Interventions with Music in PECTus excavatum treatment (IMPECT trial): a study protocol for a randomised controlled trial investigating the clinical effects of perioperative music interventions.

INTRODUCTION: Pectus excavatum repair is associated with substantial postoperative pain, despite the use of epidural analgesia and other analgesic regimens. Perioperative recorded music interventions have been shown to alleviate pain and anxiety in adults, but evidence for children and adolescents is still lacking. This study protocol describes a randomised controlled trial that evaluates the effects of recorded music interventions on postoperative pain relief in children and adolescents after pectus excavatum repair. METHODS: A multicentre randomised controlled trial was set up comparing the effects of perioperative recorded music interventions in addition to standard care with those of standard care only in patients undergoing a Nuss procedure for pectus excavatum repair. One hundred and seventy subjects (12-18 years of age) will be included in three centres in the Netherlands. Patient inclusion has started in November 2018, and is ongoing. The primary outcome is self-reported perceived pain measured on the visual analogue scale. Secondary outcomes are anxiety level, analgesics consumption, vital parameters such as heart rate, blood pressure and respiratory rate, length of hospital stay, postoperative complications, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Centre Rotterdam, The Netherlands, has approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: NL6863.

Music Interventions in Pediatric Surgery (The Music Under Surgery In Children Study): A Randomized Clinical Trial.

BACKGROUND: Perioperative music interventions have been shown to reduce anxiety and pain in adults. This inexpensive, easily applicable intervention could be of benefit to children as well. Our objective was to determine the effects of music interventions on distress, anxiety, and postoperative pain in infants undergoing surgery. METHODS: The Music Under Surgery In Children study was designed as a parallel, single-blind, randomized controlled trial with an a priori formulated hypothesis. Data were collected between August 2015 and October 2016 in a single tertiary care children's hospital. There was a 24-hour follow-up with blind primary outcome assessment. A random sample of 432 eligible 0-3 years of age infants admitted for orchidopexy, hypospadias, or inguinal hernia repair receiving general anesthesia and caudal block were asked for participation. Subjects were assigned to a preoperative music intervention, pre- and intraoperative music intervention, or no music intervention (control) via random allocation using a computer-generated list with the use of opaque envelopes. The main outcome measure was the postoperative level of distress assessed with the COMFORT-Behavior scale, which is an observational scale; furthermore, preoperative level of distress, preoperative anxiety, and physiological measurements such as heart rate (HR) and blood pressure were measured. The trial was registered at the Dutch Trial Register, number NTR5402 (www.trialregister.nl). RESULTS: One hundred ninety-five infants with median age 6.9 months (interquartile range, 3.3-11.1) were randomized, 178 of whom were included in the primary analysis. A nonsignificant difference in COMFORT-Behavior scale scores between the pre- and intraoperative music intervention group and control group at 4 hours after surgery was found (mean difference, -1.22; 95% CI, 2.60-0.17; P = .085). Additional analysis showed weak nonsignificant evidence for an interaction effect between music exposure and COMFORT-Behavior score at baseline (P = .027 with a Bonferroni-adjusted significance level of .025). General linear modeling showed a statistically significantly reduced HR after the preoperative music intervention in the holding area in the combined preoperative music intervention and intraoperative music intervention group compared to the control group (P = .003). The differences in HR among the 3 study arms at all time points were not statistically significant (P = .069). CONCLUSIONS: Music interventions do not seem to benefit all young infants undergoing surgery. The potential benefits of music interventions in the preoperative period and in more distressed children warrant further exploration.

Does the Incidence of Postoperative Complications After Inguinal Hernia Repair Justify Hospital Admission in Prematurely and Term Born Infants?

