10 research outputs found
Computer simulation of the linear and nonlinear optical properties of liquid benzene : its local fields, refractive index and second nonlinear susceptibility
No full textMolecular dynamics (MD) simulation and subsequent analysis of the macroscopic polarization developed in response to a posteriori applied electric fields or of spontaneous fluctuations in the instantaneous polarization under zero applied field is used to assess the nonlinear optical properties of a polarizable liquid. Three strategies are proposed for the electrostatic analysis, all using as input static gas phase (hyper)polarizabilities, obtained from ab initio calculations. All three strategies are shown to accurately reproduce the experimentally measured refractive index and second nonlinear susceptibility of liquid benzene. The simulation also predicts the distribution of orientations and magnitudes of the local electric fields experienced by the molecules in the liquid, and the nonlinear contributions to the local fields. This approach gives an 8% higher estimate of the second nonlinear susceptibility of liquid benzene than the Lorentz local field factor approach, in better agreement with experimental value
Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation
No full textAuthor Posting. © American Society for Clinical Investigation, 2013. This article is posted here by permission of American Society for Clinical Investigation for personal use, not for redistribution. The definitive version was published in Journal of Clinical Investigation 123 (2013): 1964–1975, doi:10.1172/JCI66387.Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients’ dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan–/– mice, we demonstrated that gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease.This work was
supported by NIH grants 1P01GM096971 (to R.D. Goldman) and
R01 NS062051 (to P. Opal) and a grant from Hannah’s Hope Fund
(to R.D. Goldman and P. Opal)
The management of HIV in pregnancy: a 10-year experience
No full textObjective: The package of care to reduce HIV mother to child transmission (MTCT) has evolved significantly since trials of ante and intrapartum antiretroviral therapy (ART) in 1994. In the UK MTCT rate has fallen from 25.6% in the 1990s to 0.46%. We review the management of HIV in pregnancy in Brighton in the context of evolving guidelines. Study design: HIV, obstetric and neonatal notes of all HIV positive women, pregnant between 2003 and 2014, were reviewed. Results: 97 pregnancies in 75 women were identified, resulting in 79 live births. Antenatal HIV diagnosis was made in 22 (28%). The proportion of pregnancies in those with known HIV at conception increased over the time period. At conception 58 (60%) were on ART, 33 (57%) of who continued on their original regimen. 34 (35%) initiated ART following conception: 14 known to be HIV positive, 20 diagnosed during pregnancy. Two did not start ART (1 due to miscarriage, 1 as diagnosed post-delivery) and in three cases ART history was unavailable due to transfer to alternative centres. ART was initiated on average at 22 weeks gestation (range 6–34). 4(5%) received Zidovudine (AZT) monotherapy, all before 2006. Choice of combination ART (cART) varied with time reflecting changing guidelines. Prior to 2008 an AZT containing regimen was used in 83% versus 8% after. Planned mode of delivery was documented in 73: 30(41%) planned a normal vaginal delivery (NVD), 43(59%) a caesarean section (CS). The viral load (VL) was?<50 copies/mL in 58(76%) at 36 weeks and 64(84%) at delivery. 90% with a detectable VL at 36 weeks delivered via CS. 100% received neonatal post-exposure prophylaxis (PEP): 68(88%) AZT monotherapy, 9(12%) cART. 84% initiated PEP within four hours. 90% completed 28 days. 8(10%) babies experienced side effects. In the 10-year review period, one infant (1.3%) was diagnosed HIV positive. Both mother and infant received care in accordance with guidelines, including neonatal PEP within 4 hours. Conclusion: Care of the HIV positive pregnant woman in Brighton has been successful with overall transmission consistent with that seen nationally. Despite effective preventative strategies MTCT remains a risk and women should be counselled accordingly
The management of HIV in pregnancy: a 10-year experience
