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Chronic kidney disease (CKD) patients can benefit from personalized education on lifestyle and nutrition management strategies to enhance healthcare outcomes. The potential use of chatbots, introduced in 2022, as a tool for educating CKD patients has been explored. A set of 15 questions on lifestyle modification and nutrition, derived from a thorough review of three specific KDIGO guidelines, were developed and posed in various formats, including original, paraphrased with different adverbs, incomplete sentences, and misspellings. Four versions of AI were used to answer these questions: ChatGPT 3.5 (March and September 2023 versions), ChatGPT 4, and Bard AI. Additionally, 20 questions on lifestyle modification and nutrition were derived from the NKF KDOQI guidelines for nutrition in CKD (2020 Update) and answered by four versions of chatbots. Nephrologists reviewed all answers for accuracy. ChatGPT 3.5 produced largely accurate responses across the different question complexities, with occasional misleading statements from the March version. The September 2023 version frequently cited its last update as September 2021 and did not provide specific references, while the November 2023 version did not provide any misleading information. ChatGPT 4 presented answers similar to 3.5 but with improved reference citations, though not always directly relevant. Bard AI, while largely accurate with pictorial representation at times, occasionally produced misleading statements and had inconsistent reference quality, although an improvement was noted over time. Bing AI from November 2023 had short answers without detailed elaboration and sometimes just answered "YES". Chatbots demonstrate potential as personalized educational tools for CKD that utilize layman's terms, deliver timely and rapid responses in multiple languages, and offer a conversational pattern advantageous for patient engagement. Despite improvements observed from March to November 2023, some answers remained potentially misleading. ChatGPT 4 offers some advantages over 3.5, although the differences are limited. Collaboration between healthcare professionals and AI developers is essential to improve healthcare delivery and ensure the safe incorporation of chatbots into patient care.
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BACKGROUND: Chronic liver disease is a common and important clinical problem.Hepatorenal syndrome (HRS) is a life threatening complication. Serum creatinine (Cr) remains the only conventional indicator of renal function. However, the interpretation of serum Cr level can be confounded by malnutrition and reduced muscle mass often observed in patients with severe liver disease. Here, we present a cross-sectional study to explore the sensitivity and specificity of other markers as urinary KIM-1 and NGAL for cases of HRS. METHODS: Cross-sectional study was conducted on 88 patients who were admitted to Alexandria main university hospital. Enrolled patients were divided in two groups; group 1: patients with advanced liver cirrhosis (child B and C) who have normal kidney functions while group 2: patients who developed HRS. Stata© version 14.2 software package was used for analysis. RESULTS: Group 1 included 18 males and 26 females compared to 25 males and 19 females in group 2 (p = 0.135). Only the urinary KIM-1 showed a statistically significant difference between both groups in the multivariate logistic regression analysis adjusted for gender, serum bilirubin, serum albumin, INR, serum K, AST and ALT levels. CONCLUSION: In conclusion, our study aligns with prior research, as seen in the consistent findings regarding Urinary NGAL elevation in cirrhotic patients with AKI. Urinary KIM-1, independent of Urinary NGAL, may have a role in precisely distinguishing between advanced liver cirrhosis and HRS and merits further exploration.
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Biomarcadores , Receptor Celular 1 do Vírus da Hepatite A , Síndrome Hepatorrenal , Lipocalina-2 , Cirrose Hepática , Humanos , Masculino , Feminino , Receptor Celular 1 do Vírus da Hepatite A/análise , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Cirrose Hepática/complicações , Cirrose Hepática/urina , Estudos Transversais , Pessoa de Meia-Idade , Lipocalina-2/urina , Lipocalina-2/sangue , Biomarcadores/urina , Biomarcadores/sangue , Adulto , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/urina , Síndrome Hepatorrenal/diagnóstico , Modelos Logísticos , Idoso , Creatinina/sangue , Creatinina/urina , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD. METHODS: Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2 days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2nd received allopurinol, the 3rd group received linagliptin, and the 4th received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2 weeks in all patients. RESULTS: 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p < 0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis. CONCLUSION: Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03470454.
