Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in viv...Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.展开更多
We previously found that the K141N mutation in heat shock protein B8 (HSPB8) was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a tr...We previously found that the K141N mutation in heat shock protein B8 (HSPB8) was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141N HSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis confirmed integration of the KI41NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141N HSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assessment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was significantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated fiber density, notable axonal edema and vacuolar degeneration in K141N HSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the KI4mHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.展开更多
Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulatin...Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulating biochemical markers of bone turnover have been found to be decreased in type 2 diabetes (T2D) and may be predictive of fractures independently of bone mineral density (BMD). Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Bone imaging technologies, including trabecular bone score (TBS) and quantitative CT testing have revealed differences in diabetic bone as compared to non-diabetic individuals. Specifically, high resolution peripheral quantitative CT (HRpQCT) imaging has demonstrated increased cortical porosity in diabetic postmenopausal women. Other factors such as bone marrow fat saturation and advanced glycation endproduct (AGE) accumulation might also relate to bone cell function and fracture risk in diabetes. These data have increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk.展开更多
AIM To evaluate the role of small bowel capsule endoscopy(SBCE) on the reclassification of colonic inflammatory bowel disease type unclassified(IBDU).METHODS We performed a multicenter, retrospective study including p...AIM To evaluate the role of small bowel capsule endoscopy(SBCE) on the reclassification of colonic inflammatory bowel disease type unclassified(IBDU).METHODS We performed a multicenter, retrospective study including patients with IBDU undergoing SBCE, between 2002 and 2014. SBCE studies were reviewed and the inflammatory activity was evaluated by determining the Lewis score(LS). Inflammatory activity was considered significant and consistent with Crohn's disease(CD) when the LS ≥ 135. The definitive diagnosis during follow-up(minimum 12 mo following SBCE) was based on the combination of clinical, analytical, imaging, endoscopic and histological elements.RESULTS Thirty-six patients were included, 21 females(58%) with mean age at diagnosis of 33 ± 13(15-64) years. The mean follow-up time after the SBCE was 52 ± 41(12-156) mo. The SBCE revealed findings consistent with significant inflammatory activity in the small bowel(LS ≥ 135) in 9 patients(25%); in all of them the diagnosis of CD was confirmed during follow-up. In 27 patients(75%), the SBCE revealed no significant inflammatory activity(LS < 135); among these patients, the diagnosis of Ulcerative Colitis(UC) was established in 16 cases(59.3%), CD in 1 case(3.7%) and 10 patients(37%) maintained a diagnosis of IBDU during follow-up. A LS ≥ 135 at SBCE had a sensitivity = 90%, specificity = 100%, positive predictive value = 100% and negative predictive value = 94% for the diagnosis of CD.CONCLUSION SBCE proved to be fundamental in the reclassification of patients with IBDU. Absence of significant inflammatory activity in the small intestine allowed exclusion of CD in 94% of cases.展开更多
Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or...Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.展开更多
Niemann-Pick disease type C(NPC) is a fatal, neurovisceral lipid storage disease, neuropathologically characterized by cytoplasmic sequestration of glycolipids in neurons, progressive neuronal loss, neurofibrillary ...Niemann-Pick disease type C(NPC) is a fatal, neurovisceral lipid storage disease, neuropathologically characterized by cytoplasmic sequestration of glycolipids in neurons, progressive neuronal loss, neurofibrillary tangles(NFTs) formation, and axonal spheroids(AS). Cytoskeletal pathology including accumulation of hyperphosphorylated cytoskeletal proteins is a neuropathological hallmark of the mouse model of NPC(npc mice). With a goal of elucidating the mechanisms underlying the lesion formation, we investigated the temporal and spatial characteristics of cytoskeletal lesions and the roles of cdc2, cdk4, and cdk5 in lesion formation in young npc mice. Cytoskeletal lesions were detectable in npc mice at three weeks of age. Importantly, concomitant activation of cdc2/cyclin B1 kinase and accumulation of a subsequently generated cohort of phospho-epitopes were detected. The activation of cdk4/cyclin D1 and cdk5/p25 kinases was observed during the fourth week of life in npc mice, and this activation contributed to the lesion formation. We concluded that the progression of cytoskeletal pathology in npc mice older than four weeks is accelerated by the cumulative effect of cdc2, cdk4, and cdk5 activation. Furthermore, cdc2/cyclin B1 may act as a key initial player one week earlier. Targeting cell cycle activation may be beneficial to slow down the NPC pathogenesis.展开更多
