To explore the relationship between hypoxic responsiveness of the patients with narcolepsy-cataplexy and their clinical features.A total of 113 patients with narcolepsy-cataplexy (narcolepsy group) at Peking University People's Hospital from June 2007 to May 2008 and 128 gender-age matched volunteers (control group) were recruited. And their status of human leukocyte antigen (HLA)-DQB1*0602 was examined to differentiate hypercapnic and hypoxic responsiveness. Among them, 93 patients with severe hypersomnolence had hypercapnic and hypoxic responsiveness tested before and after the treatment of methylphenidate and another 20 with severe cataplexy did the same before and after the treatment of chlorimiopramine.Compared with the control group, the narcolepsy group had depressed hypoxic responsiveness ((-0.135 ± 0.105) vs (-0.223 ± 0.136) L×min⁻¹ × %SpO₂⁻¹, P < 0.001). After the treatment of methylphenidate, sleepiness improved significantly in all 93 patients, but their low hypoxic responsiveness did not change ((-0.151 ± 0.111) vs (-0.149 ± 0.105) L×min⁻¹× % SpO₂⁻¹, P = 0.780). After the treatment of chlorimiopramine, cataplexy also improved in 20 patients.However their low hypoxic responsiveness had no change ((-0.114 ± 0.054) vs (-0.115 ± 0.065) L×min⁻¹ × %SpO₂⁻¹, P = 0.949).Lower hypoxic responsiveness in narcolepsy group is not related with the clinical features of disease.
Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7×10−9 OR 0.77), ZNF365 (rs10995245 max P = 1.2×10−11 OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2×10−9 OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10−9 beta −1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8×10−10 OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.
<p dir="ltr">OBJECTIVE We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly GLP-1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated haemoglobin A1c [HbA1c] of 7.0%–10.5% [53–91 mmol/mol]) were randomized to receive mazdutide 3 mg (n = 51), mazdutide 4.5 mg (n = 49), mazdutide 6 mg (n = 49), open-label dulaglutide 1.5 mg (n = 50) or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change from baseline to week 20 in HbA1c. RESULTS Mean changes in HbA1c from baseline to week 20 ranged from −1.41% to −1.67% with mazdutide (−1.35% with dulaglutide and 0.03% with placebo) (all p<0.0001 versus placebo). Mean percent changes in body weight from baseline to week 20 were dose-dependent and up to −7.1% with mazdutide (−2.7% with dulaglutide and −1.4% with placebo). At week 20, participants with mazdutide were more likely to achieve HbA1c target of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol), and body weight loss from baseline of ≥5% and ≥10%, compared with placebo-treated. The most common adverse events with mazdutide included diarrhoea (36%), decreased appetite (29%), nausea (23%), vomiting (14%) and hypoglycemia (10%; 8% with placebo). CONCLUSIONS In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reduction. Article Highlights l Despite increasing application of GLP-1 receptor agonists in glycemic control, evidence of co-agonism with glucagon receptor in the treatment of type 2 diabetes remains limited. l Does mazdutide, a once-weekly GLP-1 and glucagon receptor dual agonist, reduce HbA1c and body weight in patients with type 2 diabetes? l In this phase 2 study, 20 weeks’ treatment with mazdutide achieved mean HbA1c reductions up to 1.67% and mean body weight reductions up to 7.1%. The most common adverse events with mazdutide were gastrointestinal in nature. l The results supported future development of mazdutide for the treatment of type 2 diabetes.</p>
