Whole-Body Hypothermia vs Targeted Normothermia for Neonates With Mild Encephalopathy: A Multicenter Pilot Randomized Clinical Trial.

Importance: Although whole-body hypothermia is widely used after mild neonatal hypoxic-ischemic encephalopathy (HIE), safety and efficacy have not been evaluated in randomized clinical trials (RCTs), to our knowledge. Objective: To examine the effect of 48 and 72 hours of whole-body hypothermia after mild HIE on cerebral magnetic resonance (MR) biomarkers. Design, Setting, and Participants: This open-label, 3-arm RCT was conducted between October 31, 2019, and April 28, 2023, with masked outcome analysis. Participants were neonates at 6 tertiary neonatal intensive care units in the UK and Italy born at or after 36 weeks' gestation with severe birth acidosis, requiring continued resuscitation, or with an Apgar score less than 6 at 10 minutes after birth and with evidence of mild HIE on modified Sarnat staging. Statistical analysis was per intention to treat. Interventions: Random allocation to 1 of 3 groups (1:1:1) based on age: neonates younger than 6 hours were randomized to normothermia or 72-hour hypothermia (33.5 °C), and those 6 hours or older and already receiving whole-body hypothermia were randomized to rewarming after 48 or 72 hours of hypothermia. Main Outcomes and Measures: Thalamic N-acetyl aspartate (NAA) concentration (mmol/kg wet weight), assessed by cerebral MR imaging and thalamic spectroscopy between 4 and 7 days after birth using harmonized sequences. Results: Of 225 eligible neonates, 101 were recruited (54 males [53.5%]); 48 (47.5%) were younger than 6 hours and 53 (52.5%) were 6 hours or older at randomization. Mean (SD) gestational age and birth weight were 39.5 (1.1) weeks and 3378 (380) grams in the normothermia group (n = 34), 38.7 (0.5) weeks and 3017 (338) grams in the 48-hour hypothermia group (n = 31), and 39.0 (1.1) weeks and 3293 (252) grams in the 72-hour hypothermia group (n = 36). More neonates in the 48-hour (14 of 31 [45.2%]) and 72-hour (13 of 36 [36.1%]) groups required intubation at birth than in the normothermic group (3 of 34 [8.8%]). Ninety-nine neonates (98.0%) had MR imaging data and 87 (86.1%), NAA data. Injury scores on conventional MR biomarkers were similar across groups. The mean (SD) NAA level in the normothermia group was 10.98 (0.92) mmol/kg wet weight vs 8.36 (1.23) mmol/kg wet weight (mean difference [MD], -2.62 [95% CI, -3.34 to -1.89] mmol/kg wet weight) in the 48-hour and 9.02 (1.79) mmol/kg wet weight (MD, -1.96 [95% CI, -2.66 to -1.26] mmol/kg wet weight) in the 72-hour hypothermia group. Seizures occurred beyond 6 hours after birth in 4 neonates: 1 (2.9%) in the normothermia group, 1 (3.2%) in the 48-hour hypothermia group, and 2 (5.6%) in the 72-hour hypothermia group. Conclusions and Relevance: In this pilot RCT, whole-body hypothermia did not improve cerebral MR biomarkers after mild HIE, although neonates in the hypothermia groups were sicker at baseline. Safety and efficacy of whole-body hypothermia should be evaluated in RCTs. Trial Registration: ClinicalTrials.gov Identifier: NCT03409770.

Hypoglycaemia and hyperglycaemia in neonatal encephalopathy: a systematic review and meta-analysis.

