Dataset Information

Brain size reductions associated with endothelin B receptor mutation, a cause of Hirschsprung's disease.

ABSTRACT:

Background

ET_B has been reported to regulate neurogenesis and vasoregulation in foetal development. Its dysfunction was known to cause HSCR, an aganglionic colonic disorder with syndromic forms reported to associate with both small heads and developmental delay. We therefore asked, "is CNS maldevelopment a more general feature of ET_B mutation?" To investigate, we reviewed the micro-CT scans of an ET_B^-/- model animal, sl/sl rat, and quantitatively evaluated the structural changes of its brain constituents.

Methods

Eleven neonatal rats generated from ET_B^+/- cross breeding were sacrificed. Micro-CT scans were completed following 1.5% iodine-staining protocols. All scans were reviewed for morphological changes. Selected organs were segmented semi-automatically post-NLM filtering: TBr, T-CC, T-CP, OB, Med, Cer, Pit, and S&I Col. Volumetric measurements were made using Drishti rendering software. Rat genotyping was completed following analysis. Statistical comparisons on organ volume, organ growth rate, and organ volume/bodyweight ratios were made between sl/sl and the control groups based on autosomal recessive inheritance. One-way ANOVA was also performed to evaluate potential dose-dependent effect.

Results

sl/sl rat has 16.32% lower body weight with 3.53% lower growth rate than the control group. Gross intracranial morphology was preserved in sl/sl rats. However, significant volumetric reduction of 20.33% was detected in TBr; similar reductions were extended to the measurements of T-CC, T-CP, OB, Med, and Pit. Consistently, lower brain and selected constituent growth rates were detected in sl/sl rat, ranging from 6.21% to 11.51% reduction. Lower organ volume/bodyweight ratio was detected in sl/sl rats, reflecting disproportional neural changes with respect to body size. No consistent linear relationships exist between ET_B copies and intracranial organ size or growth rates.

Conclusion

Although ET_B^-/- mutant has a normal CNS morphology, significant size reductions in brain and constituents were detected. These structural changes likely arise from a combination of factors secondary to dysfunctional ET-1/ET-3/ET_B signalling, including global growth impairment from HSCR-induced malnutrition and dysregulations in the neurogenesis, angiogenesis, and cerebral vascular control. These changes have important clinical implications, such as autonomic dysfunction or intellectual delay. Although further human study is warranted, our study suggested comprehensive managements are required for HSCR patients, at least in ET_B^-/- subtype.

SUBMITTER: Chen KC

PROVIDER: S-EPMC8214790 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Hirschsprung's disease (HSCR) is characterized by aganglionosis from failure of neural crest cell (NCC) migration to the distal hindgut. Up to 40% of HSCR patients suffer Hirschsprung's-associated enterocolitis (HAEC), with an incidence that is unchanged from the pre-operative to the post-operative state. Recent reports indicate that signaling pathways involved in NCC migration may also be involved in the development of secondary lymphoid organs. We hypothesize that gastrointestinal (GI) mucosal immune defects occur in HSCR that may contribute to enterocolitis. EdnrB was deleted from the neural crest (EdnrBNCC-/-) resulting in mutants with defective NCC migration, distal colonic aganglionosis and the development of enterocolitis. The mucosal immune apparatus of these mice was interrogated at post-natal day (P) 21-24, prior to histological signs of enterocolitis. We found that EdnrBNCC-/- display lymphopenia of their Peyer's Patches, the major inductive site of GI mucosal immunity. EdnrBNCC-/- Peyer's Patches demonstrate decreased B-lymphocytes, specifically IgM+IgDhi (Mature) B-lymphocytes, which are normally activated and produce IgA following antigen presentation. EdnrBNCC-/- animals demonstrate decreased small intestinal secretory IgA, but unchanged nasal and bronchial airway secretory IgA, indicating a gut-specific defect in IgA production or secretion. In the spleen, which is the primary source of IgA-producing Mature B-lymphocytes, EdnrBNCC-/- animals display decreased B-lymphocytes, but an increase in Mature B-lymphocytes. EdnrBNCC-/- spleens are also small and show altered architecture, with decreased red pulp and a paucity of B-lymphocytes in the germinal centers and marginal zone. Taken together, these findings suggest impaired GI mucosal immunity in EdnrBNCC-/- animals, with the spleen as a potential site of the defect. These findings build upon the growing body of literature that suggests that intestinal defects in HSCR are not restricted to the aganglionic colon but extend proximally, even into the ganglionated small intestine and immune cells.

Project description:To test prospectively in hypertensives whether moderate and vigorous exercise produces equivalent reductions in mortality, Cox-proportional hazard analyses were applied to energy expenditure (metabolic equivalents hours/d [METh/d]) in 6973 walkers and 3907 runners who used hypertensive medications at baseline. A total of 1121 died during 10.2-year follow-up: 695 cardiovascular disease (International Classification of Diseases, Tenth Revision [ICD10] I00-99; 465 underlying cause and 230 contributing cause), 124 cerebrovascular disease, 353 ischemic heart disease (ICD10 I20-25; 257 underlying and 96 contributing), 122 heart failure (ICD10 I50; 24 underlying and 98 contributing), and 260 dysrhythmias (ICD10 I46-49; 24 underlying and 236 contributing). Relative to <1.07 METh/d, running or walking 1.8 to 3.6 METh/d produced significantly lower all-cause (29% reduction; 95% confidence interval [CI], 17%-39%; P=0.0001), cardiovascular disease (34% reduction; 95% CI, 20%-46%; P=0.0001), cerebrovascular disease (55% reduction; 95% CI, 27%-73%; P=0.001), dysrhythmia (47% reduction; 95% CI, 27%-62%; P=0.0001), and heart failure mortality (51% reduction; 95% CI, 21%-70%; P=0.003), as did ≥ 3.6 METh/d with all-cause (22% reduction; 95% CI, 6%-35%; P=0.005), cardiovascular disease (36% reduction; 95% CI, 19%-50%; P=0.0002), cerebrovascular disease (47% reduction; 95% CI, 6%-71%; P=0.03), and dysrhythmia mortality (43% reduction; 95% CI, 16%-62%; P=0.004). Diabetes mellitus and chronic kidney disease mortality also decreased significantly with METh/d. All results remained significant when body mass index adjusted. Merely meeting guideline levels (1.07-1.8 METh/d) did not significantly reduced mortality. The dose-response was significantly nonlinear for all end points except diabetes mellitus, and cerebrovascular and chronic kidney disease. Results did not differ between running and walking. Thus, walking and running produce similar reductions in mortality in hypertensives.