BACKGROUND: Postoperatively, young infants are admitted overnight in view of the risk for respiratory complications such as desaturation and apnea. This risk seems much lower than previously reported. Until what age this risk persists, and which infants might actually qualify for day-care treatment, is unknown. METHODS: We retrospectively reviewed medical charts from preterm infants <45 weeks postconceptional age (PCA), 45-60 weeks PCA, and term infants <3 months admitted overnight after inguinal hernia repair, from January 2011 to December 2015 in a large tertiary children's hospital. Postoperative complications (divided into respiratory, circulatory, neurologic, and other), recurrence, and reoperation were documented and compared between groups. RESULTS: Medical charts of 485 patients were reviewed. Postoperative respiratory complications (mainly desaturations or apnea) had been documented for 27 of 76 (35.5%) preterm infants <45 weeks PCA, for 13 of 221 (5.9%) preterm infants 45-60 weeks PCA, and for 3 of 188 (1.6%) term infants (P < .001). An analysis of the 221 preterm infants 45-60 weeks PCA showed statistically significantly more respiratory complications in 76 infants with a respiratory history (eg, bronchopulmonary dysplasia) compared with the others (respectively 13.2% vs 0.7%; P < .001). In these infants, lower gestational age at the time of surgery was statistically significantly predictive for the development of respiratory complications (odds ratio [OR], 0.68 [95% confidence interval {CI}, 0.52-0.89]; P = .005), but respiratory history (OR, 3.50 [0.34-36.28]; P = .294) and American Society of Anesthesiologists (ASA) physical status (OR, 1.54 [95% CI, 0.31-7.65]; P = .598 for ASA physical status II and OR, 6.11 [95% CI, 0.76-49.05]; P = .089 for ASA physical status III) were not predictive. CONCLUSIONS: Incidence of postoperative respiratory complications is high in preterm infants <45 weeks PCA requiring postoperative overnight saturation and heart rate monitoring. Incidence of postoperative complications in preterm born infants 45-60 weeks PCA varies. Gestational age and possibly presence of respiratory history can be used to estimate the need for overnight admission in these infants. Postoperative respiratory complications after inguinal hernia repair in ASA physical status I and II term born infants >1 month of age are uncommon, which justifies day-care admission for this type of surgical procedure.

Multilevel correlates of household anthropometric typologies in Colombian mothers and their infants.

BACKGROUND: The aim of this study was to establish the association of maternal, family, and contextual correlates of anthropometric typologies at the household level in Colombia using 2005 Demographic Health Survey (DHS/ENDS) data. METHODS: Household-level information from mothers 18-49 years old and their children <5 years old was included. Stunting and overweight were assessed for each child. Mothers were classified according to their body mass index. Four anthropometric typologies at the household level were constructed: normal, underweight, overweight, and dual burden. Four three-level [households (n = 8598) nested within municipalities (n = 226), nested within states (n = 32)] hierarchical polytomous logistic models were developed. Household log-odds of belonging to one of the four anthropometric categories, holding 'normal' as the reference group, were obtained. RESULTS: This study found that anthropometric typologies were associated with maternal and family characteristics of maternal age, parity, maternal education, and wealth index. Higher municipal living conditions index was associated with a lower likelihood of underweight typology and a higher likelihood of overweight typology. Higher population density was associated with a lower likelihood of overweight typology. CONCLUSION: Distal and proximal determinants of the various anthropometric typologies at the household level should be taken into account when framing policies and designing interventions to reduce malnutrition in Colombia.

Meta-analysis evaluating music interventions for anxiety and pain in surgery.

BACKGROUND: This study aimed to evaluate anxiety and pain following perioperative music interventions compared with control conditions in adult patients. METHODS: Eleven electronic databases were searched for full-text publications of RCTs investigating the effect of music interventions on anxiety and pain during invasive surgery published between 1 January 1980 and 20 October 2016. Results and data were double-screened and extracted independently. Random-effects meta-analysis was used to calculate effect sizes as standardized mean differences (MDs). Heterogeneity was investigated in subgroup analyses and metaregression analyses. The review was registered in the PROSPERO database as CRD42016024921. RESULTS: Ninety-two RCTs (7385 patients) were included in the systematic review, of which 81 were included in the meta-analysis. Music interventions significantly decreased anxiety (MD -0·69, 95 per cent c.i. -0·88 to -0·50; P < 0·001) and pain (MD -0·50, -0·66 to -0·34; P < 0·001) compared with controls, equivalent to a decrease of 21 mm for anxiety and 10 mm for pain on a 100-mm visual analogue scale. Changes in outcome corrected for baseline were even larger: MD -1·41 (-1·89 to -0·94; P < 0·001) for anxiety and -0·54 (-0·93 to -0·15; P = 0·006) for pain. Music interventions provided during general anaesthesia significantly decreased pain compared with that in controls (MD -0·41, -0·64 to -0·18; P < 0·001). Metaregression analysis found no significant association between the effect of music interventions and age, sex, choice and timing of music, and type of anaesthesia. Risk of bias in the studies was moderate to high. CONCLUSION: Music interventions significantly reduce anxiety and pain in adult surgical patients.

