Andrea Budreau Patters

Children With Respiratory Distress Treated With High-Flow Nasal Cannula

High-flow nasal cannula (HFNC) therapy is a treatment for respiratory distress in neonates and children. In the present study, we assessed its effectiveness, comfort, and possible mechanism of action. Methods: We reviewed records of 46 patients treated with HFNC and estimated the modified COMFORT score (7 to 35 units), the respiratory clinical scale (0 to 12 units), and the oxygen saturation level. Data were collected at time 0 (before the use of high-flow), time 2 (60 to 90 min post-application), and at time 3 (8 to 12 hours post-application). Furthermore, we measured the nasopharyngeal pressure while on continuous positive air pressure (CPAP) as well as the differences in ‘‘lung expansion’’ demonstrated by the prestudy and post-study chest x-ray. Results: There were significant improvements in the modified COMFORT score (F1,45 = 40.03, P < .05), respiratory clinical scale (F1.69,76.15 = 121.19, P < .05), and oxygen saturation (F2,90 = 101.54, P < .05). Application of HFNC therapy created a significant average positive expiratory pressure of 4.0 ± 1.99 (SE) cm H2O. X-rays taken after initiation of HFNC showed either improved aeration of the lungs or no changes in 40 of 46 patients. Mechanical ventilation was needed in 5 of 46 patients. Conclusion: Our study indicates that high-flow nasal cannula improves the respiratory scale score, the oxygen saturation, and the patient’s COMFORT scale. Its mechanism of action is application of mild positive airway pressure and lung volume recruitment.

The taurine transporter: mechanisms of regulation

Taurine transport undergoes an adaptive response to changes in taurine availability. Unlike most amino acids, taurine is not metabolized or incorporated into protein but remains free in the intracellular water. Most amino acids are reabsorbed at rates of 98–99%, but reabsorption of taurine may range from 40% to 99.5%. Factors that influence taurine accumulation include ionic environment, electrochemical charge, and post‐translational and transcriptional factors. Among these are protein kinase C (PKC) activation and transactivation or repression by proto‐oncogenes such as WT1, c‐Jun, c‐Myb and p53. Renal adaptive regulation of the taurine transporter (TauT) was studied in vivo and in vitro. Site‐directed mutagenesis and the oocyte expression system were used to study post‐translational regulation of the TauT by PKC. Reporter genes and Northern and Western blots were used to study transcriptional regulation of the taurine transporter gene (TauT). We demonstrated that (i) the body pool of taurine is controlled through renal adaptive regulation of TauT in response to taurine availability; (ii) ionic environment, electrochemical charge, pH, and developmental ontogeny influence renal taurine accumulation; (iii) the fourth segment of TauT is involved in the gating of taurine across the cell membrane, which is controlled by PKC phosphorylation of serine 322 at the post‐translational level; (iv) expression of TauT is repressed by the p53 tumour suppressor gene and is transactivated by proto‐oncogenes such as WT1, c‐Jun, and c‐Myb; and (v) over‐expression of TauT protects renal cells from cisplatin‐induced nephrotoxicity.

Taurine and the renal system.

Taurine participates in a number of different physiologic and biologic processes in the kidney, often reflected by urinary excretion patterns. The kidney is key to aspects of taurine body pool size and homeostasis. This review will examine the renal-taurine interactions relative to ion reabsorption; renal blood flow and renal vascular endothelial function; antioxidant properties, especially in the glomerulus; and the role of taurine in ischemia and reperfusion injury. In addition, taurine plays a role in the renal cell cycle and apoptosis, and functions as an osmolyte during the stress response. The role of the kidney in adaptation to variations in dietary taurine intake and the regulation of taurine body pool size are described. Finally, the protective function of taurine against several kidney diseases is reviewed.

Transcriptional Repression of Taurine Transporter Gene (TauT) by p53 in Renal Cells

Taurine, an intracellular osmolyte whose body pool size is adaptively regulated by the kidney, is required for normal renal development. Overexpression of the p53 tumor suppressor gene in p53 transgenic mice results in renal malformation, suggesting that altered expression of certain p53 target gene(s) involved in renal development may be responsible. This study shows that the taurine transporter gene (TauT) is a transcriptional target of p53. Expression of TauT was decreased after activation of p53 by doxorubicin, a DNA-damaging drug, in 293 and NRK-52E renal cells.TauT promoter activity was decreased 5–10-fold by cotransfection of a full-length TauT promoter-reporter construct with p53, which was reversed by cotransfection with a mutant p53 (p53-281). Electrophoretic mobility shift assays using nuclear extracts from p53-expressing (10)1val cells showed a putative p53-binding site in the TauT promoter region, which bound to the p53 in electrophoretic mobility shift assays. Mutation of this p53 consensus sequence abolished binding of p53. These results demonstrate that TauT may represent a downstream target gene of p53 that could link the roles of p53 in renal development and apoptosis.

