To develop a novel polyamino acid-based nanohydrogel drug delivery system for dexamethasone to enhance its delivery efficiency to the inner ear.

A fluorescein-labeled polyglutamic acid-based polyamino acid dexamethasone nanohydrogel was synthesized, and its gelation time was measured. The hydrogel was surgically injected into the round window niche of guinea pigs to determine its degradation time in the middle ear cavity in vivo. The safety, pharmacokinetics, and distribution patterns of dexamethasone in the inner ear were evaluated.

The hydrogel exhibited a gelation time of 80 seconds in a 37℃ water bath. In vivo, the hydrogel was almost completely degraded within 7 days in the middle ear cavity of guinea pigs. Transient hearing loss was observed one day after administration, but hearing gradually returned to normal over time. No significant cytotoxicity, vestibular stimulation signs, or pathological abnormalities in spiral ganglion cells were observed. Histopathological examination revealed no significant inflammatory reactions. Pharmacokinetic analysis demonstrated sustained drug release and prolonged dexamethasone activity. Immunofluorescence staining confirmed the distribution of dexamethasone in both the cochlea and vestibular organs.

The polyamino acid nanohydrogel exhibits excellent injectability and biodegradability, representing a safe and effective drug delivery system for the inner ear.

OBJECTIVE To establish the drug-induced liver injury （DILI） surveillance and assessment system （DILI-SAS）， and to improve the diagnostic efficiency of clinical DILI. METHODS The DILI-SAS was constructed by using natural language processing technology to mine and utilize all inpatient medical record data， and combined with Roussel Uclaf causality assessment method （RUCAM）. The medical records of 19 445 hospitalized patients from August 2022 to January 2023 were detected to verify the performance of the system and manually analyze the basic data of patients with DILI and the distribution of the first suspected drugs. RESULTS The overall accuracy rate of the DILI-SAS system was 91.95%， and the recall rate was 93.20%. Seventy-five DILI cases were detected， and the DILI incidence rate was 385.70/100 000 people. The efficiency of DILI monitoring by human- computer coupling was increased by about 60 times of manual monitoring； males （61.33%） and patients over 60 years old （56.00%） were the most common in the 75 cases of DILI. The clinical type of liver injury was hepatocyte injury （69.33%）， the incubation period was mainly 5-90 days after treatment （62.67%）， and the RUCAM score between 3 and 5 was the most common （66.67%）； pharmacological distribution of the first suspected drugs was mainly dihydropyridines， HMG CoA reductase inhibitors， proton pump inhibitors， etc. The specific drugs were atorvastatin， omeprazole， ceftriaxone， metronidazole and other drugs. CONCLUSIONS The establishment of DILI-SAS can improve the evaluation efficiency on the basis of ensuring the accuracy degree， and provide a solution for the early identification， diagnosis and evaluation of clinical DILI.

Background::Non-smokers account for a large proportion of lung cancer patients, especially in Asia, but the attention paid to them is limited compared with smokers. In non-smokers, males display a risk for lung cancer incidence distinct from the females—even after excluding the influence of smoking; but the knowledge regarding the factors causing the difference is sparse. Based on a large multicenter prospective cancer screening cohort in China, we aimed to elucidate the interpretable sex differences caused by known factors and provide clues for primary and secondary prevention.Methods::Risk factors including demographic characteristics, lifestyle factors, family history of cancer, and baseline comorbidity were obtained from 796,283 Chinese non-smoking participants by the baseline risk assessment completed in 2013 to 2018. Cox regression analysis was performed to assess the sex difference in the risk of lung cancer, and the hazard ratios (HRs) that were adjusted for different known factors were calculated and compared to determine the proportion of excess risk and to explain the existing risk factors.Results::With a median follow-up of 4.80 years, 3351 subjects who were diagnosed with lung cancer were selected in the analysis. The lung cancer risk of males was significantly higher than that of females; the HRs in all male non-smokers were 1.29 (95% confidence interval [CI]: 1.20-1.38) after adjusting for the age and 1.38 (95% CI: 1.28-1.50) after adjusting for all factors, which suggested that known factors could not explain the sex difference in the risk of lung cancer in non-smokers. Known factors were 7% (|1.29-1.38|/1.29) more harmful in women than in men. For adenocarcinoma, women showed excess risk higher than men, contrary to squamous cell carcinoma; after adjusting for all factors, 47% ([1.30-1.16]/[1.30-1]) and 4% ([7.02-6.75]/[7.02-1])) of the excess risk was explainable in adenocarcinoma and squamous cell carcinoma. The main causes of gender differences in lung cancer risk were lifestyle factors, baseline comorbidity, and family history.Conclusions::Significant gender differences in the risk of lung cancer were discovered in China non-smokers. Existing risk factors did not explain the excess lung cancer risk of all non-smoking men, and the internal causes for the excess risk still need to be explored; most known risk factors were more harmful to non-smoking women; further exploring the causes of the sex difference would help to improve the prevention and screening programs and protect the non-smoking males from lung cancers.

