De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy.

BACKGROUND: Very long-chain fatty acids (VLCFAs) are essential for functioning of biological membranes. ELOVL fatty acid elongase 1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs. We studied two patients with a dominant ELOVL1 mutation. Independently, Kutkowska-Kazmierczak et al. had investigated the same patients and found the same mutation. We extended our study towards additional biochemical, functional, and therapeutic aspects. METHODS: We did mutation screening by whole exome sequencing. RNA-sequencing was performed in patient and control fibroblasts. Ceramide and sphingomyelin levels were measured by LC-MS/MS. ELOVL1 activity was determined by a stable isotope-labelled [13C]malonyl-CoA elongation assay. ELOVL1 expression patterns were investigated by immunofluorescence, in situ hybridisation and RT-qPCR. As treatment option, we investigated VLCFA loading of fibroblasts. RESULTS: Both patients carried an identical heterozygous de novo ELOVL1 mutation (c.494C>T, NM_001256399; p.S165F) not deriving from a founder allele. Patients suffered from epidermal hyperproliferation and increased keratinisation (ichthyosis). Hypomyelination of the central white matter explained spastic paraplegia and central nystagmus, while optic atrophy was causative for reduction of peripheral vision and visual acuity. The mutation abrogated ELOVL1 enzymatic activity and reduced ≥C24 ceramides and sphingomyelins in patient cells. Fibroblast loading with C22:0-VLCFAs increased C24:0-ceramides and sphingomyelins. We found competitive inhibition for ceramide and sphingomyelin synthesis between saturated and monounsaturated VLCFAs. Transcriptome analysis revealed upregulation of modules involved in epidermal development and keratinisation, and downregulation of genes for neurodevelopment, myelination, and synaptogenesis. Many regulated genes carried consensus proliferator-activated receptor (PPAR)α and PPARγ binding motifs in their 5'-regions. CONCLUSION: A dominant ELOVL1 mutation causes a neuro-ichthyotic disorder possibly amenable to treatment with PPAR-modulating drugs.

Development and validation of a Score for Preoperative Prediction of Obstructive Sleep Apnea (SPOSA) and its perioperative outcomes.

BACKGROUND: Postoperative respiratory complications (PRCs) are associated with significant morbidity, mortality, and hospital costs. Obstructive sleep apnea (OSA), often undiagnosed in the surgical population, may be a contributing factor. Thus, we aimed to develop and validate a score for preoperative prediction of OSA (SPOSA) based on data available in electronic medical records preoperatively. METHODS: OSA was defined as the occurrence of an OSA diagnostic code preceded by a polysomnography procedure. A priori defined variables were analyzed by multivariable logistic regression analysis to develop our score. Score validity was assessed by investigating the score's ability to predict non-invasive ventilation. We then assessed the effect of high OSA risk, as defined by SPOSA, on PRCs within seven postoperative days and in-hospital mortality. RESULTS: A total of 108,781 surgical patients at Partners HealthCare hospitals (2007-2014) were studied. Predictors of OSA included BMI >25 kg*m-2 and comorbidities, including pulmonary hypertension, hypertension, and diabetes. The score yielded an area under the curve of 0.82. Non-invasive ventilation was significantly associated with high OSA risk (OR 1.44, 95% CI 1.22-1.69). Using a dichotomized endpoint, 26,968 (24.8%) patients were identified as high risk for OSA and 7.9% of these patients experienced PRCs. OSA risk was significantly associated with PRCs (OR 1.30, 95% CI 1.19-1.43). CONCLUSION: SPOSA identifies patients at high risk for OSA using electronic medical record-derived data. High risk of OSA is associated with the occurrence of PRCs.

Can Sarcopenia Quantified by Ultrasound of the Rectus Femoris Muscle Predict Adverse Outcome of Surgical Intensive Care Unit Patients as well as Frailty? A Prospective, Observational Cohort Study.

OBJECTIVE: To compare sarcopenia and frailty for outcome prediction in surgical intensive care unit (SICU) patients. BACKGROUND: Frailty has been associated with adverse outcomes and describes a status of muscle weakness and decreased physiological reserve leading to increased vulnerability to stressors. However, frailty assessment depends on patient cooperation. Sarcopenia can be quantified by ultrasound and the predictive value of sarcopenia at SICU admission for adverse outcome has not been defined. METHODS: We conducted a prospective, observational study of SICU patients. Sarcopenia was diagnosed by ultrasound measurement of rectus femoris cross-sectional area. Frailty was diagnosed by the Frailty Index Questionnaire based on 50 variables. Relationship between variables and outcomes was assessed by multivariable regression analysis NCT02270502. RESULTS: Sarcopenia and frailty were quantified in 102 patients and observed in 43.1% and 38.2%, respectively. Sarcopenia predicted adverse discharge disposition (discharge to nursing facility or in-hospital mortality, odds ratio 7.49; 95% confidence interval 1.47-38.24; P = 0.015) independent of important clinical covariates, as did frailty (odds ratio 8.01; 95% confidence interval 1.82-35.27; P = 0.006); predictive ability did not differ between sarcopenia and frailty prediction model, reflected by χ values of 21.74 versus 23.44, respectively, and a net reclassification improvement (NRI) of -0.02 (P = 0.87). Sarcopenia and frailty predicted hospital length of stay and the frailty model had a moderately better predictive accuracy for this outcome. CONCLUSIONS: Bedside diagnosis of sarcopenia by ultrasound predicts adverse discharge disposition in SICU patients equally well as frailty. Sarcopenia assessed by ultrasound may be utilized as rapid beside modality for risk stratification of critically ill patients.

