Sublingual vaccination and delivery systems.

Most infectious agents use mucosal tissues as entry portals, thus, mucosae are frequently defined as a first line of defense against pathogens. Mucosal protection generally operates through antibody-mediated and cytotoxic T-cell responses which can be triggered by mucosal vaccines. Sublingual vaccination provides many advantages such as systemic and mucosal responses (both locally and at remote mucosal sites), besides being a needle-free administration route with high patient compliance and limited adverse effects. Buccal mucosa complexity nonetheless represents a challenge for vaccine administration, hence, many efforts were recently deployed to improve vaccine components, mucoadhesion and/or penetration. Several innovative approaches indeed confirmed that a robust and protective immunity can be achieved by sublingual vaccines. This review will then specify the most recent delivery systems and improvements developed to increase sublingual vaccines efficiency. We will focus our description on the immune mechanisms involved and the requirements for optimal sublingual immunization and mucosal protection.

Resucitación hemostática / Hemostatic resuscitation

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Ventilatory response to acute hypoxia in transgenic mice over-expressing erythropoietin: effect of acclimation to 3-week hypobaric hypoxia.

We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V (E)) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. V (E) was found to be similar in tg6 and wt mice in normoxia (FIO2=0.21). Post-acclimation V (E) was significantly elevated in every time point in wt mice at FIO2=0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in V (E) throughout acute hypoxia exposure. Changes in V (E) are associated with adjustments in tidal volume (V(T)). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V(T) suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response.

Avian embryos in hypoxic environments.

Avian embryos at high altitude do not benefit of the maternal protection against hypoxia as in mammals. Nevertheless, avian embryos are known to hatch successfully at altitudes between 4,000 and 6,500 m. This review considers some of the processes that bring about the outstanding modifications in the pressure differences between the environment and mitochondria of avian embryos in hypoxic environments. Among species, some maintain normal levels of oxygen consumption ( VO2) have a high oxygen carrying capacity, lower the air cell-arterial pressure difference ( PAO2 - PaO2 ) with a constant pH. Other species decrease VO2, increase only slightly the oxygen carrying capacity, have a higher PAO2 - PaO2 difference than sea-level embryos and lower the PCO2 and pH. High altitude embryos, and those exposed to hypoxia have an accelerated decline of erythrocyte ATP levels during development and an earlier stimulation of 2,3-BPG synthesis. A higher Bohr effect may ensure high tissue PO2 in the presence of the high-affinity hemoglobin. Independently of the strategy used, they serve together to promote suitable rates of development and successful hatching of high altitude birds in hypoxic environments.

Optimal hemoglobin concentration and high altitude: a theoretical approach for Andean men at rest.

The beneficial role of erythrocytosis for O2 transport has been questioned by evidence from bloodletting and hemodilution research as well as by studies suggesting the existence of an "optimal" hematocrit (Hct) or hemoglobin concentration ([Hb]) value. To assess to what extent erythrocytosis is beneficial in Andean men at high altitude, we examined and discussed optimal [Hb] using a mathematical approach by modeling the mixed (mean) venous Po2 (Pv(O2)) and arterial O2 content, considering for both the relation between [Hb] and arterial Po2. Relations of [Hb] to other physiological variables such as cardiac output and convective arterial O2 transport were also discussed, revealing the importance of Pv(O2) in this model. Our theoretical analysis suggests that increasing [Hb] allows increase and maintenance of Pv(O2) with only moderate declines in arterial Po2 as a consequence of moderate increases in altitude, reaching its maximum at the optimal [Hb] of 14.7 g/dl. Our analysis also shows that [Hb] corresponding to high arterial O2 content and O2 transport values is apparently not quite advantageous for improvement of oxygenation. Furthermore, chronic mountain sickness is discussed as an insightful example of the effects of excessive erythrocytosis at high altitude.

Effect of domperidone on ventilation and polycythemia after 5 weeks of chronic hypoxia in rats.

