Thermal Index for early non-invasive assessment of brain injury in newborns treated with therapeutic hypothermia: preliminary report.

Perinatal asphyxia (PA) is the 3rd most common cause of neonatal death and one of the most common causes of severe neurological impairments in children. Current tools and measurements mainly based on the analysis of clinical evaluation and laboratory and electrophysiological tests do not give consistent data allowing to predict the severity of hypoxic-ischemic encephalopathy (HIE) until a magnetic resonance imaging (MRI) score is performed. The aim of this work is to evaluate the usefulness of the new index, called Thermal Index (TI) in the assessment of the degree of brain damage in newborns in the course of therapeutic hypothermia (TH) due to PA. This was a prospective, observational, pilot study which did not require any changes in the applicable procedures. Analysis has been applied to six newborn babies treated with TH in Neonatal/Paediatric ICU in University Hospital in Opole in 2018 due to PA. They all met criteria for TH according to the current recommendations. Brain MRI was performed after the end of TH when the children were brought back to normal temperature, with the use of a 1.5 T scanner, using T1-, T2-weighted images, fluid-attenuated inversion recovery (FLAIR), inversion recovery (IR), susceptibility-weighted imaging (SWI), and diffusion-weighted imaging (DWI). The images were assessed using MRI score according to the scoring system proposed by Weeke et al. The Thermal Index assessing endogenous heat production was calculated according to the formula proposed in this paper. A high, statistically significant positive correlation was found between MRI scores and TI values (0.98; p = 0.0003) in the 1st hour of therapy. High correlation with MRI assessment, the non-invasiveness of measurements and the availability of results within the first few hours of treatment, allow authors to propose the Thermal Index as a tool for early evaluating of the brain injury in newborns treated with TH. Further research is required to confirm the usefulness of the proposed method.

BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells.

Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-κB (NF-κB) target genes that undermines the growth and survival of mantle cell lymphoma (MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-κB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior preclinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or -resistant MCL.

Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.

The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

Pacifier use and the occurrence of otitis media in the first year of life.

PURPOSE: The purpose of this study was to assess pacifier use as a risk factor for otitis media during the first year of life. METHODS: A volunteer cohort of 1,375 infants was recruited from eight hospital postpartum units in Iowa. Parents were asked to provide detailed information on their child's health at 6 weeks, 3, 6, 9 and 12 months of age. Questions were posed concerning occurrence of specific childhood illnesses, including otitis media, at each time point, as well as other factors. RESULTS: Over 70% of children were reported to have experienced one or more episodes of otitis media during their first year of life, with its occurrence much more common during the second six months. Multivariate analyses using Generalized Estimating Equations assessed factors associated with otitis media during the entire 12-month period. These analyses showed that pacifier use, age, male sex, greater number of childcare days, and higher family incomes were significantly associated with occurrence of otitis media. CONCLUSIONS: Multivariate analyses found that the occurrence of otitis media was associated with pacifier use, one of few modifiable risk factors for otitis media.

Effects of oral habits' duration on dental characteristics in the primary dentition.

BACKGROUND: Studies dating to the 1870s have demonstrated that long-term nonnutritive sucking habits may lead to occlusal abnormalities, including open bite and posterior crossbite. However, little is known as to whether habits of shorter durations have lasting effects. METHODS: The authors collected longitudinal data on nonnutritive sucking among children through a series of questionnaires regularly completed by parents. Researchers examined the children at ages 4 to 5 years and obtained study models. The models were measured for dental arch parameters (including arch width, arch length and arch depth) and assessed for overjet, overbite and posterior crossbite. The authors compared the dental arch and occlusal conditions among groups of children with nonnutritive sucking habits of different durations. RESULTS: Children with nonnutritive sucking habits that continued to 48 months of age or beyond demonstrated many significant differences from children with habits of shorter durations: narrower maxillary arch widths, greater overjet and greater prevalence of open bite and posterior crossbite. In addition, compared with those who ceased their habit by 12 months of age, those with habits at 36 months of age had significantly greater mandibular canine arch widths, maxillary canine arch depths and overjet, while those with habits at 24 months and 36 months had significantly smaller palatal depths. Prevalence of anterior open bite, posterior crossbite and excessive overjet (> 4 millimeters) increased with duration of habits. CONCLUSIONS: While continuous nonnutritive sucking habits of 48 months or longer produced the greatest changes in dental arch and occlusal characteristics, children with shorter sucking durations also had detectable differences from those with minimal habit durations. CLINICAL IMPLICATIONS: It may be prudent to revisit suggestions that sucking habits continued to as late as 5 to 8 years of age are of little concern.

Infant oral health and oral habits.

