Specific CYP450 Genotypes in the Chinese Population Affect Sorafenib Toxicity in HBV/HCV-associated Hepatocellular Carcinoma Patients

Objective The purpose of this study was to screen for frequencies of different CYP450 genotypes in the Chinese population and explore the relationship between sorafenib toxicity and CYP450 polymorphism. Methods A total of 600 peripheral blood samples were obtained from two groups for this study. The first group of 300 samples were from Chinese patients with HBV/HCV-associated HCC, while the remaining 300 samples were from a healthy population of recruited subjects. Allele-specific PCR and long-fragment gene sequencing was used to identify the frequencies of CYP450 polymorphism. Aflatoxin-induced HCC rat models expressing CYP3A4*1, CYP3A5*3, CYP2C19*2, and CYP2D6*10 were established and treated with sorafenib at certain time points. Hepatic and renal function, along with plasma concentration of sorafenib, were monitored regularly. Results The most common forms of CYP mutations in the Chinese population were identified. The levels of sorafenib plasma concentration, as well as damage to hepatic and renal function in aflatoxin-induced HCC rat models varied significantly across the different CYP genotypes. Conclusion The mutational frequencies of CYP3A5, CYP3A4, CYP2C19, and CYP2D6 genotypes varied among different ethnic groups and populations. Individuals with CYP3A5*3 demonstrated minimal sorafenib metabolism, which led to severe hepatic and renal damage. Inter-individual variability in sorafenib-toxicity may be interpreted by CYP450 genetic polymorphisms, suggesting that identification of CYP polymorphism within a certain population should be considered in sorafenib therapy.

Multisciplinary management of patients with liver metastasis from colorectal cancer

Colorectal cancer(CRC) is one of the leading causes of cancer-related death. Surgery, radiotherapy and chemotherapy have been till now the main therapeutic strategies for disease control and improvement of the overall survival. Twenty-five per cent(25%) of CRC patients have clinically detectable liver metastases at the initial diagnosis and approximately 50% develop liver metastases during their disease course. Twentythirty per cent(20%-30%) are CRC patients with metastases confined to the liver. Some years ago various studies showed a curative potential for liver metastases resection. For this reason some authors proposed the conversion of unresectable liver metastases to resectable to achieve cure. Since those results were published, a lot of regimens have been studied for resectability potential. Better results could be obtained by the combination of chemotherapy with targeted drugs, such as anti-VEGF and antiEGFR monoclonal antibodies. However an accurate selection for patients to treat with these regimens and to operate for liver metastases is mandatory to reduce the risk of complications. A multidisciplinary team approach represents the best way for a proper patient management. The team needs to include surgeons, oncologists, diagnostic and interventional radiologists with expertise in hepatobiliary disease, molecular pathologists, and clinical nurse specialists. This review summarizes the most important findings on surgery and systemic treatment of CRC-related liver metastases.

Nonalcoholic fatty liver disease:Updates in noninvasive diagnosis and correlation with cardiovascular disease

Nonalcoholic fatty liver disease(NAFLD)refers to the accumulation of fat(mainly triglycerides)within hepatocytes.Approximately 20%-30%of adults in the general population in developed countries have NAFLD;this trend is increasing because of the pandemicity of obesity and diabetes,and is becoming a serious public health burden.Twenty percent of individuals with NAFLD develop chronic hepatic inflammation[nonalcoholic steatohepatitis(NASH)],which can be associated with the development of cirrhosis,portal hypertension,and hepatocellular carcinoma in a minority of patients.And thus,the detection and diagnosis of NAFLD is important for general practitioners.Liver biopsy is the gold standard for diagnosing NAFLD and confirming the presence of NASH.However,the invasiveness of this procedure limits its application to screening the general population or patients with contraindications for liver biopsy.The development of noninvasive diagnostic methods for NAFLD is of paramount importance.This review focuses on the updates of noninvasive diagnosis of NAFLD.Besides,we review clinical evidence supporting a strong association between NAFLD and the risk of cardiovascular disease because of the cross link between these two disorders.

