloto
7.
Cochrane Database Syst Rev ; 11: CD011770, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29121400

RESUMO

BACKGROUND: Peripheral nerve block (infiltration of local anaesthetic around a nerve) is used for anaesthesia or analgesia. A limitation to its use for postoperative analgesia is that the analgesic effect lasts only a few hours, after which moderate to severe pain at the surgical site may result in the need for alternative analgesic therapy. Several adjuvants have been used to prolong the analgesic duration of peripheral nerve block, including perineural or intravenous dexamethasone. OBJECTIVES: To evaluate the comparative efficacy and safety of perineural dexamethasone versus placebo, intravenous dexamethasone versus placebo, and perineural dexamethasone versus intravenous dexamethasone when added to peripheral nerve block for postoperative pain control in people undergoing surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, DARE, Web of Science and Scopus from inception to 25 April 2017. We also searched trial registry databases, Google Scholar and meeting abstracts from the American Society of Anesthesiologists, the Canadian Anesthesiologists' Society, the American Society of Regional Anesthesia, and the European Society of Regional Anaesthesia. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) comparing perineural dexamethasone with placebo, intravenous dexamethasone with placebo, or perineural dexamethasone with intravenous dexamethasone in participants receiving peripheral nerve block for upper or lower limb surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 35 trials of 2702 participants aged 15 to 78 years; 33 studies enrolled participants undergoing upper limb surgery and two undergoing lower limb surgery. Risk of bias was low in 13 studies and high/unclear in 22. Perineural dexamethasone versus placeboDuration of sensory block was significantly longer in the perineural dexamethasone group compared with placebo (mean difference (MD) 6.70 hours, 95% confidence interval (CI) 5.54 to 7.85; participants1625; studies 27). Postoperative pain intensity at 12 and 24 hours was significantly lower in the perineural dexamethasone group compared with control (MD -2.08, 95% CI -2.63 to -1.53; participants 257; studies 5) and (MD -1.63, 95% CI -2.34 to -0.93; participants 469; studies 9), respectively. There was no significant difference at 48 hours (MD -0.61, 95% CI -1.24 to 0.03; participants 296; studies 4). The quality of evidence is very low for postoperative pain intensity at 12 hours and low for the remaining outcomes. Cumulative 24-hour postoperative opioid consumption was significantly lower in the perineural dexamethasone group compared with placebo (MD 19.25 mg, 95% CI 5.99 to 32.51; participants 380; studies 6). Intravenous dexamethasone versus placeboDuration of sensory block was significantly longer in the intravenous dexamethasone group compared with placebo (MD 6.21, 95% CI 3.53 to 8.88; participants 499; studies 8). Postoperative pain intensity at 12 and 24 hours was significantly lower in the intravenous dexamethasone group compared with placebo (MD -1.24, 95% CI -2.44 to -0.04; participants 162; studies 3) and (MD -1.26, 95% CI -2.23 to -0.29; participants 257; studies 5), respectively. There was no significant difference at 48 hours (MD -0.21, 95% CI -0.83 to 0.41; participants 172; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. Cumulative 24-hour postoperative opioid consumption was significantly lower in the intravenous dexamethasone group compared with placebo (MD -6.58 mg, 95% CI -10.56 to -2.60; participants 287; studies 5). Perinerual versus intravenous dexamethasoneDuration of sensory block was significantly longer in the perineural dexamethasone group compared with intravenous by three hours (MD 3.14 hours, 95% CI 1.68 to 4.59; participants 720; studies 9). We found that postoperative pain intensity at 12 hours and 24 hours was significantly lower in the perineural dexamethasone group compared with intravenous, however, the MD did not surpass our pre-determined minimally important difference of 1.2 on the Visual Analgue Scale/Numerical Rating Scale, therefore the results are not clinically significant (MD -1.01, 95% CI -1.51 to -0.50; participants 217; studies 3) and (MD -0.77, 95% CI -1.47 to -0.08; participants 309; studies 5), respectively. There was no significant difference in severity of postoperative pain at 48 hours (MD 0.13, 95% CI -0.35 to 0.61; participants 227; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. There was no difference in cumulative postoperative 24-hour opioid consumption (MD -3.87 mg, 95% CI -9.93 to 2.19; participants 242; studies 4). Incidence of severe adverse eventsFive serious adverse events were reported. One block-related event (pneumothorax) occurred in one participant in a trial comparing perineural dexamethasone and placebo; however group allocation was not reported. Four non-block-related events occurred in two trials comparing perineural dexamethasone, intravenous dexamethasone and placebo. Two participants in the placebo group required hospitalization within one week of surgery; one for a fall and one for a bowel infection. One participant in the placebo group developed Complex Regional Pain Syndrome Type I and one in the intravenous dexamethasone group developed pneumonia. The quality of evidence is very low due to the sparse number of events. AUTHORS' CONCLUSIONS: Low- to moderate-quality evidence suggests that when used as an adjuvant to peripheral nerve block in upper limb surgery, both perineural and intravenous dexamethasone may prolong duration of sensory block and are effective in reducing postoperative pain intensity and opioid consumption. There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not apply to participants at risk of dexamethasone-related adverse events for whom clinical trials would probably be unsafe.There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not be apply to participants who at risk of dexamethasone-related adverse events for whom clinical trials would probably be unsafe. The nine ongoing trials registered at ClinicalTrials.gov may change the results of this review.


