A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

A Nomogram for Predicting the Recurrence of Acute Non-Cardioembolic Ischemic Stroke: A Retrospective Hospital-Based Cohort Analysis.

Non-cardioembolic ischemic stroke (IS) is the predominant subtype of IS. This study aimed to construct a nomogram for recurrence risks in patients with non-cardioembolic IS in order to maximize clinical benefits. From April 2015 to December 2019, data from consecutive patients who were diagnosed with non-cardioembolic IS were collected from Lanzhou University Second Hospital. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to optimize variable selection. Multivariable Cox regression analyses were used to identify the independent risk factors. A nomogram model was constructed using the "rms" package in R software via multifactor Cox regression. The accuracy of the model was evaluated using the receiver operating characteristic (ROC), calibration curve, and decision curve analyses (DCA). A total of 729 non-cardioembolic IS patients were enrolled, including 498 (68.3%) male patients and 231 (31.7%) female patients. Among them, there were 137 patients (18.8%) with recurrence. The patients were randomly divided into training and testing sets. The Kaplan-Meier survival analysis of the training and testing sets consistently revealed that the recurrence rates in the high-risk group were significantly higher than those in the low-risk group (p < 0.01). Moreover, the receiver operating characteristic curve analysis of the risk score demonstrated that the area under the curve was 0.778 and 0.760 in the training and testing sets, respectively. The nomogram comprised independent risk factors, including age, diabetes, platelet-lymphocyte ratio, leukoencephalopathy, neutrophil, monocytes, total protein, platelet, albumin, indirect bilirubin, and high-density lipoprotein. The C-index of the nomogram was 0.752 (95% CI: 0.705~0.799) in the training set and 0.749 (95% CI: 0.663~0.835) in the testing set. The nomogram model can be used as an effective tool for carrying out individualized recurrence predictions for non-cardioembolic IS.

Ultrasound-guided pacemaker implantation at the bedside: A lifesaving technique for cardiac emergencies.

OBJECTIVE: To investigate the safety and effectiveness of implanting temporary pacemakers using ultrasound-guidance at the bedside for rescuing patients in case of cardiac emergencies. METHODS: We enrolled 194 patients with cardiac emergencies requiring temporary pacemakers in this study, and randomly assigned them to either a bedside ultrasound-guided installation group or an electrocardiogram-guided installation group. There were 105 cases in the bedside ultrasound-guided installation group, aged approximately 66.3 ± 10.2 years, and 89 cases in the electrocardiogram-guided installation group, aged approximately 65.8 ± 9.5 years old, and disease composition was similar between the two groups. We then compared the duration of the procedure, success rates, and occurrence of adverse events between the two groups. RESULTS: The two groups showed similar clinical characteristics. The success rates of venipuncture and temporary pacemaker electrode placement were both 100% in the bedside ultrasound-guided installation group, compared to 87.8% and 96.7% respectively, in the electrocardiogram-guided installation group, with a statistically significant difference between the two groups. The duration of puncture was significantly shorter in the bedside ultrasound-guided installation group than in the electrocardiogram-guided installation group, with statistically significant differences. Moreover, no adverse events such as hematoma, pneumothorax and electrode dislodgement occurred in the bedside ultrasound-guided installation group, while 13 cases in the electrocardiogram-guided installation group experienced adverse events, and the difference was statistically significant. CONCLUSIONS: The bedside installation of temporary pacemakers using ultrasound guidance is a simple, safe, effective, and cost-efficient procedure that boasts a high success rate, does not involve radiation, and enables accurate placement of the electrode catheter.

Sleep disorders in the acute phase of coronavirus disease 2019: an overview and risk factor study.

