Clinical and genetic features of a case with juvenile onset sandhoff disease.

BACKGROUND: Sandhoff disease (SD) is a rare neurological disease with high clinical heterogeneity. SD in juvenile form is much rarer and it is often misdiagnosed in clinics. Therein, it is necessary to provide more cases and review the literature on juvenile onset SD. CASE PRESENTATION: A 14 years-old boy with eight years of walking difficulties, and was ever misdiagnosed as spinocerebellar ataxia. We found this patient after genetic testing carried rs201580118 and a novel gross deletion in HEXB (g.74012742_74052694del). Through review the literature, we found that was the first gross deletion identified at the 3'end of HEXB, associated with juvenile onset SD from China. CONCLUSION: This case expanded our knowledge about the genotype and phenotype correlations in SD. Comprehensive genetic testing is important for the diagnosis of unexplained ataxia.

Neuropathological report of propionic acidemia.

Propionic acidemia (PA) is an autosomal recessive inheritable metabolic disease caused by mutations in the propionyl CoA carboxylase gene (PCC) that affects multiple systems of the human body. Here, we report neuropathological findings of a PA patient. The patient was a male infant who presented with increasing lethargy and poor feeding from four days postpartum. He gradually became comatose and died from complications after liver transplantation at three months old. The results of laboratory examination were consistent with PA, and genetic analysis revealed compound heterozygous mutations in the gene for PCC subunit beta: c.838dupC (rs769968548) and c.1127G>T (rs142982097). Brain-restricted autopsy was performed 23 h after his death, and the neuropathological examination revealed distinct astrocytosis, oligodendrocytic loss, neuronal loss, and demyelination across the brainstem, motor cortex, basal ganglia, and thalamus. Spongiosis, vacuolization, and the appearance of Alzheimer type II astrocytes and activated microglia were observed as well. This is the first brain autopsy report of PA with a clear genetic cause.

Post-infarction ventricular septal rupture complicated with cardiogenic shock and multiple organ hemorrhage: An autopsy case report.

Ventricular septal rupture (VSR) is a catastrophic mechanical complication of acute myocardial infarction (AMI) that can result in acute heart failure. Delaying operative intervention frequently leads to cardiogenic shock and multi-organ failure. Here we report a case of massive anterior MI complicated with VSR that was discovered through cardiac Doppler ultrasound and suspected multiple organ hemorrhage. The patient showed signs of rapid cardiogenic shock and eventually died. The morphological changes of VSR and MI were identified during necropsy, and microscopic examinations of the heart, brain, and kidney revealed multiple organ hemorrhage. This autopsy case suggested that the complication of VSR caused by AMI results in a reduction of oxygen and nutrient content of the circulating blood throughout the body and, eventually, functional failure of multiple organs. We provide clinical and pathological evidence elucidating changes in multiple organs under the severe condition of post-infarction VSR and demonstrate the consequences of a lack of immediate surgery and sufficient medical intervention for a patient suffering from AMI with VSR.

Genetic and Molecular Evaluation of SQSTM1/p62 on the Neuropathologies of Alzheimer's Disease.

Sequestosome 1 (SQSTM1)/p62 is a multifunctional scaffolding protein and plays a major role in the cellular processes of autophagy, upregulation of which has been shown in several neurodegenerative disorders, including Alzheimer's disease (AD). To investigate its genetic effects and relationship with AD pathologies, we analyzed the genetic associations of SQSTM1 rs4935 with the risk of AD and the levels of AD biomarkers using the AD Neuroimaging Initiative (ADNI) Database. We further analyzed the distribution pattern of p62 immunoreactivity in relation to AD pathologies in the postmortem human brain tissues from AD and non-AD controls. We found that SQSTM1 rs4935 was not associated with the risk of AD, but its T allele was significantly associated with decreased ß-amyloid (1-42) (Aß42) levels in the cerebral spinal fluid (CSF) of patients with AD (ß = -9.336, p = 0.022). In addition, p62 immunoreactivity in AD is increased, but it shows an inverse relationship to Aß deposition. A small proportion of senile plaques show p62 positive neurites. Our results suggest that SQSTM1/p62 may play an important role in the progression of AD via associations with Aß42 levels in CSF and Aß deposition in the brain of patients with AD.

Non-motor symptoms in multiple system atrophy: A comparative study with Parkinson's disease and progressive supranuclear palsy.