Investigation and analysis of lower extremity arterial disease in hospitalized elderly type 2 diabetic patients

Background:The risk of lower extremity arterial disease (LEAD) is increased in diabetic patients.LEAD in diabetic patients occurs earlier and is often more severe and diffuse;however,it is largely underdiagnosed and untreated.The purposes of this study were to investigate and analyze LEAD situation of hospitalized elderly type 2 diabetic patients.Methods:The ankle-brachial index (ABI) was used to screen LEAD in hospitalized elderly type 2 diabetic patients.The patients were divided into 5 groups based on the screening results:non-LEAD group and LEAD group;the LEAD group was divided into mild stenosis group,moderate stenosis group,and severe stenosis group.Results:The percentage of patients who had LEAD was 43%.Significant difference in age,diabetes duration,peak velocity,microalbuminuria,and vibratory sensory neuropathy was observed between patients with and without LEAD;regression analysis showed that urinary albumin and vibratory sensory neuropathy were independent risk factors for LEAD.Significant difference in age,body mass index (BMI),peak velocity,urinary albumin,and high-density lipoprotein cholesterol (HDL-C) was observed between mild stenosis group,moderate stenosis group,and severe stenosis group;regression analysis showed that urinary albumin,BMI,and HDL-C were independent risk factors for accelerating vascular stenosis.Conclusions:The incidence of LEAD in hospitalized elderly type 2 diabetic patients is high;age,diabetes duration,peak velocity,BMI,urinary microalbumin,vibratory sensory neuropathy,and HDL-C are the maior risk factors for LEAD.Active control of risk factors is helpful to reduce or delay LEAD.

Surgical treatment and visual outcomes of cataract with persistent hyperplastic primary vitreous

AIM：To evaluate the surgical treatment and visual outcomes of eyes with cataract and persistent hyperplastic primary vitreous（PHPV）.METHODS：This retrospective study included patients with cataract and PHPV treated with various strategies.Anterior PHPV was treated using phacoemulsification with underwater electric coagulation on posterior capsule neovascularization,posterior capsulotomy,anterior vitrectomy,and intraocular lens（IOL）implantation. Posterior PHPV was treated with lensectomy,posterior vitrectomy,retinal photocoagulation,and IOL implantation or silicone oil tamponade. Visual acuity（VA）,pattern visual evoked potential（P-VEP）,anatomic recovery,postoperative complications,and amblyopia outcome were examined.Subjects were followed-up for 3-48 mo after surgery.RESULTS：Of the 30 patients（33 eyes）with congenital cataract and PHPV included（average age,39.30±35.47mo）,9 eyes had anterior PHPV and 24 had posterior PHPV. Thirty-two eyes were surgically treated. Eyes with anterior PHPV received an IOL during one-stage（6 eyes）and twostage（3 eyes）implantation. Postoperative complications included retinal detachment（1 eye）and recurrent anterior chamber hemorrhage（1 eye）. In eyes with posterior PHPV,6 and 11 eyes received IOLs in one-and two-stage procedures,respectively. Silicone oil was retained in 2 eyes,and IOLs were not implanted in 4 eyes. VA significantly improved in 25 eyes following operations and 3-48 mo of amblyopia treatment. P-VEP P_（100） was improved following surgery in both PHPV types.CONCLUSION：Our surgical strategies are appropriate and effective for anterior and posterior PHPV. Early surgical intervention and amblyopia therapy result in positive treatment outcomes.

Development and application of a closed-loop medication administration system in University of Hongkong-Shenzhen Hospital

