From neurons to the neuro-glio-vascular unit: Seizures and brain homeostasis in networks.

While seizures are undoubtedly neuronal events, an ensemble of auxiliary brain cells profoundly shapes synaptic transmission in health and disease conditions. Endothelial-astrocyte-pericyte assemblies at the blood-brain barrier (BBB) and neuroglia within the neuro-glio-vascular unit (NGVU) finely tune brain parenchymal homeostasis, safeguarding the ionic and molecular compositions of the interstitial fluid. BBB permeability with neuroinflammation and the resulting loss of brain homeostatic control are unifying mechanisms sustaining aberrant neuronal discharges, with temporal specificities linked to acute (head trauma, stroke, infections) and pre-existent (genetic) or chronic ( dysplasia, tumors, neurodegenerative disorders) pathological conditions. Within this research template, one hypothesis is that the topography of BBB damage and neuroinflammation could associate with symptoms, e.g., limbic structures for seizures or pre-frontal for psychiatric episodes. Another uncharted matter is whether seizure activity, without tissue lesions or sclerosis, is sufficient to promote stable cellular-level maladaptations in networks. Contingent to localization and duration, BBB damage and inflammation forecast pathological trajectories, and the concept of an epileptic NGVU could enable time-sensitive biomarkers to predict disease progression. The coherence between electrographic, imaging and molecular NGVU biomarkers could be established from the epileptogenic to the propagating zones. This paradigm shift could lead to new diagnostic and therapeutic modalities germane to specific epilepsies or when seizure activity represents a comorbidity.

Pneumatic piston hydrostatic bioreactor for cartilage tissue engineering.

During exercise, mechanical loads from the body are transduced into interstitial fluid pressure changes which are sensed as dynamic hydrostatic forces by cells in cartilage. The effects of these loading forces in health and disease are of interest to biologists, but the availability of affordable equipment for in vitro experimentation is an obstacle to research progress. Here, we report the development of a cost-effective hydropneumatic bioreactor system for research in mechanobiology. The bioreactor was assembled from readily available components (a closed-loop stepped motor and pneumatic actuator) and a minimal number of easily-machined crankshaft parts, whilst the cell culture chambers were custom designed by the biologists using CAD and entirely 3 D printed in PLA. The bioreactor system was shown to be capable of providing cyclic pulsed pressure waves at a user-defined amplitude and frequency ranging from 0 to 400 kPa and up to 3.5 Hz, which are physiologically relevant for cartilage. Tissue engineered cartilage was created from primary human chondrocytes and cultured in the bioreactor for five days with three hours/day cyclic pressure (300 kPa at 1 Hz), simulating moderate physical exercise. Bioreactor-stimulated chondrocytes significantly increased their metabolic activity (by 21%) and glycosaminoglycan synthesis (by 24%), demonstrating effective cellular transduction of mechanosensing. Our Open Design approach focused on using 'off-the-shelf' pneumatic hardware and connectors, open source software and in-house 3 D printing of bespoke cell culture containers to resolve long-standing problems in the availability of affordable bioreactors for laboratory research.

Preventing postnatal growth restriction in infants with birthweight less than 1300 g.

AIM: To examine nutritional and growth outcomes in very preterm infants with a birthweight (BW) of ≤1300 g before and after the introduction of enhanced enteral and parenteral nutrition protocols. METHODS: A comparison of two historical cohorts. RESULTS: There were 153 infants in cohort 1 and 118 in cohort 2. A total of 19% were growth restricted at birth in both cohorts. Feeds advanced more quickly in cohort 2, with decreased duration of central lines and TPN; breastmilk fortification occurred sooner. Calorie and protein intakes were increased during all of the first 14 days of life. Adverse clinical outcomes were unchanged, including NEC. The proportion of infants discharged <10th percentile of expected weight, decreased from 23% to 9%. In cohort 2, the z-score for body weight decreased by 0.39, compared to an average 1.03 in cohort 1 (p < 0.001). Head circumference and body weight were also significantly improved at discharge (p < 0.01), but length was improved to a lesser degree. CONCLUSION: Early and enhanced postnatal intravenous and enteral feeding can provide good postnatal growth among very immature infants without adverse effects. Calorie and particularly protein intake in early life could probably be further optimised.

Decision-making for extremely preterm infants with severe hemorrhages on head ultrasound: Science, values, and communication skills.