No full textObjective: The package of care to reduce HIV mother to child transmission (MTCT) has evolved significantly since trials of ante and intrapartum antiretroviral therapy (ART) in 1994. In the UK MTCT rate has fallen from 25.6% in the 1990s to 0.46%. We review the management of HIV in pregnancy in Brighton in the context of evolving guidelines. Study design: HIV, obstetric and neonatal notes of all HIV positive women, pregnant between 2003 and 2014, were reviewed. Results: 97 pregnancies in 75 women were identified, resulting in 79 live births. Antenatal HIV diagnosis was made in 22 (28%). The proportion of pregnancies in those with known HIV at conception increased over the time period. At conception 58 (60%) were on ART, 33 (57%) of who continued on their original regimen. 34 (35%) initiated ART following conception: 14 known to be HIV positive, 20 diagnosed during pregnancy. Two did not start ART (1 due to miscarriage, 1 as diagnosed post-delivery) and in three cases ART history was unavailable due to transfer to alternative centres. ART was initiated on average at 22 weeks gestation (range 6–34). 4(5%) received Zidovudine (AZT) monotherapy, all before 2006. Choice of combination ART (cART) varied with time reflecting changing guidelines. Prior to 2008 an AZT containing regimen was used in 83% versus 8% after. Planned mode of delivery was documented in 73: 30(41%) planned a normal vaginal delivery (NVD), 43(59%) a caesarean section (CS). The viral load (VL) was?<50 copies/mL in 58(76%) at 36 weeks and 64(84%) at delivery. 90% with a detectable VL at 36 weeks delivered via CS. 100% received neonatal post-exposure prophylaxis (PEP): 68(88%) AZT monotherapy, 9(12%) cART. 84% initiated PEP within four hours. 90% completed 28 days. 8(10%) babies experienced side effects. In the 10-year review period, one infant (1.3%) was diagnosed HIV positive. Both mother and infant received care in accordance with guidelines, including neonatal PEP within 4 hours. Conclusion: Care of the HIV positive pregnant woman in Brighton has been successful with overall transmission consistent with that seen nationally. Despite effective preventative strategies MTCT remains a risk and women should be counselled accordingly
Long-term effects of acute and of chronic hypoxia on behavior and on hippocampal histology in the developing brain
No full textTen-day-old rat pups (P10) subjected to acute hypoxia (down to 4percent O 2) had as adults increased aggression (handling test), memory impairment (water maze test), and decreased CA1 cell counts. Pups subjected to chronic hypoxia (10percent O2 from P0 to P21) had increased aggression, hyperactivity (open-field test), and decreased CA1 cell counts. Chronic hypoxia with superimposed acute hypoxia resulted in consequences that were not different from those of chronic hypoxia. © 2005 Elsevier B.V. All rights reserved.Aydin A, 2003, BRAIN DEV-JPN, V25, P494, DOI 10.1016-S0387-7604(03)00039-1; Balduini W, 2000, BRAIN RES, V859, P318, DOI 10.1016-S0006-8993(00)01997-1; Bitar FF, 2002, BRAIN INJURY, V16, P891, DOI 10.1080-02699050210147194; BOMONT L, 1992, DEV BRAIN RES, V66, P33, DOI 10.1016-0165-3806(92)90137-L; COMO AF, 2002, J THORAC CARDIOVASC, V124, P105; Daval JL, 2004, PEDIATR RES, V55, P561, DOI 10.1203-01.PDR.0000113771.51317.37; DELLANNA ME, 1991, BEHAV BRAIN RES, V45, P125, DOI 10.1016-S0166-4328(05)80078-6; GRAMATTE T, 1986, BIOMED BIOCHIM ACTA, V45, P523; Grojean S, 2003, HIPPOCAMPUS, V13, P970, DOI 10.1002-hipo.10171; GROSS J, 1993, J NEURAL TRANSM-GEN, V93, P109, DOI 10.1007-BF01245341; Hattori Haruo, 1994, No To Hattatsu, V26, P125; Jensen F. E., 1999, EPILEPSIA S1, V40, P51; JENSEN FE, 1995, EPILEPSIA, V36, P966, DOI 10.1111-j.1528-1157.1995.tb00954.x; JENSEN FE, 1995, ITAL J NEUROL SCI, V16, P59, DOI 10.1007-BF02229075; Jensen FE, 1998, J NEUROPHYSIOL, V79, P73; JENSEN FE, 1991, LIFE SCI, V49, P399, DOI 10.1016-0024-3205(91)90448-K; JENSEN FE, 1992, EPILEPSIA, V33, P971, DOI 10.1111-j.1528-1157.1992.tb01746.x; Jensen FE, 2002, INT J DEV NEUROSCI, V20, P339, DOI 10.1016-S0736-5748(02)00012-6; Koh S, 2001, ANN NEUROL, V50, P366, DOI 10.1002-ana.1122; Kuchna I, 1994, Folia Neuropathol, V32, P9; Lai JCK, 2003, NEUROCHEM RES, V28, P933, DOI 10.1023-A:1023235712524; Lilliu V, 2001, MOL BRAIN RES, V96, P133, DOI 10.1016-S0169-328X(01)00280-7; LUN A, 1990, BIOMED BIOCHIM ACTA, V49, P1021; Maiese K, 2004, TRENDS PHARMACOL SCI, V25, P577, DOI 10.1016-j.tips.2004.09.006; Mikati MA, 2003, EPILEPSIA, V44, P282, DOI 10.1046-j.1528-1157.2003.22502.x; Mikati MA, 2004, EPILEPSY BEHAV, V5, P168, DOI 10.1016-j.yebeh.2003.12.002; Mohajeri MH, 2003, NEUROBIOL DIS, V12, P174, DOI 10.1016-S0969-9961(02)00031-1; Nyakas C, 1996, PROG NEUROBIOL, V49, P1; Owens J, 1997, ANN NEUROL, V41, P187, DOI 10.1002-ana.410410210; Rafiee P, 2002, CIRCULATION, V106, P239, DOI 10.1161-01.CIR.0000022018.68965.6D; Sadowski M, 1999, J NEUROL SCI, V168, P13, DOI 10.1016-S0022-510X(99)00159-8; Sanchez RM, 2001, J NEUROSCI, V21, P8154; Simonova Z, 2003, BEHAV BRAIN RES, V141, P195; Soulier V, 1997, PEDIATR RES, V42, P30, DOI 10.1203-00006450-199707000-00006; Spandou E, 2004, BRAIN RES, V1021, P167, DOI 10.1016-j.brainres.2004.06.057; Stewart WB, 1997, BRAIN RES, V760, P17, DOI 10.1016-S0006-8993(97)00271-0; XIA Y, 1995, BRAIN RES, V675, P224, DOI 10.1016-0006-8993(95)00079-626302
Difficult tracheal intubation in neonates and infants. NEonate and Children audiT of Anaesthesia pRactice IN Europe (NECTARINE): a prospective European multicentre observational study
No full textBackground: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences.
Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes.
Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1-6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO2<90% for 60 s) was reported in 40%. No associated risk factors could be identified among co-morbidities, surgical, or anaesthesia management. Using propensity scoring to adjust for confounders, difficult anaesthesia tracheal intubation did not lead to an increase in 30 and 90 day morbidity or mortality.
Conclusions: The results of the present study demonstrate a high incidence of difficult tracheal intubation in children less than 60 weeks post-conceptual age commonly resulting in severe hypoxaemia. Reassuringly, the morbidity and mortality at 30 and 90 days was not increased by the occurrence of a difficult intubation event
Morbidity and mortality after anaesthesia in early life: results of the European prospective multicentre observational study, neonate and children audit of anaesthesia practice in Europe (NECTARINE)
No full textBackground: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown.
Methods: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events.
Results: Infants (n=5609) born at mean (standard deviation [sd]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2 <85%). Postmenstrual age influenced the incidence and thresholds for intervention. Risk of critical events was increased by prior neonatal medical conditions, congenital anomalies, or both (relative risk [RR]=1.16; 95% confidence interval [CI], 1.04-1.28) and in those requiring preoperative intensive support (RR=1.27; 95% CI, 1.15-1.41). Additional complications occurred in 16.3% of patients by 30 days, and overall 90-day mortality was 3.2% (95% CI, 2.7-3.7%). Co-occurrence of intraoperative hypotension, hypoxaemia, and anaemia was associated with increased risk of morbidity (RR=3.56; 95% CI, 1.64-7.71) and mortality (RR=19.80; 95% CI, 5.87-66.7).
Conclusions: Variability in physiological thresholds that triggered an intervention, and the impact of poor tissue oxygenation on patient's outcome, highlight the need for more standardised perioperative management guidelines for neonates and infants
Ventilation strategies and risk factors for intraoperative respiratory critical events and postoperative pulmonary complications in neonates and small infants: a secondary analysis of the NECTARINE cohort☆
No full textBackground: Optimal ventilation strategies and use of neuromuscular blocking agents (NMBAs) in neonates and small infants undergoing anaesthesia remain unclear. We examined the association of perioperative ventilation strategies and administration of NMBAs on respiratory adverse events in the NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) cohort. Methods: We performed a secondary analysis of NECTARINE, which included infants up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures. The primary endpoint was the association between ventilation mode and intraoperative respiratory adverse events. Secondary endpoints were use of NMBA, and 30-day postoperative pulmonary complications (PPCs). Results: The dataset comprised 5609 patients undergoing 6542 procedures. Pressure-controlled ventilation was the primary ventilation modality, accounting for 52.4% (n=3428) of cases. The incidence of intraoperative respiratory critical events was 20.7% (95% confidence interval [CI] 19.7–21.7%), while PPCs were observed in 17% of cases (95% CI 16.0–18.1%). Preanaesthesia respiratory conditions and NMBA use after tracheal intubation were associated with higher incidence of PPCs. Of the children receiving NMBAs, reversal was reported in 29.8%. The absence of reversal was associated with a higher incidence of PPCs, with a relative risk of 1.50 (95% CI 1.17–1.93). Conversely, NMBA reversal was associated with a reduced relative risk of 0.43 (95% CI 0.26–0.70). Conclusions: Regardless of ventilation strategy used, mechanical ventilation and baseline respiratory conditions were risk factors for a greater incidence of adverse respiratory events and PPCs. Reversal of NMBAs before tracheal extubation was significantly associated with reduced PPCs in neonates and should be routine clinical practice. Clinical trial registration: ClinicalTrials.gov (NCT02350348)
Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study
No full textBACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348