In order to investigate the neuroprotective effects of cyclin-dependent kinase-5 (cdk-5) inhibition in mice with Niemarm-Pick disease type C (NPC) (npc^-/-), recombinant adeno-associated virus (rAAV) carrying ...In order to investigate the neuroprotective effects of cyclin-dependent kinase-5 (cdk-5) inhibition in mice with Niemarm-Pick disease type C (NPC) (npc^-/-), recombinant adeno-associated virus (rAAV) carrying the small interfering RNA (siRNA) specific for cdk-5 gene was injected into 3-day-old npc^-/- mice intracerebroventricularly. The rAAV-GFP-injected age-matched npc^-/- mice and non-surgery age-matched npc^-/- mice were employed as controls (n=6-10/group). From the 4th to 8th week after the treatment, mice were weighed, and evaluated for limb motor activity by using the coat hanger test once a week. Eight-week-old npc^-/- mice were sacrificed by decapitation, and brains were quickly dissected and halved sagittally. Immunohistochemistry, Western blotting, and HE staining were used to evaluate the neuropathology in npc^-/- mice. The results showed that rAAV-cdk-5-siRNA-GFP significantly reduced the number of axonal spheroids, delayed the death of Purkinje neurons, ameliorated motor defects in npc^-/- mice, and significantly attenuated the hyperphosphorylation oftau proteins. These data suggested that inhibition of cdk-5 activity has neuroprotective effect on neurons in NPC mice.展开更多
BACKGROUND Glycogen storage disease type Ia(GSDIa) is an autosomal recessive inborn error of carbohydrate metabolism that is caused by deficiency of the enzyme glucose-6-phosphatase(G6Pase),leading to disturbed glycog...BACKGROUND Glycogen storage disease type Ia(GSDIa) is an autosomal recessive inborn error of carbohydrate metabolism that is caused by deficiency of the enzyme glucose-6-phosphatase(G6Pase),leading to disturbed glycogenolysis and gluconeogenesis.Patients with GSDIa show severe fasting hypoglycemia,hyperlipidemia,hyperlactacidemia,and hyperuricemia,which are associated with fatal outcomes in pregnant women and fetuses.CASE SUMMARY Herein,we report the case of a 24-year-old female who on her first visit to the hospital,presented with pregnancy combined with extremely high hyperlipidemia and hyperlactic acidosis with anemia,and frequent hypoglycemia occurred during the treatment.Genetic tests revealed a mutation in the G6Pase gene(G6PC) at 17q21,the patient was finally diagnosed with glycogen storage disease type Ia for the first time after 22 years of inaccurate treatment.She has been treated with a continuous double filtration plasmapheresis(DFPP) strategy to remove blood lipids,and a cornstarch diet therapy.The patient did not develop pancreatitis during the course of the disease and a healthy baby girl weighing 3 kg was delivered.CONCLUSION Patients with GSDIa may be misdiagnosed as epilepsy.DFPP can be used to control hyperlipidemia in GSDIa patients during pregnancy.展开更多
BACKGROUND A patient with type Ⅲ Kummell’s disease had a ruptured posterior cortex of the fractured vertebral body, which caused spinal cord compression. An open surgery was considered the best choice of operation. ...BACKGROUND A patient with type Ⅲ Kummell’s disease had a ruptured posterior cortex of the fractured vertebral body, which caused spinal cord compression. An open surgery was considered the best choice of operation. However, the patient and her family refused open surgery and instead demanded a minimally invasive surgical treatment such as percutaneous vertebroplasty(PVP). After preoperative discussion, we finally adopted the novel therapy of traditional Chinese medicine manipulative reduction(TCMMR) combined with PVP.CASE SUMMARY A patient with type Ⅲ Kummell’s disease exhibiting bone block-induced spinal cord compression was admitted to our hospital. She suffered from a variety of medical disorders but refused open surgery, and instead asked for PVP surgery. TCMMR, in parallel with PVP, was used to restore the height of the compressed vertebral body and reduce the symptoms of spinal cord compression by the bone block in order to strengthen the vertebral body and prevent further collapse. The surgery was very successful. The height of the compressed vertebra was restored, and the symptom of spinal cord compression by bone block was reduced successfully via TCMMR. The fractured vertebra was solidified by the PVP. The pain visual analog score declined from preoperative 7 scores to postoperative 2 scores, and the Frankel spinal cord scale increased from preoperative D degree to postoperative E degree.CONCLUSION The new method has advantages in treating patients with type Ⅲ Kummell’s disease who cannot be treated with open surgery.展开更多
Objectives To study clini- cal and coronary angiographic findings in patients with both coronary heart diseases (CHD) and type 2 diabe- tes mellitus (T2DM). Methods 215 patients with CHD confirmed by coronary angiogra...Objectives To study clini- cal and coronary angiographic findings in patients with both coronary heart diseases (CHD) and type 2 diabe- tes mellitus (T2DM). Methods 215 patients with CHD confirmed by coronary angiography were involved in this study. The patients were divided into two groups: 74 CHD patients with T2DM (mean age 64.7 ± 8.2 years, male/female 47/27), and 141 CHD pa- tients without T2DM ( mean age 66. 2 ±9. 2 years, male/female 100/41 ). The clinical features and the data from selective coronary angiographies were com- pared between type 2 diabetic and non - diabetic CHD patients. Results Compared to non - diabetic CHD patients, the patients with both CHD and T2DM suf- fered more from acute myocardial infarction, silent is- chemia and severe arrhythmias ( P < 0. 01, P < 0. 05 ) , and had higher serum triglycerides and apo - lipoprotein B, along with increased serum uric acid (P < 0. 01, P < 0.05), increased left ventricular end diastolic diameter ( P < 0. 01 ) , and decreased left ventricular ejection fraction ( P < 0. 001 ). Compared to non - diabetic CHD patients, the patients with both CHD and T2DM suffered more from triple vessel disease (P < 0. 01) , severe coronary artery stenosis, complete occlusions and diffuse lesions ( P < 0. 001). Conclusions Se- vere clinical manifestation, left ventricular dysfunction, diffuse or complicated lesions of coronary arteries weremore common in patients with both CHD and T2DM, it suggests that the type 2 diabetic CHD patients have poor prognosis.展开更多