IMPORTANCE: Although hypoglycaemia and hyperglycaemia represent the most common metabolic problem in neonates, there is still uncertainty regarding the effects of glucose homoeostasis on the neurological outcomes of infants with neonatal encephalopathy (NE). OBJECTIVE: To systematically investigate the association between neonatal hypoglycaemia and hyperglycaemia with adverse outcome in children who suffered from NE. STUDY SELECTION: We searched Pubmed, Embase and Web of Science databases to identify studies which reported prespecified outcomes and compared infants with NE who had been exposed to neonatal hypoglycaemia or hyperglycaemia with infants not exposed. DATA ANALYSIS: We assessed the risk of bias (ROBINS-I), quality of evidence (Grading of Recommendations, Assessment, Development and Evaluation (GRADE)) for each of the studies. RevMan was used for meta-analysis (inverse variance, fixed effects). MAIN OUTCOME: Death or neurodevelopmental outcomes at 18 months of age or later. RESULTS: 82 studies were screened, 28 reviewed in full and 12 included. Children who were exposed to neonatal hypoglycaemia had higher odds of neurodevelopmental impairment or death (6 studies, 685 infants; 40.6% vs 25.4%; OR=2.17, 95% CI 1.46 to 3.25; p=0.0001). Neonatal exposure to hyperglycaemia was associated with death or neurodisability at 18 months or later (7 studies, 807 infants; 46.1% vs 28.0%; OR=3.07, 95% CI 2.17 to 4.35; p<0.00001). These findings were confirmed in the subgroup analysis, which included only the infants who underwent therapeutic hypothermia. CONCLUSIONS: These data suggest that neonatal hypoglycaemia and hyperglycaemia may be associated with the neurodevelopmental outcome later on in infants with NE. Further studies with long-term follow-up are needed to optimise the metabolic management of these high-risk infants. PROSPERO REGISTRATION NUMBER: CRD42022368870.

Bloodstream Infection Due to a VIM-Metallo-ß-Lactamase-Producing Klebsiella pneumoniae Treated with Cefiderocol in a Preterm Newborn.

BACKGROUND: The prevalence of certain multidrug-resistant organisms (MDROs), especially Gram-negative bacteria, is dramatically increasing in patient care settings, including pediatric and neonatal units. However, most of the new drugs available for the treatment of MDROs have not yet been studied in children and newborns. CASE REPORT: We report the clinical case of a preterm neonate, born at 31 weeks gestation + 1 day of age by emergency Cesarean Section (CS), with a bloodstream infection (BSI) due to a Verona integron-borne metallo-ß-lactamase (VIM)-producing Klebsiella pneumoniae. We successfully treated the infection with cefiderocol in an off-label regimen at the following dose: loading dose 60 mg/kg and then 40 mg/kg every 8 h in extended infusion for 9 days. The baby showed a quick clinical and biochemical improvement and tolerated well the treatment. Follow-up blood cultures at 48 h after the start of cefiderocol were negative. CONCLUSIONS: Antimicrobial-resistant pathogens are of increasing concern in neonatal settings. More studies in this unique population are necessary to better describe the pharmacokinetic and pharmacodynamic profile of the new drugs against MDROs, such as cefiderocol, and to define a proper effective dose.

Magnetic Resonance Biomarkers and Neurological Outcome of Infants with Mild Hypoxic-Ischaemic Encephalopathy Who Progress to Moderate Hypoxic-Ischaemic Encephalopathy.

BACKGROUND: There is increasing concern that infants with mild hypoxic-ischaemic encephalopathy (HIE) may develop seizures and progress to moderate HIE beyond the therapeutic window for cooling. OBJECTIVE: The aim of this study was to examine the effect of therapeutic hypothermia on magnetic resonance imaging (MRI) biomarkers and neurological outcomes in infants with mild HIE and seizures within 24 h after birth. METHODS: This study shows an observational cohort study on 366 (near)-term infants with mild HIE and normal amplitude-integrated electroencephalography background. RESULTS: Forty-one infants showed progression (11.2%); 29/41 (70.7%) were cooled. Infants with progression showed cerebral metabolite perturbations and higher white matter injury scores compared to those without in both cooled and non-cooled groups (p = 0.001, p = 0.02). Abnormal outcomes were seen in 5/12 (42%) non-cooled and 7/29 (24%) cooled infants with progression (p = 0.26). CONCLUSIONS: Early biomarkers are needed to identify infants with mild HIE at risk of progression. Mild HIE infants with progression showed a higher incidence of brain injury and abnormal outcomes.

Characterization and Comparison of Ocular Surface Microbiome in Newborns.