Background: Non-motor symptoms (NMS) are compulsory clinical features for the clinical diagnosis of multiple system atrophy (MSA), some of which precede motor symptoms onset. To date, few studies have systematically investigated NMS in MSA and the timing of presenting NMS as the disease progresses. Clinically, MSA is difficult to be differentiated from Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and the differences in NMS between MSA and PD/PSP remain unclear. The aim of this study was to compare the burden of NMS between MSA and PD/PSP and to delineate the timing of NMS presentation relative to the onset of motor symptoms in MSA. Methods: A total of 61, 87, and 30 patients with MSA, PD, and PSP, respectively, were enrolled in this study. NMS was systematically assessed in all patients using the NMS scale (NMSS), and the onset of NMS relative to the onset of motor symptoms in MSA was investigated. Results: MSA group had higher total NMSS scores (82.15 ± 46.10) than the PD (36.14 ± 30.78) and PSP (50.30 ± 55.05) groups (p < 0.001 overall). The number distribution pattern of the NMS was significantly different among the three parkinsonian disorders (p < 0.001 overall). In total, 85.2% of patients with MSA had more than 10 NMS, which was significantly higher than PD (28.7%) and PSP (33.3%). The frequency and scores of many NMSS subdomains and symptoms were higher in MSA than in PD and PSP (all p < 0.05). Multivariate logistic regression analysis revealed that patients with fainting, lack of motivation, swallowing, and loss of sexual interest could be attributed to MSA rather than PD or PSP, while patients with loss of concentration and forgetfulness were characteristic features of PD or PSP rather than MSA. REM-sleep behavior disorder (RBD), constipation, problems having sex, and loss of sexual interest preceded the motor symptoms onset of MSA by 2.81 ± 4.51, 1.54 ± 6.32, 1.35 ± 4.70, and 0.45 ± 3.61 years, respectively. Conclusion: The NMS spectrum in MSA differs from that of PD and PSP. Patients with MSA have a higher NMS burden than patients with PD or PSP. RBD, constipation, problems having sex, and loss of sexual interest may become early diagnostic clinical markers of MSA.

Prevalence of Constipation in Elderly and Its Association With Dementia and Mild Cognitive Impairment: A Cross-Sectional Study.

BACKGROUND: Constipation and dementia have similar epidemiological characteristics. Changes in intestinal flora and characteristics of the brain-gut axis play roles in the pathogeneses of the two diseases, suggesting that there may be a close connection between the two. Most of the studies on constipation in dementia patients have focused on the population with α-synucleinopathies [Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB)]. Few studies have reported the prevalence of constipation in all-cause dementia and mild cognitive impairment (MCI) populations. OBJECTIVE: To assess the prevalence of constipation in patients with all-cause dementia and MCI subtypes and to explore the association between constipation with dementia and MCI subtypes. METHODS: From May 2019 to December 2019, we conducted a population-based cross-sectional survey. A total of 11,743 participants aged 65 or older from nine cities in China were surveyed. Participants underwent a series of clinical examinations and neuropsychological measurements. Constipation, dementia, MCI and MCI subtype were diagnosed according to established criteria through standard diagnostic procedures. RESULTS: The overall age- and sex-adjusted prevalence of constipation in individuals aged 65 years and older was 14.8% (95% CI, 14.6-15.0). The prevalence rates of constipation were19.2% (95% CI, 17.3-21.0), 19.1% (95% CI, 16.8-21.5), 14.4% (95% CI, 12.8-15.9), and 13.8% (95% CI, 13.0-14.6) in the dementia, non-amnestic (na)-MCI, amnestic (a)-MCI and normal cognition populations, respectively. Multivariate logistic regression analysis showed that higher prevalence of constipation was associated with dementia (p = 0.0.032, OR = 1.18, 95% CI: 1.02-1.38) and na-MCI (p = 0.003, OR = 1.30, 95% CI: 1.09-1.54). CONCLUSION: The present study found a high prevalence of constipation in elderly individuals in China, and higher in patients with dementia and na-MCI.

Neuroprotective effects of naloxone against light-induced photoreceptor degeneration through inhibiting retinal microglial activation.

PURPOSE: To determine the role of microglial activation in light-induced photoreceptor degeneration and the neuroprotective effects of naloxone as a novel microglial inhibitor. METHODS: Sprague-Dawley rats were exposed to intense blue light for 24 hours. Daily intraperitoneal injection of naloxone or PBS as a control was given 2 days before exposure to light and was continued for 2 weeks. Apoptotic cells were detected by the TUNEL assay, and anti-OX42 antibody was used to label retinal microglia. Western blot was applied to evaluate the retinal interleukin (IL)-1beta protein levels. Retinal histologic examination and electroretinography (ERG) were also performed to evaluate the effects of naloxone on light-induced photoreceptor degeneration. RESULTS: TUNEL-positive cells were noted in the outer nuclear layer (ONL) of the retina as early as 2 hours and peaked at 24 hours after exposure to light. OX42-positive microglia occurred in the ONL and subretinal space at 6 hours, peaked at 3 days, and changed morphologically from the resting ramified to the activated amoeboid. Expression of IL-1beta protein was also significantly increased at 3 days. Compared with the control, the number of microglia in the outer retina was significantly decreased in the naloxone-treated group at 3 days, and the thickness of ONL and the amplitudes of dark-adapted a- and b-waves were also well preserved at 14 days. CONCLUSIONS: The activation and migration of microglia and the expression of neurotoxic factor (IL-1beta) coincide with photoreceptor apoptosis, suggesting that activated microglia play a major role in light-induced photoreceptor degeneration. Inhibiting microglial activation by naloxone significantly reduces this degeneration.