BACKGROUND: Sleep disorders are common during the outbreak of pandemic diseases, and similar disorders are noted in hospitalized COVID-19 patients. It is valuable to explore the clinical manifestations and risk factors for sleep disorders in COVID-19 patients. METHODS: Inpatients with COVID-19 were enrolled. Detailed clinical information was collected, and sleep quality was assessed by PSQI. Patients were divided into a sleep disorder group and a normal group based on a PSQI ≥ 7, and the clinical features were compared between the groups. RESULTS: Fifty-three patients were enrolled, and 47.2% presented sleep disorders. Sleep disorders were associated with older age (> 50), anemia and carbon dioxide retention. Furthermore, factors associated with abnormal component scores of the PSQI were: (1) patients with older age were more likely to have decreased sleep quality, prolonged sleep latency, decreased sleep efficiency, sleep disturbances, and daytime dysfunction; (2) decreased sleep quality and prolonged sleep latency were associated with dyspnea, whereas carbon dioxide retention and more lobes involved in chest CT were associated with prolonged sleep latency; (3) decreased sleep efficiency was more prevalent in patients with anemia. CONCLUSIONS: Sleep disorders were prevalent in patients during the acute phase of COVID-19, and many risk factors (older age, anemia, carbon dioxide retention, the number of lobes involved in chest CT, and dyspnea) were identified. It is important to assess the presence of sleep disorders in patients to provide early intervention.

MIST: multiple instance learning network based on Swin Transformer for whole slide image classification of colorectal adenomas.

Colorectal adenoma is a recognized precancerous lesion of colorectal cancer (CRC), and at least 80% of colorectal cancers are malignantly transformed from it. Therefore, it is essential to distinguish benign from malignant adenomas in the early screening of colorectal cancer. Many deep learning computational pathology studies based on whole slide images (WSIs) have been proposed. Most approaches require manual annotation of lesion regions on WSIs, which is time-consuming and labor-intensive. This study proposes a new approach, MIST - Multiple Instance learning network based on the Swin Transformer, which can accurately classify colorectal adenoma WSIs only with slide-level labels. MIST uses the Swin Transformer as the backbone to extract features of images through self-supervised contrastive learning and uses a dual-stream multiple instance learning network to predict the class of slides. We trained and validated MIST on 666 WSIs collected from 480 colorectal adenoma patients in the Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School. These slides contained six common types of colorectal adenomas. The accuracy of external validation on 273 newly collected WSIs from Nanjing First Hospital was 0.784, which was superior to the existing methods and reached a level comparable to that of the local pathologist's accuracy of 0.806. Finally, we analyzed the interpretability of MIST and observed that the lesion areas of interest in MIST were generally consistent with those of interest to local pathologists. In conclusion, MIST is a low-burden, interpretable, and effective approach that can be used in colorectal cancer screening and may lead to a potential reduction in the mortality of CRC patients by assisting clinicians in the decision-making process. © 2022 The Pathological Society of Great Britain and Ireland.

What Is Different about Teratoma-Associated Anti-LGI1 Encephalitis? A Long-Term Clinical and Neuroimaging Case Series.

INTRODUCTION: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is clinically heterogeneous, especially at presentation, and though it is sometimes found in association with tumor, this is by no means the rule. METHODS: Clinical data for 10 patients with anti-LGI1 encephalitis were collected including one case with teratoma and nine cases without and compared for clinical characteristics. Microscopic pathological examination and immunohistochemical assay of the LGI1 antibody were performed on teratoma tissue obtained by laparoscopic oophorocystectomy. RESULTS: In our teratoma-associated anti-LGI1 encephalitis case, teratoma pathology was characterized by mostly thyroid tissue and immunohistochemical assay confirmed positive nuclear staining of LGI1 in some tumor cells. The anti-LGl1 patient with teratoma was similar to the non-teratoma cases in many ways: age at onset (average 47.3 in non-teratoma cases); percent presenting with rapidly progressive dementia (67% of non-teratoma cases) and psychiatric symptoms (33%); hyponatremia (78%); normal cerebrospinal fluid results except for positive LGI1 antibody (78%); bilateral hippocampal hyperintensity on magnetic resonance imaging (44%); diffuse slow waves on electroencephalography (33%); good response to immunotherapy (67%); and mild residual cognitive deficit (22%). Her chronic anxiety and presentation with status epilepticus were the biggest differences compared with the non-teratoma cases. CONCLUSION: In our series, anti-LGI1 encephalitis included common clinical features in our series: rapidly progressive dementia, faciobrachial dystonic seizures, behavioral disorders, hyponatremia, hippocampal hyperintensity on magnetic resonance imaging, and residual cognitive deficit. We observed some differences (chronic anxiety and status epilepticus) in our case with teratoma, but a larger accumulation of cases is needed to improve our knowledge base.

Paraneoplastic neurological syndrome with positive anti-Hu and anti-Yo antibodies: A case report.