The ocular microbiome is of fundamental importance for immune eye homeostasis, and its alteration would lead to an impairment of ocular functionality. Little evidence is reported on the composition of the ocular microbiota of term infants and on the impact of antibiotic prophylaxis. METHODS: A total of 20 conjunctival swabs were collected from newborns at birth and after antibiotic treatment. Samples were subjected to 16S rRNA sequencing via system MiSeq Illumina. The data were processed with the MicrobAT software and statistical analysis were performed using two-way ANOVA. RESULTS: Antibiotic prophylaxis with gentamicin altered the composition of the microbiota. In detail, a 1.5- and 2.01-fold reduction was recorded for Cutibacterium acnes (C. acnes) and Massilia timonae (M. timonae), respectively, whereas an increase in Staphylococcus spp. of 6.5 times occurred after antibiotic exposure. CONCLUSIONS: Antibiotic prophylaxis altered the ocular microbiota whose understanding could avoid adverse effects on eye health.

Impact of intrauterine growth restriction on cerebral and renal oxygenation and perfusion during the first 3 days after birth.

Intrauterine growth restriction (IUGR) is associated with a higher incidence of perinatal complications as well as cardiovascular and renal diseases later on. A better insight into the disease mechanisms underlying these sequalae is important in order to identify which IUGR infants are at a higher risk and find strategies to improve their outcome. In this prospective case-control study we examined whether IUGR had any effect on renal and cerebral perfusion and oxygen saturation in term neonates. We integrated near-infrared spectroscopy (NIRS), echocardiographic, Doppler and renal function data of 105 IUGR infants and 105 age/gender-matched controls. Cerebral and renal regional oxygen saturation values were measured by NIRS during the first 12 h after birth. Echocardiography alongside Doppler assessment of renal and anterior cerebral arteries were performed at 6, 24, 48 and 72 h of age. Glomerular and tubular functions were also assessed. We found a left ventricular dysfunction together with a higher cerebral oxygen saturation and perfusion values in the IUGR group. IUGR term infants showed a higher renal oxygen saturation and a reduced oxygen extraction together with a subclinical renal damage, as indicated by higher values of urinary neutrophil gelatinase-associated lipocalin and microalbumin. These data suggest that some of the haemodynamic changes present in growth-restricted foetuses may persist postnatally. The increased cerebral oxygenation may suggest an impaired transition to normal autoregulation as a consequence of intra-uterine chronic hypoxia. The higher renal oxygenation may reflect a reduced renal oxygen consumption due to a subclinical kidney damage.

Continuous glucose monitoring profile during therapeutic hypothermia in encephalopathic infants with unfavorable outcome.

BACKGROUND: The relation between glucose homeostasis and outcome in hypoxic-ischemic encephalopathy (HIE) is unclear. To investigate whether glucose abnormalities assessed by using continuous interstitial glucose monitoring (CGM) correlate with later neurological outcomes in HIE. METHODS: Prospective cohort study recruiting full-term neonates who received therapeutic hypothermia for HIE. CGM devices were placed soon after birth and recorded glucose profile for 3 days. The association between hypoglycemia (≤50 mg/dL), hyperglycemia (>144 mg/dL) and primary outcome defined as death or moderate or severe disability was examined with generalized estimating equations adjusted for Apgar scores, umbilical artery pH and base deficit. Neurodevelopmental outcome was assessed between 18 and 24 months. RESULTS: Fifty-four neonates had outcome data available for the analysis; 19 of them (35%) had adverse outcome. Longer duration of hypoglycemia (OR 7.1, 95% CI 1.8-20.3, P < 0.001) and hyperglycemia (OR 5.4, 95% CI 1.6-15.7, P < 0.001), a greater area under the hypoglycemic (OR 2.6, 95% CI 1.4-4.6, P = 0.04) and hyperglycemic (OR 6.4, 95% CI 1.9-16.3, P < 0.001) curve were significantly associated with adverse outcomes. CONCLUSION: Both hyper and hypoglycemia may be associated with adverse outcome in neonates with HIE. Future studies are needed to assess their prognostic association with neurological outcome. IMPACT: Glucose abnormalities during therapeutic hypothermia are associated with later neurological outcomes.Increased glucose variability correlates to the neurological outcome between 18 and 24 months.This study provides the first data on the continuous glucose profile in a group of HIE infants followed up to 2 years of age.Glucose homeostasis represents a key point in the management of HIE patients.Further research is needed to find the appropriate glycemic target in this population.

