A physiological study to determine the mechanism of carbon dioxide clearance during apnoea when using transnasal humidified rapid insufflation ventilatory exchange (THRIVE)

Clinical observations suggest that compared with standard apnoeic oxygenation, transnasal humidified rapid-insufflation ventilatory exchange using high-flow nasal oxygenation reduces the rate of carbon dioxide accumulation in patients who are anaesthetised and apnoeic. This suggests that active gas exchange takes place, but the mechanisms by which it may occur have not been described. We used three laboratory airway models to investigate mechanisms of carbon dioxide clearance in apnoeic patients. We determined flow patterns using particle image velocimetry in a two-dimensional model using particle-seeded fluorescent solution; visualised gas clearance in a three-dimensional printed trachea model in air; and measured intra-tracheal turbulence levels and carbon dioxide clearance rates using a three-dimensional printed model in air mounted on a lung simulator. Cardiogenic oscillations were simulated in all experiments. The visualisation experiments indicated that gaseous mixing was occurring in the trachea. With no cardiogenic oscillations applied, mean (SD) carbon dioxide clearance increased from 0.29 (0.04) ml.min⁻¹ to 1.34 (0.14) ml.min⁻¹ as the transnasal humidified rapid-insufflation ventilatory exchange flow rate was increased from 20 l.min⁻¹ to 70 l.min⁻¹ (p = 0.0001). With a cardiogenic oscillation of 20 ml.beat⁻¹ applied, carbon dioxide clearance increased from 11.9 (0.50) ml.min⁻¹ to 17.4 (1.2) ml.min⁻¹ as the transnasal humidified rapid-insufflation ventilatory exchange flow rate was increased from 20 l.min⁻¹ to 70 l.min⁻¹ (p = 0.0014). These findings suggest that enhanced carbon dioxide clearance observed under apnoeic conditions with transnasal humidified rapid-insufflation ventilatory exchange, as compared with classical apnoeic oxygenation, may be explained by an interaction between entrained and highly turbulent supraglottic flow vortices created by high-flow nasal oxygen and cardiogenic oscillations.     

Qualitative analysis of Adenomatous Polyposis Coli promoter: Hypermethylation, engagement and effects on survival of patients with esophageal cancer in a high risk region of the world, a potential molecular marker

Background  

Squamous cell carcinoma of esophagus (SCCE) occurs at a high incidence rate in certain parts of the world. This feature necessitates that different aspects of the disease and in particular genetic characteristics be investigated in such regions. In addition, such investigations might lead to achievement of molecular markers helpful for early detection, successful treatment and follow up of the disease. Adenomatous Polyposis Coli (APC) promoter hypermethylation has been shown to be a suitable marker for both serum and solid tumors of adenocarcinoma of esophagus. We investigated the status of APC promoter hypermethylation in Iranian patients, compared the results with the former studies, and evaluated its applicability as a candidate molecular marker by examining association between survival of SCCE patients and APC promoter methylation.     

Characterization of Homozygous Hb Setif (HBA2: c.283G>T) in the Iranian Population

Hemoglobin (Hb) variants are abnormalities resulting from point mutations in either of the two α-globin genes (HBA2 or HBA1) or the β-globin gene (HBB). Various reports of Hb variants have been described in Iran and other countries around the world. Hb Setif (or HBA2: c.283G>T) is one of these variants with a mutation at codon 94 of of the α2-globin gene that is characterized in clinically normal heterozygous individuals. We here report clinical and hematological findings in two homozygous cases of Iranian origin for this unstable Hb variant.     

The human ERG1 channel polymorphism, K897T, creates a phosphorylation site that inhibits channel activity

Single-nucleotide polymorphisms (SNPs) in the human ether-a-go-go-related gene 1, hERG1, are associated with cardiac arrhythmias. The Kv11.1 channels encoded by hERG1 are also essential for rhythmic excitability of the pituitary, where they are regulated by thyroid hormone through a signal transduction cascade involving the phosphatidylinositol 3-kinase (PI3K) and the Ser/Thr-directed protein phosphatase, PP5. Here, we show that the hERG1 polymorphism at codon 897, which is read as a Thr instead of a Lys, creates a phosphorylation site for the Akt protein kinase on the Kv11.1 channel protein. Consequently, hormonal signaling through the PI3K signaling cascade, which normally stimulates K897 channels through PP5-mediated dephosphorylation, inhibits T897 channels through Akt-mediated phosphorylation. Thus, hormonal regulation of Kv11.1 in humans with the T897 polymorphism is predicted to prolong the QT interval of cardiac myocytes. A systematic bioinformatics search for SNPs in human ion channel genes identified 15 additional candidates for such “phosphorylopathies,” which are predicted to create or destroy putative phosphorylation sites. Changes in protein phosphorylation might represent a general mechanism for the interaction of genetic variation and environment on human health.     

Molecular biology of chronic thromboembolic pulmonary hypertension

Recent efforts have seen major advances in elucidating the mechanisms underlying pulmonary arterial hypertension. However, chronic thromboembolic pulmonary hypertension (CTEPH) often has been excluded from these studies. Consequently, whereas the clinical, radiographic, and hemodynamic characteristics of CTEPH have been well described, there remains a deficit in our understanding of the cellular, molecular, and genetic mechanisms underlying CTEPH. Furthermore, although prior venous thromboembolism may act as the inciting event, it is still unclear what predisposes some patients to develop CTEPH. CTEPH has two major pathogenic components. The first is the primary obstruction of central pulmonary arteries by accumulation of thrombotic material. The second is characterized by severe pulmonary vascular remodeling, similar to that seen in idiopathic pulmonary arterial hypertension. Other articles in this series describe the pathological, surgical, and therapeutic aspects of CTEPH. Here, we review the potential molecular and cellular mechanisms that may contribute to the pathogenesis of CTEPH.     

Candidate genes for oral-facial clefts in Guatemalan families

Nonsyndromic cleft lip +/- cleft palate (CL/P) is a complex trait of unknown etiology. Most genetic studies of CL/P define affection status in a way that ignores subtle subclinical manifestations, resulting in a potential loss of statistical power. This study investigated 10 candidate genes in 155 individuals from 25 Guatemalan CL/P families. High-resolution ultrasound images of the orbicularis oris (OO) muscle were obtained. CL/P was present in 28 family members; an additional 10 had subcutaneous OO muscle defects. Family-based association studies were performed for both narrow (CL/P only) and broad (CL/P plus OO muscle defects) definitions of affection status. PVRL1 was significantly associated under both definitions (P = 0.04, narrow; P = 0.02, broad). Association with JAG2 improved from P = 0.09 under the narrow definition to P = 0.04 under the broad definition. Broadening the oral-facial cleft phenotype to include subclinical variants may improve power in genetic studies.