Prophylactic inhibition of NF-κB expression in microglia leads to attenuation of hypoxic ischemic injury of the immature brain.

BACKGROUND: Periventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. The microglia is the main cell involved in PVL pathogenesis. The goal of this study was to investigate the role of microglial NF-κB activity and its prophylactic inhibition in a neonate mouse model of HI. METHODS: Transgenic mice with specific knockout NF-κB in microglia and colony stimulating factor 1 receptor Cre with floxed IKKß (CSF-1R Cre + IKKßflox/wt ) were used. Postnatal day 5 (P5) mice underwent sham or bilateral temporary carotid artery ligation followed by hypoxia. After HI insult, inflammatory cytokines, volumetric MRI, histopathology, and immunohistochemistry for oligodendroglia and microglial activation markers were analyzed. Long-term neurobehavioral assessment, including grip strength, rotarod, and open field testing, was performed at P60. RESULTS: We demonstrate that selective inhibition of NF-κB in microglia decreases HI-induced brain injury by decreasing microglial activation, proinflammatory cytokines, and nitrative stress. Rescue of oligodendroglia is evidenced by immunohistochemistry, decreased ventriculomegaly on MRI, and histopathology. This selective inhibition leads to attenuation of paresis, incoordination, and improved grip strength, gait, and locomotion. CONCLUSION: We conclude that NF-κb activation in microglia plays a major role in the pathogenesis of hypoxic ischemic injury of the immature brain, and its prophylactic inhibition offers significant neuroprotection. Using a specific inhibitor of microglial NF-κB may offer a new prophylactic or therapeutic alternative in preterm infants affected by HI and possibly other neurological diseases in which microglial activation plays a role.

Nonlinearity of cationic aromatic amine sorption to aluminosilicates and soils: role of intermolecular cation-π interactions.

Through the study of substituted anilines and benzylamines, we demonstrated that cooperative cation-π, π-π, and van der Waals interactions can increase aromatic cationic amine sorption to Na/Ca-montmorillonite well beyond the extent expected by cation exchange alone. Cationic amines exhibiting cooperative interactions displayed nonlinear S-shaped isotherms and increased affinity for the sorbent at low surface coverage; parallel cation exchange and cooperative interactions were noted above a sorption threshold of 0.3-2.3% of exchange sites occupied. Our experiments revealed the predominance of intermolecular cation-π interactions, which occurred between the π system of a compound retained on the surface via cation exchange and the cationic amine group of an adjacent molecule. Compounds with greater amine charge/area and electron-donating substituents that allowed for greater electron density at the center of the aromatic ring showed a greater potential for cation-π interactions on montmorillonite surfaces. However, benzylamine sorption to nine soils, at charge loadings comparable to the experiments with montmorillonite, revealed no significant cooperative interactions. It appears that cation-π interactions may be likely in soils with exceptionally high cation exchange capacities (>0.7 mol charge/kg) and low organic matter contents, abundant in montmorillonite and other expanding clay minerals.

A surgical approach to Wilms' tumour with retrohepatic vena caval extension.

PURPOSE: Wilms' tumours (WT) with retrohepatic vascular extension traditionally requires cardiac bypass for complete excision. We share our experience of these complex cases. METHODS: A retrospective review was performed of children with WT with retrohepatic vascular extension presenting to two UK children's hospitals. Tumour stage, chemotherapy, level of vascular extension, operative details and complication data were analysed. RESULTS: Ten children were identified. Mean age 6.6 years (range 3.3-8.2 years); tumour side 6 right, 2 left, 2 bilateral. Level of tumour extension was to the right atrium in two, diaphragm in two, hepatic vein (HV) level in four and retrohepatic inferior vena cava (IVC) in one patient. Following chemotherapy it reduced to hepatic veins (5) or below (4). Surgery involved radical nephrectomy and complete mobilisation of the liver off the IVC, which was then clamped, opened and the thrombus excised. There were no intraoperative complications. Mean hospital stay was 9.77 days (7-20 days). Histology showed viable tumour thrombus in six patients. One patient died after 1 year from metastatic disease. CONCLUSION: Retrohepatic extension of WT can be managed without bypass using pre-operative chemotherapy and by complete liver mobilisation. The tumour was always adherent to IVC and required sharp dissection.