Music Affects Rodents: A Systematic Review of Experimental Research.

Background: There is rapidly emerging interest in music interventions in healthcare. Music interventions are widely applicable, inexpensive, without side effects, and easy to use. It is not precisely known how they exert positive effects on health outcomes. Experimental studies in animal models might reveal more about the pathophysiological mechanisms of music interventions. Methods: We performed a systematic review of experimental research in rodents. The electronic databases EMBASE, Medline(ovidSP), Web-Of-Science, PsycINFO, Cinahl, PubMed publisher, Cochrane, and Google scholar were searched for publications between January 1st 1960 and April 22nd 2017. Eligible were English-written, full-text publications on experimental research in rodents comparing music vs. a control situation. Outcomes were categorized in four domains: brain structure and neuro-chemistry; behavior; immunology; and physiology. Additionally, an overview was generated representing the effects of various types of music on outcomes. Bias in studies was assessed with the SYRCLE Risk of Bias tool. A meta-analysis was not feasible due to heterogeneous outcomes and lack of original outcome data. Results: Forty-two studies were included. Music-exposed rodents showed statistically significant increases in neuro-chemistry, such as higher BDNF levels, as well as an enhanced propensity for neurogenesis and neuroplasticity. Furthermore, music exposure was linked with statistically significantly improved spatial and auditory learning, reduced anxiety-related behavior, and increased immune responses. Various statistically significant changes occurred in physiological parameters such as blood pressure and (para)sympathetic nerve activity following music interventions. The majority of studies investigated classical music interventions, but other types of music exerted positive effects on outcomes as well. The SYRCLE risk of bias assessment revealed unclear risk of bias in all studies. Conclusions: Music interventions seem to improve brain structure and neuro-chemistry; behavior; immunology; and physiology in rodents. Further research is necessary to explore and optimize the effect of music interventions, and to evaluate its effects in humans.

Social/economic costs and health-related quality of life in patients with juvenile idiopathic arthritis in Europe.

OBJECTIVE: The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with juvenile idiopathic arthritis (JIA) in Europe. METHODS: We conducted a cross-sectional study of patients with JIA from Germany, Italy, Spain, France, the United Kingdom, Bulgaria, and Sweden. Data on demographic characteristics, healthcare resource utilization, informal care, labor productivity losses, and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D-5L) questionnaire. RESULTS: A total of 162 patients (67 Germany, 34 Sweden, 33 Italy, 23 United Kingdom, 4 France, and 1 Bulgaria) completed the questionnaire. Excluding Bulgarian results, due to small sample size, country-specific annual health care costs ranged from €18,913 to €36,396 (reference year: 2012). Estimated direct healthcare costs ranged from €11,068 to €22,138; direct non-healthcare costs ranged from €7837 to €14,155 and labor productivity losses ranged from €0 to €8715. Costs are also shown to differ between children and adults. The mean EQ-5D index score for JIA patients was estimated at between 0.44 and 0.88, and the mean EQ-5D visual analogue scale score was estimated at between 62 and 79. CONCLUSIONS: JIA patients incur considerable societal costs and experience substantial deterioration in HRQOL in some countries. Compared with previous studies, our results show a remarkable increase in annual healthcare costs for JIA patients. Reasons for the increase are the inclusion of non-professional caregiver costs, a wider use of biologics, and longer hospital stays.