Objective： This study aimed to develop and apply a closed-loop medication administration system in a hospital in order to reduce medication administration errors （MAEs）.Methods： The study was implemented in four pilot general wards. We used a before-and-after design to collect oral medication administration times before and after the implementation of the closed-loop medication administration system, evaluated MAE alert logs after the intervention, and conducted a survey of the nurses1 satisfaction with the system in the pilot wards.Results： （a） Nursing time of oral medication administration： before the adoption of the closed-loop medication administration system, the average nursing time was 31.56 ± 10.88 minutes （n = 78）; after the adoption of the system, the time was 18.74 ± 5.60 minutes （n = 54）. Independent sample Mests showed a significant difference between two groups（t= 8.85, P 〈0.00）. （b） Degree of nurses’ satisfaction with the closed-loop medication administration system： 60.00% （n = 42） of nurses considered the system to be helpful for their work and nearly half of the nurses （47.14%, n = 33） believed that the system could facilitate clinical work and reduce workload; 51.43% {n = 36） believed that the system could reduce checking time and enhance work efficiency; 82.86% （n = 58） believed that the system was helpful in improving checking accuracy to reduce MAEs and ensure patient safety. More than 60% of the nurses considered the system to be a method that could help to track MAEs to improve nursing quality, （c） The MAE alert logs during observation period： it revealed only 27 alerts from the repeated scans of 3,428 instances of medication administration.Conclusions： The nurses were satisfied with the closed-loop medication administration system because it improved their work efficiency and reduced their workload. The current investigation was limited by time; therefore, further research is needed to more closely examine the relationship between the system and MAEs.

CLINICAL AND EXPERIMENTAL STUDIES ON TONG YU LING IN THE TREATMENT OF DIABETIC HYPERLIPEMIA

72 diabetes mellitus patients(70 cases non-insulin-dependent)were treated routinely with D860.After one month,cases with persisting hyperglycemia and hyperlipemia were randomly dividedinto Group A to be treated with D860 plus Tong Yu Ling (通瘀灵 TYL),and Group B to con-tinue treatment with D860 alone,while Group C,comprising cases with persisting hyperlipemiaonly,were treated with TYL alone.Therapeutic results showed that of the total 50 cases ofGroup A and C,26 were markedly improved,14 improved,and 10 cases ineffective.Theantihyperlipemic

Clinical characterization and follow-up analysis of twenty-one cases with neonatal diabetes mellitus

Objective: We summarize the clinical and follow-up data of twenty-one children with neonatal diabetes mellitus (NDM) to strengthen the understanding of NDM and provide reference for clinical diagnosis and follow-up. Methods The clinical characteristics, growth and development of twenty-one children with NDM who were diagnosed and treated in the Children's Hospital of Nanjing Medical University from January 2011 to August 2018 were retrospectively analyzed. Results The median age of diagnosis was 97 days and the follow-up period was 0.96 to 47.6 months years. At the time of new diagnosis, 7 cases were complicated with diabetic ketoacidosis and 3 cases with diabetic ketoacidosis. Seven patients had diabetic ketoacidosis (DKA) and three patients had diabetic ketosis (DK). Three cases were unclassified because of short follow-up time. Two patients are Transient neonatal diabetes mellitus (TNDM). Sixteen cases are Permanent neonatal diabetes mellitus (PNDM). Thirteen patients underwent drug-experiential treatment with a success rate of 53.8%. Twelve patients had growth and development disorders or language and motor retardation. Eleven cases were improved by genetic testing and the positive rate of gene mutation was 81.8%. There was no significant difference in treatment regimen, complications, genotype and other factors among different growth and development conditions (P > 0.05). Fisher exact probability analysis of growth and development in different treatment schemes showed that there was no significant difference (P>0.05). Conclusions Patients with KCNJ11 and ABCC8 gene mutations often have developmental disorders and sulfonylurea drugs are effective, which can improve the outcome of developmental disorders. There was no correlation between age, complications, genotype and the outcome of growth. When conditions permit, we should perfect gene detection as soon as possible to identify the type of mutation, guiding treatment and judging prognosis.

Nursing care for diabetic toe ulcers:A case series report and literature review

This paper reports the treatment of eight cases with toe ulcers.The eight patients received nursing treatments,including debridement,dressings,decompression,anti-fungal management,and education from specialist nurses.The patients were also given drugs to control glucose,nourish the nerve,and improve blood circulation of the lower extremities.The toe ulcers of the eight diabetic patients healed after 42e168 days[average 85±36 days].Thus far,few studies have focused on diabetic toe ulcers.Timely identification of risk factors and regular toe care could decrease the prevalence of toe ulcers and shorten the recovery time in patients with diabetic mellitus.Hence,these patients must be diagnosis and treated early.Results suggest that feet,particularly toes,should be inspected and cared for regularly in diabetic patients.

