Variations and similarities in clinical management of neonatal abstinence syndrome: Findings of a Canadian survey.

BACKGROUND: There are no evidence-based national guidelines for managing neonatal abstinence syndrome (NAS) and surveys from other countries have demonstrated considerable variations in practice. OBJECTIVE: To describe NAS management practices in Canada. METHOD: The directors of all Level 2 and Level 3 neonatal intensive care units (NICUs) were contacted to request their participation in a structured telephone survey. Frequency distributions were generated and associations between practice variations and unit type (Level 2 or 3) and size were examined. RESULTS: Personnel at 65 of 103 sites (63.1%) participated. Most (92.3%) stated their hospital has a written NAS practice guideline. The majority (89.5%) use a version of Finnegan's scoring system to monitor signs. If pharmacological treatment is required, 89.2% admit infants to the NICU and 93.8% routinely use cardiorespiratory monitors when treatment is initiated. Morphine is the first-line medication at most sites (96.9%). There was greater variability in terms of other practices: 44.6% observe at-risk infants in the NICU, while 52.3% allow them to room-in with their mothers; 65.1% use adjunct medications; 36.9% and 38.9% will discharge infants on the first-line and adjunct medications respectively, and 53.8% reported that breastfeeding is always encouraged, while 44.6% discourage breastfeeding if the mother continues to use illicit drugs and 1.5% make recommendations on an individual basis. Few practice variations were associated with unit type or size. CONCLUSION: While most NICUs surveyed have an NAS practice guideline, there are some notable differences in how NAS is managed. This underscores the need for research that can be translated into best practices.

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models.

Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to cortico-striatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naïve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5±14.6%; LTD protocol 177.7±22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3±4.0% and LTD protocol: 63.3±8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naïve animals (Indirect pathway: LTP protocol: 124.4±22.0% and LTD protocol: 52.1±18.5% of baseline. Direct pathway: LTP protocol: 140.7±7.3% and LTD protocol: 58.4±6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9±21.3% and LTD protocol 52.0±14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6±13.2% and LTD protocol 166.7±15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs, which underlies the symptomatic benefits of l-DOPA. Switching from bidirectional to unidirectional plasticity drives global changes in striatal pathway excitability, and underpins parkinsonism and dyskinesia.

Secular trends in age at menarche among women born between 1955 and 1985 in Southeastern China.

BACKGROUND: Improvements in socioeconomic conditions and population health have been linked to declining age at menarche. In China, secular trends in age at menarche following extensive economic reform during recent decades have not been thoroughly investigated. This study examined the overall trend in age at menarche and assessed differences in the rate of change of age at menarche over time, and between urban and rural populations and education levels in southeastern China. METHODS: Age at menarche was retrospectively collected from 1,167,119 Han Chinese women born 1955-1985, who registered in the Perinatal Health Care Surveillance System in 19 cities and counties in two southeast provinces during 1993-2005. Multivariable linear regression was used to estimate trends in age at menarche overall and stratified by urban/rural residence and education level. RESULTS: Age at menarche declined by 0.33 [95% CI 0.33, 0.32] years/decade overall, with the fastest decline in women born in 1966-1975. For the earliest birth cohorts (1955-1965), age at menarche declined faster in urban versus rural regions, and for women with high school education or above versus primary school or less. In contrast, age at menarche declined slower among urban women born 1976-1985, and among those with higher education born 1966-1985. CONCLUSIONS: Mean age at menarche declined for women born in 1955-1985 in southeast China. Further study is warranted to identify specific factors contributing to earlier age at menarche and associated health outcomes.

Psychosocial and cognitive health differences by caregiver status among older Mexican Americans.

This study identifies the risk and protective factors associated with informal caregiving by older (≥70 years) Mexican Americans and profiles caregiving arrangements. Overall, a greater number of informal caregivers (n = 92) were married and female. They also had higher physical functioning and better cognition than non-caregivers (n = 1,888) but fewer visited a physician regularly. Informal caregivers also showed an increased risk of depressive symptoms. A third of caregivers spent more than 20 h/day caregiving and the majority (84%) of care recipients were family members. In order to support the efforts of this disproportionately burdened caregiver group, increased social support and healthcare services are needed.

Altered function of glutamatergic cortico-striatal synapses causes output pathway abnormalities in a chronic model of parkinsonism.