Severe intracranial hemorrhages are not rare in extremely preterm infants. They occur early, generally when babies require life-sustaining interventions. This may lead to ethical discussions and decision-making about levels of care. Prognosis is variable and depends on the extent, location, and laterality of the lesions, and, importantly also on the subsequent occurrence of other clinical complications or progressive ventricular dilatation. Decision-making should depend on prognosis and parental values. This article will review prognosis and the uncertainty of outcomes for different lesions and provide an outline of ways to conduct an ethically appropriate discussion on the decision of whether to continue life sustaining therapy. It is possible to communicate in a compassionate and honest way with parents and engage in decision-making, focussing on personalized information and decisions, and on function, as opposed to diagnosis.

Life and death decisions for incompetent patients: determining best interests--the Irish perspective.

AIMS: To determine whether healthcare providers apply the best interest principle equally to different resuscitation decisions. METHODS: An anonymous questionnaire was distributed to consultants, trainees in neonatology, paediatrics, obstetrics and 4th medical students. It examined resuscitation scenarios of critically ill patients all needing immediate resuscitation. Outcomes were described including survival and potential long-term sequelae. Respondents were asked whether they would intubate, whether resuscitation was in the patients best interest, would they accept surrogate refusal to initiate resuscitation and in what order they would resuscitate. RESULTS: The response rate was 74%. The majority would wish resuscitation for all except the 80-year-old. It was in the best interest of the 2-month-old and the 7-year-old to be resuscitated compared to the remaining scenarios (p value <0.05 for each comparison). Approximately one quarter who believed it was in a patient best interests to be resuscitated would nonetheless accept the family refusing resuscitation. Medical students were statistically more likely to advocate resuscitation in each category. CONCLUSION: These results suggest resuscitation is not solely related to survival or long-term outcome and the best interest principle is applied differently, more so at the beginning of life.

Bilateral renal vein thrombosis and subsequent acute renal failure due to IVC filter migration and thrombosis.

A 53-year-old man developed a deep venous thrombus (DVT) and pulmonary embolism (PE) shortly after an open Roux-en-Y gastric bypass was performed. He later suffered a life-threatening gastrointestinal bleed while on anticoagulation for the DVT. Thus, anticoagulation was held and an inferior vena cava (IVC) filter (G2, Bard Inc., Tempe, AZ, USA) was placed for PE prophylaxis. About 10 days after filter placement, he presented with severe low back pain and syncope. He also presented with hypotension and anuria unresponsive to intravenous fluids. A STAT non-contrast CT scan of the abdomen revealed that his IVC filter had migrated from an infrarenal to a suprarenal position. Given the high clinical suspicion for renal vein thrombosis, an attempt at IVC filter retrieval was made. The filter could not be retrieved because it was embedded in a large IVC thrombus that extended from the hepatic veins down to the common iliac veins. The patient received nearly 4 days of tPA that was administered at the site of the thrombus with a long thrombolytic catheter (UNIFUSE, Angiodynamics, Queensbury, NY, USA). While his creatinine peaked at 7.6 on hospital Day 4, he eventually began to produce urine and his creatinine had declined to his baseline of 1.0 on follow-up 1 month later. About 18 months after admission, his creatinine had further declined to 0.8. We report the first published case of acute renal failure due to bilateral renal vein thrombosis in the setting of IVC filter migration and thrombosis. This report highlights an important, but rare complication of IVC filter placement as well as the non-operative management of acute bilateral renal vein thrombosis.

Measurement variability of liver metastases from neuroendocrine tumors on different magnetic resonance imaging sequences.

PURPOSE: To assess dimension measurement variability of liver metastases from neuroendocrine tumors (LMNET) on different magnetic resonance imaging (MRI) sequences. MATERIAL AND METHODS: In this institutional review board-approved retrospective study from January 2011 to December 2012, all liver MRI examinations performed at our department in patients with at least one measurable LMNET according to response evaluation criteria in solid tumors (RECIST1.1) were included. Up to two lesions were selected on T2-weighted MR images. Three reviewers independently measured long axes of 135 hepatic metastases in 30 patients (16 men, 14 women, mean age 61±11.4 (SD) years; range 28-78 years), during two separate reading sessions, on T2-weighted, diffusion-weighted MRI (DWI) (b; 50, 400, 800 s/mm2) and arterial, portal and late phases after intravenous administration of a gadolinium chelate. Intraclass-correlation coefficients and Bland-Altman plots were used to assess intra-and interobserver variability. RESULTS: Intra- and interobserver agreements ranged between 0.87-0.98, and 0.88-0.97, respectively. Intersequence agreements ranged between 0.92 [95%CI: 0.82-0.98] and 0.98 [95%CI: 0.93-0.99]. 95% limits of agreement for measurements were -10.2%,+8.9% for DWI (b=50s/mm2) versus -21.9%,+24.2% and -15.8,+17.2% for arterial and portal phases, respectively. CONCLUSION: An increase<9% in measurement and a decrease of -10% on DWI should not be considered as true changes, with 95% confidence, versus 24% and -22% on arterial and 17%, -16% on portal phases, respectively. DWI might thus be the most reliable MR sequence for monitoring size variations of LMNETs.

