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To date, there are no efficacious translational solutions for end-stage urinary bladder dysfunction. Current surgical strategies, including urinary diversion and bladder augmentation enterocystoplasty (BAE), utilize autologous intestinal segments (e.g. ileum) to increase bladder capacity to protect renal function. Considered the standard of care, BAE is fraught with numerous short- and long-term clinical complications. Previous clinical trials employing tissue engineering approaches for bladder tissue regeneration have also been unable to translate bench-top findings into clinical practice. Major obstacles still persist that need to be overcome in order to advance tissue-engineered products into the clinical arena. These include scaffold/bladder incongruencies, the acquisition and utility of appropriate cells for anatomic and physiologic tissue recapitulation, and the choice of an appropriate animal model for testing. In this study, we demonstrate that the elastomeric, bladder biomechanocompatible poly(1,8-octamethylene-citrate-co-octanol) (PRS; synthetic) scaffold coseeded with autologous bone marrow-derived mesenchymal stem cells and CD34+ hematopoietic stem/progenitor cells support robust long-term, functional bladder tissue regeneration within the context of a clinically relevant baboon bladder augmentation model simulating bladder trauma. Partially cystectomized baboons were independently augmented with either autologous ileum or stem-cell-seeded small-intestinal submucosa (SIS; a commercially available biological scaffold) or PRS grafts. Stem-cell synergism promoted functional trilayer bladder tissue regeneration, including whole-graft neurovascularization, in both cell-seeded grafts. However, PRS-augmented animals demonstrated fewer clinical complications and more advantageous tissue characterization metrics compared to ileum and SIS-augmented animals. Two-year study data demonstrate that PRS/stem-cell-seeded grafts drive bladder tissue regeneration and are a suitable alternative to BAE.

We report a substantial axillary lymphangioma in a fetus delivered at 38 weeks of gestation. Detailed fetal survey at 20 weeks revealed a 5.45 × 3.72 cm nonvascular cystic axillary structure without other malformations; amniocentesis was negative. Serial surveillance was performed throughout the pregnancy. A male infant weighing 3000 g with a 16 × 12 × 9 cm septated cystic mass arising from the left axilla was delivered via cesarean section. The newborn period was complicated by cellulitis overlying the mass and interval cystic hemorrhage requiring sclerotherapy and subsequent excision. Nonnuchal lymphangiomas may be etiologically distinct entities. The prognostic factors include anatomic location, presence of septa, and association with other congenital abnormalities. A thorough evaluation, multidisciplinary approach, and close surveillance should be undertaken to optimize neonatal outcomes.

ObjectivesTo identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere.Study designThe Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected.ResultsWe enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score.ConclusionsPortal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

Context.--Rhabdomyosarcoma, the most common soft tissue sarcoma of children, is currently classified into the following 4 subtypes: embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma, based on recent molecular genetic knowledge and morphologic features. Objective.--To highlight the most recent advances of molecular genetic alterations, and to familiarize pathologists with most recent genotype and phenotype correlation in rhabdomyosarcoma. Data Sources.--Data were derived from the World Health Organization Classification of Soft Tissue and Bone Tumors, fifth edition, recently published literature (PubMed), and clinical practice experience. Conclusions.--Current classification has been significantly impacted by genotype and phenotype correlation, especially with PAX-FOXO1 fusion-positive rhabdomyosarcoma versus fusion-negative rhabdomyosarcoma, and with the emergence of 3 distinct new subtypes of spindle cell/sclerosing rhabdomyosarcoma. Although all rhabdomyosarcomas were considered a single diagnostic entity in the past, they are now considered to be a group of histologically similar but biologically diverse entities because their clinical behavior and underlying molecular alterations dramatically differ. This review outlines recent molecular genetic developments, corresponding morphologic features, and current challenges faced by pathologists in daily practice. (Arch Pathol Lab Med. 2022;146:953-959; doi: 10.5858/arpa.2021-0183-RA), Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence, comprising approximately 5% of pediatric solid cancers and 50% of pediatric soft tissue sarcomas. (1-4) The disease [...]