Assuntos
Anestésicos Locais/administração & dosagem , Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Bloqueio Nervoso/métodos , Bloqueadores Neuromusculares/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Braço/cirurgia , Humanos , Injeções Intravenosas , Perna (Membro)/cirurgia , Bloqueio Nervoso/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
8.
BMJ ; 356: j656, 2017 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-28348110

RESUMO

Objective To determine the efficacy of low intensity pulsed ultrasound (LIPUS) for healing of fracture or osteotomy.Design Systematic review and meta-analysis.Data sources Medline, Embase, CINAHL, Cochrane Central Register of Controlled Trials, and trial registries up to November 2016.Study selection Randomized controlled trials of LIPUS compared with sham device or no device in patients with any kind of fracture or osteotomy.Review methods Two independent reviewers identified studies, extracted data, and assessed risk of bias. A parallel guideline committee (BMJ Rapid Recommendation) provided input on the design and interpretation of the systematic review, including selection of outcomes important to patients. The GRADE system was used to assess the quality of evidence.Results 26 randomized controlled trials with a median sample size of 30 (range 8-501) were included. The most trustworthy evidence came from four trials at low risk of bias that included patients with tibia or clavicle fractures. Compared with control, LIPUS did not reduce time to return to work (percentage difference: 2.7% later with LIPUS, 95% confidence interval 7.7% earlier to 14.3% later; moderate certainty) or the number of subsequent operations (risk ratio 0.80, 95% confidence interval 0.55 to 1.16; moderate certainty). For pain, days to weight bearing, and radiographic healing, effects varied substantially among studies. For all three outcomes, trials at low risk of bias failed to show a benefit with LIPUS, while trials at high risk of bias suggested a benefit (interaction P<0.001). When only trials at low risk of bias trials were considered, LIPUS did not reduce days to weight bearing (4.8% later, 4.0% earlier to 14.4% later; high certainty), pain at four to six weeks (mean difference on 0-100 visual analogue scale: 0.93 lower, 2.51 lower to 0.64 higher; high certainty), and days to radiographic healing (1.7% earlier, 11.2% earlier to 8.8% later; moderate certainty).Conclusions Based on moderate to high quality evidence from studies in patients with fresh fracture, LIPUS does not improve outcomes important to patients and probably has no effect on radiographic bone healing. The applicability to other types of fracture or osteotomy is open to debate.Systematic review registration PROSPERO CRD42016050965.


Assuntos
Consolidação da Fratura , Fraturas Ósseas/terapia , Terapia por Ultrassom , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Biochim Biophys Acta Mol Basis Dis ; 1863(7): 1858-1866, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27262357

RESUMO

In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G0/G1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.