Pompe disease (PD) is a rare inborn error of metabolism due to an abnormal acid alpha-glucosidase (GAA) activity that comprises glycogen breakdown mainly in the lysosomes. Since the introduction of enzyme replacement ...Pompe disease (PD) is a rare inborn error of metabolism due to an abnormal acid alpha-glucosidase (GAA) activity that comprises glycogen breakdown mainly in the lysosomes. Since the introduction of enzyme replacement therapy (ERT), with recombinant human GAA for the early onset PD patient, a relevant field of clinical research due to the benefits regarding survival rate has been widely documented worldwide. Objective: To describe the clinical characteristics and the ERT effects in a series of Brazilian patients with infantile onset PD (IOPD) under ERT. Methods: Brazilian patients diagnosed with IOPD under ERT were recruited through their physicians participating in the International Pompe Disease Registry from 2009 to 2017. Data were collected by an online survey. Results: 10 IOPD patients were identified through the survey with a death rate of 30% and technology dependency rate reported as 80% (motor, respiratory or nutritional fields) of the patients. After the third year of ERT, motor disabilities were lost in 50% of ambulated patients. The overall characteristics were similar to international studies. Conclusion: Despite ERT benefits in cardiac involvement, motor disabilities seem to be much more compromised in IOPD patients, with high technology dependence, especially after three years of age.展开更多
Objective:This study was undertaken to evaluate the clinical efficacy of Western medicine combined with Chinese medicine for pelvic inflammatory disease(damp-heat and stasis type).Methods:Seventy-four patients who wer...Objective:This study was undertaken to evaluate the clinical efficacy of Western medicine combined with Chinese medicine for pelvic inflammatory disease(damp-heat and stasis type).Methods:Seventy-four patients who were diagnosed with pelvic inflammatory disease(damp-heat and stasis type)by our hospital during July 2021 to July 2022 were randomized into two groups:the participants in the control group received conventional Western medicine treatment,and the participants in the study group received Western medicine combined with Chinese medicine.Results:After treatment,the total effectiveness of the control group(72.98%)was significantly lower than that of the study group(94.59%),(P<0.05);the whole blood viscosity high cut,whole blood viscosity low cut,fibrinogen and plasma viscosity of the control group were all lower than those of the study group(P<0.05);the levels of CRP,IL-6,and TNF-αin the control group were higher and IL-2 levels in the control group were lower than those in the study group(P<0.05).Conclusion:Western medicine combined with Chinese medicine is more effective in curing damp-heat and stasis-type pelvic inflammatory disease by improving the blood rheological indexes and lowering the level of inflammatory factors.展开更多
Objective Modified upper abdominal cluster transplantation ( MCT) ,which was inspired by classical cluster transplant technique,has been proven more effective and feasible in the treatment of patients with end stage l...Objective Modified upper abdominal cluster transplantation ( MCT) ,which was inspired by classical cluster transplant technique,has been proven more effective and feasible in the treatment of patients with end stage liver diseases associated with insulin - dependent展开更多
BACKGROUND Glycogen storage disease type Ib(GSD-Ib)is a glycogen metabolism disorder that leads to the manifestations of inflammatory bowel disease(IBD),especially Crohn’s disease(CD)-like colitis.Although biological...BACKGROUND Glycogen storage disease type Ib(GSD-Ib)is a glycogen metabolism disorder that leads to the manifestations of inflammatory bowel disease(IBD),especially Crohn’s disease(CD)-like colitis.Although biological agents are effective for treating CD,their application in the treatment of GSD-Ib with CD-like colitis has been rarely reported.CASE SUMMARY A 13-year-old Han male was diagnosed with GSD-Ib with CD.The patient was treated with granulocyte colony-stimulating factor.When he had symptoms of CD-like colitis,he was continuously pumped with enteral nutrition and administered oral mesalazine for 2 wk;however,the symptoms did not improve significantly.Hence,infliximab(IFX)was administered.Hitherto,the patient has been followed up for 1 year,and no clinical manifestations have been observed.After 6 mo of treatment(fifth IFX treatment),the disease activity index and all inflammatory indexes decreased,and a review of the colonoscopy data showed that the ulcers appeared smooth.CONCLUSION In this study,the patient was successfully treated with IFX.In cases of GSD-Ib,IBD should be highly considered.展开更多
Atherosclerosis is a leading underlying factor in cardiovascular disease and stroke,important causes of morbidity and mortality across the globe.Abundant epidemiological studies demonstrate that high levels of high de...Atherosclerosis is a leading underlying factor in cardiovascular disease and stroke,important causes of morbidity and mortality across the globe.Abundant epidemiological studies demonstrate that high levels of high density lipoprotein(HDL) are associated with reduced risk of atherosclerosis and preclinical,animal model studies demonstrate that this association is causative.Understanding the molecular mechanisms underlying the protective effects of HDL will allow more strategic approaches to development of HDL based therapeutics.Recent evidence suggests that an important aspect of the ability of HDL to protect against atherosclerosis is its ability to trigger signaling responses in a variety of target cells including endothelial cells and macrophages in the vessel wall.These signaling responses require the HDL receptor,scavenger receptor class B type 1(SR-B1),an adaptor protein(PDZK1) that binds to the cytosolic C terminus of SR-B1,Akt1 activation and(at least in endothelial cells) activation of endothelial NO synthase(eNOS).Mouse models of atherosclerosis,exemplified by apolipoprotein E or low density lipoprotein receptor gene inactivated mice(apoE or LDLR KO) develop atherosclerosis in their aortas but appear generally resistant to coronary artery atherosclerosis.On the other hand,inactivation of each of the components of HDL signaling(above)in either apoE or LDLR KO mice renders them susceptible to extensive coronary artery atherosclerosis suggesting that HDL signaling may play an important role in protection against coronary artery disease.展开更多