A Truncating Variant of CHRNG as a Cause of Escobar Syndrome: A Multiple Pterygium Syndrome Subtype.

Escobar syndrome is a milder variant of multiple pterygium syndrome characterized by pterygia, scoliosis, and multiple congenital contractures. It is most frequently due to a genetic variant in CHRNG , which encodes the γ-subunit of the nicotinic acetylcholine receptor. Though the subunit is considered a "fetal" form and transitions to the "adult" ε-subunit by 33 weeks' gestation, the pathogenic musculoskeletal effects during fetal development render children with this condition permanently affected. We report a neonate with homozygous CHRNG c.117dupC and discuss some of the downstream clinical effects we observed with this variant.

Role of Interventional Radiology in the Management of Non-aortic Thoracic Trauma.

Trauma remains a leading cause of death for all age groups, and nearly two-thirds of these individuals suffer thoracic trauma. Due to the various types of injuries, including vascular and nonvascular, interventional radiology plays a major role in the acute and chronic management of the thoracic trauma patient. Interventional radiologists are critical members in the multidisciplinary team focusing on treatment of the patient with thoracic injury. Through case presentations, this article will review the role of interventional radiology in the management of trauma patients suffering thoracic injuries.

The Challenges in Diagnosis and Management of Acquired Thrombotic Thrombocytopenic Purpura: Consensus Report from Three Gulf Countries.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare hematological emergency characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, and multiorgan failure due to autoimmune-mediated deficiency in ADAMTS-13 activity. Currently, plasma exchange, with or without steroids, is the frontline option for the management of aTTP. The treatment should be started promptly once the disorder is clinically suspected. Besides, immunomodulators were studied in patients with aTTP to achieve stable remission and reduce the risk of relapse in patients with suboptimal response to plasma exchange; however, clinical trials showed equivocal results. Published data on early diagnosis, referral, and treatment patterns of aTTP patients in the member nations of the Arabian Gulf Cooperation Council (GCC) are still lacking. Therefore, the present consensus report aimed to present an overview of aTTP situation in GCC by bringing together a panel of experts from three GCC nations, to share their views on current trends and practices regarding aTTP. The experts discussed challenges including the lack of reliable data regarding the incidence of aTTP in GCC and delayed results of ADAMTS-13 activity testing. Limited patient access to tertiary centers and low level of awareness about the aTTP clinical spectrum among general practitioners are other challenges. The experts agreed that there is a need for national and regional consensus regarding the diagnosis and treatment of aTTP in the Gulf region.

Validity of Random Triglyceride Levels in Infants Receiving Parenteral Nutrition.

Background: Intravenous lipid emulsions (IL) are an important part of parenteral nutrition (PN) to meet essential fatty acid (EFA) requirements and metabolic demands of neonates and preterm infants. Some critically-ill neonates may not metabolize IL effectively which can lead to hypertriglyceridemia. Risks associated with this include increased pulmonary vascular resistance, displaced bilirubins, and platelet or macrophage dysfunction. Serum triglyceride (TG) concentration is used as a marker for lipid tolerance and predictor of potential complications involved with IL administration, but the clinical significance of this is still debated. Management of TG levels with regard to timing of laboratory tests, the ideal goal range, and duration of infusion of IL varies across institutions and is not standardized. Methods: Single-center, retrospective study of newborn infants receiving parenteral nutrition (PN). Fasting and non-fasting TG levels were drawn during the same lipid infusion of 2-3g/kg/day. The primary outcome was the difference between fasting and non-fasting TG levels. Statistical assessment of continuous data was done with student t-test and nominal data was evaluated using X2-test and logistic regression. Results: Forty infants were included with mean gestational age at birth of 29.5 ± 3.4 weeks and mean birth weight of 1.3 ± 0.5 kg. Mean time between lab draws while on same IL dose was 11.6 ± 0.2 h with resulting mean fasting and non-fasting (random) TG levels 82 ± 40 mg/dL (95% CI 68.4, 97.6) and 101 ± 40 mg/dL (95% CI 88.5, 115.8), respectively. Mean difference between TG levels during lipid-free interval and during infusion was -18.6 ± 51.2 mg/dL (95% CI -35.0, -2.3; p = 0.03). Conclusion: We concluded there is no difference in the management of IL, when TG level was drawn randomly or as fasting sample. Obtaining TG level during routine lab draws is appropriate. We extrapolated that the administration of IL over 24 h will not interfere with TG level.