BACKGROUND: Paraneoplastic neurological syndrome (PNS) is a rare complication in patients with cancer. PNS can affect the central, peripheral, autonomic nervous system, neuromuscular junction, or muscles and cause various neurological symptoms. Anti-Yo antibody-positive neurological paraneoplasms and anti-Hu antibody-positive neurological paraneoplasms are common, but coexistence of both types has not been described in the literature. CASE SUMMARY: Here we present a rare case of paraneoplastic neuropathy occurring in both breast and lung cancers. A 55-year-old woman was admitted to our hospital with unsteadiness while walking. The patient had a history of breast cancer two years previously. Chest computed tomography revealed a 4.6 cm × 3.6 cm mass in the right lung, which was diagnosed as small-cell lung cancer (SCLC). Blood test was positive for anti-Yo antibodies, and the cerebrospinal fluid was positive for both anti-Yo and anti-Hu antibodies, and the neurological symptoms were considered to be related to the paraneoplasm. The patient was treated with a course of intravenous immunoglobulin, without noticeable improvement. After being discharged from hospital, the patient underwent regular chemotherapy for SCLC and periodic reviews. The patient's neurological symptoms continued to deteriorate at the follow-up visit in April 2021. CONCLUSION: This case suggests the possibility of two types of tumors appearing simultaneously with two paraneoplastic antibodies. The clinical appearance of two or more paraneoplastic tumors requires additional attention.

N-salicyloyl tryptamine derivatives as potential therapeutic agents for Alzheimer's disease with neuroprotective effects.

Alzheimer's disease (AD) has become a serious threat to the developed nations with burgeoning patients and annual costs on health care system in modern society. Neuroinflammation, as one of the specific biochemical factors in the progress of neurodegeneration diseases, performs a crucial role in the pathogenesis and development of AD. Therefore, it is of great significance to develop effective anti-neuroinflammatory strategies for the treatment of AD. N-salicyloyl tryptamine derivatives were previously reported and demonstrated that possessed great potential anti-neuroinflammatory effects and favorable blood-brain barrier (BBB) permeation. Herein, a series of novel N-salicyloyl tryptamine derivatives were synthesized and their anti-AD potential was evaluated both in vitro and in vivo. Among them, L7 performed well anti-neuroinflammatory effects and excellent neuroprotective effects, as well as little toxicity. To lucubrate its potential for the treatment of AD, behavior tests including morris water maze (MWM), eight-arm radial maze, open field test and novel object recognition (NOR) test were carried out and the results showed that L7 could remarkably improve Aß-induced cognitive impairment. Moreover, the mechanism of action of L7 on improving Aß-induced AD was preliminarily investigated, and the results uncovered that the neuroprotective effects of L7 was might exerte via intervening Aß-induced pyroptosis through NLRP3-caspase-1-GSDMD axis and ameliorating neuronal apoptosis by mitochondrial apoptosis pathway. Besides, the distribution of Aß plaques in brain tissues were detected by immunohistochemical (IHC) assay and the results indicated that L7 could significantly attenuate the deposition of Aß plaques in the brain.

Correlation between serum renin-angiotensin system (RAS) level and depression and anxiety symptoms in patients with Parkinson's disease.