[Healing with art?]. / Beter met kunst?

Music and other forms of art are increasingly being integrated into hospitals. As well as the aesthetic value of art, more and more attention is being paid to its contribution to the healing of the patient. Scientific research indicates the possible benefits of specific art in healthcare facilities. Using this knowledge of the role and employability of surroundings and art in the healing of patients may be complementary to the high quality of care in the Netherlands. By means of proper, methodologically correct research, it is possible to investigate the use of different aspects of the patient's environment as simple, safe and low-cost measures in improving health and well-being of patients.

[Cost of Illness of HIV Patients under Anteretroviral Therapy in Germany - Results of the 48-Week Interim Analysis of the Prospective Multicentre Observational Study 'CORSAR']. / Krankheitskosten von HIV-Patienten unter antiretroviraler Therapie in Deutschland - Ergebnisse einer 48-Wochen-Interimsanalyse im Rahmen der prospektiven multizentrischen Kohortenstudie "CORSAR".

BACKGROUND: With the introduction of highly active combined antiretroviral therapy (c-ART) mortality and morbidity of HIV patients declined substantially. Earlier studies reported that c-ART was able to save health-care costs due to a reduction of other direct medical costs, particularly for inpatient treatments and concomitant medication. To date, analyses of costs and health-related quality of life (HRQOL) of patients under c-ART are lacking in Germany. Hence, this study aims to estimate the current cost of illness and HRQOL of HIV-patients under c-ART in different treatment lines. METHODS: A multicenter, prospective observational study was carried out in 12 specialised German centres for infectious diseases: 8 private practices/outpatient centres and 4 specialised hospitals offering both inpatient and outpatient services. Demographic, clinical and medication data were derived from patient records. Resource utilisation, information on productivity, out of pocket costs and HRQOL (EQ-5D) were collected every 12 weeks via a patient questionnaire. All costs were calculated based on price information from publicly accessible databases. RESULTS: N=1,154 patients were included in the analysis. Mean direct disease-related costs of -patients under c-ART amounted to 22,563 Euro/year. Patients beyond the 3(rd) line of treatment -incurred considerably higher costs 24,654 Euro/year. In the 1(st) treatment line, c-ART accounted for 83.2% of the total direct costs, in the 2(nd)/3(rd) line for 80.8% and in >3(rd) line for 83.4%, respectively. Indirect costs due to impaired productivity were higher in the 2(nd)/3(rd) treatment line (2,843 Euro) compared to the 1(st) (1,604 Euro) and >3(rd) (1,752 Euro) treatment lines, respectively. The average HRQOL (EQ-5D) varied between 0.77 (self-assessment via visual analogue scale) and 0.91 (utility score based on the German time trade-off tariff). CONCLUSIONS: Over the last decade, cost of illness of HIV patients under c-ART decreased slightly with average costs per year still being substantial. Main cost driver of overall costs is c-ART. There have been, however, noticeable shifts between different cost domains.

Self-assembled quantum dots in a nanowire system for quantum photonics.

Quantum dots embedded within nanowires represent one of the most promising technologies for applications in quantum photonics. Whereas the top-down fabrication of such structures remains a technological challenge, their bottom-up fabrication through self-assembly is a potentially more powerful strategy. However, present approaches often yield quantum dots with large optical linewidths, making reproducibility of their physical properties difficult. We present a versatile quantum-dot-in-nanowire system that reproducibly self-assembles in core-shell GaAs/AlGaAs nanowires. The quantum dots form at the apex of a GaAs/AlGaAs interface, are highly stable, and can be positioned with nanometre precision relative to the nanowire centre. Unusually, their emission is blue-shifted relative to the lowest energy continuum states of the GaAs core. Large-scale electronic structure calculations show that the origin of the optical transitions lies in quantum confinement due to Al-rich barriers. By emitting in the red and self-assembling on silicon substrates, these quantum dots could therefore become building blocks for solid-state lighting devices and third-generation solar cells.