Prospective Study of the Emfit Movement Monitor

Sudden unexplained death in epilepsy (SUDEP) is associated with generalized tonic-clonic seizures and occurs most often when patients are in bed. There are several seizure detection monitors on the market, but little data are available on the sensitivity and specificity of these devices. We recently tested 2 models of seizure detection alarms with disappointing results. Here we tested the Emfit movement monitor on children with various seizure types who also had standard video electroencephalography (EEG), cardiopulmonary, and nursing monitoring. Video EEG records were reviewed to detect any seizures. In 45 patients, 78 seizures were recorded by video EEG. The Emfit movement monitor captured 23 seizure events (30%) in total, and 15 of the 28 (54%) that occurred during sleep. Most importantly, the alarm was activated with 11 of the 13 (85%) generalized tonic-clonic seizures that occurred in sleeping children. The Emfit movement monitor performed very well in comparison to previously tested devices.

Prospective study of 2 bed alarms for detection of nocturnal seizures

For parents of children with epilepsy, seizures occurring in sleep are a major concern. Risk factors for sudden unexplained death in epilepsy patients include being in bed and generalized tonic-clonic seizures. A device for detecting nocturnal seizure activity would be valuable. Children with various seizure types undergoing evaluation had standard video electroencephalography (EEG), cardiopulmonary and nursing monitoring, and 1 of 2 models (ST-2 and MP5) of a Medpage bed alarm. The video EEG record was reviewed to detect any seizures missed by the bed alarms or caregivers. The ability of the bed alarms to detect motor seizures in general and specific seizure types was tested. In 15 patients, 69 seizures were recorded by video EEG. The ST-2 did not detect any nocturnal seizures. The MP5 alarm detected 1 of 15 in sleeping patients: a generalized tonic-clonic seizure. The Medpage seizure alarms do not appear to adequately detect nocturnal seizures.

Correlation of intraocular pressure with intracranial pressure in children with severe head injuries

Objective: To determine whether there was a correlation between tonometric measurements of the intraocular pressure and transducer measurements of the intracranial pressure in the acute setting, and whether intraocular pressure can be used as a surrogate measure of intracranial pressure. Children with traumatic brain injuries commonly develop increased intracranial pressure requiring surgical placement of a pressure transducer to measure the intracranial pressure during the acute recovery period. The increased intracranial pressure may cause engorgement of the orbital compartments via dilation of the episcleral veins and manifest as increased intraocular pressure. Design: Prospective study. Setting: Tertiary academic pediatric intensive care unit. Patients: Children admitted with severe traumatic brain injury. Interventions: Tonometric intraocular pressure measurements. Measurements and Main Results: We performed an Institutional Review Board-approved, prospective study on 36 children (age range, 2.9–15.1 yrs) with traumatic brain injuries, requiring intracranial pressure monitoring. A total of 274 intraocular pressure measurements were made after placement of the pressure transducer, and concordance between the sites of injury and measurement was documented. The average age of the patients was 8.3 yrs. The mean intraocular pressure, intracranial pressure difference was −0.5 ± 0.68 cm H2O, and the variance was 29.88 (sd, 5.47). The 95% confidence interval was between −11.22 and 10.22. With concordance between the sites of measurement and injury, the mean IOP, intracranial pressure difference was −0.02 ± 0.61 cm H2O (variance, 23.28; sd, 4.82; 95% confidence interval, − 9.47 to 9.42). Concordance reduced the variance of the intraocular pressure, intracranial pressure discrepancy by 20.3%. The Pearson intraocular pressure-intracranial pressure regression coefficient and the Krippendorffs &agr; reliability estimate analyses indicated good agreement. The patients age or Paco2 did not influence the intraocular pressure, intracranial pressure difference. Using 20 cm H2O as a normal intracranial pressure cutoff, the intraocular pressure had a specificity of 0.7 and sensitivity of 0.97; with concordance, the values improved to 0.78 and 0.96, respectively. Conclusions: Tonometry is a useful screening surrogate measure of intracranial pressure in children with traumatic brain injuries, but seems to lack the accuracy necessary for close management of intracranial pressure in the acute posttraumatic period.