OBJECTIVE: In Parkinson's disease, chronic striatal dopamine depletion results in over-activity and under-activity of the indirect and direct striatal output pathways respectively. In this study, we investigated changes in the function of glutamatergic cortico-striatal synapses that contribute to abnormalities in striatal efferents. METHODS: Whole-cell recordings were performed in striatal slices prepared from adult bacterial artificial chromosome mice, chronically lesioned with 6-hydroxydopamine (6-OHDA). Paired pulse facilitation, spontaneous synaptic activity, the ratio of AMPAR to NMDAR-mediated components of excitatory postsynaptic currents, AMPAR and NMDAR kinetics, current-voltage relationship and intrinsic membrane properties were assessed in indirect and direct pathway medium spiny neurons (MSNs), which were identified on the basis of expression of GFP, driven by the promoters of A2A or D1 receptor expression. The trajectory of striatal efferents, with respect to selective targeting of the globus pallidus and substantia nigra was also compared in sham-operated versus 6-OHDA-lesioned mice. RESULTS: Dopamine depletion did not affect the number of pathway specific output neurons or the trajectory of striatal outputs. In sham-operated animals, cortico-striatal synapses of both striatal efferent populations exhibited paired pulse facilitation and similar ratios of AMPAR to NMDAR-mediated components of excitatory postsynaptic currents. Following striatal dopamine depletion, indirect pathway neurons exhibited decreased levels of paired pulse facilitation, enhanced sensitivity to presynaptic stimulation and an increase in the relative contribution of NMDAR to the EPSC but no change in spontaneous synaptic activity. In sham-operated mice, neurons of the direct pathway exhibited lower firing frequency compared to the indirect pathway following current injection. However, in 6-OHDA-lesioned mice, in the direct pathway, firing threshold was reduced, spike frequency adaptation developed and the frequency of spontaneous activity was also reduced. In addition, changes in the properties of NMDAR kinetics suggest that these receptors were desensitised. DISCUSSION: Increased synchronicity between pre and postsynaptic neurons, as indicated by decreased paired pulse facilitation, and increased sensitivity to extracellular stimulation, combined with an increase in the contribution of NMDARs to the EPSC at cortico-striatal synapses, may contribute to the over-activity of indirect pathway neurons in the parkinsonian striatum. In contrast, a decrease in spontaneous activity, postsynaptic desensitisation to excitatory stimuli and spike frequency adaptation of cortico-striatal synapses may underlie under-activity of the direct pathway.

Antagonists of GLU(K5)-containing kainate receptors prevent pilocarpine-induced limbic seizures.

Developments in the molecular biology and pharmacology of GLU(K5), a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLU(K5)-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLU(K5)-containing kainate receptors prevented development of epileptiform activity--evoked by the muscarinic agonist, pilocarpine--and inhibited the activity when it was pre-established. In conscious rats, these GLU(K5) antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLU(K5) antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLU(K5) kainate receptor antagonists offer a potential new therapy for epilepsy.

Breaking down barriers: enabling care-by-parent in neonatal intensive care units in China.

BACKGROUND: Denying parents access to their infant in the Neonatal Intensive Care Unit (NICU) is a standard practice in most hospitals across China. Visitation is not usually permitted or may be strictly limited, and NICU care for most neonates is provided by health-care professionals with little participation of the parents. An exception to this rule is the level 2 "Room-In" ward in Qilu Children's Hospital, Shandong University, where parents have 24-hour access to their infants and participate in providing care. METHODS: This retrospective cohort study compared the outcomes of infants who were admitted to the NICU and remained there throughout their stay (NICU-NICU group, n=428), admitted to the NICU and then transferred to the Room-In ward (NICU-RIn group, n=1018), or admitted straight to the Room-In ward (RIn only group, n=629). RESULTS: There were no significant differences in the rates of nosocomial infection, bronchopulmonary dysplasia, intraventricular hemorrhage, and retinopathy of prematurity between the NICU-NICU and NICU-RIn groups. The rate of necrotizing enterocolitis was significantly lower in the NICU-RIn group (P=0.04), while weight gain and duration of hospital stay were significantly higher (both P<0.001). Rates of adverse outcomes were lower in RIn-only infants due to their low severity of illness on admission. CONCLUSIONS: Allowing parents access to their infant in the NICU is feasible and safe in China, and may result in improvements in infant outcomes. Further studies are required to generate stronger evidence that can inform changes to neonatal care in China.