Assuntos
Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Diclorvós/efeitos adversos , Neurônios Dopaminérgicos/metabolismo , Doenças Neurodegenerativas/metabolismo , Intoxicação por Organofosfatos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Diclorvós/farmacologia , Neurônios Dopaminérgicos/patologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Intoxicação por Organofosfatos/genética , Intoxicação por Organofosfatos/patologia , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos
10.
CMAJ ; 188(14): E352-E361, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27402075

RESUMO

BACKGROUND: Persistent pain after breast cancer surgery affects up to 60% of patients. Early identification of those at higher risk could help inform optimal management. We conducted a systematic review and meta-analysis of observational studies to explore factors associated with persistent pain among women who have undergone surgery for breast cancer. METHODS: We searched the MEDLINE, Embase, CINAHL and PsycINFO databases from inception to Mar. 12, 2015, to identify cohort or case-control studies that explored the association between risk factors and persistent pain (lasting ≥ 2 mo) after breast cancer surgery. We pooled estimates of association using random-effects models, when possible, for all independent variables reported by more than 1 study. We reported relative measures of association as pooled odds ratios (ORs) and absolute measures of association as the absolute risk increase. RESULTS: Thirty studies, involving a total of 19 813 patients, reported the association of 77 independent variables with persistent pain. High-quality evidence showed increased odds of persistent pain with younger age (OR for every 10-yr decrement 1.36, 95% confidence interval [CI] 1.24-1.48), radiotherapy (OR 1.35, 95% CI 1.16-1.57), axillary lymph node dissection (OR 2.41, 95% CI 1.73-3.35) and greater acute postoperative pain (OR for every 1 cm on a 10-cm visual analogue scale 1.16, 95% CI 1.03-1.30). Moderate-quality evidence suggested an association with the presence of preoperative pain (OR 1.29, 95% CI 1.01-1.64). Given the 30% risk of pain in the absence of risk factors, the absolute risk increase corresponding to these ORs ranged from 3% (acute postoperative pain) to 21% (axillary lymph node dissection). High-quality evidence showed no association with body mass index, type of breast surgery, chemotherapy or endocrine therapy. INTERPRETATION: Development of persistent pain after breast cancer surgery was associated with younger age, radiotherapy, axillary lymph node dissection, greater acute postoperative pain and preoperative pain. Axillary lymph node dissection provides the only high-yield target for a modifiable risk factor to prevent the development of persistent pain after breast cancer surgery.


Assuntos
Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante/estatística & dados numéricos , Dor Crônica/epidemiologia , Excisão de Linfonodo/estatística & dados numéricos , Mastectomia Segmentar/estatística & dados numéricos , Mastodinia/epidemiologia , Radioterapia Adjuvante/estatística & dados numéricos , Fatores Etários , Axila , Feminino , Humanos , Mastectomia/estatística & dados numéricos , Estudos Observacionais como Assunto , Razão de Chances , Medição da Dor , Dor Pós-Operatória/epidemiologia , Período Pré-Operatório , Fatores de Risco
11.
Syst Rev ; 5: 18, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26831725

RESUMO

BACKGROUND: Steroids are often combined with local anesthetic (LA) and injected to reduce pain associated with various chronic non-cancer pain (CNCP) complaints. The biological rationale behind injection of a steroid solution is unclear, and it is uncertain whether the addition of steroids offers any additional benefits over injection of LA alone. We propose to conduct a systematic review and meta-analysis to summarize the evidence for using steroids and LA vs. LA alone in the treatment of CNCP. METHODS: An experienced librarian will perform a comprehensive search of EMBASE, MEDLINE, and the Cochrane Central Registry of Controlled Trials (CENTRAL) databases with search terms for clinical indications, LA, and steroid agents. We will review bibliographies of all relevant published reviews in the last 5 years for additional studies. Eligible trials will be published in English and randomly allocate patients with CNCP to treatment with steroid and LA injection therapy or injection with LA alone. We will use the guidelines published by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to inform the outcomes that we collect and present. Teams of reviewers will independently and in duplicate assess trial eligibility, abstract data, and assess risk of bias among eligible trials. We will prioritize intention to treat analysis and, when possible, pool outcomes across trials using random effects models. We will report our findings as risk differences, weighted mean differences, or standardized mean differences for individual outcomes. Further, to ensure interpretability of our results, we will present risk differences and measures of relative effect for pain reduction based on anchor-based minimally important clinical differences. We will conduct a priori defined subgroup analyses and use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to evaluate the certainty of the evidence on an outcome-by-outcome basis. DISCUSSION: Our review will evaluate both the effectiveness and the adverse events associated with steroid plus LA vs. LA alone for CNCP, evaluate the quality of the evidence using the GRADE approach, and prioritize patient-important outcomes guided by IMMPACT recommendations. Our results will facilitate evidence-based management of patients with chronic non-cancer pain and identify key areas for future research. TRIAL REGISTRATION: PROSPERO CRD42015020614.


