Retinal Findings in Haemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts (HDBSCC): Case Report and Review.

We describe a child from a consanguineous family born with a rare autosomal recessive disorder affecting junctional adhesion molecule 3 (JAM3) causing profound neurological and ophthalmological injury known as haemorrhagic brain destruction, subependymal calcifications, and congenital cataracts (HDBSCC; MIM# 613730). She was the product of an unremarkable pregnancy and was born near to term but was noted shortly after birth to have congenital cataracts, poor vision, increased muscle tone, seizures, and developmental delay. Her older sister had an identical syndrome and had previously been documented to have homozygous mutations in JAM3. Examination in our patient, although difficult because of bilateral central cataracts, revealed very poor vision, attenuated retinal vessels, optic atrophy, and a retinal haemorrhage in the right eye, implying that abnormal development of the retinas and/or optic nerves may at times play a significant role in the poor vision noted in children with HDBSCC.

Minimal systemic hypothermia combined with selective head cooling evaluated in a pig model of hypoxia-ischemia.

BACKGROUND: Selective head cooling (SHC) with moderate hypothermia (HT) and whole-body cooling are beneficial following perinatal asphyxia. SHC with systemic normothermia (NT) or minimal HT is under-investigated, could obviate systemic complications of moderate HT, and be applicable to preterm infants. We hypothesized that minimal systemic HT with SHC following hypoxia-ischemia (HI) would be neuroprotective compared with systemic NT. METHODS: Newborn pigs underwent global HI causing permanent brain injury before being randomized to NT (rectal temperature (Trectal) 38.5 °C) or minimal HT (Trectal 37.0 °C) with SHC (cooling cap and body wrap) for 48 h followed by 24-h NT with 72-h survival. RESULTS: SHC did not reduce global or regional neuropathology score when correcting for insult severity or compared with a NT group matched for HI severity but increased mortality by 26%. During 48 h, the SHC mean ± SD Trectal was 37.0 ± 0.2 °C, and Tdeep brain and Tsuperficial brain were 35.0 ± 1.1 °C and 31.5 ± 1.6 °C, respectively, with stable Tbrain achieved ≥ 3 h after starting cooling. CONCLUSION: This is the first study in newborn pigs of minimal systemic HT with SHC for 48 h and a further 24 h of NT following HI. Mortality was increased in the cooled group with no neuroprotection in survivors.

Emirates Heart Health Project (EHHP): A protocol for a stepped-wedge family-cluster randomized-controlled trial of a health-coach guided diet and exercise intervention to reduce weight and cardiovascular risk in overweight and obese UAE nationals.

INTRODUCTION: Cardiovascular disease (CVD) is the most common cause of death both globally and in the United Arab Emirates. Despite public health measures and health education, the rates of death from CVD remain stable. Barriers previously identified to lifestyle changes include cultural reasons, boredom, and lack of family support. The Emirates Heart Health Project (EHHP) seeks to support healthy lifestyle changes through a family-based intervention using a health coach and fitness tracker. METHODS AND ANALYSIS: The EHHP is a stepped-wedge cluster-randomized trial with each cluster comprised of members of an extended family. Eligible participants will be ≥ 18 years of age, with BMI ≥ 25, have Emirati citizenship and be able to give informed consent for study participation. The cluster will have 16 weekly teaching sessions in the participants' family home by a health coach who will review individual weight, diet and exercise (monitored by a wearable fitness tracker). The clusters will have pre-intervention assessments of their weight and CVD risk profile and enter the intervention in randomized order. Each cluster will have a post-intervention assessment of the same measures. The primary outcome is weight reduction from baseline. Secondary outcomes will include change in CVD risk factors such as systolic and diastolic blood pressure, hemoglobin A1c, total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides, waist circumference, and BMI. A mixed linear model will be used for analysis, where the parameters measured at the end of each 16-week episode will be the outcome values. These will be analyzed such that baseline values (measured just prior to the start of an episode) will be fixed covariables. Random effects are the family units. This trial has been registered with the NIH at clinicaltrials.gov (NCT04688684) and is being reported using the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and TIDieR (Template for intervention description and replication) framework. TRIAL REGISTRATION: Clinicaltrials.gov NCT04688684.

Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigs.

OBJECTIVE: To investigate whether inhaling 50% xenon during hypothermia (HT) offers better neuroprotection than xenon or HT alone. METHODS: Ninety-eight newborn pigs underwent a 45-minute global hypoxic-ischemic insult severe enough to cause permanent brain injury, and 12 pigs underwent sham protocol. Pigs then received intravenous anesthesia and were randomized to 6 treatment groups: (1) normothermia (NT; rectal temperature 38.5 degrees C, n = 18); (2) 18 hours 50% xenon with NT (n = 12); (3) 12 hours HT (rectal temperature 33.5 degrees C, n = 18); (4) 24 hours HT (rectal temperature 33.5 degrees C, n = 17); (5) 18 hours 50% xenon with 12 hours HT (n = 18); and (6) 18 hours 50% xenon with 24 hours HT (n = 17). Fifty percent xenon was administered via a closed circle with 30% oxygen and 20% nitrogen. After 10 hours rewarming, cooled pigs remained normothermic until terminal perfusion fixation at 72 hours. Global and regional brain neuropathology and clinical neurological scores were performed. RESULTS: Xenon (p = 0.011) and 12 or 24 hours HT (p = 0.003) treatments offered significant histological global, and regional neuroprotection. Combining xenon with HT yielded an additive neuroprotective effect, as there was no interaction effect (p = 0.54). Combining Xenon with 24 hours HT offered 75% global histological neuroprotection with similarly improved regional neuroprotection: thalamus (100%), brainstem (100%), white matter (86%), basal ganglia (76%), cortical gray matter (74%), cerebellum (73%), and hippocampus (72%). Neurology scores improved in the 24-hour HT and combined xenon HT groups at 72 hours. INTERPRETATION: Combining xenon with HT is a promising therapy for severely encephalopathic infants, doubling the neuroprotection offered by HT alone.

Environmental cooling of the newborn pig brain during whole-body cooling.

AIM: Therapeutic hypothermia after perinatal asphyxia decreases brain injury in newborns, whereas hyperthermia worsens the brain injury. We examined how different clinical practices influence regional brain temperatures during hypothermia. METHODS: Six newborn pigs, which have comparable physiology and brain maturation to human term infants, were maintained at hypothermia (33.5°C) or normothermia with a servo-controlled whole-body cooling device that is in clinical use. Pigs were anesthetized and fully instrumented for cardiovascular and temperature (rectal and regional brain) monitoring. Changes in brain temperatures were measured during four different paradigms to mimic different clinical practices. RESULTS: Inserting an insulating pillow between the head and the heated surface reduced cortex temperature by 1 or 2°C during normothermia (core temperature T(core) 37°C) or hypothermia, T(core) 33.5°C. Reducing ambient temperature from 28°C to 23°C reduced cortex temperature by 3.9 ± 1.9°C. Without a hat and overhead heater at normothermia, cortex and deep brain temperatures were reduced by 1.2 ± 0.8 and 0.7 ± 0.7°C, respectively. Direct overhead heating abolished the normal cortex to deep brain temperature gradient that was maintained if using a head shield. CONCLUSION: Brain temperature may differ from core temperature during therapeutic hypothermia influenced by different clinical practices.

Validation of a neuropathology score using quantitative methods to evaluate brain injury in a pig model of hypoxia ischaemia.