False-positive troponin I elevation in a newborn with neonatal encephalopathy.

Serum biomarkers of myocardial damage are commonly used in babies after perinatal asphyxia. We present a case report of a persistently troponin I elevation without evidence of clinical or instrumental signs of myocardial ischaemia in a baby with perinatal asphyxia. When the blood was mixed with polyethylene glycol we found that the troponin I levels were falsely elevated due to interfering antibodies. This case shows that analytical errors may still occur despite modern immunoassay systems and underlines the need for further investigations to identify false-positive values in case of disagreement between clinical conditions and laboratory values.

Neuropsychiatric profile of paediatric hypothalamic hamartoma: systematic review and case series.

AIM: To evaluate neuropsychiatric comorbidities in children and adolescents with hypothalamic hamartoma. METHOD: We retrospectively analysed case notes for all individuals with hypothalamic hamartoma referred to Great Ormond Street Hospital, London, between 2000 and 2016. In addition, a systematic review aiming to identify all previous paediatric case series was performed. Psychiatric symptoms, demographics, physical comorbidities, and cognitive functioning were recorded for all cases where possible. Analyses were performed to determine which factors were associated with psychopathology and potential mechanisms investigated. RESULTS: Forty-six cases were included in the case series (28 males, 18 females; mean age at assessment 11y 8mo [1y 11mo-16y 11mo, SD 4y 0mo]). Twenty-nine papers representing data from 264 cases met inclusion criteria for the systematic review. Overall, at least 50% of cases presented with psychopathology. Epilepsy, intellectual disability, and male sex were associated with externalizing disorders (attention-deficit/hyperactivity disorder, conduct and oppositional defiance disorders, and rage attacks). Intellectual disability mediated the effects of epilepsy on externalizing psychopathology. No factors were associated with internalizing disorders (anxiety and depressive disorders), although these were not well reported. INTERPRETATION: Psychiatric comorbidities are highly prevalent in the presentation of paediatric hypothalamic hamartoma. The aetiology of psychopathology comprises a range of interacting biological and psychosocial factors with particular influence from epilepsy. Further research is required to achieve an evidence base for treatment. WHAT THIS PAPER ADDS: Over half of children with hypothalamic hamartoma present with psychiatric comorbidity. Externalizing and internalizing disorders are present in approximately 60% and 30% of children with hypothalamic hamartomas respectively. Epilepsy and male sex are associated with externalizing psychopathology. Intellectual disability mediates the association between epilepsy and externalizing symptoms. No clear associations are evident for internalizing disorders or precocious puberty.

PERFIL NEUROPSIQUIÁTRICO DEL HAMARTOMA HIPOTALÁMICO EN PEDIATRÍA: REVISIÓN SISTEMÁTICA Y SERIE DE CASOS: OBJETIVO: Evaluar las comorbilidades neuropsiquiátricas en niños y adolescentes con hamartoma hipotalámico. MÉTODO: En este estudio analizamos retrospectivamente las notas de los casos de todos los individuos con hamartoma hipotalámicos referidos al Great Ormond Street Hospital, London, entre el 2000 y 2016. Además, realizamos una revisión bibliográfica sistemática dirigida a identificar la serie de casos pediátricos. Síntomas psiquiátricos, demográfico, comorbilidades físicas y funcionamiento cognitivo fueron recolectados en todos los casos posibles.Se efectuaron análisis para determinar qué factores se asociaron con psicopatología y se investigaron mecanismos potenciales. RESULTADOS: En total 46 casos fueron incluidos en la serie de casos (28 masculinos, 18 femeninos, media de edad a la evaluación 11 años y 8 meses, DS 4 años y 0 mes). La revisión bibliográfica identifico 29 artículos describiendo 264 casos que reunieron criterios de inclusión para la extracción de datos. En total, al menos 50% de casos presentaban psicopatología. Epilepsia, discapacidad intelectual, y sexo masculino fueron asociados con desórdenes externos (déficit de atención con hiperactividad, desórdenes conductuales y oposicional desafiante, ataques de furia). Ningún factor fue asociado con la internalización de desórdenes neuropsiquiátricos (desórdenes de ansiedad y depresión), aunque éstos no fueron bien reportados. INTERPRETACIÓN: Las comorbilidades psiquiátricas son altamente prevalentes en la presentación del hamartoma hipotalámico pediátrico. La etiología de la psicopatología comprende un rango de interacciones biológicas y factores psicosociales con particular influencia de la epilepsia. Se requiere más información de investigación para reunir evidencia científica que guie el tratamiento.