Probing single-charge fluctuations at a GaAs/AlAs interface using laser spectroscopy on a nearby InGaAs quantum dot.

We probe local charge fluctuations in a semiconductor via laser spectroscopy on a nearby self-assembled quantum dot. We demonstrate that the quantum dot is sensitive to changes in the local environment at the single-charge level. By controlling the charge state of localized defects, we are able to infer the distance of the defects from the quantum dot with ±5 nm resolution. The results identify and quantify the main source of charge noise in the commonly used optical field-effect devices.

Inhibition of the hTERT promoter by the proto-oncogenic protein TAL1.

Telomerase activity, which has fundamental roles in development and carcinogenesis, strongly depends on the expression of human telomerase reverse transcriptase (hTERT), its catalytic subunit. In this report, we show that the basic helix-loop-helix factor, TAL1 (T-cell acute lymphoblastic leukemia 1), is a negative regulator of the hTERT promoter. Indeed, TAL1 overexpression leads to a decrease in hTERT mRNA abundance and hence to reduced telomerase activity. Conversely, suppression of TAL1 by RNA interference in Jurkat cells increases hTERT expression. Analysis by chromatin immunoprecipitation assays showed that TAL1 binds to the hTERT proximal promoter and recruits HDAC1. Considering the relationship recently established between TAL1 and the human T-cell leukemia virus type 1 (HTLV-1) Tax protein, which was confirmed in T lymphocyte clones derived from adult T-cell leukemia patients, we analyzed the effect of TAL1 with respect to the earlier characterized effects of Tax and HBZ (HTLV-1 basic leucine zipper) on hTERT expression. TAL1 was observed to reinforce the negative effect of Tax, whereas hTERT transactivation by the HBZ-JunD complex was repressed by TAL1 overexpression. Moreover, HBZ was found to induce proteasome-mediated degradation of TAL1. These observations support a model in which Tax and TAL1 by repressing hTERT would initially favor genomic instability, whereas expression of factors such as HBZ allows at a later stage an increase in hTERT production and consequently in telomerase activity.

Patient satisfaction and quality of life in cancer outpatients: results of the PASQOC study.

BACKGROUND: Satisfaction with care and quality of life (QoL) are indicative of the quality of care of cancer patients. The purpose of this study was to lay a cornerstone for patient-centred quality management by assessing the current status of satisfaction with care and QoL among oncological outpatients in Germany, and by identifying the key factors that determine a patient's willingness to recommend a medical facility. PATIENTS AND METHODS: A self-constructed and validated patient satisfaction questionnaire plus the SF-36 were distributed to a random sample of 3384 cancer patients who presented at 24 investigators' offices nationwide within a defined recruiting period and who met the inclusion criteria. The return rate was 81.9% (n=2772). A total of 2659 (78.6%) questionnaires were evaluable. The most common cancer types were breast (22.9%) and intestine (19.8%). RESULTS: Overall satisfaction was high, but specific reporting questions revealed many areas for improvement such as shared decision making, doctor-patient communication and organization of care. QoL was significantly impaired in many domains. Patient-provider relationship, facility setting and information on diagnosis and treatment options are major determinants of a patient's willingness to recommend a facility to a friend or relative if needed. CONCLUSIONS: This multicentre study focusing on patient perspectives highlights that, although the overall degree of satisfaction was quite high, there are numerous areas for improvement.

Neurotoxicity of exposures to aluminium welding fumes in the truck trailer construction industry.

The aim of the study was to examine aluminium welders for central nervous changes due to the exposure to aluminium containing welding fumes. A group of 44 aluminium welders in the train body and truck trailer construction industry (mean age: 43 years) with an average of 11.4 years of occupational exposure to aluminium welding fumes and a control group of 37 production workers (mean age: 40 years) of the same plants participated in this longitudinal study. Medical and neuropsychological examinations were performed in 1999 and 2001. Performance was measured with computerised (EURO-NES, motor performance, simple reaction time) and non-computerised test systems (verbal intelligence, standard progressive matrices, trail making, block design) and symptoms with a modified version of the questionnaire Q16. Data was analysed by multivariate analysis of variance including age, education, and alcohol marker as covariates (MANCOVA). The pre-/postshift average Al-urine concentrations of welders were in the range of 130-153µg/l. Welders showed significantly poorer performance in symbol-digit substitution, block design, and to some extent in switching attention. However, motor performance and other measures did not differ between welders and controls. Summing up, the results give no clear hints on neurological changes in Al-welders.