Many oral diseases and conditions, including dental caries (cavities) and malocclusions, have their origins early in life. Prudent anticipatory guidance by the medical and dental professions can help prevent many of the more common oral health problems. This article provides information on the rationale for early dental examination and instructions for pediatric and family practitioners in scheduling and conducting an early oral intervention appointment. In addition, feeding practices, non-nutritive sucking, mouth breathing, and bruxing are discussed, including their effects on orofacial growth and development.

Non-nutritive sucking behaviors in preschool children: a longitudinal study.

PURPOSE: Prolonged duration of non-nutritive sucking behaviors may have consequences in regard to the developing orofacial structures and occlusion. Little is known as to why some children have prolonged sucking habits beyond the first 2 to 3 years of life. This paper reports on non-nutritive sucking patterns among a large cohort of healthy children from birth to 36 months of age and older, and identifies factors predictive of prolonged non-nutritive sucking habits. METHODS: Over 600 children were followed from birth to at least 36 months of age using mailed questionnaires sent when children reached the ages of 6 weeks, and 3, 6, 9, 12, 16, and 24 months, and then yearly thereafter. Parents answered questions concerning non-nutritive sucking behaviors including use of pacifier and digit sucking. The study categorized children who maintained habits to 36 months of age or older as having prolonged habits, and using multivariate analyses, compared them to children without prolonged habits on various sociodemographic variables. RESULTS: The study found that for over 20% of the children, a non-nutritive sucking habit was prolonged to 36 months of age or older. Factors associated with prolonged sucking habits included older maternal age, higher maternal education level, and having no older siblings. CONCLUSIONS: Identifying factors related to prolonged non-nutritive sucking habits may be important in developing and targeting recommendations regarding such behaviors in an effort to prevent malocclusions that result from prolonged sucking habits.

Conditioning and reflex modification of the rabbit nictitating membrane response using electrical stimulation in auditory nuclei.

Electrical brain stimulation (EBS) was applied to four nuclei in the auditory system, namely, the cochlear nucleus (CN), superior olive (SO), inferior colliculus, and medial geniculate. EBS was also applied to the pontine nuclei, which are the main relays for transmitting auditory conditioned stimuli (CSs) into the cerebellar pathways for conditioning of the nictitating membrane response (NMR). EBS of the CN, but no other site, yielded reflex modification, which was an increase in the unconditioned NMR to an airpuff unconditioned stimulus (US) when preceded by EBS. Throughout the experiment, EBS of the SO produced a distinctive distribution of NMRs, in which a high proportion had latencies less than 50 ms. When EBS was repeatedly paired with the airpuff US, conditioned responses (CRs) were acquired to comparable levels across all sites. At each site, response likelihood was an increasing function of the EBS parameters of pulse amplitude, pulse frequency, and pulse width. Combined with anatomical findings, these results indicate that multiple encodings of an auditory CS are sent to the pathways for the NMR.

Characteristics of patients with autistic disorder (AD) presenting for dental treatment: a survey and chart review.

A group of 43 patients with AD (mean age, 13.5; SD, 5.9 yrs) was identified from the University Hospital School Pediatric Dentistry Clinic. We reviewed the patients' charts to obtain demographic data, dental findings, and the management techniques used for treatment. The patients were divided into groups according to Frankl's categories of behavior, ranging from definitely negative to positive. Descriptive data are provided for each group. Commonly used communications and pharmacological management techniques, as well as physical restraints, enabled us to treat all the patients in the traditional dental setting, when simple procedures were planned. Treatment under general anesthesia in the operating room was necessary in 37% of all patients when comprehensive care was required or difficult procedures were carried out. A questionnaire was also sent out to the caregivers to gather data on patients' nutrition and eating/chewing habits. In the sample surveyed, two-thirds of the individuals reportedly exhibited a normal eating pattern, while 14% pouched food. Soft, sweet, or sticky foods were preferred by 41% of the patients.

Autistic disorder: a review for the pediatric dentist.

Dental publications on autism have been sparse since the first comprehensive article geared for the dental profession. New findings on the etiology of autistic disorder (AD) have been discovered, suggesting that it is an organic disorder characterized by abnormalities in the brain, especially the cerebellum and limbic system. This article summarizes the latest medical findings on the etiology, diagnosis, and treatment approaches of AD, and reviews the dental literature since 1969. The main dental topics reviewed are: oral health status and dental needs of patients with AD, characteristics of patients with AD, and self-injurious behavior (SIB) in the context of AD. Clinical behavior-management issues such as pharmacological and communicative techniques and physical restraint and desensitization are described. The affect of the dental office's environment and appointment structure on a patient with AD are presented.

Practices and attitudes concerning oral health in pediatric cardiology clinics to prevent infective endocarditis.

A survey of 121 pediatric cardiology clinics investigated the current practices and attitudes toward oral health education and oral screenings in pediatric cardiology clinics for patients susceptible to infective endocarditis. Most pediatric cardiology clinics do not provide oral health education and oral screenings, but believe it would be beneficial.

