Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats.

Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. By utilizing gas exchange manipulations and optogenetics in the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.

Hypocapnic hypothesis of Leigh disease.

Leigh syndrome (LS) is a neurogenetic disorder of children caused by mutations in at least 75 genes which impair mitochondrial bioenergetics. The changes have typical localization in basal ganglia and brainstem, and typical histological picture of spongiform appearance, vascular proliferation and gliosis. ATP deprivation, free radicals and lactate accumulation are suspected to be the causes. Hypocapnic hypothesis proposed in the paper questions the energy deprivation as the mechanism of LS. We assume that the primary harmful factor is hypocapnia (decrease in pCO2) and respiratory alkalosis (increase in pH) due to hyperventilation, permanent or in response to stress. Inside mitochondria, the pH signal of high pH/low bicarbonate ion (HCO-3) is transmitted by soluble adenyl cyclase (sAC) through cAMP dependent manner. The process can initiate brain lesions (necrosis, apoptosis, hypervascularity) in OXPHOS deficient cells residing at the LS area of the brain. The major message of the article is that it is not the ATP depletion but intracellular alkalization (and/or hyperoxia?) which seem to be the cause of LS. The paper includes suggestions concerning the methodology for further research on the LS mechanism and for therapeutic strategy.

Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome.

An uncharacterized multisystemic mitochondrial cytopathy was diagnosed in two infants from consanguineous Palestinian kindred living in a single village. The most significant clinical findings were tubulopathy (hyperuricemia, metabolic alkalosis), pulmonary hypertension, and progressive renal failure in infancy (HUPRA syndrome). Analysis of the consanguineous pedigree suggested that the causative mutation is in the nuclear DNA. By using genome-wide SNP homozygosity analysis, we identified a homozygous identity-by-descent region on chromosome 19 and detected the pathogenic mutation c.1169A>G (p.Asp390Gly) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. The same homozygous mutation was later identified in a third infant with HUPRA syndrome. The carrier rate of this mutation among inhabitants of this Palestinian isolate was found to be 1:15. The mature enzyme catalyzes the ligation of serine to two mitochondrial tRNA isoacceptors: tRNA(Ser)(AGY) and tRNA(Ser)(UCN). Analysis of amino acylation of the two target tRNAs, extracted from immortalized peripheral lymphocytes derived from two patients, revealed that the p.Asp390Gly mutation significantly impacts on the acylation of tRNA(Ser)(AGY) but probably not that of tRNA(Ser)(UCN). Marked decrease in the expression of the nonacylated transcript and the complete absence of the acylated tRNA(Ser)(AGY) suggest that this mutation leads to significant loss of function and that the uncharged transcripts undergo degradation.

Acid-base disturbances in cardiogenic pulmonary edema.

Eighty-one consecutive cases of uncomplicated cardiogenic pulmonary edema (CPE) were retrospectively graded for severity of chest roentgenogram (CXR) changes and grouped according to primary acid-base abnormalities, either single or mixed. Mean age was 72, 50 male, 31 female. Twenty-three percent had no acid-base disturbances (ABD). Isolated respiratory alkalosis was most common (41%), followed by metabolic acidosis, 22%; metabolic alkalosis, 10%, and respiratory acidosis, 9%. Age, sex, race distribution, morbidity and mortality were not significantly different between the groups. Overall mortality was 17%. Significantly higher mortality was associated with age over 70, pH less than 7.4, and presence of acute myocardial infarction. CXR scores did not correlate with pH, pCO2 or pO2, mortality or morbidity. Some patients with the most severe ABDs recovered while others, who had no ABD on presentation, eventually died. Thus, in 81 consecutive episodes of uncomplicated CPE, isolated respiratory alkalosis was the commonest ABD, occurring in 41%. No correlation was found between ABD and severity of CPE, morbidity or mortality.