PERFIL NEUROPSIQUIÁTRICO DO HAMARTOMA HIPOTALÂMICO PEDIÁTRICO: REVISÃO SISTEMÁTICA E SÉRIE DE CASOS: OBJETIVO: Avaliar comorbidades neuropsiquiátricas em crianças e adolescentes com hamartoma hipotalâmico. MÉTODO: Nós analisamos retrospectivamente os registros de casos de todos os indivíduos encaminhados para o Hospital Great Ormond Street, Londres, entre 2000 e 2016. Além disso, uma revisão sistemática visando identificar todos os casos pediátricos prévios foi realizada. Sintomas psiquiátricos, dados demográficos, comorbidades físicas, e funcionamento cognitivo foram registrados para todos os casos em que foi possível. Análises foram realizadas para determinar quais fatores se associavam com psicopatologia e potenciais mecanismos foram investigados. RESULTADOS: Quarenta e seis casos foram incluídos na série de casos (28 do sexo masculino, 18 do sexo feminino; média de idade na avaliação 11a 8m (1a 11m-16a 11m, DP 4a 0m). Vinte e nove artigos representando dados de 264 casos atenderam aos critérios de inclusão para a revisão sistemática. No total, pelo menos 50% dos casos apresentaram psicopatologia. Epilepsia, deficiência intelectual, e sexo masculino eram associados com desordens externalizantes (transtorno de déficit de atenção e hiperatividade, transtornos de conduta e de desafio oposicional, e ataques de raiva). A deficiência intelectual mediou os efeitos da epilepsia e da psicopatologia externalizante. Nenhum fator foi associado com transtornos internalizantes (ansiedade e transtornos depressivos), embora estes não tenham sido bem reportados. INTERPRETAÇÃO: Comorbidades psiquiátricas são altamente prevalentes na apresentação do hamartoma hipotalâmico pediátrico. A etiologia da psicopatologia envolve uma variedade de fatores biológicos e psicossociais que interagem, com particular influência da epilepsia. Mais pesquisas são necessárias para se atingir uma base de evidências para o tratamento.

Electrocardiographic and echocardiographic changes during therapeutic hypothermia in encephalopathic infants with long-term adverse outcome.

AIM: To assess the electrocardiography and echocardiography changes during therapeutic hypothermia and rewarming period in encephalopathic infants with long-term adverse neurological outcome. METHODS: Prospective multicentre longitudinal study. We included 64 consecutive infants with moderate or severe hypoxic ischaemic encephalopathy undergoing therapeutic hypothermia who had 18-24 month-outcome data. We analysed electrocardiography and heart rate changes before, during and after therapeutic hypothermia. Superior vena cava flow, left ventricular cardiac output and stroke volume were studied using echocardiography during and immediately after therapeutic hypothermia. An abnormal outcome was defined as death or moderate/severe disability at 18-24 months. RESULTS: Neonates with higher superior vena cava flow pre-rewarming had significantly higher odds of documented long-term adverse outcome when compared to newborns with good outcome (OR 1.57; 95%CI, 1.1-1.78; p = 0.01 after adjustment). QTc and RR intervals were significantly longer at 12, 24, 36 and 48 h in infants with good outcome compared with those with adverse outcome (p < 0.001). During therapeutic hypothermia, infants with poor outcome had a higher heart rate at 12, 24, 36, 48, 60 h after birth compared with those with good outcome (p < 0.001). From 36 h on, heart rate gradually increased and RR and QTc intervals progressively shortened with values back to normal after rewarming. CONCLUSIONS: Infants with hypoxic ischaemic encephalopathy who have adverse neurological outcome show a preferential cerebral blood flow redistribution during therapeutic hypothermia. Infants with poor outcome have higher heart rate and shorter RR and QTc intervals during therapeutic hypothermia.