Chronically hypoxic humans and some mammals have attenuated ventilatory responses, which have been associated with high dopamine level in carotid bodies. Alveolar hypoventilation and blunted ventilatory response have been recognized to be at the basis of Chronic Mountain Sickness by generating arterial hypoxemia and polycythemia. To investigate whether dopamine antagonism could decrease the hemoglobin concentration by stimulating resting ventilation (VE) and/or hypoxic ventilatory response, 18 chronically hypoxic rats (5 weeks, PB=433 Torr) were studied with and without domperidone treatment (a peripheral dopamine antagonist). Acute and prolonged treatment significantly increased poikilocapnic ventilatory response to hypoxia (RVE ml/min/kg=VE at 0.1 FI(O(2))-VE at 0.21 FI(O(2))), from 506+/-36 to 697+/-48; and from 394+/-37 to 660+/-81, respectively. In addition, Domperidone treatment decreased hemoglobin concentration from 21.6+/-0.29 to 18.9+/-0.19 (P<0.01) in rats chronically exposed to hypobaric hypoxia. Our study suggests that the stimulant effect of D(2)-R blockade on ventilatory response to hypoxia seems to compensate the low hypoxic peripheral chemosensitivity after chronic exposure and the latter in turn decrease hemoglobin concentration.

Ventilatory and cardiovascular responses to hypoxia and exercise in Andean natives living at sea level.

This study was designed to determine in subjects born at high altitude who move to sea level (HA-SL: born at 3500 m or above; n = 25) whether their cardiorespiratory responses to hypoxia and exercise are similar to those of sea level natives (SL,n = 25). The average age (39 +/- 7.3 yr), weight (72 +/- 7.3 kg), and height (1.71 +/- 0.01 m) did not differ between the SL and HA-SL subjects. All subjects were studied at rest or during exercise (60 W on cycle ergometer) while breathing room air (F(IO2) = 0.21 and P(B) = 760) or hypoxia (F(IO2) = 0.115 and PB = 760) in the following order: (1) normoxia at rest (NX-Rs), (2) hypoxia at rest (HX-Rs, 11.5% O(2)), hypoxia at exercise (HX-Ex), and normoxia at exercise (NX-Ex). Each period lasted 5 min. In absolute values, HA-SL showed significantly higher ventilation (V(E), L/min) during exercise in both normoxia and hypoxia and higher oxygen saturation (Sa(O2), %) during hypoxia both at rest and in exercise. They also had lower end-tidal CO(2) values (P(ETCO2), torr) at rest in both normoxia and hypoxia, but a higher P(ETCO2) in hypoxic exercise. Heart rate (HR, beats/min) was lower at rest in both normoxia and hypoxia, but higher in exercise. With acute hypoxia, Sa(O2) decreased less in the HA-SL than in the SL at rest (HA-SL, 9.2 +/- 0.8; SL, 12.0 +/- 0.82) and during exercise (HA-SL, 18.3 +/- 1.1; SL, 21.2 +/- 1.2). In conclusion, this study shows that HA-SL natives have increased ventilation and heart rate during exercise once their lifelong hypoxia is relieved.

Energetic metabolism in mouse cerebral cortex during chronic hypoxia.

We measured the activities of Na(+)K(+) ATPase and of enzymes of the glycolytic pathway, Krebs cycle, and the respiratory chain in cerebral cortex of mice exposed to chronic hypoxia for three weeks and compared their values with those of sea level controls. There were no differences in Na(+)K(+) ATPase activity or in the activity of glycolytic enzymes. In the Krebs cycle, a 66% increase of succinate dehydrogenase activity was found due to a lower Km. In contrast, respiratory chain cytochrome oxidase activity was reduced by 12% in mice exposed to hypoxia. This suggested that the metabolic demand would be satisfied despite the respiratory chain depression (cytochrome oxidase), probably due to anaerobic energy production within the mitochondria (succinate dehydrogenase).