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Injúria Renal Aguda , Alopurinol , Meios de Contraste , Nefropatias Diabéticas , Linagliptina , Substâncias Protetoras , Humanos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Alopurinol/administração & dosagem , Alopurinol/uso terapêutico , Nefropatias Diabéticas/classificação , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/diagnóstico , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Linagliptina/administração & dosagem , Linagliptina/uso terapêutico , Estudos Prospectivos , Insuficiência Renal Crônica/classificação , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Meios de Contraste/efeitos adversos , Quimioprevenção/métodos , Quimioterapia Combinada , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/efeitos adversos , Substâncias Protetoras/uso terapêutico , Solução Salina/administração & dosagem , Solução Salina/uso terapêuticoRESUMO
OBJECTIVES: Uric acid (UA) control may be insufficient in chronic kidney disease (CKD) patients in the current era. It is unclear, however, whether this is the result of environmental effects, patient anthropometrics or insufficient dosing of medical therapy (allopurinol). METHODS: We have collected data on multiple clinical and laboratory parameters of 114 CKD clinic patients attending the nephrology clinic of the University of Mississippi Medical Center with an estimated glomerular filtration rate <45 mL · min-1 · 1.73 m2. We assessed the correlates of UA levels and the allopurinol doses along with achieved serum UA and urine pH. RESULTS: The cohort consisted of middle-aged to elderly patients with a mean (± standard deviation) age of 62.1 (11.6) years; 45.6% were female, 68.4% were African American and 47.4% had a history of gout. The mean UA level was 7.7 (2.49) mg/dL (range 3.1-16), allopurinol dose was 192 (99) mg/day (range 50-450) and estimated glomerular filtration rate was 23.8 (11.3) mL · min-1 · 1.73 m2. While the overall serum bicarbonate level was 25 (3.2) mEq/L, urine pH was <6 in 60.5% of the cohort. Significant univariate correlates of the administered doses of allopurinol were weight (r 0.317, P = 0.001), body mass index (BMI; r 0.313, P = 0.001), and female sex (r -0.198; P = 0.035). Achieved UA levels correlated directly with BMI (r 0.201, r = 0.036) but inversely with the allopurinol dose (r -0.196; P = 0.036). During logistic regression analysis with stepwise selection, only weight (ß 0.313, P = 0.001) and sex (ß -0.190, P = 0.039) proved to be predictive of the allopurinol dose; as for the achieved UA level, only BMI (ß 0.271, P = 0.006) and the allopurinol dose (ß -0.258; P = 0.009) had a significant effect. CONCLUSIONS: In patients with advanced CKD, conventional dosing recommendations for allopurinol are unlikely to suffice in reaching target serum UA goals. In our cohort, larger-than-usual allopurinol doses were well tolerated.
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Alopurinol/administração & dosagem , Antimetabólitos/administração & dosagem , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Ácido Úrico/sangue , Idoso , Bicarbonatos/sangue , Índice de Massa Corporal , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mississippi/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Sudeste dos Estados Unidos/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND: The natural evolution of C1q nephropathy (C1qNP) during immunosuppressive treatment is relatively little studied or understood. CASE PRESENTATION: A 30 year-old Caucasian female was referred to us for further management of biopsy-proven C1qNP and severe nephrotic syndrome. Serologic work-up remained negative, including complement C3 and C4 levels and repeated testing for antinuclear antibodies. A renal biopsy revealed minimal change nephropathy vs. focal sclerosis on light microscopy and C1qNP on immunopathology. She has failed trials of high-dose oral prednisone, mycophenolate mofetil 1,500 mg twice a day and a subsequent regimen of monthly IV cyclophosphamide 750 mg × 9 cycles. She also received the maximum tolerated angiotensin-converting enzyme inhibitor and spironolactone therapy. Random urine protein-to-creatinine (UPC) ratio predicted proteinuria in the range between 5-35 gm/day, while serum creatinine rose progressively from 1.0 mg/dL to 1.4 mg/dL (to convert to µmol/L, multiply by 88.4). A decision was made to repeat renal biopsy to reassess the underlying histology. The biopsy revealed focal sclerosis but no C1q deposition. CONCLUSIONS: Our case illustrates at least two points: first, an established pathologic diagnosis does not obviate the need for repeated renal biopsy later on, should diagnostic uncertainty persist. Second, histological diagnoses may evolve over time, especially in a patient receiving active and powerful immune-modulating treatment. In our case, the clinical nephrosis did not change with immunosuppressive therapy while C1q deposition ceased, making this latter entity likely the immunologically mediated process.