Congenital pulmonary airway malformation (CPAM) is the most common congenital lesion detected in the neonatal lung, which may lead to respiratory distress, infection, and pneumothorax. CPAM is thought to result from abnormal branching morphogenesis during fetal lung development, arising from different locations within the developing respiratory tract. However, the pathogenic mechanisms are unknown, and previous studies have focused on abnormalities in airway epithelial cells. We have analyzed 13 excised lung specimens from infants (age

Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common). Inactive lesions showed bland replacement by collagen and fibrous cords with little or no inflammation. Heterogeneity was common within a given remnant; however, relatively homogenous histologic patterns, defined as 3 or more inactive or active levels in the hepatic ducts levels, characterized most remnants. Homogeneity did not correlate with age at KHPE, presence/absence of congenital anomalies at laparotomy indicative of heterotaxy and outcome. Remnants from youngest subjects were more likely than older subjects to be homogenously inactive suggesting significantly earlier onset in the youngest subset. Conversely remnants from the oldest subjects were often homogenously active suggesting later onset or slower progression. More data are needed in remnants from subjects

The liver biopsy guides diagnostic investigation and therapy in infants with undiagnosed cholestasis. Histologic features in the liver may also have prognostic value in the patient with biliary atresia (BA). We assessed the relative value of histologic features in 227 liver needle biopsies in discriminating between BA and other cholestatic disorders in infants enrolled in a prospective Childhood Liver Disease Research Network (ChiLDReN) cohort study by correlating histology with clinical findings in infants with and without BA. In addition, we reviewed 316 liver biopsies from clinically proven BA cases and correlated histologic features with total serum bilirubin 6 months after hepatoportoenterostomy (the Kasai procedure, HPE) and transplant-free survival up to 6 years. Review pathologists were blinded to clinical information except age. Semiquantitative scoring of 26 discrete histologic features was based on consensus. Bile plugs in portal bile ducts/ductules, moderate to marked ductular reaction, and portal stromal edema had the largest odds ratio for predicting BA versus non-BA by logistic regression analysis. The diagnostic accuracy of the needle biopsy was estimated to be 90.1% (95% confidence interval [CI]: 85.2%, 94.9%), whereas sensitivity and specificity for a diagnosis of BA are 88.4% (95% CI: 81.4, 93.5) and 92.7% (95% CI: 84.8, 97.3), respectively. No histologic features were associated with an elevated serum bilirubin 6 months after HPE, although it (an elevated serum bilirubin) was associated with an older age at HPE. Higher stages of fibrosis, a ductal plate configuration, moderate to marked bile duct injury, an older age at HPE, and an elevated international normalized ratio were independently associated with a higher risk of transplantation.

Diffusion of native defects such as vacancies and their interactions with impurities are fundamental to semiconductor crystal growth, device processing, and design. However, the transient equilibration of native defects is difficult to directly measure. We used (AlxGa1−x)2O3/Ga2O3 superlattices (SLs) to detect and analyze transient diffusion of cation vacancies during annealing in O2 at 1000–1100 °C. Using a novel finite difference scheme for diffusion with time- and space-varying diffusion constants, we determined diffusion constants for Al, Fe, and cation vacancies, including the vacancy concentration dependence for Al. In the case of SLs grown on Sn-doped β-Ga2O3 (010) substrates, gradients observed in the extent of Al diffusion indicate a supersaturation of vacancies in the substrates that transiently diffuse through the SLs coupled strongly to Sn and thus slowed compared to undoped cases. In the case of SLs grown on (010) Fe-doped substrates, the Al diffusion is uniform through the SLs, indicating a depth-uniform concentration of vacancies. We find no evidence for the introduction of VGa from the free surface at rates sufficient to affect Al diffusion at at. % concentrations, establishing an upper bound on surface injection. In addition, we show that unintentional impurities in Sn-doped Ga2O3 such as Fe, Ni, Mn, Cu, and Li also diffuse toward the surface and accumulate. Many of these likely have fast interstitial diffusion modes capable of destabilizing devices, thus suggesting that impurities may require further reduction. This work provides a method to measure transients in diffusion-mediating native defects otherwise hidden in common processes such as ion implantation, etching, and film growth. [ABSTRACT FROM AUTHOR]