Elevated upper body position improves pregnancy-related OSA without impairing sleep quality or sleep architecture early after delivery.

BACKGROUND: During pregnancy, upper airway resistance is increased, predisposing vulnerable women to pregnancy-related OSA. Elevation of the upper body increases upper airway cross-sectional area (CSA) and improves severity of OSA in a subgroup of nonpregnant patients (positional-dependent sleep apnea). We tested the hypothesis that elevated position of the upper body improves OSA early after delivery. METHODS: Following institutional review board approval, we conducted a randomized, crossover study on two postpartum units of Massachusetts General Hospital. Women during the first 48 h after delivery were included. Polysomnography was performed in nonelevated and 45° elevated upper body position. Upper airway CSA was measured by acoustic pharyngometry in nonelevated, 45° elevated, and sitting body position. RESULTS: Fifty-five patients were enrolled, and measurements of airway CSA obtained. Thirty patients completed polysomnography in both body positions. Elevation of the upper body significantly reduced apnea-hypopnea index (AHI) from 7.7 ± 2.2/h in nonelevated to 4.5 ± 1.4/h in 45° elevated upper body position (P = .031) during sleep. Moderate to severe OSA (AHI > 15/h) was diagnosed in 20% of postpartum patients and successfully treated by elevated body position in one-half of them. Total sleep time and sleep architecture were not affected by upper body elevation. Change from nonelevated to sitting position increased inspiratory upper airway CSA from 1.35 ± 0.1 cm2 to 1.54 ± 0.1 cm2 during wakefulness. Position-dependent increase in CSA and decrease in AHI were correlated (r = 0.42, P = .022). CONCLUSIONS: Among early postpartum women, 45° upper body elevation increased upper airway CSA and mitigated sleep apnea. Elevated body position might improve respiratory safety in women early after delivery. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01719224; URL: www.clinicaltrials.gov.

Anesthesia and increased hypercarbic drive impair the coordination between breathing and swallowing.

BACKGROUND: Coordination between breathing and swallowing helps prevent aspiration of foreign material into the respiratory tract. The authors examined the effects of anesthesia and hypercapnia on swallowing-breathing coordination. METHODS: In a randomized controlled crossover study, general anesthesia with propofol or sevoflurane was titrated using an up-down method to identify the threshold for suppression of the motor response to electrical stimulation of the forearm. Additional measurements included bispectral index, genioglossus electromyogram, ventilation (pneumotachometer), and hypopharyngeal pressure. During wakefulness and at each level of anesthesia, carbon dioxide was added to increase the end-tidal pressure by 4 and 8 mmHg. A swallow was defined as increased genioglossus activity with deglutition apnea and an increase in hypopharyngeal pressure. Spontaneous swallows were categorized as physiological (during expiration or followed by expiration) or pathological (during inspiration or followed by an inspiration). RESULTS: A total of 224 swallows were analyzed. Anesthesia increased the proportion of pathological swallows (25.9% vs. 4.9%) and decreased the number of swallows per hour (1.7±3.3 vs. 28.0±22.3) compared to wakefulness. During anesthesia, hypercapnia decreased hypopharyngeal pressure during inspiration (-14.1±3.7 vs. -8.7±2 mmHg) and increased minute ventilation, the proportion of pathological swallows (19.1% vs. 12.3%), and the number of swallows per hour (5.5±17.0. vs. 1.3±5.5). CONCLUSIONS: Anesthesia impaired the coordination between swallowing and respiration. Mild hypercapnia increased the frequency of swallowing during anesthesia and the likelihood of pathological swallowing. During anesthesia, the risk for aspiration may be further increased when ventilatory drive is stimulated.

Etomidate and Ketamine: Residual Motor and Adrenal Dysfunction that Persist beyond Recovery from Loss of Righting Reflex in Rats.

We tested the hypothesis that etomidate and ketamine produce residual effects that modify functional mobility (measured by the balance beam test) and adrenal function (adrenocorticotropic hormone (ACTH) stimulation) immediately following recovery from loss of righting reflex in rats. Intravenous etomidate or ketamine was administered in a randomized, crossover fashion (2 or 4 mg/kg and 20 or 40 mg/kg, respectively) on eight consecutive days. Following recovery of righting reflex, animals were assessed for residual effects on functional mobility on the balance beam, motor behavior in the open field and adrenal function through ACTH stimulation. We evaluated the consequences of the effects of the anesthetic agent-induced motor behavior on functional mobility. On the balance beam, etomidate-treated rats maintained their grip longer than ketamine-treated rats, indicating greater balance abilities (mean ± SD, 21.5 ± 25.1 s vs. 3.0 ± 4.3 s respectively, p < 0.021). In the open field test, both dosages of etomidate and ketamine had opposite effects on travel behavior, showing ketamine-induced hyperlocomotion and etomidate-induced hypolocomotion. There was a significant interaction between anesthetic agent and motor behavior effects for functional mobility effects (p < 0.001). Corticosterone levels were lower after both 40 mg/kg ketamine and 4 mg/kg etomidate anesthesia compared to placebo, an effect stronger with etomidate than ketamine (p < 0.001). Following recovery from anesthesia, etomidate and ketamine have substantial side effects. Ketamine-induced hyperlocomotion with 20 and 40 mg/kg has stronger effects on functional mobility than etomidate-induced hypolocomotion with 2 and 4 mg/kg. Etomidate (4 mg/kg) has stronger adrenal suppression effects than ketamine (40 mg/kg).