<p dir="ltr">OBJECTIVE We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly GLP-1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated haemoglobin A1c [HbA1c] of 7.0%–10.5% [53–91 mmol/mol]) were randomized to receive mazdutide 3 mg (n = 51), mazdutide 4.5 mg (n = 49), mazdutide 6 mg (n = 49), open-label dulaglutide 1.5 mg (n = 50) or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change from baseline to week 20 in HbA1c. RESULTS Mean changes in HbA1c from baseline to week 20 ranged from −1.41% to −1.67% with mazdutide (−1.35% with dulaglutide and 0.03% with placebo) (all p<0.0001 versus placebo). Mean percent changes in body weight from baseline to week 20 were dose-dependent and up to −7.1% with mazdutide (−2.7% with dulaglutide and −1.4% with placebo). At week 20, participants with mazdutide were more likely to achieve HbA1c target of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol), and body weight loss from baseline of ≥5% and ≥10%, compared with placebo-treated. The most common adverse events with mazdutide included diarrhoea (36%), decreased appetite (29%), nausea (23%), vomiting (14%) and hypoglycemia (10%; 8% with placebo). CONCLUSIONS In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reduction. Article Highlights l Despite increasing application of GLP-1 receptor agonists in glycemic control, evidence of co-agonism with glucagon receptor in the treatment of type 2 diabetes remains limited. l Does mazdutide, a once-weekly GLP-1 and glucagon receptor dual agonist, reduce HbA1c and body weight in patients with type 2 diabetes? l In this phase 2 study, 20 weeks’ treatment with mazdutide achieved mean HbA1c reductions up to 1.67% and mean body weight reductions up to 7.1%. The most common adverse events with mazdutide were gastrointestinal in nature. l The results supported future development of mazdutide for the treatment of type 2 diabetes.</p>
Tafolecimab, a fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody developed for the treatment of hypercholesterolemia, demonstrated robust lipid-lowering efficacy and favorable safety in previous short-term studies. We aimed to assess the long-term efficacy and safety of tafolecimab in Chinese non-familial hypercholesterolemia (non-FH) patients. Non-FH patients at high or very-high cardiovascular risk with screening low-density lipoprotein cholesterol (LDL-C) level ≥1.8 mmol/L or non-FH patients with screening LDL-C level ≥3.4 mmol/L and on stable lipid-lowering therapy for at least 4 weeks, were randomized in a 2:2:1:1 ratio to receive subcutaneous tafolecimab 450 mg Q4W, tafolecimab 600 mg Q6W, placebo 450 mg Q4W, or placebo 600 mg Q6W, respectively, in the 48-week double-blind treatment period. The primary endpoint was the percent change from baseline to week 48 in LDL-C levels. A total of 618 patients were randomized and 614 patients received at least one dose of tafolecimab (n = 411) or placebo (n = 203). At week 48, tafolecimab induced significant reductions in LDL-C levels (treatment differences versus placebo [on-treatment estimand]: -65.0% [97.5% CI: -70.2%, -59.9%] for 450 mg Q4W; -57.3% [97.5% CI: -64.0%, -50.7%] for 600 mg Q6W; both P < 0.0001). Significantly more patients treated with tafolecimab achieved ≥50% LDL-C reductions, LDL-C < 1.8 mmol/L, and LDL-C < 1.4 mmol/L than placebo group at both dose regimens (all P < 0.0001). Furthermore, tafolecimab significantly reduced non-HDL-C, apolipoprotein B, and lipoprotein(a) levels. The most commonly-reported treatment emergent adverse events in the tafolecimab groups included upper respiratory infection, urinary tract infection and hyperuricemia. Tafolecimab dosed at 450 mg Q4W and 600 mg Q6W was safe and showed superior lipid-lowering efficacy versus placebo, providing a novel treatment option for Chinese hypercholesterolemia patients. This study was sponsored by Innovent Biologics, Inc.