The cytotoxic and mechanistic effects of aaptamine on hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the third most frequent cause of cancer-associated mortality worldwide. We isolated aaptamine from the marine sponge Aaptos, and synthesized derivatives of this compound. Aaptamine and synthetic derivatives displayed various biological activities. This represents the first account of studies on the effects of aaptamine and its derivatives in hepatocarcinogenesis. In this study, Cell Counting Kit (CCK8) was used to evaluate the anti-proliferative effect of aaptamine on HCC in vitro. Additionally, a subcutaneous xenograft model was used to determine if aaptamine could inhibit hepatocellular carcinoma in vivo. We also used RT-PCR and Western blot to analyze the mechanisms behind these effects. Our results showed that aaptamine has anti-proliferation effects on the cell lines LM3 and HepG2. Aaptamine also suppressed the colony-formation ability of HCC cells. We found that aaptamine treatment led to cell cycle arrest in HCC cells, reduced the expression of SOX9 and CDK2. Significant anti-tumor effects were observed in aaptamine-administered tumor-bearing mice as compared to controls. However, structural changes made to aaptamine yielded two derivatives for which all the effects listed above were considerably reduced as compared to the original compound aaptamine. In conclusion, aaptamine is demonstrated for the first time to inhibit liver cancer progression. The aaptamine-induced cell cycle arrest was associated with the increased binding of p21 to Cdk2-cyclin D/E complexes, inhibition of Cdk2 kinase activity in HCC cells. Furthermore, aaptamine appears to be a promising and efficient treatment of liver cancer HCC-LM3 in vivo. We have also uncovered structural changes that might affect the biological activity. The work provides a promising drug candidate for HCC treatment.

[Effects of pirenzepine on lens-induced myopia in the guinea-pig].

OBJECTIVE: To determine the efficacy of the M(1)-selective muscarinic antagonist, pirenzepine, in preventing lens-induced myopia in the guinea-pig and to study the mechanism and the possibility of treatment of myopia with pirenzepine. METHODS: Fifteen 4-week-old guinea-pigs were monocularly fitted with -10.00 D lenses for a period of 11 days. In Group I (n = 7), both eyes received topical administration of 0.24% saline vehicle as the controls. In Group II (n = 8), the lens-fitted eyes were topically treated with 10% pirenzepine, while the other eyes received the vehicle control. Ocular refraction and biometric measurements were collected on the first and the 11th days. All eyes were finally enucleated for histopathological examination to evaluate the possible toxic effects of pirenzepine. RESULTS: In Group I, 11 days of lens-fitting produced -2.45 D myopia (t = 3.141, P < 0.05) with 0.05 mm elongation of axial dimension (t = 2.500, P < 0.05) as compared to the contralateral eyes. There were no significantly differences of refractive error and axial dimensions between the experimental eyes and the controls in Group II. Histological examinations revealed no obviously toxic effects in the pirenzepine-treated eyes. CONCLUSIONS: Topical administration of the M(1)-selective muscarinic antagonist, pirenzepine, prevents lens-induced experimental myopia in guinea-pig by inhibiting the elongation of axial dimension with no obvious damage to the ocular tissues.

Comparing pegaptanib and triamcinolone efficacy in the rat choroidal neovascularization model.

OBJECTIVE: To evaluate the prophylactic effect of intravitreal pegaptanib sodium on choroidal neovascularization membrane (CNVM) development and compare its performance with that of triamcinolone acetonide. METHODS: In drug-treated and control groups, CNVMs were induced by laser trauma. Immediately after undergoing the laser procedure, animals received intravitreal injections of pegaptanib sodium, 8 or 17 mug; triamcinolone acetonide, 200 mug; or a vehicle solution. After 21 days, fluorescein angiography was performed. The CNVM mean diameters and radial thicknesses were measured histologically. RESULTS: Mean CNVM diameters were 10% to 13% smaller in pegaptanib-treated eyes and 43% smaller in triamcinolone-treated eyes compared with laser-only control eyes. Late-stage fluorescein angiography leakage scores, on a scale of 0 to 3, suggested a statistical difference between triamcinolone- (0.6) and pegaptanib(8 microg)-treated (1.5) groups compared with the laser-only control group (2.0). The CNVM mean thicknesses were greater in the pegaptanib(8 microg)- (79 microm) and pegaptanib(17 microg)-treated (71 microm) groups and significantly smaller in the triamcinolone-treated group (26 microm) compared with the laser-only control group (67 microm). CONCLUSION: In this animal model of choroidal neovascularization, intravitreal pegaptanib exhibited marginal or no effect on CNVM development; whereas intravitreal triamcinolone evoked robust inhibition of CNVMs. Clinical Relevance Pegaptanib treatment may be insufficient to prevent CNVM formation.