RESUMO
We report a comparative venomic and antivenomic characterization of the venoms of newborn and adult specimens of the Central American rattlesnake, Crotalus simus, and of the subspecies cumanensis, durissus, ruruima, and terrificus of South American Crotalus durissus. Neonate and adult C. simus share about 50% of their venom proteome. The venom proteome of 6-week-old C. simus is predominantly made of the neurotoxic heterodimeric phospholipase A(2) (PLA(2) crotoxin) (55.9%) and serine proteinases (36%), whereas snake venom Zn(2+)-metalloproteinases (SVMPs), exclusively of class PIII, represent only 2% of the total venom proteins. In marked contrast, venom from adult C. simus comprises toxins from 7 protein families. A large proportion (71.7%) of these toxins are SVMPs, two-thirds of which belong to the PIII class. These toxin profiles correlate well with the overall biochemical and pharmacological features of venoms from adult (hemorrhagic) and newborn (neurotoxic) C. simus specimens. The venoms of the South American Crotalus subspecies belong to one of two distinct phenotypes. C. d. cumanensis exhibits high levels of SVMPs and low lethal potency (LD(50)), whereas C. d. subspecies terrificus, ruruima, and durissus have low SVMP activity and high neurotoxicity to mice. Their overall toxin compositions explain the outcome of envenomation by these species. Further, in all C. simus and C. durissus venoms, the concentration of neurotoxins (crotoxin and crotamine) is directly related with lethal activity, whereas lethality and metalloproteinase activity show an inverse relationship. The similar venom toxin profiles of newborn C. simus and adult C. durissus terrificus, ruruima, and durissus subspecies strongly suggests that the South American taxa have retained juvenile venom characteristics in the adult form (paedomorphism) along their North-South stepping-stone dispersal. The driving force behind paedomorphism is often competition or predation pressure. The increased concentration of the neurotoxins crotoxin and crotamine in South American rattlesnake venoms strongly argues that the gain of neurotoxicity and lethal venom activities to mammals may have represented the key axis along which overall venom toxicity has evolved during Crotalus durissus invasion of South America. The paedomorphic trend is supported by a decreasing LNC (lethal neurotoxicity coefficient, defined as the ratio between the average LD(50) of the venom and the crotoxin + crotamine concentration) along the North-South axis, coincident with the evolutionary dispersal pattern of the Neotropical rattlesnakes. The indistinguisable immunoreactivity patterns of Costa Rican and Venezuelan polyvalent antivenoms toward C. simus and C. durissus venoms strongly suggest the possibility of using these antivenoms indistinctly for the management of snakebites by adult C. simus and by certain C. d. cumanensis populations exhibiting a hemorrhagic venom phenotype. The antivenomic results also explain why the antivenoms effectively neutralize the hemorrhagic activity of adult C. simus venoms but does not protect against adult C. durissus sp. and newborn C. simus envenomations. The identification of evolutionary trends among tropical Crotalus, as reported here, may have an impact in defining the mixture of venoms for immunization to produce an effective pan-American anti-Crotalus antivenom.
Assuntos
Antivenenos/metabolismo , Venenos de Crotalídeos/genética , Crotalus/genética , Proteínas de Répteis/genética , Fatores Etários , Sequência de Aminoácidos , Animais , Venenos de Crotalídeos/química , Venenos de Crotalídeos/metabolismo , Crotalus/metabolismo , Evolução Molecular , Dados de Sequência Molecular , Neurotoxinas/genética , Neurotoxinas/metabolismo , Proteoma , Proteínas de Répteis/química , Proteínas de Répteis/metabolismo , América do Sul , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
OBJECTIVE: Noninvasive mechanical ventilation has been of use in the treatment of some forms of chronic and acute respiratory failure. However, the benefits of its use in patients in the stable phase of severe chronic obstructive pulmonary disease (COPD) remain unclear. A combination of continuous positive airway pressure (CPAP) and pressure support ventilation (PSV) may improve respiratory mechanics and alveolar ventilation, and reduce inspiratory muscle effort. In this study, we analyzed the physiologic effects of differing levels of CPAP and CPAP plus PSV in patients with stable severe COPD. PATIENTS AND METHODS: Work of breathing, breathing pattern, oxygen saturation measured by pulse oximetry, PaO2, and PaCO2 were analyzed in a group of 18 patients under the following conditions: a) baseline; b) CPAP, 3 cm H20; c) CPAP, 6 cm H20; d) CPAP 3 cm H20 plus PSV 8 cm H20; and e) CPAP 3 cm H20 plus PSV 12 cm H20. RESULTS: CPAP at pressures of 3 and 6 cm H20 was associated with an increase in tidal volume (VT) from a mean (SD) baseline value of 0.52 (0.04) L to 0.62 (0.04) and 0.61 (0.03) L, respectively. Minute ventilation increased from 8.6 (0.5) L/min to 10.8 (0.6) and 10.9 (0.5) L/min, respectively. Mean inspiratory flow (VT/Ti) increased from 0.35 (0.02) L/s to 0.44 (0.02) and 0.41 (0.02) L/s, respectively, and dynamic intrinsic positive end-expiratory pressure (PEEPi,dyn) was reduced from 1.63 (0.7) cm H20 to 1.1 (0.06) and 0.37 (0.4) cm H20, respectively. CPAP did not reduce the work of breathing. Association of CPAP at 3 cm H20 with PSV of 8 or 12 cm H20 increased VT to 0.72 (0.07) and 0.87 (0.08) L, respectively, while minute ventilation increased to 12.9 (0.8) and 14.9 (1.1) L/s, respectively. Mean inspiratory flow also increased to 0.50 (0.03) and 0.57 (0.03) L/s, respectively. Work of breathing was reduced from 0.90 (0.01) J/L to 0.48 (0.06) and 0.30 (0.06) J/L, respectively, while PEEPi,dyn increased to 1.30 (0.02) and 2.42 (0.08) cm H20, respectively. With combined CPAP of 3 cm H20 and PSV of 12 cm H20, PaCO2 was reduced from a baseline value of 41.2 (1.5) mm Hg to 38.7 (1.9) mm Hg. All of the changes were statistically significant (P< .05). CONCLUSIONS: CPAP of 3 cm H20 in combination with PSV improved breathing pattern, increased alveolar ventilation, and reduced work of breathing. These results offer a rational basis for the use of noninvasive mechanical ventilation in the treatment of patients with stable severe COPD.