Background Adaptor proteins containing PH domain, PTB domain, and leucine zipper motif 1 and 2 (APPL1/2) play a key role in cell proliferation in many tissues. APPL1 or APPL2 as an adaptor for adiponectin receptors ...Background Adaptor proteins containing PH domain, PTB domain, and leucine zipper motif 1 and 2 (APPL1/2) play a key role in cell proliferation in many tissues. APPL1 or APPL2 as an adaptor for adiponectin receptors mediates the signaling pathway of adiponectin which acts as an anti-atherosclerotic adipokine. This study aimed to investigate whether genetic variations in the APPL 1/2 genes affect the risk of coronary artery disease (CAD) in Chinese patients with type 2 diabetes mellitus (T2DM). Methods Seven haplotype-tagging single nucleotide polymorphisms (tag-SNPs) were selected from CHB HapMap database (Phase II) and total 203 CAD-positive cases and 106 CAD-negative controls with T2DM were genotyped for the 7 tag-SNPs by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Results The minor allele G of rs4640525 at APPL1 locus was protective from CAD in patients with T2DM, with the carriers of genotype CC at higher risk of CAD compared with non-carriers (OR=2.830, 95% Cl 1.285-6.230, P=0.010; OR'=4.992, 95% C1=1.758-14.173, P'0.003, after adjustment for the other known CAD risk factors); the homozygotes of AA at rs11112412 in APPL2 gene had higher risk of CAD compared with those of GG (adjusted OFt=5.697, 95% Cl 1.006-32.257, P=0.049). Conclusion Genetic variation(s) in APPL 1/2 may be associated with CAD risk in T2DM in Chinese population.展开更多
Background Susceptibility to coronary artery disease (CAD) and diabetes is encoded by distinct, tightly-linked single nucleotide polymorphisms on chromosome 9p21. This study aimed to examine the association of varia...Background Susceptibility to coronary artery disease (CAD) and diabetes is encoded by distinct, tightly-linked single nucleotide polymorphisms on chromosome 9p21. This study aimed to examine the association of variant rs1333049 on chromosome 9p21.3 with early-onset and severity of CAD in Chinese patients with and without type 2 diabetes, and to determine the possible impact of rs1333049 on glucose metabolism and inflammation pathways. Methods Genotyping of variant rs1333049 on chromosome 9p21.3 was performed in 2387 patients with and without diabetes who were undergoing coronary angiography to evaluate suspected or established CAD. Serum levels of glucose, glycosylated hemoglobin Alc (HbAlo), insulin, high-sensitivity C-reactive protein, tumor necrosis factor-a, and interleukin-6 were also measured, and compared with each patient's genotype. Results The homozygous CC genotype of rs1333049 was significantly associated with CAD in diabetic (OR: 1.270, P=-0.044) and non-diabetic (OR: 1.369, P=0.011) patients after adjusting for traditional risk factors. There was an association between CC genotype and number of diseased vessels in diabetics (P=0.019), but not in non-diabetics (P=0.126). Among diabetic patients, CC genotype carriers had an increased risk of early-onset CAD (OR:. 2.367, ,~=-0.008) and greater cumulative atherosclerotic burden compared with non-CC genotype carriers (Gensini score: 31.80+17.20 vs. 23.09+_21.63, P=-0.039). No significant differences were observed between genotypes of rs1333049 in serum levels of glucose, insulin, HbAlc, or inflammatory cytokines for diabetic or non-diabetic patients with CAD. Conclusions This study demonstrated a significant association of rs1333049 polymorphism on chromosome 9p21.3 with CAD in Chinese diabetic and non-diabetic patients. The homozygous CC genotype of rs1333049 confers a magnified risk of early-onset and more severe CAD in diabetic patients through a novel biological pathway unrelated to glucose metabolism or inflammation.展开更多
Background: Pompe disease is a rare lysosomal glycogen storage disorder linked to the acid alpha-glucosidase gene (GAA). A wide clinical and genetic variability exists between patients from different ethnic populat...Background: Pompe disease is a rare lysosomal glycogen storage disorder linked to the acid alpha-glucosidase gene (GAA). A wide clinical and genetic variability exists between patients from different ethnic populations, and the genotype-phenotype correlations are still not well understood. The aim of this study was to report the clinicopathological and genetic characteristics of five Chinese patients with late-onset Pompe disease (LOPD) who carried novel GAA gene mutations. Methods: Clinical and pathological data of patients diagnosed with glycogen storage disease at our institution from April 1986 to August 2017 were collected, and next-generation sequencing of frozen muscle specimens was conducted. Results: Of the five patients included in the study, the median disease onset age was 13 years, with a median 5 years delay in diagnosis. The patients mainly manifested as progressive weakness in the proximal and axial muscles, while one patient developed respiratory insufficiency that required artificial ventilation. In muscle biopsies, vacuoles with variable sizes and shapes appeared inside muscle fibers, and they stained positive for both periodic acid-Schiff and acid phosphatase staining. Ten GAA gene mutations, including seven novel ones (c.796C〉A, c. 1057C〉T, c. 1201C〉A, c. 1780C〉T, c. 1799G〉C, c.2051C〉A, c.2235dupG), were identified by genetic tests. Conclusions: The seven novel GAA gene mutations revealed in this study broaden the genetic spectrum of LOPD and highlight the genetic heterogeneity in Chinese LOPD patients.展开更多
基金supported by the Natural Science Foundation of Fujian Province,No.2020J02027the National Natural Science Foundation of China,No.31970461the Foundation of NHC Key Laboratory of Technical Evaluation of Fertility Regulation for Non-human Primate,Fujian Maternity and Child Health Hospital,No.2022-NHP-05(all to WC).
