Perioperative Autonomic Dysfunction in a Patient With Charcot-Marie-Tooth Disease: A Case Report

Autonomic dysfunction can lead to unexpected hemodynamic instability during surgery, and best practices for the perioperative care of patients with this condition are not well-defined. We report the case of a 63-year-old woman with Charcot-Marie-Tooth disease who experienced perioperative autonomic dysfunction characterized by severe fluctuations in blood pressure while under spinal anesthesia. However,later, a second hip surgery performed under general anesthesia with special precautions resulted in an uncomplicated perioperative course, with only mild fluctuations in blood pressure

Two heterozygous mutations in NFATC1 in a patient with Tricuspid Atresia.

Tricuspid Atresia (TA) is a rare form of congenital heart disease (CHD) with usually poor prognosis in humans. It presents as a complete absence of the right atrio-ventricular connection secured normally by the tricuspid valve. Defects in the tricuspid valve are so far not associated with any genetic locus, although mutations in numerous genes were linked to multiple forms of congenital heart disease. In the last decade, Knock-out mice have offered models for cardiologists and geneticists to study the causes of congenital disease. One such model was the Nfatc1(-/-) mice embryos which die at mid-gestation stage due to a complete absence of the valves. NFATC1 belongs to the Rel family of transcription factors members of which were shown to be implicated in gene activation, cell differentiation, and organogenesis. We have previously shown that a tandem repeat in the intronic region of NFATC1 is associated with ventricular septal defects. In this report, we unravel for the first time a potential link between a mutation in NFATC1 and TA. Two heterozygous missense mutations were found in the NFATC1 gene in one indexed-case out of 19 patients with TA. The two amino-acids changes were not found neither in other patients with CHDs, nor in the control healthy population. Moreover, we showed that these mutations alter dramatically the normal function of the protein at the cellular localization, DNA binding and transcriptional levels suggesting they are disease-causing

Low Pressure Robot-assisted Radical Prostatectomy With the AirSeal System at OLV Hospital: Results From a Prospective Study

Micro-Abstract Limited studies examined the effects of pneumoperitoneum during robot-assisted radical prostatectomy (RARP) and with AirSeal. The aim of this study was to assess the effect on hemodynamics of lower pressure pneumoperitoneum (8 mmHg) with AirSeal, during RARP in steep Trendelenburg 45\ub0, proving how the combination of steep Trendelenburg, lower pressure pneumoperitoneum and the extreme surgeon's experience allows to safely perform RARP using a low-impact surgery. Background Limited studies examined effects of pneumoperiotneum during robot-assisted radical prostatectomy (RARP) and with AirSeal. The aim of this study was to assess the effect on hemodynamics of a lower pressure pneumoperitoneum (8 mmHg) with AirSeal, during RARP in steep Trendelenburg 45\ub0 (ST). Materials and Methods This is an institutional review board-approved, prospective, interventional, single-center study including patients treated with RARP at OLV Hospital by one extremely experienced surgeon (July 2015-February 2016). Intraoperative monitoring included: arterial pressure, central venous pressure, cardiac output, heart rate, stroke volume, systemic vascular resistance, intrathoracic pressure, airways pressures, left ventricular end-diastolic and end-systolic areas/volumes and ejection fraction, by transesophageal echocardiography, an esophageal catheter, and FloTrac/Vigileo system. Measurements were performed after induction of anesthesia with patient in horizontal (T0), 5 minutes after 8 mmHg pneumoperitoneum (TP), 5 minutes after ST (TT1) and every 30 minutes thereafter until the end of surgery (TH). Parameters modification at the prespecified times was assessed by Wilcoxon and Friedman tests, as appropriate. All analyses were performed by SPSS v. 23.0. Results A total of 53 consecutive patients were enrolled. The mean patients age was 62.6 \ub1 6.9 years. Comorbidity was relatively limited (51% with Charlson Comorbidity Index as low as 0). Despite the ST, working always at 8 mmHg with AirSeal, only central venous pressure and mean airways pressure showed a statistically significant variation during the operative time. Although other significant hemodynamic/respiratory changes were observed adding pneumoperitoneum and then ST, all variables remained always within limits safely manageable by anesthesiologists. Conclusion The combination of ST, lower pressure pneumoperitoneum and extreme surgeon's experience enables to safely perform RAR