Brain tumor resection in children: neurointensive care unit course and resource utilization.

Objective: To describe the pediatric intensive care unit (PICU) course and resource utilization for children with brain tumor resection and to identify factors predicting prolonged (>1 day) PICU length of stay. After craniotomy for brain tumor resection, children recover in the PICU. A few require critical care interventions and a >24-hr length of stay. Design: We reviewed all brain tumor resection patients admitted to the PICU over 2 yrs. Preoperative, intraoperative, and postoperative variables and tumor characteristics were examined. The extracted variables were compared between two groups with a length of stay in the PICU of >1 or <1 day. Setting: Pediatric intensive care unit in a tertiary academic childrens medical center. Patients: A total of 105 patients post brain tumor resection were admitted to the PICU over the study period and analyzed. Interventions: Record review. Measurements and Main Results: Thirty-two (31%) of 105 patients remained in the PICU for >1 day. The mean age of patients in the >1 day group was 5.0 ± 0.81 yrs and 8.78 ± 0.65 yrs in the <1 day group (p < .05). The estimated blood loss was 20 ± 2.37 mL/kg in the >1 day and 9 ± 0.92 mL/kg in the <1 day group (p < .05). Fifteen (14.3%) patients were mechanically ventilated on arrival in the PICU; these patients more often had a length of stay of >1 day (p < .05). The number of unexpected intensive care unit interventions were 0.7 per patient, were more common in the >1 day group, and included treatment of sodium abnormalities, new neurologic deficits, paresis, or seizures (p < .05). In a logistic regression model, estimated blood loss and intubation on arrival predicted longer lengths of stay in the PICU (odds ratio, 1.1; 95% confidence interval, 1.05−1.18; and odds ratio, 33; 95% confidence interval, 2.57−333, respectively), with a receiver operating characteristic curve of 0.86 and 95% confidence interval, 0.78−0.94. Conclusions: Large intraoperative estimated blood loss and intubation on arrival may be predictive of PICU lengths of stay of >1 day for children who have had a craniotomy for brain tumor resection. Intensive care unit interventions are more common in these children.

Knockout of the TauT gene predisposes C57BL/6 mice to streptozotocin-induced diabetic nephropathy.

Diabetic nephropathy is the leading cause of end stage renal disease in the world. Although tremendous efforts have been made, scientists have yet to identify an ideal animal model that can reproduce the characteristics of human diabetic nephropathy. In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus. This hypothesis was tested in vivo in TauT heterozygous (TauT +/-) and homozygous (TauT-/-) knockout in C57BL/6 background mice. We have shown that alteration of the TauT gene (also known as SLC6A6) has a substantial effect on the susceptibility to development of extensive diabetic kidney disease in both TauT +/- and TauT-/-mouse models of diabetes. These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis. Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations. Our results demonstrated that both homozygous and heterozygous TauT gene deletion predispose C57BL/6 mice to develop end-stage diabetic kidney disease, which closely replicates the pathological features of diabetic nephropathy in human diabetic patients.

Transactivation of TauT by p53 in MCF-7 Cells

The p53 tumor suppressor gene functions as a cell cycle checkpoint, blocking cell division in the G1 phase to allow repair of damaged DNA or even triggering apoptosis in cells that have defective genomes 1. Numerous stimuli trigger increases in the level of p53, including DNA-damaging drugs, ionizing radiation, ultraviolet light, and hypoxia 2–5. MCF-7, a human breast cancer estrogen receptor-positive (ER+) cell line, expresses a high level of wild-type p53, which is up-regulated by 17-s-estradiol (E2) 6. However, p53 function is largely inactivated in MCF-7 cells, caused by misallocation of p53 from nuclei to cytosol 7, which may result in the altered expression of certain p53 target genes. Studies have shown that the taurine transporter gene (TauT) is a putative target of p53 8, and that mutation of TauT results in severe and progressive retinal degeneration, a small brain, and shrunken kidneys 9. In the present study, we show that TauT is up-regulated by p53 and E2 in MCF-7 human breast cancer cells in a manner that appears to be mediated by estrogen receptor α (ERα).