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BACKGROUND: Historically, cytomegalovirus (CMV) infection in immunocompetent patients has been considered to have a relatively indolent and self-limited course, not warranting specific treatment. CASE PRESENTATION: We are presenting a 72-year-old African-American male transferred to our intensive care unit (ICU) with methicillin-resistant Staphylococcus aureus bacteremia, respiratory failure, and dialysis-dependent acute kidney injury. While he recovered from bacteremia, he remained difficult to wean from respiratory support, had labile blood pressure, and manifested persistent diarrhea. Stool antigen testing for C. difficile colitis returned repeatedly negative. Flexible sigmoidoscopy described diffuse ulceration, attributed to ischemic colitis. The colon biopsy specimen, however, described tissue-invasive cytomegalovirus (CMV) infection. Polymerase chain reaction (PCR) testing confirmed viremia with 8,900 copies/mL viral DNA. Human immunodeficiency virus antibody and PCR testing were both negative. Absolute lymphocyte count varied between 80 and 450/mm3 during the admission. After IV ganciclovir initiation, diarrhea and respiratory failure resolved, while renal function recovered to the patient's baseline. CONCLUSION: The combination of critical illness and recent bacteremia likely represented a state of profound immunosuppression in this formerly healthy patient. CMV colitis may be under-diagnosed in sick ICU patients with renal failure and otherwise unexplained diarrhea. Serum PCR testing may aid the diagnosis.
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Injúria Renal Aguda/virologia , Colite/virologia , Infecções por Citomegalovirus/diagnóstico , Diálise Renal , Injúria Renal Aguda/terapia , Idoso , Antivirais/uso terapêutico , Estado Terminal , Ganciclovir/uso terapêutico , Humanos , MasculinoRESUMO
A 52-year-old African American male was admitted with acute kidney injury (AKI) four days after renal cryotherapy. He was started on continuous veno-venous hemodiafiltration (CVVHDF) immediately but his subsequent course was complicated by recurrent hypoglycemia, poorly responding to conventional therapy. To address the recalcitrant hypoglycemia, we changed the replacement fluid to 5% dextrose in water with 150 mEq/L of sodium bicarbonate, Y-connected with 0.9% sodium chloride at a global rate of 2000 mL/hr, with resolution of refractory hypoglycemia. A modified CVVHDF employing hyperglycemic solution can be a valuable addition in treatment of AKI complicated by severe refractory hypoglycemia.
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Injúria Renal Aguda , Criocirurgia/efeitos adversos , Glucose/administração & dosagem , Hemodiafiltração , Soluções para Hemodiálise , Hipoglicemia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/terapia , Antibacterianos/administração & dosagem , Criocirurgia/métodos , Hemodiafiltração/efeitos adversos , Hemodiafiltração/métodos , Soluções para Hemodiálise/administração & dosagem , Soluções para Hemodiálise/efeitos adversos , Soluções para Hemodiálise/química , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/tratamento farmacológico , Hipoglicemia/etiologia , Hipoglicemia/fisiopatologia , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The relative effectiveness of anticoagulation strategies during continuous renal replacement therapy (CRRT) may vary according to the clinical circumstances. In this study, the case of a 46-year-old man who developed fungal mediastinitis with the pathogen Scedosporium prolificans after coronary bypass surgery is reported. Numerous debridements and multiple antifungal agents were not effective in this patient. Miltefosine, a non-Food and Drug Administration-approved agent, was started after institutional review board request and approval. CRRT was initiated with regional citrate anticoagulation (RCA) for clinical sepsis with acute kidney injury. Subsequently, crescendo clotting of the extracorporeal circuit (ECC) occurred. Multiple interventions, including escalating RCA, adding increasing heparin to RCA and exchanging the dialysis catheter, were not effective. Argatroban anticoagulation was started without further ECC clotting, and the patient recovered from both acute kidney injury and septic shock, despite continued miltefosine administration. Sepsis may contribute to recurrent ECC clotting. Argatroban, a direct thrombin inhibitor, had a disproportionate effectiveness to maintain ECC patency in this patient.
