A quest for genetic causes underlying signaling pathways associated with neural tube defects.

Neural tube defects (NTDs) are serious congenital deformities of the nervous system that occur owing to the failure of normal neural tube closures. Genetic and non-genetic factors contribute to the etiology of neural tube defects in humans, indicating the role of gene-gene and gene-environment interaction in the occurrence and recurrence risk of neural tube defects. Several lines of genetic studies on humans and animals demonstrated the role of aberrant genes in the developmental risk of neural tube defects and also provided an understanding of the cellular and morphological programs that occur during embryonic development. Other studies observed the effects of folate and supplementation of folic acid on neural tube defects. Hence, here we review what is known to date regarding altered genes associated with specific signaling pathways resulting in NTDs, as well as highlight the role of various genetic, and non-genetic factors and their interactions that contribute to NTDs. Additionally, we also shine a light on the role of folate and cell adhesion molecules (CAMs) in neural tube defects.

FRMD7 Gene Alterations in a Pakistani Family Associated with Congenital Idiopathic Nystagmus.

Congenital idiopathic nystagmus (CIN) is an oculomotor disorder characterized by repetitive and rapid involuntary movement of the eye that usually develops in the first six months after birth. Unlike other forms of nystagmus, CIN is widely associated with mutations in the FRMD7 gene. This study involves the molecular genetic analysis of a consanguineous Pakistani family with individuals suffering from CIN to undermine any potential pathogenic mutations. Blood samples were taken from affected and normal individuals of the family. Genomic DNA was extracted using an in-organic method. Whole Exome Sequencing (WES) and analysis were performed to find any mutations in the causative gene. To validate the existence and co-segregation of the FRMD7 gene variant found using WES, sanger sequencing was also carried out using primers that targeted all of the FRMD7 coding exons. Additionally, the pathogenicity of the identified variant was assessed using different bioinformatic tools. The WES results identified a novel nonsense mutation in the FRMD7 (c.443T>A; p. Leu148 *) gene in affected individuals from the Pakistani family, with CIN resulting in a premature termination codon, further resulting in the formation of a destabilized protein structure that was incomplete. Co-segregation analysis revealed that affected males are hemizygous for the mutated allele c.443T>A; p. Leu148 * and the affected mother is heterozygous. Overall, such molecular genetic studies expand our current knowledge of the mutations associated with the FRMD7 gene in Pakistani families with CIN and significantly enhance our understanding of the molecular mechanisms involved in genetic disorders.

The Potential Dangers of Recruitment Maneuvers During One Lung Ventilation Surgery.

BACKGROUND: Existing evidence regarding lung-protective ventilation (LPV) during one-lung ventilation (OLV) focuses on surrogate outcomes. Our objective was to assess whether an LPV protocol during OLV surgery is associated with reduced respiratory complications. MATERIALS AND METHODS: This was a matched control retrospective cohort study of patients undergoing pulmonary resection at a tertiary Canadian hospital. The experimental group (n = 50) was derived from primary data of two crossover RCTs, which utilized protocolized LPV strategies with varying levels of positive end-expiratory pressure and recruitment maneuvers. The control group was drawn from a prospectively maintained database; these patients received conventional nonprotocolized ventilation (2000-2010). Each experimental group patient was matched 1:1 with a control group patient with respect to clinically relevant variables (age, sex, diagnosis, smoking status, cardiovascular disease status, comorbidity, BMI, preoperative forced expiratory volume in 1 s, surgery type). Major respiratory complications were defined as composite of acute respiratory distress syndrome, need for new positive-pressure ventilation, and atelectasis requiring bronchoscopy. Paired and unpaired statistical tests were used. RESULTS: Patients appeared well matched. Major respiratory complications occurred in 8% (n = 4) and 2% (n = 1) of patients in experimental and control groups, respectively (P = 0.50). There was a trend toward increased mortality (4 versus 0, P = 0.06) with protocolized LPV. The patients who died had respiratory complications; one had acute respiratory distress syndrome and two had profound hypoxemia. CONCLUSIONS: There was a nonsignificant trend toward increased mortality with LPV during OLV. Although limited by a small sample size, our findings identify a potential danger to excessive recruitment maneuvers. Larger studies, with clinically important outcomes are needed to better define the risk/benefit trade-offs for LPV during OLV.

RBC transfusion is associated with increased risk of respiratory failure after pneumonectomy.

BACKGROUND AND OBJECTIVES: Pneumonectomy is associated with high risk of respiratory complications. Our objective was to determine if transfusions are associated with increased rate of ARDS and respiratory failure in adults undergoing elective pneumonectomy. METHODS: Retrospective cohort study of consecutive pneumonectomies undertaken at a tertiary hospital (2003-2013). Multivariable logistic regression was performed to adjust for confounding factors. RESULTS: ARDS and respiratory failure occurred in 12.4% (n = 20) and 19.2% (n = 31) of 161 pneumonectomy patients, respectively, and were more likely to occur in transfused patients (P = 0.03, P < 0.001). pRBCs, FFP and platelets were transfused in 27% (n = 43), 6% (n = 9), and 2% (n = 3), respectively. On multivariable analyses utilizing blood products as continuous and binary variables, pRBC use was the only independent predictor of ARDS with odds ratio (OR) = 1.23 (95%CI:1.08-1.39, P = 0.002) and OR = 2.45 (95%CI:1.10-5.49, P = 0.03), respectively. On multivariable analyses utilizing blood products as continuous and binary variables, pRBCs were the only independent predictor of respiratory failure with OR = 1.37 (95%CI:1.16-1.60, P < 0.001) and OR = 3.17 (95%CI:1.25-8.02, P = 0.02), respectively. CONCLUSIONS: Peri-operative pRBC use appears to be an independent risk factor for ARDS and respiratory failure after pneumonectomy. There is a significant dose-response relationship. Platelets and FFP did not appear to increase ARDS risk but this may be due to low utilization.