In this paper, we find some conditions under which a sequence \{\alpha (n)\} will satisfy the Laguerre inequality of any order asymptotically. Using this method, we prove that for any r and some constant c, the Maclaurin coefficients \gamma (n) of the Riemann Xi-function satisfy the Laguerre inequality of order r when n>cr^3, which provides a necessary condition for the Riemann hypothesis. We also prove that the partition function satisfies the Laguerre inequality of order r\geq 5 when n\geq 6r^4. As a consequence, it gives an affirmative answer to Wagner's conjecture on the threshold for the Laguerre inequalities of order no more than 10 for the partition function. Moreover, motivated by the study of Craven and Csordas on the complete monotonicity of the Maclaurin coefficients of entire functions in Laguerre-Pólya class, we consider the complete monotonicity of the sequences \{\alpha (n)\}. We give the criteria for the asymptotically complete monotonicity of the sequence \{\alpha (n)\} and \{\log \alpha (n)\}, respectively. With this criteria, we show that (-1)^r \Delta ^r \gamma (n)>0 for n>ce^{r^3} and (-1)^{r-1} \Delta ^r \log \gamma (n)>0 for n>cr^2. Furthermore, we propose some open problems. [ABSTRACT FROM AUTHOR]

Calcium is a strong inducer of keratinocyte differentiation. We have previously demonstrated that extracellular calcium promotes keratinocyte differentiation via E-cadherin-catenin complex-mediated phospholipase C-γ1 (PLC-γ1) activation in the plasma membrane. However, it is unclear whether dietary calcium regulates keratinocyte proliferation, differentiation or carcinogenesis. To address this issue, the rates of oral tumor and levels of proliferation and differentiation in the oral epithelium were assessed in mice on different calcium diets and the carcinogen 4-nitroquinoline-1-oxide. The results showed that mice on the high calcium diet had lower rates of oral tumors, lower levels of proliferation and higher levels of differentiation in the normal oral epithelium than those on the normal calcium diet. Higher levels of E-cadherin, β-catenin, p120-catenin (p120), epidermal growth factor receptor (EGFR), and calcium and lower levels of PLC-γ1 were also noted in the normal oral epithelium in mice on high calcium diet than the control mice. In contrast, mice on low calcium diet had opposite effects. However, dietary calcium had no effect on the proliferation, differentiation or the levels of E-cadherin, β-catenin, p120, PLC-γ1 and EGFR in oral tumors. These data indicate that dietary calcium increases calcium levels in oral epithelium, suppresses oral carcinogenesis, inhibits proliferation and promotes differentiation of normal oral epithelium. Increased E-cadherin, β-catenin, p120 and EGFR and decreased PLC-γ1 may participate in the inhibitory effect of dietary calcium in oral carcinogenesis.

Necrotizing enterocolitis (NEC) affects up to 10% of premature infants, has a mortality of 30%, and can leave surviving patients with significant morbidity. Neuregulin-4 (NRG4) is an ErbB4-specific ligand that promotes epithelial cell survival. Thus, this pathway could be protective in diseases such as NEC, in which epithelial cell death is a major pathologic feature. We sought to determine whether NRG4-ErbB4 signaling is protective in experimental NEC. NRG4 was used i) in the newborn rat formula feeding/hypoxia model; ii) in a recently developed model in which 14- to 16-day-old mice are injected with dithizone to induce Paneth cell loss, followed by Klebsiella pneumoniae infection to induce intestinal injury; and iii) in bacterially infected IEC-6 cells in vitro. NRG4 reduced NEC incidence and severity in the formula feed/hypoxia rat model. It also reduced Paneth cell ablation-induced NEC and prevented dithizone-induced Paneth cell loss in mice. In vitro, cultured ErbB4(-/-) ileal epithelial enteroids had reduced Paneth cell markers and were highly sensitive to inflammatory cytokines. Furthermore, NRG4 blocked, through a Src-dependent pathway, Cronobacter muytjensii-induced IEC-6 cell apoptosis. The potential clinical relevance of these findings was demonstrated by the observation that NRG4 and its receptor ErbB4 are present in human breast milk and developing human intestine, respectively. Thus, NRG4-ErbB4 signaling may be a novel pathway for therapeutic intervention or prevention in NEC.