Intraoperative mechanical power and postoperative pulmonary complications in low-risk surgical patients: a prospective observational cohort study

Abstract Background Inadequate intraoperative mechanical ventilation (MV) can lead to ventilator-induced lung injury and increased risk for postoperative pulmonary complications (PPCs). Mechanical power (MP) was shown to be a valuable indicator for MV outcomes in critical care patients. The aim of this study is to assess the association between intraoperative MP in low-risk surgical patients undergoing general anesthesia and PPCs. Methods Two-hundred eighteen low-risk surgical patients undergoing general anesthesia for elective surgery were included in the study. Intraoperative mechanical ventilatory support parameters were collected for all patients. Postoperatively, patients were followed throughout their hospital stay and up to seven days post discharge for the occurrence of any PPCs. Results Out of 218 patients, 35% exhibited PPCs. The average body mass index, tidal volume per ideal body weight, peak inspiratory pressure, and MP were significantly higher in the patients with PPCs than in the patients without PPCs (30.3 ± 8.1 kg/m2 vs. 26.8 ± 4.9 kg.m2, p < 0.001; 9.1 ± 1.9 ml/kg vs. 8.6 ± 1.4 ml/kg, p = 0.02; 20 ± 4.9 cmH2O vs. 18 ± 3.7 cmH2O, p = 0.001; 12.9 ± 4.5 J/min vs. 11.1 ± 3.7 J/min, p = 0.002). A multivariable regression analysis revealed MP as the sole significant predictor for the risk of postoperative pulmonary complications [OR 1.1 (95% CI 1.0–1.2, p = 0.036]. Conclusions High intraoperative mechanical power is a risk factor for developing postoperative pulmonary complications. Furthermore, intraoperative mechanical power is superior to other traditional mechanical ventilation variables in identifying surgical patients who are at risk for developing postoperative pulmonary complications. Clinical trial registration NCT03551899; 24/02/2017

NFATC1 mutations impair functional interactions with GATA5 and HAND2.

<p>A- Wt NFATC1 or NFATC1 Mutants (P66L, I701L, P66L/I701L) were transfected with/without HAND2 and the DEGS1 promoter coupled to luciferase reporter construct in Hela cells. Six hours post transfection, media was changed and cells were harvested for luciferase assay after 36 hours. Relative luciferase activities are represented as fold activation. The data are the mean of three independent experiments done in duplicates +/− standard deviation. Wt NFATC1 and HAND2 synergistically activate DEGS1 promoter. This synergy was abrogated in all NFATC1 mutants. Significance (p<0.05) was assessed using the one-way Anova test. (* p<0.01, ** p<0.05) B- Wt NFATC1 or NFATC1 Mutants (P66L, I701L, P66L/I701L) were transfected with/without PPP3CA and with/without GATA5 to assess their combinatorial regulation of the DEGS1 promoter in HeLa cells. Six hours post transfection, media was changed and cells were harvested for luciferase assay after 36 hours. Relative luciferase activities are represented as fold activation. The data are the mean of three independent experiments done in duplicates +/− standard deviation. Wt NFATC1 cotransfected with GATA5 caused a synergistic activation of 35 fold, while transfection of Wt NFATC1 with PPP3CA and GATA5 caused even a stronger synergy reaching 68 fold. The synergestic activation was maintained in all mutants except for P66L/I701L double mutant where the synergy was totally lost. Significance (p<0.05) was assessed using the one-way Anova test. (* p<0.01, ** p<0.05).</p

Hypothetical pathway involving NFATC1 in endocardial cushion proliferation and valve maturation.