A 55-year-old male patient presented with plaques on the face for more than 20 years,and no immunodeficiency diseases were diagnosed.Skin examination showed large areas of pink plaques on the nose,bilateral cheeks and upper oral lips with slight desquamation,verrucous hyperplasia on the dorsal area of the nose,and a bean-sized verrucous protuberance on the tip of the nose.Histopathological examination of the skin lesions revealed pseudoepitheliomatous hyperplasia in the epidermis and hyphae-like structures in the stratum corneum.Moreover,there was diffuse infiltration of inflammatory cells in the dermis,which mainly included neutrophils,lymphocytes,histiocytes and multinucleated giant cells.Periodic acid-Schiff (PAS)-positive spore-like structures were observed in the multinucleated giant cells.Culture of the lesional tissues on Sabouraud dextrose agar (SDA) medium showed grey-brown villous colonies.Microculture on the potato dextrose agar (PDA) medium yielded dark septate hyphae and pycnidia filled with a large number of spores.Microsphaeropsis arundinis was identified by fungal molecular biological techniques.The patient was diagnosed with cutaneous phaeohyphomycosis caused by Microsphaeropsis arundinis.The patient was treated with CO2 laser for the removal of verrucous protuberance on the tip of the nose,and oral itraconazole capsules at a dose of 200 mg twice a day.After 3-month treatment,the skin lesions subsided and the drug was withdrew.During 6-month follow-up,no relapse occurred.

Objective To evaluate the effect ofT-cell immunoglobulin and mucin domain-3 (TIM-3) on TRP-2180-188 peptide-stimulated murine spleen lymphocytes co-cultured with B16F10 murine melanoma cells.Methods A recombinant plasmid pFUSE-TIM-3-mIgG2Aae1-Fc2 encoding TIM-3 was constructed.Then,the recombinant plasmid and an empty plasmid pFUSE-mIgG2Aae1-Fc2 were transfected into human 293T epithelial cells followed by 48-hour culture for the preparation of supernatants containing TIM-3 and Ig-tail respectively.C57BL/6 mice were immunized with the TRP-2180-188 peptide vaccine for 4 sessions.One week after the last vaccination,C57BL/6 mice were sacrificed,and spleen lymphocytes were collected and then cultured with the TRP-21180-188 peptide and interleukin-2 (IL-2) for 5 days,with lymphocytes untreated with the TRP-2180-188 peptide or IL-2 serving as the control group.Mitomycin-treated B16F10 murine melanoma cells and TRP-2180-188 peptide-stimulated lymphocytes were co-cultured with the presence of supernatants of 293T cells that had been cultured for 48 hours (blank control group),TIM-3-containing supernatants (TIM-3 group) and Ig-tail-containing supernatants (negative control group) separately.After 24 and 48 hours of co-culture,cell counting kit-8 (CCK-8) assay was performed to estimate the proliferative activity of lymphocytes,enzyme-linked immunosorbent assay (ELISA) to determine the supernatant levels of interferon (INF)-γ and tumor necrosis factor (TNF)-α,flow cytometry to determine the percentage of CD8 + T cells in the co-culture system.Results Enzyme digestion and sequence analysis showed that the TIM-3 gene was successfully inserted into the eukaryotic expression plasmid.After 48-hour culture,TIM-3 and Ig-tail expressions were detected in the supernatants of 293T cells transfected with the recombinant plasmid and empty plasmid respectively.As CCK-8 assay showed,the proliferative activity of lymphocytes was significantly lower in the TIM-3 group than in the blank control group and negative control group after 24-and 48-hour culture (78.06％ ± 6.37％ vs.100.00％ ± 10.42％ and 108.70％ ± 9.90％ at 24 hours,42.93％ ± 5.93％ vs.100.00％ ± 6.24％ and 168.00％ ± 2.98％at 48 hours,all P ＜ 0.05),so was the ratio of cellular proliferative activity at 48 hours to that at 24 hours (all P ＜ 0.05).Compared with the blank control group and negative control group,the TIM-3 group showed significantly decreased supernatant levels of IFN-γ and TNF-α after 24-hour (IFN-γ:192.96 γ 5.05 ng/L vs.216.44 ± 7.85 ng/L and 223.67 ±7.79 ng/L,both P＜ 0.05;TNF-α:58.43 ± 0.26 ng/L vs.26.43 ± 0.01 ng/L and 86.85 ± 1.12 ng/L,both P＜ 0.05) and 48-hour culture (IFN-γ:54.95 ± 0.57 ng/L vs.230.06 ± 4.23 ng/L and 167.24 ± 3.33 ng/L,both P ＜ 0.05;TNF-α:30.23 ±0.26 ng/L vs.26.84 ± 0.20 ng/L and 45.34 ± 0.22 ng/L,both P ＜ 0.05).In addition,the median percentage of CD8+ T cells was significantly increased in the TIM-3 group compared with the blank control group and negative control group after 24-and 48-hour culture (3.30％ vs.0.421％ and 2.22％ at 24 hours,4.06％ vs.0.577％ and 0.691％ at 48 hours,all P＜ 0.05).Conclusion TIM-3 in vitro can suppress the proliferative activity of and secretion of IFN-γand TNF-α by lymphocytes,but increase the percentage of CD8 + T cells in the co-culture system of TRP-2180-188 peptide-stimulated lymphocytes and B16F10 cells.