Longitudinal study examining the neurotoxicity of occupational exposure to aluminium-containing welding fumes.

OBJECTIVES: The neurotoxicity of occupational exposure to aluminium (Al)-containing welding fumes has been discussed with controversial results. The aim of the longitudinal study was to examine a group of Al welders for significant central nervous changes in comparison with a non-exposed cohort. METHODS: A group of 98 Al welders (mean age 37 years) in the car-body construction industry, with a median of 6 years of occupational exposure to Al welding fumes, and an education-matched, gender-matched, age-matched control group of 50 car-production workers (mean age 36 years) at the same plant, were included in this longitudinal study. Two cross-sectional studies were done in 1999 and 2001. In the second cross-sectional study 97 welders and 50 controls could be examined. The examination programme consisted, for example, of a standardised anamnesis, focussing on occupational history, education, illnesses, medication, accidents and current alcohol consumption, a physical examination that included neurological status, and the assessment of Al concentration in plasma and urine. The neurobehavioral methods included a symptom questionnaire, modified Q16, and computerised and non-computerised tests: psychomotor performance (steadiness, line tracing, aiming, tapping), verbal intelligence (WST), simple reaction time, digit span, block design (HAWIE), symbol-digit substitution, digit span, switching attention (European neurobehavioral evaluation system, EURO-NES), and standard progressive matrices. The data were analysed by multivariate analysis of covariance (MANCOVA) for repeated measurements with covariates age, education, and carbohydrate-deficient transferrin in plasma (CDT). RESULTS. The median Al urine concentration (mean preshift/postshift) was 52.4 microg/g creatinine (2001) and 57.6 microg/g creatinine (1999). Median respirable air dust was 0.67 mg/m(3) (2001) and 0.47 mg/m(3) (1999). Welders and controls did not report significantly more symptoms in the modified Q16. Furthermore, no significant differences in psychomotor performance and other neurobehavioral tasks, except for reaction time, were seen between welders and non-welders. Regression analyses reveal a significant relationship between reaction time and Al excretion in urine that was confounded by other factors. CONCLUSIONS: At present the outcome for reaction time has to be interpreted as a single result. However, as the modified Q16 questionnaire and the rest of the psychomotor performance showed no significant changes, the next cross-sectional study, in 2003, will provide further information on which a final conclusion can be based.

ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy.

AIMS/HYPOTHESIS: It was the aim of our study to investigate the influence of a selective ET-A receptor antagonist LU 135252 alone and in combination with the ACE-inhibitor, trandolapril on podocyte number and morphology in streptozotocin diabetic rats. METHODS: Male Sprague-Dawley rats were injected with 65 mg streptozotocin i.v. and subsequently developed diabetes. Animals were left untreated or received daily either trandolapril (0.3 mg/kg body weight), LU 135252 (50 mg/kg body weight) or a combination of both. After 6 months the experiment was terminated. Glomerular geometry and cellularity were assessed by stereological techniques. Protein expression of TGF-beta, ET-1, PDGF-AB, fibronectin, desmin and alpha-smooth muscle cell actin was investigated by immunohistochemistry. RESULTS: The mean number of podocytes per glomerulus was lower (86+/-17 vs. 138+/-25; p<0.05) and mean podocyte volume was higher in untreated diabetic animals than in non-diabetic controls. Only ACE-i alone and in combination, but not ET(A)-RB alone prevented loss of podocytes and podocyte hypertrophy. In diabetic rats, increased numbers of PCNA positive and p27(kip1) positive cells (mainly podocytes) were reduced by all treatments, but only ACE-i decreased numbers of desmin positive podocytes and tubulointerstitial expression of TGF-beta. Albuminuria was increased in untreated diabetes and was prevented only by ACE-i and combination treatment. CONCLUSION/INTERPRETATION: Podocyte hypertrophy and degeneration is an early event in diabetic nephropathy leading to a loss of podocytes. Treatment with an ACE-i, but not with an ET(A)-RB, prevented the development of albuminuria as well as damage and loss of podocytes. The well known anti-proteinuric effect of ACE-i is presumably due at least in part to conservation of podocyte structure. Increased plasma endothelin-1 (ET-1) concentrations and urine excretion of ET-1 have been documented in patients with diabetes and proteinuria [1]. It has been shown that experimental diabetes mellitus increases renal ET-1 gene transcription [2]. To assess the relevance of the ET-system in the pathogenesis of renal structural changes in the model of the STZ-induced diabetic rat we compared the effect of an ET(A)-receptor specific antagonist with the well known beneficial effect of an ACE-i, especially on podocyte cell number and morphology.