To investigate the correlation between serum renin-angiotensin system (RAS) level and Symptoms of anxiety and depression in Parkinson disease patients (PD). A number of 90 PD patients (47 males and 43 females) were collected on an empty stomach 12 h after stopping taking anti-PD medicines. ELISA has been found in Serum RAS ((Ang) I, Ang II, Ang (1-7), Angiotensin converting enzyme (ACE), ACE2). Depression scale (HAMD) and Anxiety scale (HAMA) in Hamilton are used for the assessment of signs of depression and anxiety. The 90 patients were diagnosed with moderate depression (HAMD score 8 ~ 19); in 32 of those (35.56 percent), and 12 (13.33%) were diagnosed as moderate and severe depression (HAMD score ≥ 20). 20 cases (22.22%) were diagnosed as possible anxiety disorder (HAMA score 7 ~ 13) and 16 cases (17.78%) as definite anxiety disorder (HAMA score ≥ 14). The association of serum Ang I, Ang II and Ang (1-7) with HAMD (r= - 0.820, P < 0.001; r = -0.846, P < 0.001) showed negative linkage with HAMD (r = -0.887, P < 0.003; P < 0.001; Negative correlation of the settings with HAMA (r = -0.850, P < 0.001; r = -0.887, P < 0.001; r = 0.003; r = 0.001, P < 0.001, Fig. 2, Fig. 3); The HAMD score and the HAMA score (all P > 0.05) were not associated to the serum ACE and ACE2. The serum Ang I, Ang II, and Ang (1-7) were found to be adversely associated with HAMD score (r = 0.826, P < 0,001; r = -0.818, p> >0,001; r = -0.876, P < 0,001; P = 0,001) P < 0,001; And have been negatively correlated (r = 0.870, Fig. 1, Fig. 2, Fig. 3) with AMA-scores (r = -0.876, P < 0.001, Table 1, Fig. 3), R = -0.862, P > 0.001; The HAMD score and the HAMA score (all P > 0.05) were not correlated to the serum ACE and ACE2. Finally, in PD patients, non-engine signs, including depression and anxiety, are normal. Thus, Serum levels Ang I, Ang II and Ang (1-7) were substantially decreased in female and male patients and associated with symptoms of depression and anxiety, ACE and ACE2 levels have not been attributed to signs of depression and anxiety. Serum Ang I, Ang II, and Ang (1-7) are important markers of depression and anxiety prevention and diagnosis in patients with DP.

Acute psychological impact on COVID-19 patients in Hubei: a multicenter observational study.

We conducted a multicentre cross-sectional survey of COVID-19 patients to evaluate the acute psychological impact on the patients with coronavirus disease 2019 (COVID-19) during isolation treatment based on online questionnaires from 2 February to 5 March 2020. A total of 460 COVID-19 patients from 13 medical centers in Hubei province were investigated for their mental health status using online questionnaires (including Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Patient Health Questionnaire-15, and Insomnia Severity Index scales). Among all 460 COVID-19 patients, 187 (40.65%) of them were healthcare workers (HCWs). 297 (64.57%) of them were females. The most common psychological problems were somatization symptoms (66.09%, n = 304), followed by depression (53.48%, n = 246), anxiety (46.30%, n = 213), problems of insomnia (42.01%, n = 171), and then self-mutilating or suicidal thoughts (23.26%, n = 107). Of all the patients, 15.65% (n = 72) had severe somatization symptoms, and 2.83% (n = 13) had severe (almost every day) self-mutilating or suicidal thoughts. The most common psychological problems for HCWs were somatization symptoms (67.84%, n = 125), followed by depression (51.87%, n = 97), anxiety (44.92%, n = 84), problems of insomnia (36.18%, n = 55), and then self-mutilating or suicidal thoughts (20.86%, n = 39). Patients with lower education levels were found to be associated with higher incidence of self-mutilating or suicidal thoughts (odds ratio [OR], 2.68, 95% confidence interval [95% CI], 1.66-4.33 [P < 0.001]). Patients with abnormal body temperature were found to be associated with higher incidence of self-mutilating or suicidal thoughts (OR, 3.97, 95% CI, 2.07-7.63 [P < 0.001]), somatic symptoms (OR, 2.06, 95% CI, 1.20-3.55 [P = 0.009]) and insomnia (OR, 1.66, 95% CI, 1.04-2.65 [P = 0.033]). Those with suspected infected family members displayed a higher prevalence of anxiety than those without infected family members (OR, 1.61, 95% CI, 1.1-2.37 [P = 0.015]). Patients at the age of 18-44 years old had fewer somatic symptoms than those aged over 45 years old (OR, 1.91, 95% CI, 1.3-2.81 [P = 0.001]). In conclusion, COVID-19 patients tended to have a high prevalence of adverse psychological events. Early identification and intervention should be conducted to avoid extreme events such as self-mutilating or suicidal impulsivity for COVID-19 patients, especially for those with low education levels and females who have undergone divorce or bereavement.

Outcomes and prognostic factors in 70 non-survivors and 595 survivors with COVID-19 in Wuhan, China.