Association between admission temperature and mortality and major morbidity in preterm infants born at fewer than 33 weeks' gestation.

IMPORTANCE: Neonatal hypothermia has been associated with higher mortality and morbidity; therefore, thermal control following delivery is an essential part of neonatal care. Identifying the ideal body temperature in preterm neonates in the first few hours of life may be helpful to reduce the risk for adverse outcomes. OBJECTIVES: To examine the association between admission temperature and neonatal outcomes and estimate the admission temperature associated with lowest rates of adverse outcomes in preterm infants born at fewer than 33 weeks' gestation. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational study at 29 neonatal intensive care units in the Canadian Neonatal Network. Participants included 9833 inborn infants born at fewer than 33 weeks' gestation who were admitted between January 1, 2010, and December 31, 2012. EXPOSURE: Axillary or rectal body temperature recorded at admission. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite adverse outcome defined as mortality or any of the following: severe neurological injury, severe retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, or nosocomial infection. The relationships between admission temperature and the composite outcome as well as between admission temperature and the components of the composite outcome were evaluated using multivariable analyses. RESULTS: Admission temperatures of the 9833 neonates were distributed as follows: lower than 34.5°C (1%); 34.5°C to 34.9°C (1%); 35.0°C to 35.4°C (3%); 35.5°C to 35.9°C (7%); 36.0°C to 36.4°C (24%); 36.5°C to 36.9°C (38%); 37.0°C to 37.4°C (19%); 37.5°C to 37.9°C (5%); and 38.0°C or higher (2%). After adjustment for maternal and infant characteristics, the rates of the composite outcome, severe neurological injury, severe retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, and nosocomial infection had a U-shaped relationship with admission temperature (α > 0 [P < .05]). The admission temperature at which the rate of the composite outcome was lowest was 36.8°C (95% CI, 36.7°C-37.0°C). Rates of severe neurological injury, severe retinopathy of prematurity, necrotizing enterocolitis (95% CI, 36.3°C-36.7°C), bronchopulmonary dysplasia, and nosocomial infection (95% CI, 36.9°C-37.3°C) were lowest at admission temperatures ranging from 36.5°C to 37.2°C. CONCLUSIONS AND RELEVANCE: The relationship between admission temperature and adverse neonatal outcomes was U-shaped. The lowest rates of adverse outcomes were associated with admission temperatures between 36.5°C and 37.2°C.

Parents as practitioners in preterm care.

The very preterm birth of an infant is physiologically traumatic for the infant and physiologically and psychologically traumatic for the parents. The manner of care delivery in the first few days and weeks of the infant's life plays a large role in determining the impact of that trauma. For optimal outcomes parents need to be integrated into the care process as the primary practitioners of their infant's care in the neonatal intensive care unit. Supporting and enabling parents to be central to the care process establishes a consistent care environment where parents are in control and able to support their infant's physiological and psychological needs, thereby improving infant outcomes and reducing parent stress and anxiety. This article reviews the role of parents in the optimal development of preterm neonates, and discusses the elements crucial to promoting parent involvement in the neonatal intensive care unit and supporting parents following discharge.

Quality improvement initiatives in neonatal intensive care unit networks: achievements and challenges.

Neonatal intensive care unit networks that encompass regions, states, and even entire countries offer the perfect platform for implementing continuous quality improvement initiatives to advance the health care provided to vulnerable neonates. Through cycles of identification and implementation of best available evidence, benchmarking, and feedback of outcomes, combined with mutual collaborative learning through a network of providers, the performance of health care systems and neonatal outcomes can be improved. We use examples of successful neonatal networks from across North America to explore continuous quality improvement in the neonatal intensive care unit, including the rationale for the formation of neonatal networks, the role of networks in continuous quality improvement, quality improvement methods and outcomes, and barriers to and facilitators of quality improvement.

Development of a unilaterally-lesioned 6-OHDA mouse model of Parkinson's disease.

