Trofinetide Treatment Demonstrates a Benefit Over Placebo for the Ability to Communicate in Rett Syndrome.

BACKGROUND: Trofinetide was approved by the US Food and Drug Administration for the treatment of Rett syndrome (RTT) in March 2023. Benefiting the ability to communicate in RTT is often identified as the most important caregiver goal for new therapies. This analysis reports the communication-related end points from the phase 3 LAVENDER study of trofinetide in RTT. METHODS: Females with RTT, aged five to 20 years, were randomized 1:1 to trofinetide or placebo for 12 weeks. Secondary efficacy end points related to communication were based on change from baseline to week 12 and included the caregiver-rated Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite score (key secondary end point; scores ranged from 0 to 26 [higher scores indicated better communication]) and novel clinician rating scales (0 [normal] to 7 [severe impairment]) measuring the ability to communicate choices nonverbally (RTT-COMC) and verbally (RTT-VCOM). RESULTS: Trofinetide demonstrated a statistically significant difference versus placebo for the CSBS-DP-IT Social Composite score (least squares mean [LSM] difference = 1.0; 95% confidence interval [CI], 0.3 to 1.7; P = 0.0064; Cohen's d effect size = 0.43) and a nominally significant difference for the RTT-COMC (LSM difference: -0.3; 95% CI, -0.6 to -0.0; P = 0.0257; Cohen's d effect size = 0.36). As expected, there was no difference for the RTT-VCOM. CONCLUSIONS: Significant treatment benefit for trofinetide versus placebo was observed in scales measuring the ability to communicate. These scales may be appropriate for future clinical studies in RTT and other neurodevelopmental disorders.

Combined Effects of Transcranial Magnetic Stimulation and Argatroban on Balance Function and Daily Living Activities in Hemiplegic Patients Following Cerebral Infarction.

Objective: This study aimed to investigate the impact of combining transcranial magnetic stimulation (TMS) with argatroban on balance function and activities of daily living in patients with hemiplegia following cerebral infarction (CI). Methods: A retrospective analysis was conducted on the clinical data of 104 patients with hemiplegia after CI who were admitted to our hospital from July 2020 to July 2021. The patients were randomly assigned to either the experimental group (EG) or the control group (CG), with 52 patients in each group. The EG received TMS in combination with argatroban, while the CG received argatroban alone. The Berg Balance Scale (BBS) and modified Barthel index (BI) were used to assess the balance function and activities of daily living in both groups after treatment. Results: After treatment, the EG demonstrated significantly higher BBS and BI scores compared to the CG (P < .001). Additionally, the EG showed significantly improved upper limb and lower limb Functional Ambulation Profile (FAM) scores compared to the CG (P < .05). Conclusions: The combination of TMS and argatroban proves to be an effective approach for enhancing balance function and activities of daily living in hemiplegic patients with CI. Therefore, it is recommended as a valuable rehabilitation treatment for such patients.

Protection of Oxygen Glucose Deprivation-Induced Human Brain Vascular Pericyte Injury: Beneficial Effects of Bellidifolin in Cellular Pyroptosis.

Pericytes play critical roles in the maintenance of brain vascular homeostasis. However, very little is currently known about how pericytes regulate ischemic stroke-induced brain injury. Inflammation is a key event in the pathobiology of stroke, in which the nod-like receptor protein-3 (NLRP3) inflammasome is involved in, triggering sterile inflammatory responses and pyroptosis. In the current study, an immortalized cell line derived from human brain vascular pericytes (HBVPs) was constructed, and it showed that HBVPs challenged with oxygen glucose deprivation (OGD) displays pronounced cellular excretion of LDH, IL-1ß, IL-18 and increased PI positive staining. Mechanistically, upon OGD treatment, NLRP3 forms an inflammasome with its adaptor protein apoptosis-associated speck-like protein, containing a caspase recruitment domain (ASC) and caspase-1, manifested as much more co-stainings of NLRP3, ASC and Caspase-1 in HBVPs, accompanied by the increased protein levels of NLRP3, ASC, caspase-1 as well as the pyroptosis-associated protein gasdermin D (GSDMD). Intriguingly, GSDMD-N shuttled to the mitochondrial membrane triggered by OGD exposure, which promoted massive mitochondria-derived ROS generation. Importantly, the invention value of the specific targets was evaluated by treatment with bellidifolin, a kind of ketone compound derived from Swertia chirayita in traditional Tibetan medicine. It showed that bellidifolin exerts beneficial effects and attenuates the formation of NLRP3/ASC/Caspase-1 complex, thereby impeding GSDMD-N shuttling and resultant ROS generation, protecting against OGD-induced HBVPs pyroptosis. Overall, these findings unravel the potential mechanisms of pericyte injury induced by OGD and indicate that bellidifolin may exert its beneficial effects on pyroptosis, thus providing new therapeutic insights into stroke.

Exploring the underlying mechanisms on starch restricted swelling-induced reduction in digestion rate of buckwheat noodles.

To elucidate the slower digestion rate of buckwheat starch in noodles-matrix, the digestion kinetics of Tartary (TBN) and common (CBN) buckwheat starch reconstituted noodles as well as wheat starch reconstituted noodles (WSN) were compared using a simulated oral-gastric-intestinal in vitro digestion. The swelling degree of starch in cooked noodles can be expressed by quantitative analysis of microstructure. The digestion rate of WSN was 2.3-2.9 times higher as compared to CBN and TBN. The swelling degree of starch in CBN and TBN was restricted due to their denser structure, which led to the reduction of the contact area between starch molecules and amylase. Additionally, the stronger water retention ability and higher cohesiveness of CBN and TBN could hinder the water migration, and ultimately affect the accessibility of enzymes. These results demonstrated that the restricted swelling of starch in CBN and TBN during cooking was the important reason for their slower digestibility.