Relationship of ovarian hormones to hypoxemia in women residents of 4,300 m.

Prevalence of excessive erythrocytosis, the main sign of chronic mountain sickness (CMS), is greater in postmenopausal Andean women than in premenopausal women. It is uncertain whether this greater prevalence is related to the decline in female hormones and ventilatory function after the occurrence of the menopause. To study this, we compared the physiological variables involved in the physiopathology of CMS [end-tidal CO(2) (PET(CO(2)), Torr) and end-tidal O(2) (PET(O(2)), Torr), arterial oxygen saturation (Sa(O(2)), %), and Hb concentration (g/dl)] and progesterone and estradiol levels between postmenopausal and premenopausal women, both in the luteal and follicular phases. Women residing in Cerro de Pasco (n = 33; 4,300 m) aged 26--62 yr were studied. Postmenopausal women compared with premenopausal women in the luteal phase had lower PET(O(2)) (48 +/- 4 vs. 53 +/- 2 Torr, P = 0.005) and Sa(O(2)) levels (82 +/- 12 vs. 88 +/- 12%, P < 0.005) and higher PET(CO(2)) (34 +/- 2 vs. 29 +/- 3 Torr, P = 0.005) and Hb concentration (19 +/- 1 vs. 14 +/- 2 g/dl, P < 0.005). In addition, plasma progesterone was negatively correlated with PET(CO(2)) and positively correlated with PET(O(2)) and Sa(O(2)). No clear relationship was found among the cycle phases between estradiol and the variables studied. In conclusion, our results reveal that, before menopause, there is better oxygenation and lower Hb levels in women long residing at altitude, and this is associated with higher levels of progesterone in the luteal phase of the cycle.

Hernia crural. Resultados tras 10 años de tratamiento mediante plug de Lichtenstein / Femoral hernia: result after ten years of employing Lichtenstein's plug

Introducción. Desde el año 1989 utilizamos la técnica descrita por Lichtenstein para el tratamiento de la hernia crural. Con el objetivo de evaluar los resultados de la técnica, se han incluido todos los pacientes en el presente estudio. Pacientes y métodos. Se estudian prospectivamente 224 pacientes (228 herniorrafias) intervenidos entre junio de 1989 y junio de 1999; 178 fueron mujeres (79,4 por ciento). La edad media fue de 57,7 años (rango, 16-98). La intervención fue urgente en el 32,9 por ciento de los casos, y el 5,3 por ciento de éstos necesitó resección intestinal. Se empleó anestesia general en 161 casos (70,5 por ciento), regional en 58 (25,6 por ciento), y local en 9 (3,9 por ciento). Se utilizó polipropileno monofilamento en todos los casos. El seguimiento medio mediante exploración periódica es de 57 meses (rango, 1-120). Resultados. La estancia media fue de 3,5 días. Se produjeron complicaciones locales en 15 casos (6,6 por ciento), e intolerancia a la prótesis en un caso (0,4 por ciento); un paciente (0,4 por ciento) precisó reintervención por protrusión de la malla con dolor persistente; una hernia (0,4 por ciento) recidivó; una paciente (0,4 por ciento) intervenida de urgencia falleció; 3 pacientes (1,3 por ciento) han presentado posteriormente hernia inguinal del mismo lado. Conclusiones. Creemos que la herniorrafia crural con prótesis cilíndrica es la técnica de elección en la hernia crural, si bien en los casos de hernia recidivada o incarcerada pueden contemplarse otras alternativas (AU)

Hemoglobin affinity for oxygen in three subspecies of toads (Bufo sp.) living at different altitudes.