The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) has proved to be invaluable in advancing our understanding of the mechanisms underlying parkinsonian symptoms, since it recapitulates the changes in basal ganglia circuitry and pharmacology observed in parkinsonian patients(1-4). However, the precise cellular and molecular changes occurring at cortico-striatal synapses of the output pathways within the striatum, which is the major input region of the basal ganglia remain elusive, and this is believed to be site where pathological abnormalities underlying parkinsonian symptoms arise(3,5). In PD, understanding the mechanisms underlying changes in basal ganglia circuitry following degeneration of the nigro-striatal pathway has been greatly advanced by the development of bacterial artificial chromosome (BAC) mice over-expressing green fluorescent proteins driven by promoters specific for the two striatal output pathways (direct pathway: eGFP-D1; indirect pathway: eGFP-D2 and eGFP-A2a)(8), allowing them to be studied in isolation. For example, recent studies have suggested that there are pathological changes in synaptic plasticity in parkinsonian mice(9,10). However, these studies utilised juvenile mice and acute models of parkinsonism. It is unclear whether the changes described in adult rats with stable 6-OHDA lesions also occur in these models. Other groups have attempted to generate a stable unilaterally-lesioned 6-OHDA adult mouse model of PD by lesioning the medial forebrain bundle (MFB), unfortunately, the mortality rate in this study was extremely high, with only 14% surviving the surgery for 21 days or longer(11). More recent studies have generated intra-nigral lesions with both a low mortality rate >80% loss of dopaminergic neurons, however expression of L-DOPA induced dyskinesia(11,12,13,14) was variable in these studies. Another well established mouse model of PD is the MPTP-lesioned mouse(15). Whilst this model has proven useful in the assessment of potential neuroprotective agents(16), it is less suitable for understanding mechanisms underlying symptoms of PD, as this model often fails to induce motor deficits, and shows a wide variability in the extent of lesion(17, 18). Here we have developed a stable unilateral 6-OHDA-lesioned mouse model of PD by direct administration of 6-OHDA into the MFB, which consistently causes >95% loss of striatal dopamine (as measured by HPLC), as well as producing the behavioural imbalances observed in the well characterised unilateral 6-OHDA-lesioned rat model of PD. This newly developed mouse model of PD will prove a valuable tool in understanding the mechanisms underlying generation of parkinsonian symptoms.

Generation of a model of L-DOPA-induced dyskinesia in two different mouse strains.

Prolonged use of the dopamine precursor L-DOPA for the treatment of Parkinson's disease commonly results in abnormal involuntary movements, which are termed L-DOPA-induced dyskinesia (LID). Over-activity at corticostriatal synapses onto neurons of the direct and indirect striatal output pathways has been implicated in the development of dyskinesia, but it has proved difficult to investigate the pathways separately due to their morphological similarities. The recent development of bacterial artificial chromosome mice that express green fluorescent protein in either the direct or indirect pathway allows visual identification of the output neurons in each pathway. Here we describe the use of two different strains of these transgenic mice (pure FVB and FVB crossed with C57BL6) in the development of mouse models of L-DOPA-induced dyskinesia. This model will allow the direct and indirect pathways to be studied individually to delineate the cellular and molecular mechanisms underlying dyskinesias. These studies demonstrate that mouse strain impacts on behavioural responses and L-DOPA sensitivity. Therefore, when generating mouse models of LID, strain must be taken into consideration when choosing the L-DOPA dosing regimen.

The provision of diabetes-monitoring exams to older Latinos.

OBJECTIVES: To explore factors associated with the provision of diabetes-monitoring practices among older Latinos with type 2 diabetes. METHOD: Data from 547 Latinos (≥ 55 years) were analyzed from the 2007 California Health Interview Survey. Multivariate logistic regression modeled the relationship between health status and sociodemographic factors and the receipt of semiannual HbA1c tests, annual foot exams, and annual retinal exams. RESULTS: The majority of older Latino diabetics received foot exams (87%) and retinal exams (77%), but the provision of semiannual HbA1c tests (30%) was low. Higher English-language proficiency and health insurance coverage were associated with the provision of HbA1c tests and foot exams, but not retinal exams. Insulin therapy was positively associated with semiannual HbA1c testing, but negatively associated with foot exams. DISCUSSION: There are considerable missed opportunities in the provision of diabetes monitoring for older Latinos, particularly those with limited English proficiency, less comprehensive insurance, and noninsulin therapy.