Moral distress in the neonatal intensive care unit: caregiver's experience.

BACKGROUND: The Neonatal Intensive Care Unit (NICU) can be ethically charged, which can create challenges for health-care workers. OBJECTIVE: To determine the frequency with which nurses and residents have experienced ethical confrontations and what factors are associated with increased frequency. DESIGN/METHODS: An anonymous questionnaire was distributed to nurses in a university center, a high-risk obstetric service, a maternity hospital NICU with 85% in-born patients and an outborn NICU, most of whose preterm admissions are those with surgical complications. Obstetric and pediatric residents in the four universities of the province also received the questionnaire, which included demographics, opinions regarding the gestational age threshold at which resuscitation of a premature infant with bradycardia was appropriate, knowledge of cerebral palsy (CP) outcomes (as an indicator of knowledge about long-term sequelae of prematurity) and questions about ethical confrontation in the NICU. RESULTS: Two hundred and seventy-nine caregivers participated (115 full time nurses and 164 residents). All the distributed questionnaires were completed. Frequent ethical confrontation was reported by 35% of the nurses and 19% of the residents. Among the nurses, moral distress differed significantly between work environments. Nurses working in an out-born NICU and obstetric nurses were more likely to overestimate CP prevalence (P<0.05). Nurses who overestimated CP rates had higher thresholds for resuscitation and were more likely to experience ethical confrontations. Of the residents, 60% were pediatric and 40% obstetric. All groups of residents frequently overestimated the prevalence of CP, and knowledge differed significantly by residency program (P<0.05). The residents who overestimated CP rates had higher thresholds for resuscitation, had more incorrect answers regarding prematurity outcomes and were less likely to have ethical confrontations. CONCLUSIONS: A large proportion of nurses and residents report frequent ethical confrontations. Many residents and nurses have limited knowledge of outcomes and high threshold for resuscitation. Ethical confrontation is more common among nurses with poor knowledge about outcomes, and less common in residents with poor knowledge about outcomes.

[Speaking about life and death in neonatology: How can communication with families be optimized?] / Parler de la vie et de la mort en néonatologie : comment optimiser la communication avec les parents ?

Technological progress and improved clinical knowledge have increased survival of neonates who would previously have died. Survival is sometimes accompanied by a risk of short- or long-term adverse outcomes, which may lead to complex decisions about withholding or withdrawing life-sustaining interventions. These decisions are among the most difficult decisions in pediatric practice. They also involve communicating with parents and are emotionally charged. Many articles examining end-of-life decisions in neonatology state the need for healthcare providers to be caring, compassionate, and human without offering clear, practical advice. In this article, the way in which neonates die and the ethical decision-making surrounding these decisions will be reviewed. Guidelines to reflect on the life trajectories of neonates will be offered, as well as recommendations to optimize communication with families during these difficult moments.

International variations in application of the best-interest standard across the age spectrum.

OBJECTIVE: Ethically and legally, assertions that resuscitation is in a patient's best interest should be inversely correlated with willingness to forego intensive care (and accept comfort care) at the surrogate's request. Previous single country studies have demonstrated a relative devaluation of neonates when compared with other critically ill patients. STUDY DESIGN: In this international study, physicians in Argentina, Australia, Canada, Ireland, The Netherlands, Norway and the United States were presented with eight hypothetical vignettes of incompetent critically ill patients of different ages. They were asked to make assessments about best interest, respect for surrogate autonomy and to rank the patients in a triage scenario. RESULTS: In total, 2237 physicians responded (average response rate 61%). In all countries and scenarios, participants did not accept to withhold resuscitation if they estimated it was in the patient's best interest, except for scenarios involving neonates. Young children (other than neonates) were given high priority for resuscitation, regardless of existing disability. For neonates, surrogate autonomy outweighed assessment of best interest. In all countries, a 2-month-old-infant with meningitis and a multiply disabled 7-year old were resuscitated first in the triage scenario, with more variable ranking of the two neonates, which were ranked below patients with considerably worse prognosis. CONCLUSIONS: The value placed on the life of newborns is less than that expected according to predicted clinical outcomes and current legal and ethical theory relative to best interests. Value assessments on the basis of age, disability and prognosis appear to transcend culture, politics and religion in this domain.