Assuntos
Corticosteroides , Anestésicos Locais , Dor Crônica/tratamento farmacológico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como Assunto
12.
Can J Anaesth ; 63(3): 311-25, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26659198

RESUMO

PURPOSE: To determine whether ketamine added to morphine or hydromorphone patient-controlled analgesia (PCA) provides clinically relevant reductions in postoperative pain, opioid requirements, and adverse events when compared with morphine or hydromorphone PCA in adults undergoing surgery. SOURCE: We systematically searched six databases up to June 2, 2015 for randomized controlled trials (RCTs) comparing ketamine plus morphine/hydromorphone PCA vs morphine/hydromorphone PCA for postoperative pain in adults. PRINCIPAL FINDINGS: Thirty-six RCTs including 2,502 patients proved eligible, and 22 of these were at low risk of bias. The addition of ketamine to morphine/hydromorphone PCA decreased postoperative pain intensity at six to 72 hr when measured at rest (weighted mean difference [WMD] on a 10-cm visual analogue scale ranged from -0.4 to -1.3 cm) and during mobilization (WMD ranged from -0.4 to -0.5 cm). Adjunctive ketamine also significantly reduced cumulative morphine consumption at 24-72 hr by approximately 5-20 mg. Predefined subgroup analyses and meta-regression did not detect significant differences across subgroups, including a dose-response relationship. There was no significant difference in patient satisfaction scores at 24 and 48 hr. Nevertheless, the addition of ketamine to morphine/hydromorphone PCA significantly reduced postoperative nausea and vomiting (relative risk, 0.71; 95% confidence interval [CI], 0.60 to 0.85; absolute risk reduction, 8.9%; 95% CI, 4.6 to 12.2). Significant effects on other adverse events (e.g., hallucinations, vivid dreams) were not detected, though only a few studies reported on them. CONCLUSIONS: Adding ketamine to morphine/hydromorphone PCA provides a small improvement in postoperative analgesia while reducing opioid requirements. Adjunctive ketamine also reduces postoperative nausea and vomiting without a detected increase in other adverse effects; however, adverse events were probably underreported.


Assuntos
Dor Aguda/tratamento farmacológico , Analgesia Controlada pelo Paciente/métodos , Hidromorfona/administração & dosagem , Ketamina/administração & dosagem , Morfina/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , Adulto , Combinação de Medicamentos , Humanos , Hidromorfona/efeitos adversos , Ketamina/efeitos adversos , Morfina/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde , Satisfação do Paciente , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Biol Open ; 2(11): 1119-24, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24244848

RESUMO

The two hallmarks of Alzheimer's disease (AD) are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are formed due to the hyperphosphorylation of tau protein. There is an urgent need to develop a reliable biomarker for the diagnosis of AD. Cerebrospinal fluid (CSF) is surrounding the brain and reflects the major neuropathological features in the AD brain. Diagnosis, disease progression and drug actions rely on the AD biomarkers. Mainly CSF tau and phosphorylated tau (p-Tau) have been observed to serve the purpose for early AD. Keeping in view the early appearance of p-Tau in CSF, we analyzed p-Tau levels in 23 AD, 23 Non AD type dementia (NAD), 23 Neurological control (NC) and 23 Healthy control (HC) North Indian patients. The levels of p-Tau were found to be increased in AD patients (67.87±18.05 pg/ml, SEM 3.76) compared with NAD (47.55±7.85 pg/ml, SEM 1.64), NC (34.42±4.51 pg/ml, SEM 0.94) and HC (27.09±7.18 pg/ml, SEM 1.50). The resulting sensitivity for AD with NAD was 80.27% whereas with respect to the NAD, NC and HC was 85.40%. Therefore elevated levels of p-Tau in AD can be exploited as a predictive biomarker in North Indian AD patients.