文摘Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.
基金funded by the National Natural Science Foundation of China,No.81071001,30900805
文摘We previously found that the K141N mutation in heat shock protein B8 (HSPB8) was responsible for Charcot-Marie-Tooth disease type 2L in a large Chinese family. The objective of the present study was to generate a transgenic mouse model bearing the K141N mutation in the human HSPB8 gene, and to determine whether this K141NHSPB8 transgenic mouse model would manifest the clinical phenotype of Charcot-Marie-Tooth disease type 2L, and consequently be suitable for use in studies of disease pathogenesis. Transgenic mice overexpressing K141N HSPB8 were generated using K141N mutant HSPB8 cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. PCR and western blot analysis confirmed integration of the KI41NHSPB8 gene and widespread expression in tissues of the transgenic mice. The K141N HSPB8 transgenic mice exhibited decreased muscle strength in the hind limbs and impaired motor coordination, but no obvious sensory disturbance at 6 months of age by behavioral assessment. Electrophysiological analysis showed that the compound motor action potential amplitude in the sciatic nerve was significantly decreased, but motor nerve conduction velocity remained normal at 6 months of age. Pathological analysis of the sciatic nerve showed reduced myelinated fiber density, notable axonal edema and vacuolar degeneration in K141N HSPB8 transgenic mice, suggesting axonal involvement in the peripheral nerve damage in these animals. These findings indicate that the KI4mHSPB8 transgenic mouse successfully models Charcot-Marie-Tooth disease type 2L and can be used to study the pathogenesis of the disease.
文摘Substantial evidence exists that in addition to the well-known complications of diabetes, increased fracture risk is an important morbidity. This risk is probably due to altered bone properties in diabetes. Circulating biochemical markers of bone turnover have been found to be decreased in type 2 diabetes (T2D) and may be predictive of fractures independently of bone mineral density (BMD). Serum sclerostin levels have been found to be increased in T2D and appear to be predictive of fracture risk independent of BMD. Bone imaging technologies, including trabecular bone score (TBS) and quantitative CT testing have revealed differences in diabetic bone as compared to non-diabetic individuals. Specifically, high resolution peripheral quantitative CT (HRpQCT) imaging has demonstrated increased cortical porosity in diabetic postmenopausal women. Other factors such as bone marrow fat saturation and advanced glycation endproduct (AGE) accumulation might also relate to bone cell function and fracture risk in diabetes. These data have increased our understanding of how T2D adversely impacts both bone metabolism and fracture risk.
文摘AIM To evaluate the role of small bowel capsule endoscopy(SBCE) on the reclassification of colonic inflammatory bowel disease type unclassified(IBDU).METHODS We performed a multicenter, retrospective study including patients with IBDU undergoing SBCE, between 2002 and 2014. SBCE studies were reviewed and the inflammatory activity was evaluated by determining the Lewis score(LS). Inflammatory activity was considered significant and consistent with Crohn's disease(CD) when the LS ≥ 135. The definitive diagnosis during follow-up(minimum 12 mo following SBCE) was based on the combination of clinical, analytical, imaging, endoscopic and histological elements.RESULTS Thirty-six patients were included, 21 females(58%) with mean age at diagnosis of 33 ± 13(15-64) years. The mean follow-up time after the SBCE was 52 ± 41(12-156) mo. The SBCE revealed findings consistent with significant inflammatory activity in the small bowel(LS ≥ 135) in 9 patients(25%); in all of them the diagnosis of CD was confirmed during follow-up. In 27 patients(75%), the SBCE revealed no significant inflammatory activity(LS < 135); among these patients, the diagnosis of Ulcerative Colitis(UC) was established in 16 cases(59.3%), CD in 1 case(3.7%) and 10 patients(37%) maintained a diagnosis of IBDU during follow-up. A LS ≥ 135 at SBCE had a sensitivity = 90%, specificity = 100%, positive predictive value = 100% and negative predictive value = 94% for the diagnosis of CD.CONCLUSION SBCE proved to be fundamental in the reclassification of patients with IBDU. Absence of significant inflammatory activity in the small intestine allowed exclusion of CD in 94% of cases.
基金grants from the National Science and Technology Pillar Program in the Eleventh Five-year Plan Period, No. 2006BAI05A07the Major State Basic Research Development Program of China (973 Program), No. 2006cb500700+5 种基金the National Key Technologies Research and Development Program of China, No. 2004BA720A03the National Natural Science Foundation of China, No. 30871354, 30710303061 and 30470619the Key Project in the Natural Science Foundation of Hunan Province, No. 08JJ3048the Natural Science Foundation of Hunan Province, No. 11JJ5071the Science and Technology Planning Project of Hunan Province, No. 2009SK3172the Graduate Degree Thesis Innovation Foundation of Central South University, No. 2008yb030
文摘Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.