Blood oxygen affinity and red blood cell properties were measured in three subspecies of genus Bufo: Bufo spinulosus limensis, collected at sea level and at an average day temperature of 20 degrees C; Bufo spinulosus trifolium, from 3100 m, average day temperature of 15 degrees C; and Bufo spinulosus flavolineatus, from 4100 m, average day temperature of 10 degrees C. Electrophoresis of the hemoglobin showed the same component in each of the three subspecies. At 20 degrees C the blood oxygen affinities (P50) showed small differences between Bufo spinulosus limensis and Bufo spinulosus trifolium, whereas the value for Bufo spinulosus flavolineatus was markedly lower. At 10 degrees C, the ambient temperature of Bufo spinulosus flavolineatus, the P50 was extremely low compared with the other two subspecies at their corresponding ambient temperatures.

Evolution of human hypoxia tolerance physiology.

Analysis of human responses to hypobaric hypoxia in different lineages (lowlanders, Andean natives, Himalayan natives, and East Africans) indicates 'conservative' and 'adaptable' physiological characters involved in human responses to hypoxia. Conservative characters, arising by common descent, dominant and indeed define human physiology, but in five hypoxia response systems analyzed, we also found evidence for 'adaptable' characters at all levels of organization in all three high altitude lineages. Since Andeans and Himalayans have not shared common ancestry with East Africans for most of our species history, we suggest that their similar hypoxia physiology may represent the 'ancestral' condition for humans--an interpretation consistent with recent evidence indicating that our species evolved under 'colder, drier, and higher' conditions in East Africa where the phenotype would be simultaneously advantageous for endurance performance and for high altitude hypoxia. It is presumed that the phenotype was retained in low capacity form in highlanders and in higher capacity form in most lowland lineages (where it would be recognized by most physiologists as an endurance performance phenotype). Interestingly, it is easier for modern molecular evolution theory to account for the origin of 'adaptable' characters through positive selection than for conserved traits. Many conserved physiological systems are composed of so many gene products that it seems difficult to account for their unchanging state (for unchanging structure and function of hundreds of proteins linked in sequence to form the physiological system) by simple models of stabilizing selection.

Hernia inguinal recidivada: tratamiento mediante abordaje preperitoneal y prótesis amplia de malla de polipropileno / Recurrent inguinal hernia: treatment involving the preperitoneal approach and placement of a large sheet of prosthetic polypropylene mesh

Introducción. El objetivo del presente trabajo es evaluar los resultados de la reparación de las hernias recidivadas de la región inguinal mediante abordaje preperitoneal y colocación de una prótesis amplia de malla de polipropileno, siguiendo las técnicas descritas por Nyhus y Stoppa. Pacientes y método. Se estudian prospectivamente 72 pacientes tratados de 76 hernias recidivadas de la región inguinal (74 inguinales y 4 crurales) mediante esta técnica, entre marzo de 1990 y diciembre de 1998. En 8 casos (4 pacientes) la hernia fue bilateral. El número de intervenciones previas osciló entre 1 y 4. Se comentan aspectos técnicos. Resultados. El período de seguimiento oscila entre 2 meses y 8,7 años (media 3,9 años). Las complicaciones observadas han sido: infección de la herida en un 2,6 por ciento (n = 2), seroma en un 1,3 por ciento (n = 1) e íleo en un 1,3 por ciento (n = 1). No se han presentado complicaciones hemorrágicas, intolerancia a la malla, ni orquitis isquémica. Tampoco ha habido mortalidad postoperatoria y hasta el momento no se ha producido ninguna recidiva. Conclusiones. Con el abordaje preperitoneal y la colocación de una malla de polipropileno monofilamemto se obtienen unos buenos resultados que nos permiten considerar esta técnica como de elección en el tratamiento de las hernias recidivadas de la región inguinal (AU)

Hematological parameters in high altitude residents living at 4,355, 4,660, and 5,500 meters above sea level.