Since the first outbreak of coronavirus disease 2019 (COVID-19) occurred in December 2019, more than 51 million cases had been reported globally. We aimed to identify the risk factors for in-hospital fatal outcome and severe pneumonia of this disease. This is a retrospective, multicentre study, which included all confirmed cases of COVID-19 with definite outcomes (died or discharged) hospitalized between 1 January and 4 March 2020 in Wuhan. Of all 665 patients included, 70 died and 595 discharged (including 333 mild and 262 severe cases). Underlying comorbidity was more commonly observed among deaths (72.9%) than mild (26.4%) and severe (61.5%) survivors, with hypertension, diabetes and cardiovascular as dominant diseases. Fever and cough were the primary clinical magnifications. Older age (≥65 years) (OR = 3.174, 95% CI = 1.356-7.755), diabetes (OR = 2.540, 95% CI = 0.995-6.377), dyspnoea (OR = 7.478, 95% CI = 3.031-19.528), respiratory failure (OR = 10.528, 95% CI = 4.484-25.829), acute cardiac injury (OR = 25.103, 95% CI = 9.057-76.590) and acute respiratory distress syndrome (OR = 7.308, 95% CI = 1.501-46.348) were associated with in-hospital fatal outcome. In addition, older age (OR = 2.149, 95% CI = 1.424-3.248), diabetes (OR = 3.951, 95% CI = 2.077-7.788), cardiovascular disease (OR = 3.414, 95% CI = 1.432-8.799), nervous system disease (OR = 4.125, 95% CI = 1.252-18.681), dyspnoea (OR = 31.944, 95% CI = 18.877-92.741), achieving highest in-hospital temperature of >39.0°C (OR = 37.450, 95% CI = 7.402-683.403) and longer onset of illness to diagnosis (≥9 days) were statistically associated with higher risk of developing severe COVID-19. In conclusion, the potential risk factors forolder age, diabetes, dyspnoea, respiratory failure, acute cardiac injury and acute respiratory distress syndrome could help clinicians to identify patients with poor prognosis at an early stage.

Diabetes-Induced H3K9 Hyperacetylation Promotes Development of Alzheimer's Disease Through CDK5.

The connection between diabetes and Alzheimer's disease (AD) is not fully determined. Hyperphosphorylation of tau protein is mediated by binding and stabilization of truncated p25 with cyclin-dependent kinase-5 (CDK5) in AD. We recently showed that diabetes-associated hyperglycemia increased the CDK5 levels to promote development of AD. Here, we examined the underlying mechanisms. Hyperglycemia and glucose intolerance were induced in rats that had received a low dose of streptozotocin (STZ) and a high fat diet (HFD). Compared to the control rats that received no STZ and normal diet-fed, the STZ + HFD rats exhibited poorer performance in the behavioral test and showed hyperacetylation of H3K9 histone on CDK5 promoter, likely resulting from upregulation of a histone acetyltransferase, GCN5. Inhibition of acetylation of H3K9 histone by a specific GCN5 inhibitor, MB3, attenuated activation of CDK5, resulting in decreased tau phosphorylation in rat brain and improved performance of the rats in the behavior test. Thus, these data suggest that diabetes may promote future development of AD through hyperacetylation of H3K9 histone on CDK5 promoter.

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

M2-Like Microglia Polarization Attenuates Neuropathic Pain Associated with Alzheimer's Disease.

Many Alzheimer's disease (AD) patients suffer from persistent neuropathic pain (NP), which is mediated, at least partially, but microglia. Nevertheless, the exact underlying mechanism is unknown. Moreover, a clinically translatable approach through modulating microglia for treating AD-associated NP is not available. Here, in a doxycycline-induced mouse model (rTg4510) for AD, we showed development of NP. We found that the total number of microglia in the CA3 region was not increased, but polarized to pro-inflammatory M1-like phenotype, with concomitant increases in production and secretion of pro-inflammatory cytokines. To examine whether this microglia polarization plays an essential role in the AD-associated NP, we generated an adeno-associated virus (AAV) serotype PHP.B (capable of crossing the blood-brain barrier) carrying shRNA for DNA methyltransferase 1 (DNMT1) under a microglia-specific TMEM119 promoter (AAV-pTMEM119-shDNMT1), which specifically targeted microglia and induced a M2-like polarization in vitro and in vivo in doxycycline-treated rTg4510 mice. Intravenous infusion of AAV-pTMEM119-shDNMT1 induced M2-polarization of microglia and attenuated both AD-associated behavior impairment but also NP in the doxycycline-treated rTg4510 mice. Thus, our data suggest that AD-associated NP may be treated through M2-polarization of microglia.