The Lacuna Trial: a double-blind randomized controlled pilot trial of lactoferrin supplementation in the very preterm infant.

OBJECTIVE: To determine tolerability of bovine lactoferrin (bLF) in very preterm infants, and whether the intervention can be adequately masked. STUDY DESIGN: In a single-center masked pilot trial infants under 31 weeks gestation were randomized before 48 h of age to receive milk with 100 mg per day of bLF or control. The primary outcome was feeding tolerance, defined as time to achieve full feeds (140 ml kg(-1) per day). Parents answered a short questionnaire regarding acceptability of the intervention. RESULTS: Seventy-nine infants were enrolled and analyzed according to intention to treat. There was no effect of bLF on the primary outcome. In addition, mortality, late onset sepsis and other complications of prematurity were no different. Equal numbers of parents in both groups believed their infant received bLF. CONCLUSION: We demonstrated that bLF is well tolerated, easy to administer and its presence in prepared milk is not evident. Trial registration number ISRCTN66482337.

MR imaging of pelvic extraperitoneal masses: A diagnostic approach.

Pelvic extraperitoneal pelvic masses are relatively uncommon conditions and generally raise diagnostic imaging challenges. Magnetic resonance (MR) imaging plays a central role in the diagnosis of these masses due to its unique tissue-specific multiplanar capabilities that allow optimal pelvic mass localization and internal characterization. This article reviews the MR imaging presentation of extraperitoneal pelvic masses, gives clues that allow identifying their extraperitoneal and/or specific origin as well as suggests different steps for narrowing the differential diagnosis. These steps include systematic analysis of the clinical context, tumor location, relationships with major pelvic structures and close study of the internal components of the lesions.

Intestinal absorption of lipid emulsion in premature infants: a pilot study.

BACKGROUND: Adequate nutritional intake is essential in the very-low-birth-weight infant, but difficult to achieve in the first few postnatal days. Can lipids be given enterally in the first few days of life in sick preterm infants? OBJECTIVE: To determine tolerance and absorption of lipid emulsion when fed enterally to very-low-birth-weight infants. DESIGN/METHODS: Infants had a birth weight <1,500 g, an appropriate weight for gestational age, and were receiving parenteral nutrition. We performed a progressive series of studies, enrolling 5 infants in each group. Group 1 infants were fed enteral lipid emulsion at 1 g/kg/day for 4 days, starting when 60 ml/kg/day of breast milk was tolerated enterally. Simultaneously, a matched control group which received no oral lipid emulsion was enrolled. We then enrolled group 2 infants who were fed 3 g/kg/day with the same protocol as group 1. Group 3 infants were fed enteral lipid emulsion starting in the first 72 h of life. The infants were fed 1, 2 and 3 g/kg/day subsequently for 48 h each. Fat absorption was measured. RESULTS: Gestational age was 24.6-30.8 weeks and birth weight was 620-1,400 g. One infant (group 1) developed necrotizing enterocolitis 1 week after the study. There were no other adverse clinical findings. On average, enteral lipid emulsion was started on day 8 of life in groups 1 and 2, and on day 2 in group 3. The intestinal lipid absorption was 93.6% (min. = 76%). There was no difference in fat absorption between the 4 groups (p > 0.05). CONCLUSIONS: Lipid emulsions are an isotonic high-calorie source which can be given safely enterally instead of intravenously in the immediate neonatal period of very-low-birth-weight infants without clinical adverse effects and with almost complete absorption. There are potential advantages to oral administration of a lipid emulsion starting in early life which require further investigation.

Anesthetic technique and postoperative outcome in preterm infants undergoing PDA closure.