基金supported by the National Natural Science Foundation of China(No.81271406)
文摘Niemann-Pick disease type C(NPC) is a fatal, neurovisceral lipid storage disease, neuropathologically characterized by cytoplasmic sequestration of glycolipids in neurons, progressive neuronal loss, neurofibrillary tangles(NFTs) formation, and axonal spheroids(AS). Cytoskeletal pathology including accumulation of hyperphosphorylated cytoskeletal proteins is a neuropathological hallmark of the mouse model of NPC(npc mice). With a goal of elucidating the mechanisms underlying the lesion formation, we investigated the temporal and spatial characteristics of cytoskeletal lesions and the roles of cdc2, cdk4, and cdk5 in lesion formation in young npc mice. Cytoskeletal lesions were detectable in npc mice at three weeks of age. Importantly, concomitant activation of cdc2/cyclin B1 kinase and accumulation of a subsequently generated cohort of phospho-epitopes were detected. The activation of cdk4/cyclin D1 and cdk5/p25 kinases was observed during the fourth week of life in npc mice, and this activation contributed to the lesion formation. We concluded that the progression of cytoskeletal pathology in npc mice older than four weeks is accelerated by the cumulative effect of cdc2, cdk4, and cdk5 activation. Furthermore, cdc2/cyclin B1 may act as a key initial player one week earlier. Targeting cell cycle activation may be beneficial to slow down the NPC pathogenesis.
基金supported by a grant from the National Natural Sciences Foundation of China (No. 30400141, 30670737)
文摘In order to investigate the neuroprotective effects of cyclin-dependent kinase-5 (cdk-5) inhibition in mice with Niemarm-Pick disease type C (NPC) (npc^-/-), recombinant adeno-associated virus (rAAV) carrying the small interfering RNA (siRNA) specific for cdk-5 gene was injected into 3-day-old npc^-/- mice intracerebroventricularly. The rAAV-GFP-injected age-matched npc^-/- mice and non-surgery age-matched npc^-/- mice were employed as controls (n=6-10/group). From the 4th to 8th week after the treatment, mice were weighed, and evaluated for limb motor activity by using the coat hanger test once a week. Eight-week-old npc^-/- mice were sacrificed by decapitation, and brains were quickly dissected and halved sagittally. Immunohistochemistry, Western blotting, and HE staining were used to evaluate the neuropathology in npc^-/- mice. The results showed that rAAV-cdk-5-siRNA-GFP significantly reduced the number of axonal spheroids, delayed the death of Purkinje neurons, ameliorated motor defects in npc^-/- mice, and significantly attenuated the hyperphosphorylation oftau proteins. These data suggested that inhibition of cdk-5 activity has neuroprotective effect on neurons in NPC mice.
文摘BACKGROUND Glycogen storage disease type Ia(GSDIa) is an autosomal recessive inborn error of carbohydrate metabolism that is caused by deficiency of the enzyme glucose-6-phosphatase(G6Pase),leading to disturbed glycogenolysis and gluconeogenesis.Patients with GSDIa show severe fasting hypoglycemia,hyperlipidemia,hyperlactacidemia,and hyperuricemia,which are associated with fatal outcomes in pregnant women and fetuses.CASE SUMMARY Herein,we report the case of a 24-year-old female who on her first visit to the hospital,presented with pregnancy combined with extremely high hyperlipidemia and hyperlactic acidosis with anemia,and frequent hypoglycemia occurred during the treatment.Genetic tests revealed a mutation in the G6Pase gene(G6PC) at 17q21,the patient was finally diagnosed with glycogen storage disease type Ia for the first time after 22 years of inaccurate treatment.She has been treated with a continuous double filtration plasmapheresis(DFPP) strategy to remove blood lipids,and a cornstarch diet therapy.The patient did not develop pancreatitis during the course of the disease and a healthy baby girl weighing 3 kg was delivered.CONCLUSION Patients with GSDIa may be misdiagnosed as epilepsy.DFPP can be used to control hyperlipidemia in GSDIa patients during pregnancy.
文摘BACKGROUND A patient with type Ⅲ Kummell’s disease had a ruptured posterior cortex of the fractured vertebral body, which caused spinal cord compression. An open surgery was considered the best choice of operation. However, the patient and her family refused open surgery and instead demanded a minimally invasive surgical treatment such as percutaneous vertebroplasty(PVP). After preoperative discussion, we finally adopted the novel therapy of traditional Chinese medicine manipulative reduction(TCMMR) combined with PVP.CASE SUMMARY A patient with type Ⅲ Kummell’s disease exhibiting bone block-induced spinal cord compression was admitted to our hospital. She suffered from a variety of medical disorders but refused open surgery, and instead asked for PVP surgery. TCMMR, in parallel with PVP, was used to restore the height of the compressed vertebral body and reduce the symptoms of spinal cord compression by the bone block in order to strengthen the vertebral body and prevent further collapse. The surgery was very successful. The height of the compressed vertebra was restored, and the symptom of spinal cord compression by bone block was reduced successfully via TCMMR. The fractured vertebra was solidified by the PVP. The pain visual analog score declined from preoperative 7 scores to postoperative 2 scores, and the Frankel spinal cord scale increased from preoperative D degree to postoperative E degree.CONCLUSION The new method has advantages in treating patients with type Ⅲ Kummell’s disease who cannot be treated with open surgery.