N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning.

The present study demonstrates that impairments of spatial learning and hippocampal long-term potentiation in rats chronically exposed to lead are associated with changes in gene and protein expression of N-methyl-D-aspartate receptor subunits. Rats exposed to 750 and 1500 ppm lead acetate were found to exhibit deficits in acquisition of a water maze spatial learning task. Furthermore, lead-exposed rats show dose-dependent reductions in the maintenance of in vivo hippocampal long-term potentiation induced in entorhinal cortex-dentate gyrus synapses. We found an unexpected, but significant (P<0.05), correlation between spatial learning and long-term potentiation when control and lead-exposed rats were analysed as a single, combined population. Dentate gyrus NR1 subunit messenger RNA was reduced 18% and 28% by exposure to 750 and 1500 ppm lead acetate, respectively. NR2A subunit messenger RNA was reduced 18% but only in the dentate gyrus of rats exposed to 1500 ppm lead acetate. No significant changes in dentate NR2B messenger RNA expression were measured in either of the lead-exposed groups. NR1 subunit protein was reduced 24% and 58% in hippocampal homogenates from rats exposed to 750 and 1500 ppm lead acetate. In contrast, no changes in NR2A or NR2B subunit protein were observed in the same hippocampal homogenates. These data show that reductions of specific N-methyl-D-aspartate receptor subunits are associated with deficits of both hippocampal long-term potentiation and spatial learning, induced in rats by chronic exposure to environmentally relevant levels of lead. These findings strongly suggest that the effects of lead on N-methyl-D-aspartate receptors may be the mechanistic basis for lead-induced deficits in cognitive function.

Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity.

The peripheral benzodiazepine receptor (PBR) is currently used as a marker of inflammation and gliosis following brain injury. Previous reports suggest that elevated PBR levels in injured brain tissue are specific to activated microglia and infiltrating macrophages. We have produced hippocampal lesions using the neurotoxicant trimethyltin (TMT) to examine the cellular and subcellular nature of the PBR response. Degenerating, argyrophilic pyramidal neurons were observed in the hippocampus at 2 and 14 days after TMT exposure. Reactive microglia were also evident at both times with a maximal response observed at 14 days, subsiding by 6 weeks. Astrocytosis was observed at 14 days and 6 weeks, but not 2 days, after TMT administration, suggesting that the onset of the astroglia response is delayed, but more persistent, compared with microgliosis. Morphological evidence from [3H]PK11195 microautoradiography and PBR immunohistochemistry indicates that both astrocytes and microglia are capable of expressing high levels of PBR after injury. This was confirmed by double labeling of either Griffonia simplicifolia isolectin B4, a microglial-specific marker, or glial fibrillary acidic protein, an astrocyte-specific protein with PBR fluorescence immunohistochemistry. These results demonstrate that PBR expression is increased after brain injury in both activated microglia and astrocytes. Our findings also provide the first evidence for in situ nuclear localization of PBR in glial cells.