Elicitation, modification, and conditioning of the rabbit nictitating membrane response by electrical stimulation in the spinal trigeminal nucleus, inferior olive, interpositus nucleus, and red nucleus.

Elicitation of responses by electrical brain stimulation (EBS) was related to the synaptic distance of the target nucleus from the accessory abducens. Specifically, responses to EBS in the spinal trigeminal nucleus (TRIG) and red nucleus (RN) increased as a positive function of stimulation parameters. Responding to EBS in the interpositus nucleus (IP) was lower, and responding to EBS in the inferior olive (IO) was negligible. EBS in the TRIG, IP, and RN nuclei was then paired with a tone conditioned stimulus (CS). The CS modified responses for EBS in RN and TRIG but not IP. CS-EBS pairings yielded conditioned response (CR) acquisition, in which Groups TRIG, IP, and RN reached asymptotes of 90%, 70%, and 43% CRs, respectively. Thus, contrary to previous findings, EBS in the efferent pathway can support CR acquisition. The results are discussed with respect to the role of projections from the RN to the cerebellar cortex and the TRIG nucleus.

Using anticipatory guidance to provide early dental intervention.

While the infectious-disease model continues to dominate the design of preventive programs for children, ample evidence supports the need to consider other aspects of caries prevention such as functional and developmental considerations--and to do it earlier than conventional wisdom would suggest--if further gains are to be made in caries reduction. Anticipatory guidance provides a framework for prevention that goes beyond caries to address all aspects of children's oral health.

Imaging evaluation of breast-feeding and bottle-feeding systems.

OBJECTIVE: To compare infant sucking and swallowing patterns during feeding with a new artificial nipple and during breast-feeding. METHODS: Fifteen healthy, term infants were fed successfully for 1 week with use of the new tricut nipple; then each infant's oral cavity was examined during feeding by using real-time ultrasonography. Measurements of nipple length and compression were made, together with observations concerning the integrity of the seal formed by the infant's mouth around the nipple. These data were compared with similar data from previous studies of 16 breast-fed infants. RESULTS: Although no artificial feeding system exactly simulates breast-feeding, the new tricut nipple was sucked in a manner similar to the way the human nipple is sucked and delivered milk posteriorly to the foramen cecum region of the tongue, just as the breast does. CONCLUSION: Although further studies are necessary, to evaluate other characteristics of the new tricut nipple, the measurements from this investigation are useful additions to the ultrasound data these investigators have accumulated on various artificial feeding systems. These data may also prove helpful in determining the most appropriate nipples for infants with various feeding disorders.

Sickle cell anemia: a review of the dental concerns and a retrospective study of dental and bony changes.

This paper is a review of the medical concerns pertinent to dental care and a preliminary study of dental findings of the sickle cell anemia (SS) patient. The dental characteristics observed in 21 dental patients with SS are described. Radiographic findings included "stepladder" trabeculae pattern (70%), enamel hypomineralization (24%), calcified canals (5%), increased overbite (30-80%), and increased overjet (56%). Comparisons are made with other studies of the sickle cell patient, and the need for further study is suggested.

Oral opening and other selected facial dimensions of children 6 weeks to 36 months of age.

Four hundred twenty-two children (Caucasians, Asians, and blacks) aged 6 weeks to 36 months were recruited. Five measurements (incisal edge distance, alveolar crest distance, closed mouth breadth, open mouth breadth, and nose-lip distance) were made by two calibrated examiners and an average was recorded. Because there were no statistically significant differences among races or genders the data were combined. The normative data for seven age groups (6 weeks to 36 months) and five oral-facial parameters are presented.

Imaging evaluation of artificial nipples during bottle feeding.

OBJECTIVES: To determine whether real-time ultrasonography can be used to directly visualize artificial nipples in vivo while an infant is sucking, to compare deformation differences of the artificial nipple with the human nipple during sucking, and to compare the suck mechanism used by the infant with four types of artificial nipples. DESIGN: Nonrandomized clinical study with a control group. SETTING: University-affiliated teaching hospital in Iowa City, Iowa. PARTICIPANTS: A volunteer sample of 35 healthy infants 6 to 12 weeks of age. INTERVENTION: None. MEASUREMENTS/MAIN RESULTS: Images produced by real-time ultrasound of infants during sucking using artificial nipples were measured to determine the percentage lengthening, the percentage lateral compression, and the percentage flattening of nipples. These results were compared with data obtained from studies using breast-fed infants. None of the artificial nipples lengthened like the human nipple. One artificial nipple was significantly more compressible than the human nipple and the remaining three artificial nipples. CONCLUSION: Real-time ultrasonography can be used to visualize artificial nipples in vivo during sucking.