Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target

Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. We identified high-levels of LIN28A and LIN28B in AT/RT primary tumors and cell lines, with corresponding low levels of the LIN28-regulated microRNAs of the let-7 family. Knockdown of LIN28A by lentiviral shRNA in the AT/RT cell lines CHLA-06-ATRT and BT37 inhibited growth, cell proliferation and colony formation and induced apoptosis. Suppression of LIN28A in orthotopic xenograft models led to a more than doubling of median survival compared to empty vector controls (48 vs 115 days). LIN28A knockdown led to increased expression of let-7b and let-7g microRNAs and a down-regulation of KRAS mRNA. AT/RT primary tumors expressed increased mitogen activated protein (MAP) kinase pathway activity, and the MEK inhibitor selumetinib (AZD6244) decreased AT/RT growth and increased apoptosis. These data implicate LIN28/RAS/MAP kinase as key drivers of AT/RT tumorigenesis and indicate that targeting this pathway may be a therapeutic option in this aggressive pediatric malignancy.     

Effects of patient-triggered automatic switching between mandatory and supported ventilation in the postoperative weaning period

OBJECTIVE: To compare two ventilator settings in the postoperative weaning period. Patient-triggered automatic switching between controlled ventilation and supported spontaneous breathing (Automode, AM) was compared to synchronised intermittent mandatory ventilation (SIMV) with stepwise manual adjustment of mandatory frequency according to the breathing activity. DESIGN: Prospective clinical investigation. SETTING: Eighteen-bed intensive care unit in a university hospital. PATIENTS: Forty postoperative patients with healthy lungs who had undergone brain tumour surgery. INTERVENTIONS: Randomisation either to the AM or SIMV weaning procedure after entering the ICU. MEASUREMENTS AND RESULTS: Total weaning time and number of manipulations on the ventilator were observed. Cardiocirculatory and respiratory parameters were measured consecutively at five points during the weaning period. No significant differences were seen for cardiocirculatory parameters, airway pressures and oxygenation between the two groups. There was a trend to shorter weaning times with AM (136 +/- 46 min vs 169 +/- 68 min, n.s.), the average number of manipulations on the ventilator was lower (0.55 +/- 0.69 vs 5.05 +/- 1.19,p < 0.001) and arterial partial pressure of carbon dioxide (PaCO2) levels showed fewer variations in the late phase of the weaning period (39.5 +/- 3.1 vs 38.3 +/- 7.2, p < 0.001 for differences in variance). CONCLUSIONS: Automatic, patient-triggered switching between controlled and supported mode of ventilation can be used for postoperative weaning of neurosurgical patients with healthy lungs. Compared to a SIMV weaning procedure, fewer manipulations on the ventilator are necessary and individual adaptation of ventilation seems to be more accurate.     

Assessing awareness in early-stage Alzheimer's disease: Development and piloting of the Memory Awareness Rating Scale

There are indications that awareness may have an important impact on functioning and response to rehabilitative interventions in early-stage Alzheimer's disease (AD), yet studies have so far produced few clear findings, and a comprehensive explanatory model is needed together with a reliable assessment method. A theory-driven approach to assessing awareness in early-stage Alzheimer's disease was used to develop the Memory Awareness Rating Scale (MARS), a measure that addresses key methodological limitations of the assessment methods adopted in existing studies. The MARS was piloted with 12 couples where one partner had a diagnosis of AD. This demonstrated that the MARS has satisfactory psychometric properties, and suggested some refinements to the scale that may improve its usefulness. Results obtained with the MARS allow further consideration of theoretical and methodological issues that arise in attempting to understand and assess awareness. The development of this rigorous method of assessing awareness of memory difficulties in early-stage AD provides a basis for further investigation of the relationship between awareness of memory difficulties and outcome of neuropsychological rehabilitation in early-stage AD.     

Clinical Validation of a Digital Transcutaneous PCO<Subscript>2</Subscript>/SpO<Subscript>2</Subscript> Ear Sensor in Adult Patients after Cardiac Surgery

Objective The aim of this study was to validate the V-Sign digital sensor (SenTec AG, Therweil, Switzerland) for combined noninvasive assessment of pulse oxymetric oxygen saturation (SpO₂) and transcutaneous carbon dioxide tension (PtcCO₂) in adults after cardiac surgery. Methods In twenty one patients, aged 51–86 years, simultaneous measurements of blood gases with the V-Sign Sensor and with two Nellcor Durasensors (model DS-100A), one at the opposite earlobe and one with a finger clip, were compared first during hyper-, normo- and hypocapnia and at different pulse rates using a pacemaker, and then at 2-h intervals up to 8 h. Agreement was assessed by Bland-Altman analysis. Results PtcCO₂ data of three patients were excluded because of calibration failure of the device. Median (range) PtcCO₂ for the remaining patients was 5.49 (3.3–7.6) kPa and arterial carbon dioxide tension (PaCO₂) was 5.43 (3.61–7.41) kPa. Corresponding mean bias was +0.05 kPa and limits of agreement (LOA) were −1.2/+1.3 kPa. During normo- and hypoventilation, mean bias was good at +0.02 and +0.04 kPa respectively, but limits of agreement were poor at −0.67/+0.69 and −0.81/+0.88 kPa. In 10 patients, an initial overshoot of PtcCO₂ was observed. Mean bias of SpO₂ and pulse rate was close to zero (−1.5% and +0.001 bpm respectively), but limits of agreement were unacceptably high (−21.4/+18.4% and −22.3/+22.3 bpm). Conclusions In the present state of development the SenTeC Digital monitor V-Sign device has serious limitations. Additional efforts are necessary to eliminate calibration failures and the initial overshoot of PtcCO₂ as well as to improve detection of SpO₂ and pulse rate. Baulig W, Schütt P, Roth HR, Hayoz J, Schmid ER. Clinical validation of a digital transcutaneous PCO₂/SpO₂ ear sensor in adult patients after cardiac surgery.     