There have been a number of reports describing the hematological indicators of Andean residents living at altitudes above 4,000 m, but several confounding factors have made the published results difficult to interpret. To clear up the effect of hypoxia on hemoglobin concentration (Hb, g/dL), hematocrit (Hct, %) and red blood cell concentration (RBC, cells/microL), this publication describes and analyzes these variables in children, men, and women from three large and homogeneous populations living at 4,355 m (n = 151), 4,660 m (n = 400), and 5,500 m (n = 273) in the Southern Peruvian Andes. Hb, Hct, and RBC increase with age in men (p < 0.001), as well as in women (p < 0.001) at the three altitudes of the study. In children (boys and girls) living at 5,500, Hb increases 11% when compared with children living at 4,355 m, and in adults, Hb increases 9.6% when comparing the same altitudes. The maximum percentage increase in Hb with age was 5.6% at 5,500 m, in men and 3.2% at 4,355 m, in women. The average percentage of difference for the Hb concentration between adult men and women is 6.6% at 4,355 m, 9.8% at 4,660 m, and 11.6% at 5,500 m. The differences in Hb concentration between men and women can only be seen after puberty. Finally, Hb is higher in older than younger women, which confirms the role of menopause in the development of erythremia. The result of this analysis reinforces the notion that Hb and Hct seem to be stable and useful parameters for acclimatization only at moderate altitudes; with aging or with increasing altitude, they may become excessive and lose their efficiency to protect the venous oxygen pressure.

Carbonic anhydrase activity in the red blood cells of sea level and high altitude natives.

Red blood cell carbonic anhydrase (CA) activity has not been studied in high altitude natives. Because CA is an intraerythocytic enzyme and high altitude natives are polycythemic, it is important to know if the activity of CA per red cell volume is different from that of their sea level counterparts. Blood was collected from healthy subjects living in Lima (150m) and from twelve subjects from Cerro de Pasco (4330m), and hematocrit and carbonic anhydrase activity were measured. As expected, the high altitude natives had significantly higher hematocrits than the sea level controls (p = 0.0002). No difference in the CA activity per milliliter of red cells was found between the two populations. There was no correlation between the hematocrit and CA activity.

Reduced oxygen diffusion across the shell of Gray gull (Larus modestus) eggs.

Gray gulls, Larus modestus, nest 1500 m above sea level in northern Chile's Atacama Desert, one of the driest in the world. Their eggshell gas permeability, one third of that found in other Larus species, is an adaptation that reduces water loss, but at the expense of oxygen diffusion into the air cell with resultant hypoxia and reduced metabolic rate. This contrasts with characteristics found in birds nesting at very high altitudes where oxygen diffusion across the egg shell is maximized at the expense of water conservation. The oxygen consumption (MO2) of Larus modestus is 66% that of Larus argentatus; the oxygen conductance (GO2) is equivalent to 48% of that obtained in 5 other bird species. The oxygen partial pressure (PAO2) in the air chamber of Larus modestus (84 Torr) is lower than that of 10 other bird species whose average (PAO2) is 106 Torr. The CO2 partial pressure (PACO2) in the air chamber of Larus modestus is 68 Torr, a higher value than that found in 9 other bird species whose average (PACO2) is 39 Torr.

Reduced oxygen diffusion across the shell of Gray gull (Larus modestus) eggs

Gray gulls, Larus modestus, nest 1500 m above sea level in northern Chile's Atacama Desert, one of the driest in the world. Their eggshell gas permeability, one third of that found in other Larus species, is an adaptation that reduces water loss, but at the expense of oxygen diffusion into the air cell with resultant hypoxia and reduced metabolic rate. This contrasts with characteristics found in birds nesting at very high altitudes where oxygen diffusion across the egg shell is maximized at the expense of water conservation. The oxygen consumption (MO2) of Larus modestus is 66% that of Larus argentatus; the oxygen conductance (GO2) is equivalent to 48% of that obtained in 5 other bird species. The oxygen partial pressure (PAO2) in the air chamber of Larus modestus (84 Torr) is lower than that of 10 other bird species whose average (PAO2) is 106 Torr. The CO2 partial pressure (PACO2) in the air chamber of Larus modestus is 68 Torr, a higher value than that found in 9 other bird species whose average (PACO2) is 39 Torr.