文摘Objectives To study clini- cal and coronary angiographic findings in patients with both coronary heart diseases (CHD) and type 2 diabe- tes mellitus (T2DM). Methods 215 patients with CHD confirmed by coronary angiography were involved in this study. The patients were divided into two groups: 74 CHD patients with T2DM (mean age 64.7 ± 8.2 years, male/female 47/27), and 141 CHD pa- tients without T2DM ( mean age 66. 2 ±9. 2 years, male/female 100/41 ). The clinical features and the data from selective coronary angiographies were com- pared between type 2 diabetic and non - diabetic CHD patients. Results Compared to non - diabetic CHD patients, the patients with both CHD and T2DM suf- fered more from acute myocardial infarction, silent is- chemia and severe arrhythmias ( P < 0. 01, P < 0. 05 ) , and had higher serum triglycerides and apo - lipoprotein B, along with increased serum uric acid (P < 0. 01, P < 0.05), increased left ventricular end diastolic diameter ( P < 0. 01 ) , and decreased left ventricular ejection fraction ( P < 0. 001 ). Compared to non - diabetic CHD patients, the patients with both CHD and T2DM suffered more from triple vessel disease (P < 0. 01) , severe coronary artery stenosis, complete occlusions and diffuse lesions ( P < 0. 001). Conclusions Se- vere clinical manifestation, left ventricular dysfunction, diffuse or complicated lesions of coronary arteries weremore common in patients with both CHD and T2DM, it suggests that the type 2 diabetic CHD patients have poor prognosis.
文摘Pompe disease (PD) is a rare inborn error of metabolism due to an abnormal acid alpha-glucosidase (GAA) activity that comprises glycogen breakdown mainly in the lysosomes. Since the introduction of enzyme replacement therapy (ERT), with recombinant human GAA for the early onset PD patient, a relevant field of clinical research due to the benefits regarding survival rate has been widely documented worldwide. Objective: To describe the clinical characteristics and the ERT effects in a series of Brazilian patients with infantile onset PD (IOPD) under ERT. Methods: Brazilian patients diagnosed with IOPD under ERT were recruited through their physicians participating in the International Pompe Disease Registry from 2009 to 2017. Data were collected by an online survey. Results: 10 IOPD patients were identified through the survey with a death rate of 30% and technology dependency rate reported as 80% (motor, respiratory or nutritional fields) of the patients. After the third year of ERT, motor disabilities were lost in 50% of ambulated patients. The overall characteristics were similar to international studies. Conclusion: Despite ERT benefits in cardiac involvement, motor disabilities seem to be much more compromised in IOPD patients, with high technology dependence, especially after three years of age.
文摘Objective:This study was undertaken to evaluate the clinical efficacy of Western medicine combined with Chinese medicine for pelvic inflammatory disease(damp-heat and stasis type).Methods:Seventy-four patients who were diagnosed with pelvic inflammatory disease(damp-heat and stasis type)by our hospital during July 2021 to July 2022 were randomized into two groups:the participants in the control group received conventional Western medicine treatment,and the participants in the study group received Western medicine combined with Chinese medicine.Results:After treatment,the total effectiveness of the control group(72.98%)was significantly lower than that of the study group(94.59%),(P<0.05);the whole blood viscosity high cut,whole blood viscosity low cut,fibrinogen and plasma viscosity of the control group were all lower than those of the study group(P<0.05);the levels of CRP,IL-6,and TNF-αin the control group were higher and IL-2 levels in the control group were lower than those in the study group(P<0.05).Conclusion:Western medicine combined with Chinese medicine is more effective in curing damp-heat and stasis-type pelvic inflammatory disease by improving the blood rheological indexes and lowering the level of inflammatory factors.
文摘Objective Modified upper abdominal cluster transplantation ( MCT) ,which was inspired by classical cluster transplant technique,has been proven more effective and feasible in the treatment of patients with end stage liver diseases associated with insulin - dependent
基金the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority,No.XXZ0505.
文摘BACKGROUND Glycogen storage disease type Ib(GSD-Ib)is a glycogen metabolism disorder that leads to the manifestations of inflammatory bowel disease(IBD),especially Crohn’s disease(CD)-like colitis.Although biological agents are effective for treating CD,their application in the treatment of GSD-Ib with CD-like colitis has been rarely reported.CASE SUMMARY A 13-year-old Han male was diagnosed with GSD-Ib with CD.The patient was treated with granulocyte colony-stimulating factor.When he had symptoms of CD-like colitis,he was continuously pumped with enteral nutrition and administered oral mesalazine for 2 wk;however,the symptoms did not improve significantly.Hence,infliximab(IFX)was administered.Hitherto,the patient has been followed up for 1 year,and no clinical manifestations have been observed.After 6 mo of treatment(fifth IFX treatment),the disease activity index and all inflammatory indexes decreased,and a review of the colonoscopy data showed that the ulcers appeared smooth.CONCLUSION In this study,the patient was successfully treated with IFX.In cases of GSD-Ib,IBD should be highly considered.
基金supported by funds from the Canadian Institutes of Health Research (MOP74765)the Heart and Stroke Foundation of Canada(G-13-0002833 and G-15-0009016)
文摘Atherosclerosis is a leading underlying factor in cardiovascular disease and stroke,important causes of morbidity and mortality across the globe.Abundant epidemiological studies demonstrate that high levels of high density lipoprotein(HDL) are associated with reduced risk of atherosclerosis and preclinical,animal model studies demonstrate that this association is causative.Understanding the molecular mechanisms underlying the protective effects of HDL will allow more strategic approaches to development of HDL based therapeutics.Recent evidence suggests that an important aspect of the ability of HDL to protect against atherosclerosis is its ability to trigger signaling responses in a variety of target cells including endothelial cells and macrophages in the vessel wall.These signaling responses require the HDL receptor,scavenger receptor class B type 1(SR-B1),an adaptor protein(PDZK1) that binds to the cytosolic C terminus of SR-B1,Akt1 activation and(at least in endothelial cells) activation of endothelial NO synthase(eNOS).Mouse models of atherosclerosis,exemplified by apolipoprotein E or low density lipoprotein receptor gene inactivated mice(apoE or LDLR KO) develop atherosclerosis in their aortas but appear generally resistant to coronary artery atherosclerosis.On the other hand,inactivation of each of the components of HDL signaling(above)in either apoE or LDLR KO mice renders them susceptible to extensive coronary artery atherosclerosis suggesting that HDL signaling may play an important role in protection against coronary artery disease.
