A novel mutation in intron 1 of Wnt1 causes developmental loss of dopaminergic neurons in midbrain and ASD-like behaviors in rats.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with a strong genetic liability. Despite extensive studies, however, the underlying pathogenic mechanism still remains elusive. In the present study, we identified a homozygous mutation in the intron 1 of Wnt1 via large-scale screening of ASD risk/causative genes and verified that this mutation created a new splicing donor site in the intron 1, and consequently, a decrease of WNT1 expression. Interestingly, humanized rat models harboring this mutation exhibited robust ASD-like behaviors including impaired ultrasonic vocalization (USV), decreased social interactions, and restricted and repetitive behaviors. Moreover, in the substantia nigra compacta (SNpc) and the ventral tegmental area (VTA) of mutant rats, dopaminergic (DAergic) neurons were dramatically lost, together with a comparable decrease in striatal DAergic fibers. Furthermore, using single-cell RNA sequencing, we demonstrated that the decreased DAergic neurons in these midbrain areas might attribute to a shift of the boundary of the local pool of progenitor cells from the hypothalamic floor plate to the midbrain floor plate during the early embryonic stage. Moreover, treatments of mutant rats with levodopa could attenuate the impaired USV and social interactions almost completely, but not the restricted and repetitive behaviors. Our results for the first time documented that the developmental loss of DAergic neurons in the midbrain underlies the pathogenesis of ASD, and that the abnormal progenitor cell patterning is a cellular underpinning for this developmental DAergic neuronal loss. Importantly, the effective dopamine therapy suggests a translational significance in the treatment of ASD.

NR1 Splicing Variant NR1a in Cerebellar Granule Neurons Constitutes a Better Motor Learning in the Mouse.

As an excitatory neuron in the cerebellum, the granule cells play a crucial role in motor learning. The assembly of NMDAR in these neurons varies in developmental stages, while the significance of this variety is still not clear. In this study, we found that motor training could specially upregulate the expression level of NR1a, a splicing form of NR1 subunit. Interestingly, overexpression of this splicing variant in a cerebellar granule cell-specific manner dramatically elevated the NMDAR binding activity. Furthermore, the NR1a transgenic mice did not only show an enhanced motor learning, but also exhibit a higher efficacy for motor training in motor learning. Our results suggested that as a "junior" receptor, NR1a facilitates NMDAR activity as well as motor skill learning.

Impact of a Telephone Intervention on Bowel Preparation Quality for Colonoscopy in the Elderly.

Bowel preparation is the basis of colonoscopy, and adequate bowel preparation is essential to the success of colonoscopy. Studies have been reported that telephone intervention can improve the quality of bowel preparation, while it remains unclear regarding effectiveness with the elderly. The purpose of this study was to evaluate the effect of telephone intervention on the quality of bowel preparation for colonoscopy in elderly outpatients. In total, 162 outpatients older than 65 years were enrolled and randomly divided into a control group and a study group. Patients in the study group were re-educated through telephone by a specific nurse 2 days before colonoscopy, whereas participants in the control group received education only on the day of appointment. The Ottawa score was used to evaluate the quality of bowel preparation between the two groups. In this study, no significant differences were observed in age, gender, body mass index, educational level, smoking and/or alcohol drinking, waiting time to colonoscopy, reasons for colonoscopy, and colonoscopic findings between the control group and the study group. Participants in the study group had higher adequate bowel preparation and compliance than the control group (83.1% vs. 59.5%, p = .03; 96.4% vs. 74.7%, p < .001). Univariate analysis showed that only noncompliance with start time was significantly associated with satisfactory bowel preparation in elderly patients. In conclusion, telephone intervention 2 days before colonoscopy can improve the quality of bowel preparation in the elderly.

Acupuncture for obesity and related diseases: Insight for regulating neural circuit.

Obesity is defined as abnormal or excessive fat accumulation that may impair health. Obesity is associated with numerous pathological changes including insulin resistance, fatty liver, hyperlipidemias, and other obesity-related diseases. These comorbidities comprise a significant public health threat. Existing anti-obesity drugs have been limited by side effects that include depression, suicidal thoughts, cardiovascular complications and stroke. Acupuncture treatment has been shown to be effective for treating obesity and obesity-related conditions, while avoiding side effects. However, the mechanisms of acupuncture in treating obesity-related diseases, especially its effect on neural circuits, are not well understood. A growing body of research has studied acupuncture's effects on the endocrine system and other mechanisms related to the regulation of neural circuits. In this article, recent research that was relevant to the use of acupuncture to treat obesity and obesity-related diseases through the neuroendocrine system, as well as some neural circuits involved, was summarized. Based on this, acupuncture's potential ability to regulate neural circuits and its mechanisms of action in the endocrine system were reviewed, leading to a deeper mechanistic understanding of acupuncture's effects and providing insight and direction for future research about obesity. Please cite this article as: Jiang LY, Tian J, Yang YN, Jia SH, Shu Q. Acupuncture for obesity and related diseases: insight for regulating neural circuit. J Integr Med. 2024; 22(2): 93-101.

Factors affecting the effectiveness of oral ibuprofen in the treatment of patent ductus arteriosus in preterm infants.

Background Data on the effectiveness of oral ibuprofen treatment for patent ductus arteriosus are limited, and the factors affecting its effectiveness remain unclear. Objective The aim was to identify the potential factors affecting the clinical effectiveness of oral ibuprofen in preterm infants. Setting Neonatal intensive care unit in a prefecture-level maternal and child healthcare hospital in China. Method Over a 5-years period, the medical records of 327 preterm infants with patent ductus arteriosus who were admitted to the neonatal intensive care unit of our hospital to receive a single course of oral ibuprofen were retrospectively reviewed. Main outcome measures The prevalence of risk factors affecting the effectiveness of oral ibuprofen. Results In total, 201 (61.47%) preterm infants were considered to have undergone "effective therapy" and classified accordingly, whereas 11 (3.36%) showed certain adverse events. Factors affecting therapeutic effectiveness were postnatal age at the initiation of treatment and Day 1/Day 0 ratio of urine output/fluid intake during the treatment course, with odds ratios of 0.892 (95% CI: 0.835-0.953; P = 0.001) and 0.473 (95% CI 0.265-0.845; P = 0.011), respectively. Conclusion A single course of oral ibuprofen for patent ductus arteriosus closure among preterm infants is effective and safe. Preterm infants with postnatal age of ≤ 9 days at the initiation of treatment and Day 1/Day 0 ratio of ≤ 0.708 of the urine output/fluid intake during the treatment course can be considered predictors of effectiveness of patent ductus arteriosus.