Clarithromycin synergizes with cisplatin to inhibit ovarian cancer growth in vitro and in vivo.

BACKGROUND: Cisplatin-based chemotherapy is the first-line treatment for ovarian cancer. However, acquired resistance to cisplatin treatment often occurs in epithelial ovarian cancer, and effective and practical methods for overcoming this obstacle are urgently needed. The study aimed to demonstrate the synergistic effect of clarithromycin (CAM) with cisplatin to inhibit ovarian carcinoma cells growth in vitro and in vivo. RESULTS: We performed CCK-8 assay to detect apoptosis rates in response to CAM alone or in combination with cisplatin, which were further confirmed by Annexin V and PI staining methods and western blotting. Mechanistically, CAM could reduce endogenous antioxidant enzyme expression and increase the levels of reactive oxygen species (ROS) to augment the cytotoxic effect of cisplatin. Meanwhile, a tumor xenograft model in athymic BALB/c-nude mice demonstrated that CAM combined with cisplatin resulted in reduced tumor growth and weight compared with cisplatin alone. CONCLUSION: Collectively, our results indicate that CAM works synergistically with cisplatin to inhibit ovarian cancer cell growth, which may be manipulated by a ROS-mediated mechanism that enhances cisplatin therapy, and offers a novel strategy for overcoming cisplatin therapy resistance.

Elevated serum macrophage migration inhibitory factor levels correlate with benign paroxysmal positional vertigo and recurrence events.

Objective: We aimed to assess the possible relations between serum levels of macrophage migration inhibitory factor (MIF), a central cytokine of the innate immunity and inflammatory response, and benign paroxysmal positional vertigo (BPPV) risk and BPPV recurrence events.Methods: In the present study, 154 patients with BPPV, and 100 age-and sex-matched control subjects were enrolled in the study. All the patients and controls underwent a complete audio-vestibular test battery including the Dix-Hallpike maneuver and supine roll test. In the BPPV group, measurements of MIF levels were repeated 1 month after the vertigo attack. The patients were also divided into the recurrence group and the nonrecurrence group in the 1-year follow-up.Results: The serum levels of MIF in patients with BPPV were higher than in those controls (13.9[interquartile range {IQR}, 8.9-18.4] ng/ml vs. 9.8[7.8-11.8]; P<0.001). As a continuous variable, MIF was associated with increased risk of BPPV (odds ratio [OR] 1.21, 95% confidence interval [CI]: 1.11-1.39; P=0.004) in multiple regression analyses. Recurrent attacks of BPPV were reported in 35 patients, and those patients had higher levels of MIF than those patients were not recurrence (18.0[IQR, 13.6-22.2] ng/ml vs. 12.6[9.3-16.8] ng/ml). In multivariate models comparing the second (Q2), third (Q3) and fourth(Q4) quartiles against the first (Q1) quartile of MIF, levels of MIF in Q4 were associated with recurrent BPPV, and the odds were increased by approximately 305% (OR = 4.05; 95%CI: 1.65-15.44; P=0.009).Conclusions: Elevated MIF is positively correlated with BPPV risk and BPPV recurrence events, requiring further efforts to clarify the exact mechanism.

Epigenetic Control of CDK5 Promoter Regulates Diabetes-Associated Development of Alzheimer's Disease.

Cyclin-dependent kinase-5 (CDK5) is activated by p35 and then binds to both p35 and its truncated form p25 to promote hyperphosphorylation of tau protein, thereby facilitating the pathological progression of Alzheimer's disease (AD). However, it is unknown whether a patient's diabetic status promotes the later onset of AD in a CDK5-dependent manner. Here, we induced pro-diabetic insulin resistance and glucose intolerance in rats using a combined high fat and high glucose diet. Compared to normal diet-fed rats, these pro-diabetic rats exhibited poorer behavioral performance in the Morris water maze test and the novel object recognition test. Increased phosphorylation of tau protein was detected in the hippocampal CA1 region of the rat brain, suggesting neurodegeneration. Moreover, CDK5 transcriptional activity was significantly increased in the HFGD-rat brain, likely resulting from an increase in acetylation and a decrease in methylation of the CDK5 promoter. Together, these data suggest that epigenetic control of the CDK5 promoter by acetylation and methylation may regulate the diabetes-associated development of AD.