<p>Hypothetical pathway involving NFATC1 in endocardial cushion proliferation and valve maturation.</p

Frequency of the NFATC1 mutations according to the Exome Sequencing Project (ESP).

<p> <b>rs ID</b></p><p>dbSNP reference SNP identifier.</p><p> <b>EA Allele Count</b></p><p>The observed allele counts for the listed alleles in European American population. (delimited by /).</p><p> <b>AA Allele Count</b></p><p>The observed allele counts for the listed alleles in African American population. (delimited by /).</p><p> <b>Allele Count</b></p><p>The observed allele counts for the listed alleles in all populations. (delimited by /).</p><p> <b>MAF (%) (EA/AA/All):</b></p><p>the minor-allele frequency in percent listed in the order of European American (EA), African American(AA) and all populations (All). (delimited by /).</p

Effect of the NFATC1 missense SNPs on the cellular localization of the protein.

<p>A- Immunofluorescence of HeLa cells transfected with plasmids encoding for the Wt NFATC1 and NFATC1 Mutants (P66L, I701L, P66L/I701L). The localization of NFATC1 was visualized using an anti-Flag antibody. Nuclei of cells were visualized using the Hoechst dye (blue color). Wt and NFATC1 mutants localized to the cytoplasm in the absence of PPP3CA (red color). (Magnification ×40). B- Immunofluorescence of HeLa cells transfected with plasmids encoding for the Wt NFATC1 and NFATC1 Mutants (P66L, I701L, P66L/I701L) co-transfected with PP3CA. The localization of NFATC1 was visualized using an anti-Flag antibody (red color) while PP3CA was visualized using anti-HA antibody (green color). Nuclei of cells were visualized using Hoechst dye (blue color). Most of the cells co-transfected with the double NFATC1 mutant were retained in the cytoplasm around the nuclear membrane, whereas in the other cases, the protein was totally translocated to the nucleus. (Magnification ×40). Yellow arrows indicate cytoplasmic (peri-nuclear) staining, while red arrows indicate nuclear staining.</p

Sequencing results showing the different NFATC1 SNPs.

<p>Representative chromatograms of the different missense SNPs in exons 2 and 8 (A and B respectively) and synonymous SNPs in exon 2 and 3 (C and D respectively).The boxed region indicates the place of the polymorphisms in the patient as compared to a normal sequence. In all cases, the SNPs occur on one allele as visualized by overlapping peaks at the indicated position inside the box. In (A) a cytosine is substituted by a thymine, in (B) an adenine is substituted by a cysteine, in (C) a guanine is substituted by a thymine, and in (D) a cytosine is substituted by a thymine.</p

Transcriptional activity of the mutated NFATC1 proteins.

<p>A- Wt NFATC1 or NFATC1 Mutants (P66L, I701L, P66L/I701L) were cotransfected with the human CCND1 promoter coupled luciferase reporter construct in the presence or absence of activated clacineurin (PPP3CA) in Hela cells. Six hours post transfection, media was changed and cells were harvested for luciferase assay after 36 hours. Relative luciferase activities are represented as fold activation. The data are the mean of three independent experiments done in duplicates +/− standard deviation. Significance (p<0.05) was assessed using the one-way Anova test. (* p<0.01, ** p<0.05) B- Wt NFATC1 or NFATC1 Mutants (P66L, I701L, P66L/I701L) were cotransfected with the human DEGS1 promoter coupled luciferase reporter construct in the presence or absence of activated clacineurin (PPP3CA) in Hela cells. Six hours post transfection, media was changed and cells were harvested for luciferase assay after 36 hours. Relative luciferase activities are represented as fold activation. The data are the mean of three independent experiments done in duplicates +/− standard deviation. Significance (p<0.05) was assessed using the one-way Anova test. (* p<0.01, ** p<0.05).</p