14.
Am J Alzheimers Dis Other Demen ; 28(4): 318-26, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23687185

RESUMO

Alzheimer's disease (AD), the most common neurodegenerative and dementing disorder, is characterized by extracellular amyloid deposition, intracellular neurofibrillary tangle formation, and neuronal loss. We are still behind in AD research in terms of knowledge regarding understanding its pathophysiology and designing therapeutics because of the lack of an accurate animal model for AD. A complete animal model of AD should imitate all the cognitive, behavioral, and neuropathological features of the disease. Partial models are currently in use, which only mimic specific and not all of the components of AD pathology. Currently the transgenic animals are the popular models for AD research, but different genetic backgrounds of these transgenic animals remain a major confounding factor. This review attempts to summarize the current literature on nontransgenic animal models of AD and to highlight the potential of exploiting spontaneous and induced animal models for neuropathological, neurochemical, neurobehavioral, and neuroprotective studies of AD.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Encéfalo/patologia , Modelos Animais de Doenças , Emaranhados Neurofibrilares/patologia , Doença de Alzheimer/genética , Animais , Humanos
15.
Am J Alzheimers Dis Other Demen ; 28(3): 258-62, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23612909

RESUMO

The etiology of Alzheimer's disease (AD) is multifactorial involving both genetic and environmental factors. Apolipoprotein E (ApoE) gene plays a pivotal role in risk and age of onset of AD. Although it is broadly accepted that ApoE genotype is linked to the pathogenesis of AD, there are still controversial results regarding the association of ApoE levels in cerebrospinal fluid (CSF) with the occurrence of AD. Some studies have shown a positive correlation between CSF ApoE levels and AD, whereas others showed no link. In this study, we measured ApoE levels to assess the usefulness of CSF ApoE as a diagnostic marker of AD by comparing the levels in 3 patient groups and in control participants. No significant difference was observed in CSF ApoE concentrations between the patients with AD and the controls. So, it appears that CSF ApoE measurement does not offer any diagnostic advantage for AD.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Apolipoproteína E4/líquido cefalorraquidiano , Apolipoproteínas E/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Feminino , Frequência do Gene , Genótipo , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
16.
Cochrane Database Syst Rev ; (2): CD003845, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23450545

RESUMO

BACKGROUND: Acute lung injury and acute respiratory distress syndrome are syndromes of severe respiratory failure. Children with acute lung injury or acute respiratory distress syndrome have high mortality and the survivors have significant morbidity. Partial liquid ventilation is proposed as a less injurious form of respiratory support for these children. Uncontrolled studies in adults have shown improvements in gas exchange and lung compliance with partial liquid ventilation. A single uncontrolled study in six children with acute respiratory syndrome showed some improvement in gas exchange during three hours of partial liquid ventilation. This review was originally published in 2004, updated in 2009 and again in 2012. OBJECTIVES: To assess whether partial liquid ventilation reduces mortality or morbidity, or both, in children with acute lung injury or acute respiratory distress syndrome. SEARCH METHODS: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 11); CINAHL (Cumulative Index to Nursing & Allied Health Literature) via Ovid (1982 to November 2011); Ovid MEDLINE (1950 to November 2011); and Ovid EMBASE (1982 to November 2011). The search was last performed in August 2008. SELECTION CRITERIA: We included randomized controlled trials (RCTs) which compared partial liquid ventilation with other forms of ventilation in children (aged 28 days to 18 years) with acute lung injury or acute respiratory distress syndrome. Trials had to report one or more of the following: mortality; duration of mechanical ventilation, respiratory support, oxygen therapy, stay in the intensive care unit, or stay in hospital; infection; long-term cognitive impairment, neurodevelopmental progress, or other long-term morbidities. DATA COLLECTION AND ANALYSIS: We independently evaluated the quality of the relevant studies and extracted the data from the included studies. MAIN RESULTS: Only one study enrolling 182 patients (reported as an abstract in conference proceedings) was identified and found eligible for inclusion; the authors reported only limited results. The trial was stopped prematurely and was, therefore, under-powered to detect any significant differences and at high risk of bias. The only available outcome of clinical significance was 28-day mortality. There was no statistically significant difference between groups, with a relative risk for 28-day mortality in the partial liquid ventilation group of 1.54 (95% confidence interval 0.82 to 2.9). AUTHORS' CONCLUSIONS: There is no evidence from RCTs to support or refute the use of partial liquid ventilation in children with acute lung injury or acute respiratory distress syndrome. Adequately powered, high quality RCTs are still needed to assess its efficacy. Clinically relevant outcome measures should be assessed (mortality at discharge and later, duration of both respiratory support and hospital stay, and long-term neurodevelopmental outcomes). The studies should be published in full.