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Antitrombinas/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Ponte de Artéria Coronária/efeitos adversos , Mediastinite , Micoses , Ácidos Pipecólicos/administração & dosagem , Complicações Pós-Operatórias , Terapia de Substituição Renal , Scedosporium , Sepse , Antifúngicos/administração & dosagem , Arginina/análogos & derivados , Humanos , Masculino , Mediastinite/etiologia , Mediastinite/microbiologia , Mediastinite/terapia , Pessoa de Meia-Idade , Micoses/etiologia , Micoses/microbiologia , Micoses/terapia , Fosforilcolina/administração & dosagem , Fosforilcolina/análogos & derivados , Sepse/etiologia , Sepse/microbiologia , Sepse/terapia , SulfonamidasRESUMO
We are reporting on a series of two patients with end-stage renal disease on hemodialysis, presented for surgical parathyroidectomy secondary refractory hyperparathyroidism. Both patients had failed maximized medical managements, including higher-than-usual doses of the calcimimetic cinacalcet (270 and 180 mg/day, respectively). On physical exam, both patients had marked symmetrical craniofacial hypertrophy with coarse distortion of facial features, similar in appearance to past reports of Sagliker syndrome. On X-ray and computed tomographic exam, they had peculiar areas of bone absorption on the skull, imitating the radiologic appearance of multiple myeloma. Bone biopsy of the maxilla, however, did not show the expected brown tumor, but rather described only fibrosis and reactive bone formations. This phenotype developed while being on cinacalcet, progressed despite escalation of therapy, and improved only after parathyroidectomy. Both patients developed massive "hungry bone syndrome" after parathyroidectomy necessitating prolonged i.v. calcium infusion. This pattern of severe facial distortion likely represented an adverse consequence of severe tertiary hyperparathyroidism, along with supraphysiologic dose of cinacalcet administration and 25-hydroxy vitamin D deficiency in sensitive individuals. The genetic base of this observation remained unexplained.
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Hiperparatireoidismo Secundário/complicações , Falência Renal Crônica/terapia , Seio Maxilar/patologia , Naftalenos/efeitos adversos , Adolescente , Adulto , Cálcio/administração & dosagem , Cinacalcete , Feminino , Humanos , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/cirurgia , Hipertrofia/patologia , Falência Renal Crônica/cirurgia , Masculino , Naftalenos/administração & dosagem , Paratireoidectomia , Diálise Renal/efeitos adversosRESUMO
Recent epidemiological reports showed that smoking has a negative impact on renal function and elevates the renal risk not only in the renal patient but perhaps also in the healthy population. Studies suggested that nicotine, a major tobacco alkaloid, links smoking to renal dysfunction. While several studies showed that smoking/chronic nicotine exposure exacerbates the progression of chronic renal diseases, its impact on acute kidney injury is virtually unknown. Here, we studied the effects of chronic nicotine exposure on acute renal ischemic injury. We found that chronic nicotine exposure increased the extent of renal injury induced by warm ischemia-reperfusion as evidenced by morphological changes, increase in plasma creatinine level, and kidney injury molecule-1 expression. We also found that chronic nicotine exposure elevated markers of oxidative stress such as nitrotyrosine as well as malondialdehyde. Interestingly, chronic nicotine exposure alone increased oxidative stress and injury in the kidney without morphological alterations. Chronic nicotine treatment not only increased reactive oxygen species (ROS) production and injury but also exacerbated oxidative stress-induced ROS generation through NADPH oxidase and mitochondria in cultured renal proximal tubule cells. The resultant oxidative stress provoked injury through JNK-mediated activation of the activator protein (AP)-1 transcription factor in vitro. This mechanism might exist in vivo as phosphorylation of JNK and its downstream target c-jun, a component of the AP-1 transcription factor, is elevated in the ischemic kidneys exposed to chronic nicotine. Our results imply that smoking may sensitize the kidney to ischemic insults and perhaps facilitates progression of acute kidney injury to chronic kidney injury.