OBJECTIVETo observe the level of blood sodium in patients hospitalized for heart failure with water-sodium retention treated with loop diuretics and risk factors of low blood sodium.

METHODSWe selected 1 378 acute decompensated heart failure patients who visited Anzhen Hospital, and they are treated with loop diuretics, 259 patients with weight loses more than 1 kg in one week was enrolled in the final analysis, and divided into 3 groups: Group A (weight reduction between 1-3 kg), Group B (weight reduction between 3-5 kg) and Group C (weight reduction over 5 kg). Blood sodium, creatinine and uric acid were compared among groups and risk factors of low blood sodium were analyzed.

RESULTSBlood sodium was similar before and post loop diuretics treatment in Group A, and reduced in group B ((138.28 ± 3.73) mmol/L vs. (139.34 ± 3.66) mmol/L, P < 0.05) and in Group C((137.60 ± 4.07) mmol/L vs. (139.44 ± 4.12) mmol/L, P < 0.05). Forty-six (17.8%) patients developed hyponatremia post loop diuretics treatment. Duration of loop diuretics use was the independent risk infector for hyponatremia (OR = 1.191, 95%CI 1.010-1.385).

CONCLUSIONSLoop diuretics use is safe for treating hospitalized patients for heart failure with water-sodium retention and the risk of developing hyponatremia is low. Duration of loop diuretics use is the independent risk factor of hyponatremia.

Acute Disease ; Creatinine ; Heart Failure ; complications ; drug therapy ; Humans ; Hyponatremia ; Risk Factors ; Sodium ; blood ; Sodium Potassium Chloride Symporter Inhibitors ; adverse effects ; therapeutic use ; Sodium, Dietary