OBJECTIVE: To describe the various anesthetic techniques used for surgical closure of PDA in premature infants at the Montreal Children's Hospital and assess their impact on postoperative outcome. STUDY DESIGN: The charts of all preterms who underwent PDA ligation during a 21-month period were reviewed for preoperative status, intraoperative anesthetic management and postoperative outcome. We determined the associations between independent variables and two postoperative outcome variables: unstable postoperative respiratory course (UPRC) and hypotension. RESULT: The mean weight at surgery of the 33 infants was 1.031±0.29 kg. All infants, but one, received intraoperative opioids. Eight patients presented UPRC. Mean fentanyl doses were 5.3±2.6 mcg kg(-1) for patients with UPRC vs 22.6±16.6 mcg kg(-1) for patients without UPRC (P=0.004). Applying the receiver-operator characteristic curve (ROC), 10.5 mcg kg(-1) of fentanyl was established as the dose that discriminated and identified patients who experienced UPRC. The postnatal and postmenstrual age of the patient, birthweight, current weight, ventilator settings preoperatively, previous courses of indomethacin, sex and preoperative creatinine, were not correlated with the dose of fentanyl equivalent used. Logistic regression did not show a relationship between any of the previously mentioned factors and receiving a fentanyl equivalent of >10.5 mcg kg(-1). The only factor associated with the total fentanyl equivalent dose (as a continuous variable) or receiving <10.5 mcg kg(-1) (as a dichotomous variable) was the identity of the anesthetist involved, P<0.001. CONCLUSION: We conclude that the use of at least 10.5 mcg kg(-1) of fentanyl equivalent as a component of the anesthetic regimen for surgical closure of a PDA in premature infants, avoids an unstable postoperative respiratory course.

Nobody likes premies: the relative value of patients' lives.

OBJECTIVE: The objective of this study was to examine whether patient selection or triage requires placing a relative value on human lives and whether the values placed on these lives are consistent with current ethical theories. STUDY DESIGN: An anonymous questionnaire was administered to groups of physicians and students in Montreal. It presented eight currently incompetent patients with potential neurological sequelae requiring emergency care. Predicted outcomes were explicitly described. Four patients had a predicted 50% survival and a 50% chance of impairment; they were a preterm and a term neonate, a 2-month-old and a 50-year-old. Two already disabled patients, a 7-year-old and an 80-year-old, had 50% predicted survival. A 14-year-old and a 35-year-old had 5% survival, but differing impairment. Respondents were asked if they would resuscitate and in what order they would resuscitate if all needed intervention simultaneously. RESULT: Eighty-five percent response rate, n=524. The proportion stating they would always resuscitate was smallest for the 80-year-old (18% P<0.001 compared to other patients), then the preterm (35%, P<0.001), then the term and the 50-year-old (53 and 58%, P<0.01). The 2-month-old and the 7-year-old would be resuscitated most frequently (74 and 77%, P<0.01), followed by the patients with 5% survival (64 and 68%, P<0.001). The median order of triage was first the 2-month-old, followed by the 7-year-old, the 14-year-old, the term newborn, the 50-year-old, the 35-year-old, the premature newborn and the 80-year-old. CONCLUSION: Order of resuscitation was not closely related to the predicted survival, impairment or potential life years gained. Age appeared to have a strong influence, with children's lives being valued more than the adults'. This tendency was reversed for the newborn infants who were undervalued compared with older children, and most particularly for the premature. The value placed on the life of newborns, in particular the premature, is less than that expected by any objective medical data and was not consistent with any ethical theory that we tested.

Caregivers attitudes for very premature infants: what if they knew?

BACKGROUND: Decisions about resuscitation of extremely premature babies are controversial. Such decisions may reflect poor understanding of outcomes. OBJECTIVE: To compare caregivers' attitudes towards the resuscitation of a premature infant if they are only told the infant's gestational age or if they are only given prognostic information for infants at that gestational age. DESIGN/METHODS: Residents and nurses involved in perinatal care were asked whether they would resuscitate a depressed AGA 24-week gestation infant at birth. In another question they were asked whether they would resuscitate a depressed preterm infant with a 50% chance of survival, knowing that of those who survived, 50% would have a development 'within normal limits', 20-25% a serious handicap and 40% with behavioural and/or learning disability. RESULTS: Two hundred and seventy-nine caregivers responded (91% response rate). In the scenario that only presented gestational age, 21% of respondents would resuscitate. In the scenario that only presented prognostic statistics, 51% of respondents would resuscitate (p<0.05). CONCLUSIONS: Providers of perinatal health care respond to vignettes differently depending upon the format in which information is provided. The relative unwillingness to resuscitate a baby of 24-week gestation is surprising since outcomes for such babies are the same or better than those we described in the scenario that provided only outcome data without specifying gestational age. Two explanations are possible: (1) respondents have irrational negative associations with low gestational ages or (2) respondents are unaware of actual outcomes.