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Injúria Renal Aguda/patologia , Isquemia/patologia , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Adenoviridae/genética , Animais , Western Blotting , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cotinina/sangue , Cotinina/metabolismo , Rim/metabolismo , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Luciferases/metabolismo , MAP Quinase Quinase 4/genética , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/patologia , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/fisiologiaRESUMO
Recent in vitro studies have reported that heme oxygenase 1 (HO-1) downregulates the angiostatic protein soluble fms-like tyrosine kinase 1 from placental villous explants and that the HO-1 metabolites CO and bilirubin negatively regulate endothelin 1 and reactive oxygen species. Although soluble fms-like tyrosine kinase 1, endothelin 1, and reactive oxygen species have been implicated in the pathophysiology of hypertension during preeclampsia and in response to placental ischemia in pregnant rats, it is unknown whether chronic induction of HO-1 alters the hypertensive response to placental ischemia. The present study examined the hypothesis that HO-1 induction in a rat model of placental ischemia would beneficially affect blood pressure, angiogenic balance, superoxide, and endothelin 1 production in the ischemic placenta. To achieve this goal we examined the effects of cobalt protoporphyrin, an HO-1 inducer, in the reduced uterine perfusion pressure (RUPP) placental ischemia model and in normal pregnant rats. In response to RUPP treatment, mean arterial pressure increases 29 mm Hg (136±7 versus 106±5 mm Hg), which is significantly attenuated by cobalt protoporphyrin (118±5 mm Hg). Although RUPP treatment causes placental soluble fms-like tyrosine kinase 1/vascular endothelial growth factor ratios to alter significantly to an angiostatic balance (1.00±0.10 versus 1.27±0.20), treatment with cobalt protoporphyrin causes a significant shift in the ratio to an angiogenic balance (0.68±0.10). Placental superoxide increased in RUPP (952.5±278.8 versus 243.9±70.5 relative light units/min per milligram) but was significantly attenuated by HO-1 induction (482.7±117.4 relative light units/min per milligram). Also, the preproendothelin message was significantly increased in RUPP, which was prevented by cobalt protoporphyrin. These data indicate that HO-1, or its metabolites, is a potential therapeutic for the treatment of preeclampsia.
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Pressão Sanguínea/fisiologia , Heme Oxigenase-1/metabolismo , Hipertensão/enzimologia , Isquemia/enzimologia , Placenta/enzimologia , Útero/enzimologia , Animais , Western Blotting , Feminino , Hipertensão/etiologia , Hipertensão/fisiopatologia , Isquemia/complicações , Isquemia/fisiopatologia , Placenta/irrigação sanguínea , Placenta/efeitos dos fármacos , Placenta/fisiopatologia , Gravidez , Protoporfirinas/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Útero/irrigação sanguínea , Útero/efeitos dos fármacos , Útero/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Severe hyperhomocysteinemia (HHC) is associated with atherosclerosis. In hemodialysis (HD) patients, one of the main causes of death is cardiovascular disease. In animals, trace elements such as cobalt, copper, iron, and nickel ameliorated vitamin B(12) deficiency-induced HHC. However, correlations between plasma total homocysteine (tHcy) and trace elements in HD patients have not been investigated. Therefore, tHcy, folate, vitamin B(12), trace elements (cobalt, copper, iron, and nickel), and some laboratory parameters such as serum total protein, albumin, transferrin, ferritin, C-reactive protein (CRP), and interleukin-6 concentrations were determined in 122 hemodialysis patients. When patients were divided into groups according to their tHcy, we found no significant differences in concentrations of cobalt, copper, and total protein, while nickel was higher, and folate, vitamin B(12), and iron were lower in patients with lower than higher tHcy. In univariate regression analysis, tHcy negatively correlated with concentrations of folate (r = -0.302, p < 0.006), vitamin B(12) (r = -0.347, p < 0.0001), nickel (r = -0.289, p < 0.006), and CRP (r = -0.230, p < 0.02) and positively with serum albumin (r = 0.316, p < 0.0004) and hemoglobin (r = 0.329, p < 0.0001) values. No relationship between tHcy and serum concentrations of cobalt, copper, iron, or other laboratory parameters was found in HD patients. The effect of cobalt and nickel on homocysteine production was assessed in human peripheral mononuclear cells (PBMCs). Nickel but not cobalt at concentrations found in HD patients significantly inhibited homocysteine, cysteine, and S-adenosylhomocysteine production in human PBMCs. These results suggest that nickel might also be involved in the regulation of the methionine-folate cycle in humans, as was demonstrated in animal experiments.