To explore the association of narcolepsy with human leukocyte histocompatibility antigen (HLA)-DQB1*0602 allele in Chinese narcoleptic patients and examine its relationship with different phenotypes.A total of 1 223 narcoleptic patients (NC, narcolepsy with typical cataplexy, n = 1 132; NWC, narcolepsy without cataplexy, n = 91) diagnosed at Sleep Center of Peking University People's Hospital from August 1998 to July 2011 were recruited into this retrospective study. According to the onset age, they were divided into early-onset group (onset age ≤ 15 y, n = 1 037) and late-onset group (onset age >15 y, n = 181). All of them underwent a polymerase chain reaction with specific sequence primer (PCR-SSP) HLA-DQB1*0602 typing. And the cerebrospinal fluid levels of hypocretin-1 (hcrt-1) were measured in 156 narcoleptic patients and they were divided into hcrt deficiency group (hcrt-1<138 ng/L, n = 115) and hcrt normal group (hcrt-1 ≥ 138 ng/L, n = 41). And 728 healthy volunteers were selected as control group. The expression positivity of HLA-DQB1*0602 gene was analyzed for each group.There were 1 223 narcoleptic patients including 825 males (67.5%) and 398 females (32.5%) with an average age of (16.6 ± 12.6) years on visiting. There were 728 normal controls including 443 males (60.9%) and 285 females (39.1%) with an average age of (26.6 ± 11.4) years on blood sampling. The positive rate of HLA-DQB1*0602 in narcoleptic, NC and NWC groups was 94.7% (1 158/1 223), 97.0% (1 098/1 132) and 65.9% (60/91) respectively.NC group had a higher rate of HLA-DQB1*0602 positivity (χ² = 155.4, P = 0.000). Both groups were higher than that in control group of 19.5% (142/728). The positive rate of HLA-DQB1*0602 in early-onset group was 95.5% (990/1 037) versus 90.1% (163/181) in late-onset group (χ² = 9.25, P = 0.010). Among those with hcrt-1 measurement, 98.3% (113/115) were HLA-DQB1*0602 positive in hcrt deficiency narcolepsy group versus 25.6% (11/43) in hcrt non-deficiency group (χ² = 94.6, P = 0.001).HLA-DQB1* 0602 is an important marker in this large sample of Chinese patients with narcolepsy.Its frequency is much higher in patients with cataplexy, early-onset age and hcrt-1 deficiency.
To validate the use of the event detection capabilities in an auto-CPAP system used by patients with sleep apnea hypopnea syndrome (SAHS).A total of 28 subjects with SAHS were recruited in the study. All the underwent tests of polysomnography (PSG) before and during treatment by an-auto-CPAP system with advanced event detection (AED) in the sleep lab. Apnea-hypopnea index (AHI), apnea index (AI) and hypopnea index (HI) by PSG and PAP machine were compared.The mean AHI derived from PSG and AED was (6.1 ± 5.6) and (7.1 ± 5.3) times/h (P>0.05), AI was (5.4 ± 5.4) and (4.6 ± 4.2) times/h (P>0.05), HI was (0.77 ± 1.07) and (2.54 ± 1.98) times/h (P<0.05). The Spearman correlation coefficient of AHI was 0.698 (P<0.05), AI was 0.767 (P<0.05), HI was 0.141 (P>0.05). Bland-Altman plot also showed a high agreement between AHI derived from PSG and AHI derived from AED.AED showed a high agreement with PSG in the detection of AHI and AI, but not in HI. This technique may be helpful to monitor the efficacy of PAP treatment at home for long-term follow-up.
Diabetic retinopathy (DR) is one of the serious complications of diabetes and an important cause of blindness. Despite much research on the pathogenesis of DR, there is still a lack of safe and effective treatment methods. Hu-zhang-qing-mai-yin (HZQMY), a Chinese medicine formula, has been clinically used in the safe and effective treatment of DR for many years. However, the systematic pharmacological research is lacking. The aim of this study was to evaluate the anti-DR effects of HZQMY and explore the possible mechanism involved.The constituents of HZQMY were analyzed by LC-MS/MS. DR model was established by high glucose simulation on human retinal capillary endothelial cells (HRCECs) in vitro. The cell viability, cell proliferation, cell apoptosis, and tube formation were assessed. Subsequently the related mechanisms were analyzed by assays for JC-1 mitochondrial membrane potential (MMP), intracellular ROS, ATP, western blot and proteomics.27 main chemical components contained in HZQMY were identified. HZQMY significantly inhibited the viability and proliferation of HRCECs exposed to high glucose, and promoted the apoptosis. In addition, HZQMY also boosted the release of ROS and suppressed tube formation of HRCECs under high glucose exposure. Meanwhile, HRCECs treated with high glucose released more ROS than normal cells, which could be markedly inhibited by HZQMY in a dose-dependent manner. Additionally, western blot assay indicated that HZQMY increased the expression of proteins related to the P38 signaling pathway and inhibited nuclear factor kappa-B (NF-κB) pathway. Proteomic analysis predicted that HSPA4, MAPK3, ENO1, EEF2 and ERPS may be the candidate targets of HZQMY in HRCECs.HZQMY inhibited the proliferation and promoted the Mitochondria related apoptosis of HRCECs exposed to high glucose possibly through regulating P38 and NF-κB signaling pathway.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)