Immunogenicity and reactogenicity of BNT162b2 booster in BBIBP-CorV-vaccinated individuals compared with homologous BNT162b2 vaccination: Results of a pilot prospective cohort study from Lebanon.

Facing new COVID-19 waves, the effectiveness of BBIBP-CorV has been noted to be low in countries whose populations were already administered two doses of the vaccine. Heterologous vaccination using ChAdOx1-S/BNT162b2 elicited higher immunogenicity compared with homologous immunization. BBIBP-CorV/BNT162b2 combination is worth testing. In this pilot prospective cohort study conducted at Makassed General Hospital, Beirut, Lebanon, from February 17, 2021, to June 30, 2021, we tested the safety and immunogenicity of a BNT162b2 booster dose in COVID-19-naïve individuals who had received two doses of the BBIBP-CorV vaccine. Heterologous booster vaccination was found to be safe and well tolerated. It was significantly associated with higher anti-spike IgG geometric mean titers compared to that after homologous BNT162b2 immunization in COVID-19-naïve individuals [(8040BAU/mL, 95%confidence interval (CI), 4612-14016) vs (1384BAU/mL, 95%CI, 1063-1801), respectively, (P < 0.0001)]. In countries with limited access to mRNA vaccines and where populations have already received BBIBP-CorV, mixing BBIBP-CorV/BNT162b2 is seen to overcome the low immunogenicity induced by BBIBP-CorV alone, thus potentially providing protection against emerging variants.

A Retrospective Review Following the Addition of Clonidine to a Neonatal Abstinence Syndrome Treatment Algorithm.

Objective: To investigate the outcomes associated with the implementation of a neonatal abstinence syndrome (NAS) treatment algorithm utilizing dual therapy with morphine sulfate and clonidine in a level four neonatal intensive care unit (NICU). Study Design: A cohort of neonates (≥35 weeks gestation) born at an academic tertiary medical center between January 1, 2015 and December 31, 2018 who were diagnosed with NAS were retrospectively evaluated following the implementation of a new NAS treatment algorithm. Neonates were categorized in two groups based on if they were treated pre- or post-implementation of the protocol. The primary efficacy outcome was length of hospital stay. Secondary outcomes included the incidence of adverse drug reactions, length of treatment for NAS, and maximum as well as total cumulative dose of each medication used to treat NAS. Results: The implementation of this NAS treatment algorithm significantly reduced the length of hospital stay (30 days vs. 20 days, p = 0.001). In addition, there was a significant decrease in duration of morphine sulfate exposure as well as cumulative dose of morphine required to successfully treat a neonate with NAS in the post-implementation group (26 days vs. 15 days, p = 0.002 and 6.9 mg/kg vs. 3.4 mg/kg, p = 0.031). Conclusion: Addition of clonidine to morphine sulfate as initial therapy for NAS significantly reduced the cumulative exposure as well as duration of exposure to morphine sulfate compared to morphine monotherapy and decrease length of hospital stay.

Genetic Characterization of a Model Ciliopathy: Bardet-Biedl Syndrome.

Bardet-Biedl syndrome (BBS) is a rare ciliopathy affecting multiple organ systems. Patients with BBS are usually diagnosed later in childhood when clinical features of the disease become apparent. In this article, we presented a case of BBS discovered by whole genome sequencing in a newborn with heterotaxy, duodenal atresia, and complex congenital heart disease. Early diagnosis is important not only for prognostication but also to explore ways to mitigate the cone-rod dysfunction and for exploring newer therapies. Our case highlights the importance of a high index of suspicion and the utility of advanced genetic testing to provide an early diagnosis for a rare disease.

Caudal Regression Syndrome.

Caudal Regression Syndrome (CRS) or Caudal dysgenesis syndrome (CDS) is characterized by maldevelopment of the caudal half of the body with variable involvement of the gastrointestinal, genitourinary, skeletal, and nervous systems. CRS affects 1-3 newborn infants per 100,000 live births. The prevalence in infants of diabetic mothers is reported at 1 in 350 live births which includes all the variants. A related condition is sirenomelia sequence or mermaid syndrome or symmelia and is characterized by fusion of the legs and a variable combination of the other abnormalities. The Currarino triad is a related anomaly that includes anorectal atresia, coccygeal and partial sacral agenesis, and a pre-sacral lesion such as anterior meningocele, lipoma or dermoid cyst. A multidisciplinary management approach is needed that includes rehabilitative services, and patients need a staged surgical approach.

