Challenges and opportunities in the investigation of unexplained intellectual disability using family-based whole-exome sequencing.

Intellectual disability (ID), characterized by an intellectual performance of at least 2 SD (standard deviations) below average is a frequent, lifelong disorder with a prevalence of 2-3%. Today, only for at most half of patients a diagnosis is made. Knowing the cause of the ID is important for patients and their relatives, as it allows for appropriate medical care, prognosis on further development of the disorder, familial counselling or access to support groups. Whole-exome sequencing (WES) now offers the possibility to identify the genetic cause for patients for which all previously available genetic tests, including karyotyping, specific gene analysis, or microarray analysis did not reveal causative abnormalities. However, data analysis of WES experiments is challenging. Here we present an analysis workflow implementable in any laboratory, requiring no bioinformatics knowledge. We demonstrated its feasibility on a cohort of 10 patients, in which we found a conclusive diagnosis in 3 and a likely diagnosis in 2 more patients. Of the three conclusive diagnoses, one was a clinically suspected mutation missed by Sanger sequencing, and one was an atypical presentation of a known monogenic disorder, highlighting two essential strengths of WES-based diagnostics.

Gastric tonometry in healthy volunteers: effect of ranitidine on calculated intramural pH.

OBJECTIVE: To determine if intraluminal production of CO2 leads to underestimation of gastric intramural pH (pHi) by tonometry. DESIGN: Nonrandomized controlled study. PATIENTS: Healthy volunteers. INTERVENTIONS: NG tonometers were placed in healthy volunteers. Some of the volunteers (n = 11) were pretreated with ranitidine to prevent secretion of protons into the gastric lumen. Others (n = 13) were untreated (i.e., gastric acid secretion was uninhibited). MEASUREMENTS AND MAIN RESULTS: Gastric pHi was calculated from the arterial (HCO3-) and the tonometrically determined intraluminal PCO2 using the Henderson-Hasselbalch equation. Intraluminal PCO2 was significantly higher in the control group (54 +/- 14 torr [7.2 +/- 1.9 kPa]) than in the ranitidine-treated group (42 +/- 4 torr [5.6 +/- 0.4 kPa], p = .02). Mean gastric luminal pH was 1.9 +/- 0.6 in the control group as compared with 6.7 +/- 0.7 in volunteers treated with ranitidine (p less than .01). Mean calculated gastric pHi was 7.30 +/- 0.11 in the untreated group and 7.39 +/- 0.03 in the ranitidine-treated group (p less than .03). CONCLUSIONS: These data suggest that intraluminal production of CO2 from the titration of gastric HCO3- by secreted H+ can result in the underestimation of gastric pHi by tonometry. This phenomenon can be eliminated by H2-receptor blockade.

Are low tidal volumes safe?

High airway pressure may be injurious to lung parenchyma, but lowering airway pressure using conventional mechanical ventilation necessitates lowering tidal volume (VT). Intubated patients in the surgical intensive care unit (SICU) were randomly assigned to group 1 (VT = 12 ml/kg, n = 56) or group 2 (VT = 6 ml/kg, n = 47). Variables recorded included acute physiology and chronic health evaluation (APACHE II) score, mean peak airway pressure (MPAP), mean PaO2/FIO2, incidence of pulmonary infectious complications (PIC), duration of intubation (DOI), and duration of SICU stay (DOS). Results in the table are means +/- SE. (table; see text) The incidence of pulmonary infection tended to be lower and DOI and DOS tended to be shorter for nonneurosurgical and noncardiac surgical patients randomized to low VT, suggesting that morbidity may be decreased. The use of low VT was associated with a statistically significant but clinically irrelevant decrease in oxygenation. The routine use of low VT appeared to be safe in a selected population of patients in the SICU.

The efficacy of an oscillating bed in the prevention of lower respiratory tract infection in critically ill victims of blunt trauma. A prospective study.

We tested the hypothesis that the incidence of LRTI in critically ill blunt trauma victims can be reduced by employing continuous postural oscillation. Within 24 h of admission to the SICU, 106 patients were prospectively randomized to either a conventional bed or a RRKTT. Seven patients who were discharged from the SICU in less than 24 h were excluded from the data analyses. Until discharge from the SICU, patients were monitored daily for development of LRTI or pneumonia. Among 48 patients in the control group, 28 met criteria for LRTI and 19 met criteria for pneumonia. Among 51 patients in the RRKTT group, 13 developed LRTI and 7 developed pneumonia. The differences between groups for all LRTI and pneumonia were both significant. We conclude that continuous postural oscillation decreases the risk of pulmonary sepsis in victims of major blunt trauma.

Comparison of the safety and efficacy of parenteral ticarcillin/clavulanate and clindamycin/gentamicin in serious intra-abdominal infections.

One hundred and twelve patients with proven or suspected serious intra-abdominal infections were randomized for treatment with either ticarcillin/clavulanate (3.1 g every 4 h) or gentamicin (dosage schedule adjusted according to serum concentrations) plus clindamycin (in most cases 900 mg every 8 h). Positive intraperitoneal and/or blood cultures were available in 47 cases. Considering only fully evaluable cases, 15/20 (75%) were clinically cured or improved in the ticarcillin/clavulanate group and 16/25 (64%) in the gentamicin/clindamycin group, the difference not being significant (P greater than 0.05). Bacteraemia was documented in nine of 45 fully evaluable cases. During the course of the study, the serum creatinine concentration increased by more than 5 mg/l in only one patient (ticarcillin/clavulanate group). Two patients (one in each group) had apparent allergic reactions. No other drug-related adverse effects were noted. In-vitro sensitivity testing of anaerobic isolates revealed that, of those tested, 5/38, 1/38 and 2/37 were resistant to ticarcillin, ticarcillin/clavulanate and clindamycin, respectively. Among aerobic Gram-negative isolates, 34/78, 6/78 and 4/78 were resistant to ticarcillin, ticarcillin/clavulanate, and gentamicin, respectively. Among aerobic Gram-positive isolates, 2/32, 2/32, and 5/14 were resistant to ticarcillin, ticarcillin/clavulanate, and clindamycin, respectively. We conclude that ticarcillin/clavulanate is a safe and efficacious preparation for treating serious intra-abdominal infections.