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Homocisteína/sangue , Níquel/sangue , Diálise Renal , Idoso , Proteína C-Reativa/metabolismo , Feminino , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Oligoelementos/sangue , Vitamina B 12/sangueRESUMO
Body mass--strictly speaking: the adipose tissue mass--is regulated in a feed-back system by the hypothalamus and brainstem, where adiposity signals (leptin, insulin, amylin) and intestinal peptides (ghrelin, PYY, PP, GLP-1, OXM, CCK) and the vagal nerve provide afferent information to the central controller on the size of white adipose tissue and the actual nutritional state, respectively. Two distinct groups of neurons in the arcuate nucleus accept and process the afferent information provided by leptin produced by white adipocytes in proportion to their mass. Leptin binding to the leptin-receptors on the surface of these neurons initiates intracellular signal transduction and activation of target genes, resulting in the synthesis and release of neuropeptides (POMC, CART) with anorectic effects. Secondary centers in the brain are also activated, and finally integrated effector mechanisms are generated in order to regulate the balance between energy intake and expenditure. The regulation of body weight is carried out by the central nervous system in a complex and redundant way, characterized by interconnections and overlaps with other neuroendocrine functions, such as growth, thyroid and adrenal function, memory, addictive and reward mechanisms. Targeting one or another component of this complicated system with drugs might result in interference with other systems and functions, so the occurrence of adverse events is probable. The worldwide epidemic of obesity--resulting mostly from the abundance of energy-dense foods and sedentary lifestyle coupled with a regulatory system unable to cope with this environment--has resulted in a continuous increase of research activities in both academic and industrial centers to develop new drugs and treatment strategies beyond lifestyle changes (diet, physical activity and behavioral therapy) to fight obesity more effectively.
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Tecido Adiposo Branco/metabolismo , Índice de Massa Corporal , Encéfalo/metabolismo , Metabolismo Energético , Hormônios Gastrointestinais/metabolismo , Sistemas Neurossecretores/metabolismo , Obesidade/metabolismo , Amiloide/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Apetite/efeitos dos fármacos , Regulação do Apetite/efeitos dos fármacos , Composição Corporal , Peso Corporal , Tronco Encefálico/metabolismo , Ingestão de Alimentos , Ingestão de Energia , Grelina/metabolismo , Saúde Global , Humanos , Hipotálamo/metabolismo , Insulina/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Leptina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Hormônios Peptídicos/metabolismo , Pró-Opiomelanocortina/metabolismo , Resposta de Saciedade/efeitos dos fármacos , Transdução de SinaisRESUMO
Overweight and obesity are worldwide problems, its health and psychosocial burden on the individual and on society are tremendous. Diagnosing obesity is rather easy, and is based on simple anthropometric measurements, such as body weight, height and waist circumference. The different classes of obesity are determined by body mass index, which, together with waist circumference and comorbid conditions and other risk factors determine the individual risk for mortality and morbidity. Obesity is due to genetic and environmental factors, mainly is the consequence of excess calorie intake and sedentary lifestyle. The fat mass of the body is under neuroendocrine control, the central controller is the hypothalamus. Leptin, produced by adipocytes in proportion to fat mass, is the afferent signal to the hypothalamus. Decreasing or increasing levels of leptin result in orexigen and anorexigen neurotransmission, which mediate efferent activation towards food consumption and energy storage, or towards food restriction and energy expenditure, respectively. The balance of these events and/or the ,set point" of the controller--if leptin resistance is present--is shifted towards higher body/fat mass in obesity. Management of obesity is complex, however, in all stages of obesity lifestyle changes are mandatory--including diet, exercise and behavior modification. Pharmacotherapy might be needed if lifestyle changes alone do not result an acceptable weight loss. For the long-term treatment of obesity sibutramin and orlistat are the available approved drugs. In case of morbid obesity (body mass index > 40 kg/m2, or > 35 kg/m2 plus comorbid conditions and other risk factors) surgery might be the treatment of choice. There are different surgical methods, among those a widely used method nowadays is the laparoscopic adjustable gastric banding procedure.