Unusual ureteric duplication abnormality in a child with pelvoureteric junction obstruction.

A 5-year-old girl underwent an elective left pyeloplasty for pelvoureteric junction obstruction (PUJO). At laparoscopy, two ureters were seen to be draining a left duplex kidney, with a PUJO of the lower moiety. Interestingly, however, the upper moiety ureter was bifurcating to drain both upper and lower moiety as well. All the preoperative investigations were suggestive of a single system. The ureteric bifurcation of this type has not been reported so far. It is of paramount importance to demonstrate anatomy clearly at an operation to prevent risk to the less defined ureters.

Unique Case of Congenital Duodenal Atresia and a Choledochal Cyst and the Hypothesis of Their Embryological Evolution.

The concomitant occurrence of duodenal atresia (DA) and a choledochal cyst (CC) has rarely been reported. Knowledge of both the presentation and management of this rare co-occurrence is imperative in avoiding potential complications and sequelae, such as biliary metaplasia. Herein we describe a female infant born at 32 weeks gestational age who was diagnosed with duodenal atresia and annular pancreas postnatally, who had subsequent findings of malrotation and a choledochal cyst, as seen from contrast imaging. Uncomplicated repair of the DA and obstruction was performed at 4 days of life. She re-presented 2 years later with non-bloody, nonbilious emesis and was found to have elevated amylase, lipase and liver enzymes. Imaging revealed dilated intra-hepatic ducts, a distended gallbladder and a large choledochal cyst. She underwent a cholecystostomy tube placement followed by a definitive choledochal cyst excision with immediate improvement following surgery and full resolution of symptoms before discharge.

The Shanfield anastomosis revisited: Its applications and early outcome.

BACKGROUND: Shanfield first described a simple ureteric implantation technique involving a U-stitch anchoring the spatulated end of the transplant ureter to the interior of the intact bladder through a small stab wound. We present an extrapolation of this principle to Mitrofanoff channels and native ureteric reimplantations and further extend it to a laparoscopic approach in some. METHODS: A retrospective case-note reviewing the Shanfield ureteric reimplantation in fifteen children between October 2014 and May 2017 was performed. RESULTS: Fifteen children (females n = 9), median age 6 years (range 8 months-15 years), underwent a Shanfield anastomosis for ureteric (n = 3) or Mitrofanoff (n = 12) implantation into the bladder. Their diagnoses were: vesicoureteric reflux (n = 2), vesicoureteric obstruction (n = 1), neuropathic bladder (n = 4), exstrophy (n = 2, bladder and cloacal), nonneuropathic bladder (n = 3), cloaca (n = 2), and one with failed urethral reconstruction of a Y-duplication. Two ureteric reimplantations and one appendix-Mitrofanoff were undertaken entirely laparoscopically. The bladder was not opened in 9/15, with the remaining six in an ileocystoplasty and one complex cloaca. Fourteen patients were available for follow-up at a median 18.2 (5.8-43.3) months. There was no anastomotic leakage in any, and one stenosis was successfully managed with simple dilatation. One complex patient required a new Mitrofanoff channel. CONCLUSION: Our preliminary data suggest that the Shanfield anastomosis offers a safe, robust, and simple antireflux implantation technique without the need to formally open the bladder. The technique offers several advantages as it allows overcoming the problem of inadequate tunnelling when the bladder template is deficient. Meanwhile, its simplicity permits it to be faithfully reproduced with laparoscopy in select patients. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: IV.

Second-generation antipsychotics cause a rapid switch to fat oxidation that is required for survival in C57BL/6J mice.