Assuntos
Lesão Pulmonar Aguda/terapia , Ventilação Líquida/métodos , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , /terapia , Lesão Pulmonar Aguda/complicações , Lesão Pulmonar Aguda/mortalidade , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Ventilação Líquida/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , /mortalidade , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Síndrome do Desconforto Respiratório do Recém-Nascido/mortalidade
17.
Toxicol Lett ; 215(1): 62-9, 2012 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-23041170

RESUMO

Aluminum phosphide (AlP), a widely used fumigant and rodenticide leads to high mortality if ingested. Its toxicity is due to phosphine liberated when it comes in contact with moisture. The exact mechanism of action of phosphine is not known. In this study male Wistar rats were used. The animals received a single dose (20mg AlP/kg body weight i.g.) orally. Basic serum biochemical parameters, activity of mitochondrial complexes, antioxidant enzymes and parameters of oxidative stress, individual mitochondrial cytochrome levels were measured along with tissue histopathology and immunostaining for cytochrome c and compared with controls. The serum levels of creatinine kinase-MB, lactate dehydrogenase, magnesium and cortisol were higher (p<0.01); the activities of mitochondrial complexes I, II, IV were observed to be significantly decreased in liver tissue in treated rats (p<0.01). The activity of catalase was lower (p<0.05) with a significant increase in lipid peroxidation (p<0.05) whereas superoxide dismutase and glutathione peroxidase were unaffected in them. There was a significant decrease in all the cytochromes in brain and liver tissues (p<0.05) with the exception of cytochrome b in brain, the levels of which remained same. Histopathology revealed congestion in most organs with centrizonal hemorrhagic necrosis in liver. Ultra structural changes indicating mitochondrial injury was observed in heart, liver and kidney tissues. There was also a marked reduction in the cytochrome-c immunostaining compared to the controls. Toxicity due to AlP appears to result as a consequence of both-energy insufficiency and oxidative stress, with a possible and preferential interaction with the tissue cytochromes.


Assuntos
Compostos de Alumínio/toxicidade , Praguicidas/toxicidade , Fosfinas/toxicidade , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Catalase/metabolismo , Citocromos c/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Glutationa Peroxidase/metabolismo , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Microscopia Eletrônica , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , NADH Desidrogenase/metabolismo , Fosforilação Oxidativa , Ratos , Ratos Wistar , Succinato Desidrogenase/metabolismo , Superóxido Dismutase/metabolismo
18.
Pathobiology ; 79(2): 55-71, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22205086

RESUMO

Alzheimer's disease (AD), the most common cause of dementia, results from the interplay of various deregulated mechanisms triggering a complex pathophysiology. The neurons suffer from and slowly succumb to multiple irreversible damages, resulting in cell death and thus memory deficits that characterize AD. In spite of our vast knowledge, it is still unclear as to when the disease process starts and how long the perturbations continue before the disease manifests. Recent studies provide sufficient evidence to prove amyloid ß (Aß) as the primary cause initiating secondary events, but Aß is also known to be produced under normal conditions and to possess physiological roles, hence, the questions that remain are: What are the factors that lead to abnormal Aß production? When does Aß turn into a pathological molecule? What is the chain of events that follows Aß? The answers are still under debate, and further insight may help us in creating better diagnostic and therapeutic options in AD. The present article attempts to review the current literature regarding AD pathophysiology and proposes a pathophysiologic cascade in AD.


Assuntos
Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/fisiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Morte Celular/fisiologia , Humanos , Transtornos da Memória/etiologia , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/fisiologia
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