Continuous subcutaneous insulin infusion in preschool children: butt or tummy, which is the best infusion set site?

BACKGROUND: Choosing the right infusion set site can be an important factor in obtaining good glycemic control, especially in very young children. In an attempt to identify the best infusion site, we performed a crossover study in six preschool children with type 1 diabetes using insulin pump therapy. SUBJECTS AND METHODS: We enrolled six patients 5.2±0.7 years old (range, 4-6 years), with type 1 diabetes for more than 1.5 years, using insulin pump therapy for at least 6 months. For each patient, body mass index, glycated hemoglobin, and all data downloaded from the system were evaluated on two occasions: the first with the infusion set placed on the buttock and the second on the abdomen, each for 3 days. The order of infusion set placement was randomized. Mean capillary blood glucose, mean continuous glycemia, mean area under the curve (AUC) using the trapezoidal rule for both >140 mg/dL and <70 mg/dL, insulin daily dose, carbohydrate/insulin ratio, total basal insulin, total bolus insulin, and mean amplitude of glucose excursions (MAGE) were evaluated. RESULTS: Mean glycemic values, mean AUC >140 mg/dL, and MAGE were significantly lower when the infusion set was placed on the buttock versus the abdomen (144.6±31.9 mg/dL vs. 166.0±34.8 mg/dL [P=0.000], 28.4±18.3% vs. 48.8±28.2% [P=0.000], and 32±10 vs. 60±15 mg/dL [P<0.001], respectively), whereas mean AUC <70 mg/dL was higher (1.47±2.77% vs. 0.87±1.03% [P<0.001]). CONCLUSIONS: The present findings suggest that preschool children with type 1 diabetes using insulin pump therapy could benefit from inserting the infusion set in the buttock instead of the abdomen.

Small renal size in newborns with spina bifida: possible causes.

BACKGROUND: Previous studies reported that children with neural tube defects, but without any history of intrinsic renal diseases, have small kidneys when compared with age-matched standard renal growth. The aim of this study was to investigate the possible causes of small renal size in children with spina bifida by comparing growth hormone deficiency, physical limitations and hyperhomocysteinemia. METHODS: The sample included 187 newborns with spina bifida. Renal sizes in the patients were assessed by using maximum measurement of renal length and the measurements were compared by using the Sutherland monogram. According to the results, the sample was divided into two groups--a group of 120 patients with small kidneys (under the third percentile) and a control group of 67 newborns with normal kidney size. Plasma total homocysteine was investigated in mothers and in their children. Serum insulin-like growth factor-1 (IGF-1) levels were measured. RESULTS: Serum IGF-1 levels were normal in both groups. Children and mothers with homocysteine levels >10 µmol/l were more than twice as likely to have small kidneys and to give to birth children with small kidneys, respectively, compared with newborns and mothers with homocysteine levels <10 µmol/l. An inverse correlation was also found between the homocysteine levels of mothers and kidney sizes of children (r = - 0.6109 P ≤ 0.01). CONCLUSIONS: It is highly important for mothers with hyperhomocysteinemia to be educated about benefits of folate supplementation in order to reduce the risk of small renal size and lower renal function in children.

Identification of candidate children for maturity-onset diabetes of the young type 2 (MODY2) gene testing: a seven-item clinical flowchart (7-iF).