文摘Background Adaptor proteins containing PH domain, PTB domain, and leucine zipper motif 1 and 2 (APPL1/2) play a key role in cell proliferation in many tissues. APPL1 or APPL2 as an adaptor for adiponectin receptors mediates the signaling pathway of adiponectin which acts as an anti-atherosclerotic adipokine. This study aimed to investigate whether genetic variations in the APPL 1/2 genes affect the risk of coronary artery disease (CAD) in Chinese patients with type 2 diabetes mellitus (T2DM). Methods Seven haplotype-tagging single nucleotide polymorphisms (tag-SNPs) were selected from CHB HapMap database (Phase II) and total 203 CAD-positive cases and 106 CAD-negative controls with T2DM were genotyped for the 7 tag-SNPs by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Results The minor allele G of rs4640525 at APPL1 locus was protective from CAD in patients with T2DM, with the carriers of genotype CC at higher risk of CAD compared with non-carriers (OR=2.830, 95% Cl 1.285-6.230, P=0.010; OR'=4.992, 95% C1=1.758-14.173, P'0.003, after adjustment for the other known CAD risk factors); the homozygotes of AA at rs11112412 in APPL2 gene had higher risk of CAD compared with those of GG (adjusted OFt=5.697, 95% Cl 1.006-32.257, P=0.049). Conclusion Genetic variation(s) in APPL 1/2 may be associated with CAD risk in T2DM in Chinese population.
文摘Background Susceptibility to coronary artery disease (CAD) and diabetes is encoded by distinct, tightly-linked single nucleotide polymorphisms on chromosome 9p21. This study aimed to examine the association of variant rs1333049 on chromosome 9p21.3 with early-onset and severity of CAD in Chinese patients with and without type 2 diabetes, and to determine the possible impact of rs1333049 on glucose metabolism and inflammation pathways. Methods Genotyping of variant rs1333049 on chromosome 9p21.3 was performed in 2387 patients with and without diabetes who were undergoing coronary angiography to evaluate suspected or established CAD. Serum levels of glucose, glycosylated hemoglobin Alc (HbAlo), insulin, high-sensitivity C-reactive protein, tumor necrosis factor-a, and interleukin-6 were also measured, and compared with each patient's genotype. Results The homozygous CC genotype of rs1333049 was significantly associated with CAD in diabetic (OR: 1.270, P=-0.044) and non-diabetic (OR: 1.369, P=0.011) patients after adjusting for traditional risk factors. There was an association between CC genotype and number of diseased vessels in diabetics (P=0.019), but not in non-diabetics (P=0.126). Among diabetic patients, CC genotype carriers had an increased risk of early-onset CAD (OR:. 2.367, ,~=-0.008) and greater cumulative atherosclerotic burden compared with non-CC genotype carriers (Gensini score: 31.80+17.20 vs. 23.09+_21.63, P=-0.039). No significant differences were observed between genotypes of rs1333049 in serum levels of glucose, insulin, HbAlc, or inflammatory cytokines for diabetic or non-diabetic patients with CAD. Conclusions This study demonstrated a significant association of rs1333049 polymorphism on chromosome 9p21.3 with CAD in Chinese diabetic and non-diabetic patients. The homozygous CC genotype of rs1333049 confers a magnified risk of early-onset and more severe CAD in diabetic patients through a novel biological pathway unrelated to glucose metabolism or inflammation.
基金This work was supported by grants of National Natural Science Foundation of China (No. 81501083 and 81671236).
文摘Background: Pompe disease is a rare lysosomal glycogen storage disorder linked to the acid alpha-glucosidase gene (GAA). A wide clinical and genetic variability exists between patients from different ethnic populations, and the genotype-phenotype correlations are still not well understood. The aim of this study was to report the clinicopathological and genetic characteristics of five Chinese patients with late-onset Pompe disease (LOPD) who carried novel GAA gene mutations. Methods: Clinical and pathological data of patients diagnosed with glycogen storage disease at our institution from April 1986 to August 2017 were collected, and next-generation sequencing of frozen muscle specimens was conducted. Results: Of the five patients included in the study, the median disease onset age was 13 years, with a median 5 years delay in diagnosis. The patients mainly manifested as progressive weakness in the proximal and axial muscles, while one patient developed respiratory insufficiency that required artificial ventilation. In muscle biopsies, vacuoles with variable sizes and shapes appeared inside muscle fibers, and they stained positive for both periodic acid-Schiff and acid phosphatase staining. Ten GAA gene mutations, including seven novel ones (c.796C〉A, c. 1057C〉T, c. 1201C〉A, c. 1780C〉T, c. 1799G〉C, c.2051C〉A, c.2235dupG), were identified by genetic tests. Conclusions: The seven novel GAA gene mutations revealed in this study broaden the genetic spectrum of LOPD and highlight the genetic heterogeneity in Chinese LOPD patients.