BACKGROUND: Neuropathological examination is the classic outcome measure in experimental studies of newborn brain injury to evaluate novel therapies. We have used a graded neuropathology score in an established global model of perinatal hypoxic-ischaemic (HI) injury. We wished to validate the score using cell counting in our model. NEW METHOD: 32 newborn pigs underwent a 45 min global HI insult then maintained at normothermia (NT, rectal temperature, Trectal 38.5 °C) for 72 h or mild total body hypothermia (HT, Trectal 37.0 °C) combined with selective head cooling for 48 h and subsequently maintained at NT for 24h before brain perfusion fixation. A perinatal pathologist scored haematoxylin and eosin stained 6 µm histological sections for injury in the hippocampus and basal ganglia on a 9-step scale (0.0=no injury, 4.0=>75% injury). We counted the number of healthy neurons in the hippocampus CA1 region and putamen using morphological criteria in eight random, non-overlapping fields from representative sections. RESULTS: Healthy neuronal cell density correlated with neuropathology score in the hippocampus CA1 (r = -0.74) and in the putamen (r = -0.75) and both measures detected a difference between groups. The correlation coefficients were better for the NT compared to the HT group in both the hippocampus (r = -0.87 vs. -0.53) and putamen (r = -0.77 vs. -0.54). COMPARISON WITH EXISTING METHOD: We have validated a histological neuropathological scoring system in our model of perinatal HI by showing correlation between neuronal cell count and estimated injury. CONCLUSIONS: Our neuropathology score is a valid method to assess brain injury with good reproducibility and sensitivity.

Decorin and colchicine as potential treatments for post-haemorrhagic ventricular dilatation in a neonatal rat model.

BACKGROUND: Post-haemorrhagic ventricular dilatation (PHVD) after intraventricular haemorrhage (IVH) remains a significant problem in preterm infants. Due to serious disadvantages of ventriculoperitoneal shunt dependence, there is an urgent need for non-surgical interventions. Considerable experimental and clinical evidence implicates transforming growth factor ß (TGFß) in the pathogenesis of PHVD. Colchicine and decorin are both compounds with anti-TGFß properties. The former downregulates TGFß production and is in clinical use for another fibrotic disease, and the latter inactivates TGFß. OBJECTIVES: We hypothesized that administration of decorin or colchicine, which both have anti-TGFß properties, would reduce ventricular dilatation in a model of PHVD. METHODS: 142 rat pups underwent intraventricular blood injection on postnatal days (PN) 7 and 8. Sixty-nine pups were randomized to colchicine 20 and 50 µg/kg/day or water by gavage for 13 days. Seventy were randomized to decorin 4 mg/kg or saline by intraventricular injection on PN8 and PN13. At PN21, the ventricular area was measured on coronal brain sections. Negative geotaxis was tested at PN14 in controls and in the decorin study group. RESULTS: Ventricular size was not different between animals receiving either drug or water/saline. Intraventricular blood impaired neuromotor performance, but decorin had no effect. CONCLUSION: Two drugs that block TGFß by different mechanisms do not reduce ventricular dilatation in this model. Together with our previous work on losartan and pirfenidone, we conclude that blocking TGFß alone does not prevent the development of PHVD.

A comparison of cooling methods used in therapeutic hypothermia for perinatal asphyxia.

OBJECTIVE: The objective of this study was to compare cooling methods during therapeutic hypothermia (TH) for moderate or severe perinatal asphyxia with regard to temperature and hemodynamic stability. METHODS: A total of 73 newborns received TH in our center between 1999 and 2009 by 4 methods: (1) selective head cooling with mild systemic hypothermia by using cap (SHC; n = 20); (2) whole-body cooling with mattress manually controlled (WBCmc; n = 23); (3) whole-body cooling with body wrap servo-controlled (WBCsc; n = 28); and (4) whole-body cooling with water-filled gloves (n = 2). Target rectal temperatures (Trec) were 34.5 +/- 0.5 degrees C (SHC) and 33.5 +/- 0.5 degrees C (WBC). Trec, mean arterial blood pressure, and heart rate were collected from retrospective chart review. RESULTS: Groups had similar baseline characteristics and condition at birth. Trec was within target temperature +/-0.5 degree C for 97% of the time in infants with WBCsc, 81% in infants with WBCmc, 76% in infants with SHC, and 74% in infants who were cooled with gloves. Mean overshoot was 0.3 degree C for WBCsc, 1.3 degrees C for WBCmc, and 0.8 degree C for SHC groups. There was no difference in mean arterial blood pressure or mean heart between groups during the maintenance of cooling. In infants who were rewarmed at similar speed, there was greater variation in Trec in the SHC compared with the WBCsc group. CONCLUSIONS: Manually controlled cooling systems are associated with greater variability in Trec compared with servo-controlled systems. A manual mattress often causes initial overcooling. It is unknown whether large variation in temperature adversely affects the neuroprotection of TH.