Adaptation to Moderate Altitude Hypoxemia: The Example of the Valley of Mexico.

A large world population resides at moderate altitude. In the Valley of Mexico (2,240 m above sea level), its inhabitants, breathe approximately 29% more on average and have 10% increased hemoglobin concentrations compared to sea level residents, among other differences. These compensations reduce but not eliminate the impact of altitude hypoxemia. The objective of the manuscript is to review and describe the information available on health and disease at moderate altitudes, mainly with data in Spanish language from Latin-American countries. Young adults in Mexico City have an SaO2 between 92% and 94% versus 97% at sea level, frequently decreasing below 90% during sleep and intense exercise. It is likely that among the population living at this altitude, lung growth, and development during pregnancy and infancy are enhanced, and that after residing for several tens of thousands of years, more important adaptations in oxygen transport and utilization have developed, but we are not certain about it. For patients with respiratory diseases, residing at moderate altitudes implies increased hypoxemia and clinical deterioration, unless supplementary oxygen is prescribed or patients move to sea level. Hyperventilation increases exposure of residents to air pollutants compared to those living in cities with similar concentrations of pollutants, although at sea level. Humans evolved at sea level and lack the best-known adaptations to reside at moderate or high altitudes. Residents of moderate altitudes breathe deeply the city´s air with all its pollutants, and more often require supplementary oxygen.

A (H1N1) pdm09 HA D222 variants associated with severity and mortality in patients during a second wave in Mexico.

BACKGROUND: Pandemic type A (H1N1) influenza arose in early 2009, probably in Mexico and the United States, and reappeared in North America in September for seven more months. An amino acid substitution in the hemagglutinin (HA), D222G, has been reported in a significant proportion of patients with a severe and fatal outcome. We studied the prevalence of HA222 substitutions in patients in Mexico during the second wave and its association with clinical outcome and pathogenicity in a mouse model. METHODS: The nucleotide sequences of hemagglutinin (HA) from viruses collected from 77 patients were determined including 50 severe and fatal cases and 27 ambulatory cases. Deep sequencing was done on 5 samples from severe or fatal cases in order to determine the quasispecies proportion. Weight loss and mortality due to infection with cultured influenza viruses were analyzed in a mouse model. RESULTS: Viruses from 14 out of 50 hospitalized patients (28%) had a non aspartic acid residue at the HA 222 position (nD222), while all 27 ambulatory patients had D222 (p=0.0014). G222 was detected as sole species or in coexistence with N222 and D222 in 12 patients with severe disease including 8 who died. N222 in coexistence with D222 was detected in 1 patient who died and co-occurrence of A222 and V222, together with D222, was detected in another patient who died. The patients with a nD222 residue had higher mortality (71.4%), compared to the group with only D222 (22.2%, p=0.0008). Four of the 14 viruses from hospitalized patients were cultured and intranasally infected into mice. Two viruses with G222 were lethal while a third virus, with G222, caused only mild illness in mice similar to the fourth virus that contained D222. CONCLUSIONS: We confirm the elevated incidence of HA222 (H1N1)pdm09 variants in severe disease and mortality. Both clinical and mouse infection data support the idea that nD222 mutations contribute to increased severity of disease but additional determinants in disease outcome may be present.

[Cytochrome P450 and NAT2 polymorphisms and drug metabolism in DOTS]. / Polimorfismos en los genes CYP450 y NAT2 y metabolismo de fármacos para el tratamiento antituberculosis estandarizado.

It has been described an increase of the frequency of Directly Observed Therapy Short-course (DOTS) failure in countries with high rates of mycobacterial drug resistance. This increase could be due to the standardized doses of DOTS results in low or insufficient dosage of drugs in plasma. Several members of cytochrome P450 enzymes superfamily could explain the variations on acetylation velocity and in drug disposition. A population with slow acetylation has a higher risk of toxicity, as that potent inhibition of cytochrome P450 (CYP450) isoforms by isoniazid (CYP2C19 y CYP3A) are dependent of INH plasmatic concentration. This inhibitory effect has been described also for CYP12, CYP2C9 and CYP2E1. INH is metabolized by N-acetyltransferase 2 (NAT2). The wide variability interethnic and intraethnic in acetylation velocity is associated with the polymorphisms of NAT2. Patients with rapid acetylation have plasmatic concentration of INH low or insufficient which induces treatment failure. The study of genotypes of P450 and NAT2 allow us to predict therapeutic and individualized dosages.