Estudo morfológico no músculo gastrocnêmio de camundongos C57 BL10 submetidos à ingestão prolongada de etanol Study of ultrastructural alterations in gastrocnemius muscle of C57 BL10 mice after prolonged ethanol ingestion

Os efeitos do alcoolismo crônico no músculo gastrocnêmio de camundongos bem nutridos foram estudados morfologicamente com a finalidade de se avaliar a hipótese de que o etanol exerce um papel tóxico direto sobre o músculo esquelético. Foram usados 30 camundongos C57BL10 machos, adultos jovens, divididos em dois grupos: Grupo A (controle) consistindo de 10 camundongos que beberam água e Grupo B (alcoólico) de 20 camundongos que beberam etanol a 25%. Todos os animais receberam" uma ração balanceada de laboratório e foram mantidos nesse regime ad libitum nas mesmas condições ambientais durante 48 semanas e pesados uma vez por semana. O consumo diário de dieta e a ingestão calórica foram calculados tendo os animais apresentado substancial ganho de peso, não mostrando qualquer sinal de desnutrição. Ao final do experimento os animais foram sacrificados para estudos morfológicos. Pela microscopia óptica não foram encontradas alterações. Importantes anormalidades foram observadas pela microscopia eletrônica em todos os espécimens.O retículo sarcoplasmático mostrou-se freqüentemente dilatado, resultando na formação de grandes vesículas e envolvendo as cisternas terminais com deslocamento das tríades. Áreas de estreitamento, ruptura e perda de miofibrilas ocorreram assim como zonas de completa desorganização de miofibrilas com perda do padrão estriado normal. As mitocondrias estavam em linhas gerais dentro dos limites da normalidade. Agregados tubulares peculiares vistos comumente na paralisia periódica e outras condições patológicas humanas, foram encontrados tanto no músculo dos camundongos controles como no dos alcoólicos. Os nervos intramusculares assim como as junções neuromusculares mostravam-se normais. Importantes anormalidades nos capilares musculares foram observadas, consistindo de tumefação das células endoteliais e de espessamento da lâmina basal. Difusa infiltração lipídica microvesicular foi vista no citoplasma dos hepatócitos parecendo constituir uma evidência a mais da ação tóxica do etanol sobre o organismo. Concluímos que a ingestão prolongada de etanol, representando 14,4% de calorias totais, produz no músculo gastrocnêmio de camundongos C57BL10 bem nutridos um elenco de alterações ultraestruturais que refletem um efeito tóxico direto sobre o músculo esquelético. As alterações constatadas são semelhantes àquelas descritas na miopatia alcoólica crônica humana<br>The effects of chronic alcoholism on gastrocnemius muscle of well-nourished mice were morphologically studied to test the direct toxic role of ethanol on skeletal muscle. Thirty male young adult C57BL10 mice were divided in two groups: Group A (control) consisting of ten mice that drank water and Group B (alcoholic) consisting of twenty mice that drank 25% ethanol. All mice were allowed a balanced laboratory chow. The animals were kept on this ad libitum regimen under the same conditions of environment for 48 weeks and were weighed once a week. The daily dietary consumption and caloric intake were estimated, the animals having had a substantial weight gain, showing no signs of malnutrition. At the end of the experiment the animals were killed for morphological studies. No abnormalities were observed by conventional microscopy.Striking deviations from normal were verified by electron microscopy in all specimens. Dilatation of sarcoplasmic reticulum was a common feature, sometimes resulting in the formation of large vesicles and involving the terminal cisternae with the displacement of the triads. Areas of narrowing, splitting and loss of myofibrils were seen. Zones of complete disorganization of miofibrils could be occasionally observed. Mitochondria were generally normal. Peculiar tubular aggregates seen commonly in periodic paralysis and other human pathological conditions, were encountered in both control and alcoholic mice. Intramuscular nerves and neuromuscular junctions were normal. Important abnormalities in muscle capillaries were observed, consisting of swelling of endothelial cells and thickening of the basal lamina. A diffuse microvesicular lipid infiltration was seen in the cytoplasm of the hepatocytes which seems to be a further evidence of the toxic role played by ethanol. We concluded that prolonged ingestion of ethanol, representing 14.4% of total calories, produces in the gastrocnemius muscle of well-nourished C57BL10 mice a distinct spectrum of ultrastructural changes which reflects a direct toxic effect on the skeletal muscle. These alterations are similar to those described in human chronic alcoholic myopathy

A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache

OBJECTIVE: To compare the effectiveness and side effects of migraine prophylactic medications. DESIGN: We performed a network meta-analysis. Data were extracted independently in duplicate and quality was assessed using both the JADAD and Cochrane Risk of Bias instruments. Data were pooled and network meta-analysis performed using random effects models. DATA SOURCES: PUBMED, EMBASE, Cochrane Trial Registry, bibliography of retrieved articles through 18 May 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included randomized controlled trials of adults with migraine headaches of at least 4 weeks in duration. RESULTS: Placebo controlled trials included alpha blockers (n = 9), angiotensin converting enzyme inhibitors (n = 3), angiotensin receptor blockers (n = 3), anticonvulsants (n = 32), beta-blockers (n = 39), calcium channel blockers (n = 12), flunarizine (n = 7), serotonin reuptake inhibitors (n = 6), serotonin norepinephrine reuptake inhibitors (n = 1) serotonin agonists (n = 9) and tricyclic antidepressants (n = 11). In addition there were 53 trials comparing different drugs. Drugs with at least 3 trials that were more effective than placebo for episodic migraines included amitriptyline (SMD: -1.2, 95% CI: -1.7 to -0.82), -flunarizine (-1.1 headaches/month (ha/month), 95% CI: -1.6 to -0.67), fluoxetine (SMD: -0.57, 95% CI: -0.97 to -0.17), metoprolol (-0.94 ha/month, 95% CI: -1.4 to -0.46), pizotifen (-0.43 ha/month, 95% CI: -0.6 to -0.21), propranolol (-1.3 ha/month, 95% CI: -2.0 to -0.62), topiramate (-1.1 ha/month, 95% CI: -1.9 to -0.73) and valproate (-1.5 ha/month, 95% CI: -2.1 to -0.8). Several effective drugs with less than 3 trials included: 3 ace inhibitors (enalapril, lisinopril, captopril), two angiotensin receptor blockers (candesartan, telmisartan), two anticonvulsants (lamotrigine, levetiracetam), and several beta-blockers (atenolol, bisoprolol, timolol). Network meta-analysis found amitriptyline to be better than several other medications including candesartan, fluoxetine, propranolol, topiramate and valproate and no different than atenolol, flunarizine, clomipramine or metoprolol. CONCLUSION: Several drugs good evidence supporting efficacy. There is weak evidence supporting amitriptyline\u27s superiority over some drugs. Selection of prophylactic medication should be tailored according to patient preferences, characteristics and side effect profiles