Pain Scores Improve Analgesic Administration Patterns for Trauma Patients in the Emergency Department

OBJECTIVE: To determine the efficacy of pain scores in improving pain management practices for trauma patients in the emergency department (ED). METHODS: A prospective, observational study of analgesic administration to trauma patients was conducted over a nine-week period following educational intervention and introduction of verbal pain scores (VPSs). All ED nursing and physician staff in an urban Level I trauma center were trained to use the 0-10 VPS. Patients younger than 12 years old, having a Glasgow Coma Scale score (GCS) <8, or requiring intubation were excluded from analysis. Demographics, mechanism of injury, vital signs, pain scores, and analgesic data were extracted from a computerized ED database and patients' records. The staff was blinded to the ongoing study. RESULTS: There were 150 patients studied (183 consecutive trauma patients seen; 33 patients excluded per criteria). Pain scores were documented for 73% of the patients. Overall, 53% (95% confidence interval [CI] = 45% to 61%) of the patients received analgesics in the ED. Of the patients who had pain scores documented, 60% (95% CI = 51% to 69%) received analgesics, whereas 33% (95% CI = 18% to 47%) of the patients without pain scores received analgesics. No patient with a VPS < 4 received analgesics, whereas 72% of patients with a VPS > 4 and 82% with a VPS > 7 received analgesics. Mean time to analgesic administration was 68 minutes (95% CI = 49 to 87). CONCLUSIONS: Pain assessment using VPS increased the likelihood of analgesic administration to trauma patients with higher pain scores in the ED.     

The role of a mineralocorticoid receptor gene functional polymorphism in the symptom dimensions of persistent ADHD

Attention-deficit/hyperactivity disorder (ADHD) affects approximately 5 % of school-aged children and 2.5 % of adults. Genetic studies in ADHD have pointed to genes in different neurobiological systems, with relatively small individual effects. The mineralocorticoid receptor is the main receptor involved in the initial triggering of stress response. Therefore, its encoding gene (NR3C2) is a candidate for psychiatric disorder studies, including ADHD, and behavioral phenotypes. There is evidence that the Val allele of the MRI180V polymorphism (rs5522) increases the risk of depression, attention and cognitive deficits. We investigated the possible role of the mineralocorticoid receptor gene in the symptom dimensions and susceptibility to persistent ADHD. We compared genotype and allele frequencies in 478 adult patients with ADHD and 597 controls and symptom dimensions in 449 patients and 132 controls. Diagnoses were based on the DSM-IV criteria. ADHD symptom dimensions were investigated with SNAP-IV for ADHD severity and Barkley scales for severity and impairment. Carriers of the Val allele presented higher inattention, hyperactivity/impulsivity and impairment scores, while genotype and allele frequencies did not differ between patients and controls. These results are consistent with a possible link between genetic variations in the HPA axis and inattention and hyperactivity measures.     

Diffusion-weighted MRI and PET–CT in the follow up of chronic periaortitis

Aim of the present study is to compare magnetic resonance imaging (MRI) and positron emission tomography (PET) parameters in the follow up of chronic periaortitis (CP), with a focus on changes in the apparent diffusion coefficient (ADC) and standardized uptake values (SUV). 127 patients with CP were treated in our urology between 2007 and 2017. We identified 14 patients with parallel abdominal MRI and PET–CT examinations before therapy and in the follow up resulting in a total of 56 examinations. Relative contrast uptake and diffusion-weighted MRI parameters were compared to SUV in the corresponding PET–CT examinationsand laboratory infection markers. All examined MRI and PET–CT parameters showed significant changes between basis and follow-up examinations. Median ADC values increased significantly (p?<?0.001) in the follow up. SUVmax and the other MR parameter (contrast uptake, DWI-signal) declined significantly. We observed a strong negative correlation between ADC and SUVmax (rho: ??0.61; p?<?0.001). In addition, we found an inverse correlation of ADC with the inflammation markers ESR (rho: ??0.64; p?<?0.001) and CRP (rho: ??0.54; p?=?0.001). MRI and PET–CT showed comparable results in the individual follow up of CP and compared to laboratory inflammation markers. Our data support MRI as first imaging modality due to absent radiation and the necessity of repetitive follow-up examinations in patients with CP.     

Mitochondrial membrane protein-associated neurodegeneration: a case report and literature review

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an autosomal recessive disorder caused by mutation in the C19orf12 gene. We report a compound heterozygous c.[32C>T];[205G>A;424A>G] (p.[Thr11Met];[Gly69Arg;Lys142Glu]) Czech patient who manifested with right foot dystonia, impaired handwriting, attention deficit, and signs of iron accumulation on brain MRI. Gradually, he developed dysarthria, spastic-dystonic gait, pedes cavi, and atrophy of leg muscles. Additionally, we report demographic parameters, clinical signs, and allelic frequencies of C19orf12 mutations of all published MPAN cases. We compared the most frequent mutations, p.Thr11Met and p.Gly69ArgfsX10; the latter was associated with younger age at onset and more frequent optic atrophy in homozygotes.