Some second-generation antipsychotics (SGAs) increase insulin resistance and fat oxidation, but counter intuitively they do not activate lipolysis. This seems unsustainable for meeting energy demands. Here, we measured dose-dependent effects of SGAs on rates of oxygen consumption (VO2), respiratory exchange ratio (RER), and physical activity in C57BL/6J mice. The role of H1-histamine receptors and consequences of blocking fat oxidation were also examined. Olanzapine, risperidone, and clozapine (2.5-10mg/kg) elicited rapid drops in dark-cycle RER (~0.7) within minutes, whereas aripiprazole exerted only modest changes. Higher doses of olanzapine decreased VO2, and this was associated with accumulation of glucose in plasma. Clozapine and risperidone also lowered VO2, in contrast to aripiprazole, whereas all decreased physical activity. Astemizole and terfenadine had no significant effects on RER, VO2, or physical activity. The VO2 and RER effects appear independent of sedation/physical activity or H1-receptors. CPT-1 inhibitors can enhance muscle glucose utilization and prevent fat oxidation. However, after etomoxir (2 × 30 mg/kg), a low dose of olanzapine that did not significantly affect VO2 by itself caused precipitous drops in VO2 and body temperature, leading to death within hours or a moribund state requiring euthanasia. One 30 mg/kg dose of either etomoxir or 2-tetradecylglycidate followed by olanzapine, risperidone, or clozapine, but not aripiprazole, dramatically lowered VO2 and body temperature. Thus, mice treated with some SGAs shift their fuel utilization to mostly fat but are unable to either switch back to glucose or meet their energy demands when either higher doses are used or when fat oxidation is blocked.

Paediatric penetrating thoraco-abdominal injury: role of minimallly invasive surgery.

We report two cases of penetrating thoraco-abdominal injuries who presented to our trauma centre. One with stab to lower left chest and the other one had pallet injury to right upper abdomen. The clinical presentation, radiological investigations and operative intervention are reviewed.

Central venous catheters in the left-sided superior vena cava: clinical implications.

AIM: Left-sided superior vena cava (LSVC) is a congenital venous anomaly with an incidence of about 0.3%, and which is sometimes discovered during vascular intervention [Le Cat. Histoire de l'acadroyale des sciences .Paris 1738:62, I Steinberg, W Dubilier, D Lucas. Persistence of left superior vena cava. Dis Chest 1953;24:479-88]. There is little clear guidance on what to do in this event. METHODS: Children with LSVC were identified from our prospectively collected database of percutaneous central venous catheter (CVC) insertions between 2004 and 2011. If a LSCV was suspected, usually a venogram was performed. All available documentation was reviewed to identify complications. RESULTS: Eleven children with LSVC had 12 CVCs during the study period. Mean age at operation was 5.8 years (range 27 days to 15 years). Cardiovascular anomalies were already known in three cases. After CVC insertion, the line tip lay in the LSVC in eight cases and in the RA in 4. In 11 cases there was no immediate problem, but in 1 case there were postoperative bradyarrhythmias, which caused the CVC to be removed on day 1. This case was later found to have abdominal sepsis. The mean duration the CVCs were retained was 331days (range 1 day to 4 years). Other reasons for CVC removal were infection (n=1), damaged line (n=2), no longer required (n=2), and death unrelated to CVC (n=2). CONCLUSIONS: Our experience suggests that a LSVC (i) is often first discovered during CVC insertion, (ii) can be safely used for parenteral nutrition or chemotherapy, and (iii) the best practice would be to leave the CVC tip high in the LSVC or in the RA via another route.

The testicular regression syndrome--do remnants require routine excision?

AIM: Excision of testicular remnants is debatable in the scenario where hypoplastic vas and vessels can be seen entering a closed internal ring during laparoscopy for impalpable testes. We aimed to establish how frequently excised remnants have identifiable testicular tissue and, hence, malignant potential. METHODS: This study is a retrospective review of all excised testicular remnants in children with impalpable testis. Specimens that were excised for indications other than testicular regression syndrome were excluded. Pathology reports of excised specimens were reviewed, and the presence of multiple histologic features was noted. Histologic confirmation of testicular/paratesticular tissue required the presence of 1 or more of the following: seminiferous tubules, germ cells, Sertoli cells, Leydig cells, vas deferens, or epididymal structures. Malignancy potential was defined by the presence of germ cells or seminiferous tubules. All patients with seminiferous tubules were further examined by a single histopathologist. RESULTS: A total of 208 testicular remnants from 206 children were excised over the 11-year period (1999-2009). Histologic evidence confirmed excision of testicular/paratesticular tissue in 180 cases (87%). Seminiferous tubules were noted in 27 (15%), and germ cells were present in 19 (11%) cases. CONCLUSION: Viable germ cells were found in 11% of examined remnants, which, in our opinion, justifies their removal.