MODY2 is the most prevalent monogenic form of diabetes in Italy with an estimated prevalence of about 0.5-1.5%. MODY2 is potentially indistinguishable from other forms of diabetes, however, its identification impacts on patients' quality of life and healthcare resources. Unfortunately, DNA direct sequencing as diagnostic test is not readily accessible and expensive. In addition current guidelines, aiming to establish when the test should be performed, proved a poor detection rate. Aim of this study is to propose a reliable and easy-to-use tool to identify candidate patients for MODY2 genetic testing. We designed and validated a diagnostic flowchart in the attempt to improve the detection rate and to increase the number of properly requested tests. The flowchart, called 7-iF, consists of 7 binary "yes or no" questions and its unequivocal output is an indication for whether testing or not. We tested the 7-iF to estimate its clinical utility in comparison to the clinical suspicion alone. The 7-iF, in a prospective 2-year study (921 diabetic children) showed a precision of about the 76%. Using retrospective data, the 7-iF showed a precision in identifying MODY2 patients of about 80% compared to the 40% of the clinical suspicion. On the other hand, despite a relatively high number of missing MODY2 patients, the 7-iF would not suggest the test for 90% of the non-MODY2 patients, demonstrating that a wide application of this method might 1) help less experienced clinicians in suspecting MODY2 patients and 2) reducing the number of unnecessary tests. With the 7-iF, a clinician can feel confident of identifying a potential case of MODY2 and suggest the molecular test without fear of wasting time and money. A Qaly-type analysis estimated an increase in the patients' quality of life and savings for the health care system of about 9 million euros per year.

Reversible disruption of pre-pulse inhibition in hypomorphic-inducible and reversible CB1-/- mice.

Although several genes are implicated in the pathogenesis of schizophrenia, in animal models for such a severe mental illness only some aspects of the pathology can be represented (endophenotypes). Genetically modified mice are currently being used to obtain or characterize such endophenotypes. Since its cloning and characterization CB1 receptor has increasingly become of significant physiological, pharmacological and clinical interest. Recently, its involvement in schizophrenia has been reported. Among the different approaches employed, gene targeting permits to study the multiple roles of the endocannabinoid system using knockout ((-/-)) mice represent a powerful model but with some limitations due to compensation. To overcome such a limitation, we have generated an inducible and reversible tet-off dependent tissue-specific CB1(-/-) mice where the CB1R is re-expressed exclusively in the forebrain at a hypomorphic level due to a mutation (IRh-CB1(-/-)) only in absence of doxycycline (Dox). In such mice, under Dox(+) or vehicle, as well as in wild-type (WT) and CB1(-/-), two endophenotypes motor activity (increased in animal models of schizophrenia) and pre-pulse inhibition (PPI) of startle reflex (disrupted in schizophrenia) were analyzed. Both CB1(-/-) and IRh-CB1(-/-) showed increased motor activity when compared to WT animals. The PPI response, unaltered in WT and CB1(-/-) animals, was on the contrary highly and significantly disrupted only in Dox(+) IRh-CB1(-/-) mice. Such a response was easily reverted after either withdrawal from Dox or haloperidol treatment. This is the first Inducible and Reversible CB1(-/-) mice model to be described in the literature. It is noteworthy that the PPI disruption is not present either in classical full CB1(-/-) mice or following acute administration of rimonabant. Such a hypomorphic model may provide a new tool for additional in vivo and in vitro studies of the physiological and pathological roles of cannabinoid system in schizophrenia and in other psychiatric disorders.

Association between exposure to secondhand smoke and sleep bruxism in children: a randomised control study.

BACKGROUND: Exposure to secondhand smoke (SHS) is a serious public health threat and represents a preventable cause of morbidity among children. Sleep bruxism is characterised by teeth grinding or clenching movements during sleep and may begin in adulthood as well as in childhood. OBJECTIVES: To investigate the association between SHS exposure and sleep bruxism in children. METHODS: Sleep bruxism was investigated in 498 children (mean age: 9.2±1.9). Family members were interviewed and asked whether they smoked in the presence of their children. Children were classified according to their exposure to SHS into heavily, moderately, lightly and occasionally exposed. Children with sleep bruxism and exposed to SHS were randomly divided into two groups: children in group 1 were not exposed to SHS for 6 months, whereas children in group 2 were. RESULTS: Thirty-one per cent of the children under investigation suffered from bruxism. Among them, 116 children (76%) were exposed to SHS. Exposed children showed a higher risk of sleep bruxism (p<0.05). After 6 months, sleep bruxism was found in 38% and in 90% of children, in the first and in the second group, respectively, this difference was statistically significant (p<0.05). In group 1, changes were statistically significant in those who were heavily and moderately exposed (p<0.05) but not in those lightly and occasionally exposed (p>0.05). In group 2, changes were not statistically significant (p>0.05). CONCLUSION: The findings showed that high and moderate exposure to SHS is associated with sleep bruxism in children.