Effects of Biofeedback Combined With Pilates Training on Post-prostatectomy Incontinence.

OBJECTIVE: To verify the effect of Pilates training combined with biofeedback training, Kegel training combined with biofeedback training, and Kegel training alone on post-prostatectomy incontinence in male patients. MATERIAL AND METHODS: Forty-two patients were randomly divided into 3 groups. The changes occurring to the 3 groups before and after treatment and the differences between the 3 groups were assessed using a 1-hour pad test, number of incontinent episodes, the ICIQ questionnaire, and the Oxford Grading Scale. The 3 groups were required to undergo daily training for an 8-week period. RESULTS: At 8 weeks, groups A, B and C experienced a 34.3%, 61.9%, and 67% improvement in the 1-hour pad test, respectively, and 32.1%, 52.9%, and 58.8% reduction in the number of urinary incontinence episodes, respectively, and a 29.4%, 50%, and 64.7% reduction in the ICIQ Scale, respectively, and a 33.3%, 50%, and 50% in Oxford Grading Scale improvement, respectively. The graph results showed that the effect was noted after 3 weeks of treatment and a significant effect occurred by the eighth week of treatment. CONCLUSION: Three methods were shown to optimize urinary continence and pelvic floor muscle strength of patients with post-prostatectomy incontinence. The treatment effect of group C was better than group B, but there was no statistically significant difference in the 1-hour pad tests. It is particularly important to understand the time sensitivity for patient training.

Metformin inhibits Aß25-35 -induced apoptotic cell death in SH-SY5Y cells.

Metformin, a first-line drug for type-2 diabetes, plays a potentially protective role in preventing Alzheimer's disease (AD), but its underlying mechanism is unclear. In this study, Aß25-35 -treated SH-SY5Y cells were used as a cell model of AD to investigate the neuroprotective effect of metformin, as well as its underlying mechanisms. We found that metformin decreased the cell apoptosis rate and death, ratio of Bcl-2/Bax, and expression of NR2A and NR2B, and increased the expression of LC3 in Aß25-35 -treated SH-SY5Y cells. Metformin also reduced intracellular and extracellular Glu concentrations, as well as the intracellular concentration of Ca2+ and ROS in Aß25-35 -treated SH-SY5Y cells. These findings suggest that metformin inhibits Aß25-35 -treated SH-SY5Y cell death by inhibiting apoptosis, decreasing intracellular Ca2+ and ROS by reducing neurotoxicity of excitatory amino acids, and by possibly reversing autophagy disorder via regulating autophagy process.

Genistein inhibits Aß25-35 -induced SH-SY5Y cell damage by modulating the expression of apoptosis-related proteins and Ca2+ influx through ionotropic glutamate receptors.

In this study, we investigated the protective effects of genistein against SH-SY5Y cell damage induced by ß-amyloid 25-35 peptide (Aß25-35 ) and the underlying mechanisms. Aß-induced neuronal death, apoptosis, glutamate receptor subunit expression, Ca2+ ion concentration, amino acid transmitter concentration, and apoptosis-related factor expression were evaluated to determine the effects of genistein on Aß-induced neuronal death and apoptosis. The results showed that genistein increased the survival of SH-SY5Y cells and decreased the level of apoptosis induced by Aß25-35 . In addition, genistein reversed the Aß25-35 -induced changes in amino acid transmitters, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, and N-methyl-d-aspartate (NMDA) receptor subunits in SH-SY5Y cells. Aß25-35 -induced changes in Ca2+ and B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X (Bax) protein and gene levels in cells were also reversed by genistein. Our data suggest that genistein protects against Aß25-35 -induced damage in SH-SY5Y cells, possibly by regulating the expression of apoptosis-related proteins and Ca2+ influx through ionotropic glutamate receptors.

Zn2+ reduction induces neuronal death with changes in voltage-gated potassium and sodium channel currents.

In the present study, cultured rat primary neurons were exposed to a medium containing N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a specific cell membrane-permeant Zn2+ chelator, to establish a model of free Zn2+ deficiency in neurons. The effects of TPEN-mediated free Zn2+ ion reduction on neuronal viability and on the performance of voltage-gated sodium channels (VGSCs) and potassium channels (Kvs) were assessed. Free Zn2+ deficiency 1) markedly reduced the neuronal survival rate, 2) reduced the peak amplitude of INa, 3) shifted the INa activation curve towards depolarization, 4) modulated the sensitivity of sodium channel voltage-dependent inactivation to a depolarization voltage, and 5) increased the time course of recovery from sodium channel inactivation. In addition, free Zn2+ deficiency by TPEN notably enhanced the peak amplitude of transient outward K+ currents (IA) and delayed rectifier K+ currents (IK), as well as caused hyperpolarization and depolarization directional shifts in their steady-state activation curves, respectively. Zn2+ supplementation reversed the effects induced by TPEN. Our results indicate that free Zn2+ deficiency causes neuronal damage and alters the dynamic characteristics of VGSC and Kv currents. Thus, neuronal injury caused by free Zn2+ deficiency may correlate with its modulation of the electrophysiological properties of VGSCs and Kvs.