A 44-year-old male presented with a neoplasm on the buccal side of the right nasolabial fold for more than two months.Dermatological examination showed a hemispherical bulge sized 1.5 cm × 1.5 cm with central crater-like ulceration on the buccal side of the right nasolabial fold,as well as a crescent-shaped elevation measuring 1.5 cm × 2.5 cm above the hemispherical lesion.Histopathology of the hemispherical lesion revealed irregularly downward proliferation of epidermis,crater-like holes filled with eosinophilic keratinous plug in the center which were surrounded by collar-shaped epithelial cell projections.Small neutrophil abscesses were found in the clumps of epithelial cells,and massive lymphocyte infiltration with a clear bottom boundary was observed around the proliferating epithelial cells.Histopathologic examination of the crescent lesion showed multiple irregularly-shaped lobular-like structures of various sizes with sebaceous glands at different degrees of maturity in the mid dermis,which were surrounded by proliferating connective tissue.Immunohistochemical studies showed that the squamous cells stained positive for cytokeratin (CK),CK5,CK14,CK17,carcinoembryonic antigen (CEA) and epithelial membrane antigen (EMA) in the keratoacanthoma,and the sebaceous cells for CK,CK5,CK14 and EMA in the sebaceous adenoma.The pathological diagnosis was keratoacanthoma and sebaceous adenoma.The patient was diagnosed with moderately and poorly differentiated rectal adenocarcinoma in 2008.A diagnosis of Muir-Torre syndrome presenting as keratoacanthoma and sebaceous adenoma was finally made.

Aged ; Humans ; Male ; Metals ; Percutaneous Coronary Intervention ; adverse effects ; Stents ; adverse effects ; Thrombosis ; diagnosis ; Time Factors

Objective To observe the level of blood sodium in patients hospitalized for heart failure with water-sodium retention treated with loop diuretics and risk factors of low blood sodium .Methods We selected 1 378 acute decompensated heart failure patients who visited Anzhen Hospital , and they are treated with loop diuretics , 259 patients with weight loses more than 1 kg in one week was enrolled in the final analysis, and divided into 3 groups:Group A (weight reduction between 1-3 kg), Group B(weight reduction between 3-5 kg)and Group C(weight reduction over 5 kg).Blood sodium, creatinine and uric acid were compared among groups and risk factors of low blood sodium were analyzed .Results Blood sodium was similar before and post loop diuretics treatment in Group A , and reduced in group B ( (138.28 ± 3.73) mmol/L vs.(139.34 ±3.66) mmol/L, P<0.05) and in Group C((137.60 ±4.07) mmol/L vs.(139.44 ±4.12 ) mmol/L, P <0.05 ).Forty-six ( 17.8%) patients developed hyponatremia post loop diuretics treatment.Duration of loop diuretics use was the independent risk infector for hyponatremia (OR=1.191, 95%CI 1.010-1.385).Conclusions Loop diuretics use is safe for treating hospitalized patients for heart failure with water-sodium retention and the risk of developing hyponatremia is low.Duration of loop diuretics use is the independent risk factor of hyponatremia .

Objective To study the effect of Neuregulin-1 (NRG) on rat heart failure(HF) after myocardial infarction,and to investigate the underlying mechanism involving in NRG-mediated cardioprotection.Methods 60 adult Wister rats underwent sham operation (n=12) or coronary ligation (n=48) to induce HF.Four weeks after ligation,28 animals with HF were randomly divided into NRG group (rats received rhNRG-1 10 μg · kg-1 · d-1 intravenously for 10 days) or HF group (rats received an equal volume of water intravenously for 10 days).Left ventricular function was detected by echocardiography.Mitochondrial ultrastructure in non-infarcted myocardium was observed by transmission electronic microscopy.Cell apoptosis was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay.Mitochondrial membrane potential was measured by immunofluorescence method.Caspase-3 activity was determined by commercial kit.The expression of cytochrome C protein in cytoplasm was detected by Western blot.Results Compared with HF group,the left ventricular end-systolic diameter was decreased,and left ventricular ejection fraction and fractional shortening were increased in NRG group (P＜0.05 or 0.01).Apoptosis index was reduced inNRG group as compared with HFgroup [(18.1±3.0)％ vs.(11.9±1.4)％,P＜0.01].Mitochondrial membrane potential was increased and the release of cytochrome c in cytoplasm was reduced in NRG group as compared with HF group [(249.8±7.4) mV vs.(222.2±7.5) mV,(0.356±0.024) vs.(0.664±0.085),both P＜0.01].Caspase-3 activity was decreased in NRG group as compared with HF group (P＜0.01).Conclusions NRG attenuats mitochondrial stress and inhibits myocardial cells apoptosis in heart failure rats after myocardial infarction,which may play an important role in the cardioprotection by NRG.