Effects of α-zinc sulfate combined with yiqiyangyinghuoxue therapy on related factors in patients with type 2 diabetes peripheral neuropathy

Objective: To study the effects of -zinc sulfate combined with yiqiyangyinghuoxue therapy on related factors in patients with type 2 diabetes peripheral neuropathy. Methods: A total of 90 patients with type 2 diabetes peripheral neuropathy in our hospital from September 2015 to September 2018 were enrolled in this study. The subjects were divided into the control group (n=45) and the treatment group (n=45) randomly. The control group were treated with -zinc sulfate, the treatment group were treated with -zinc sulfate combined with yiqiyangyinghuoxue therapy, the two groups were treated for 3 months. The serum NSE, UA, Hcy, hs-CRP, BDNF, HMGB1, CysC, TGF-β1, 25-(OH)D3, ESM-1, NO and plasma ET, TNF of the two groups before and after treatment were compared. Results: There were no significantly differences of the serum NSE, UA, Hcy, hs-CRP, BDNF, HMGB1, CysC, TGF-β1, 25-(OH)D3, ESM-1, NO and plasma ET, TNF of the two groups before treatment. After treatment, the serum NSE, UA, Hcy, hs-CRP, HMGB1, CysC, TGF-β1, ESM-1 and plasma ET, TNF of the two groups were significantly lower than before treatment, the serum BDNF, 25-(OH)D3, NO of the two groups were significantly higher than before treatment, and that of the treatment group after treatment were significantly better than the control group. Conclusion: α-zinc sulfate combined with yiqiyangyinghuoxue therapy on patients with type 2 diabetes peripheral neuropathy has a good efficacy, can improve the neuropathy and vascular endothelial damage, improve related factors, and it was worthy clinical application.

Features analysis on Traditional Chinese Medicine syndromes in patients with diabetic peripheral neuropathy

OBJECTIVE:To study the features of the distribution and differentiation ofTraditional Chinese Medicine(TCM)syndromes in patients with diabetic peripheral neuropathy(DPN).METHODS:We collected clinical data on illness course,age,fasting blood glucose,saccharogenic hemoglobin,TCM syndromes,tongue,and pulse of238 DPN patients.Differentiated main syndromes(Yin deficiency and exuberant heat,invasion of spleen by damp-heat,deficiency of both Qi and Yins,and deficiency of both Yin and Yang)and accompanying syndromes(blood stasis and phlegm-dampness)of diabetes were also recorded.The features of DPN syndromes were then analyzed.RESULTS:Among the four main syndromes of diabetes,deficiency of both Yin and Yang was the most common in the 238 DPN patients,of which89%-96%had blood stasis.CONCLUSION:The method of differentiating syndromes of diabetes can be applied to DPN patients.Deficiency of both Yin and Yang,often accompanied by blood stasis,is commonly seen.

Maxingxiongting mixture attenuates hypoxia pulmonary arterial hypertension to improve right ventricular hypertrophy by inhibiting the rho-kinase signaling pathway

OBJECTIVE:To explore the mechanism of Maxingxiongting mixture(MXXTM)on pulmonary hypertension in a rat model established by intraperitoneal injection of monocrotaline solution,smoking and forced swimming.METHODS:A total of 30 male Sprague-Dawley rats were randomly divided into five groups:control group,model group,high-dose of MXXTM group(HM),low-dose of MXXTM group(LM),and fasudil group.The mean pulmonary artery pressure(m PAP)was measured by using a miniature catheter.Lung tissue and right ventricular tissue sections were stained with hematoxylin-eosin.The right ventricle(RV)and left ventricle+septum(LV+S)were weighted.RV/(LV+S)was calculated to reflect the degree of right ventricular hypertrophy.Rho/Rho-kinase signaling pathway key proteins(Rho A,ROCKⅠand ROCKⅡ)in rat right ventricular tissue were measured by Western blot analysis.The levels of serum hypoxia-inducible factor-1α(HIF-1α),vascular endothelial growth factor(VEGF)and the levels of plasma renin activity(PRA),angiotensinⅡ(ANG-Ⅱ),aldosterone(ALD)in rat anticoagulated plasma were all measured by enzyme-linked immunosorbent assay.RESULTS:Compared with the control group,the m PAP and RV/(LV+S)in the model group were significantly increased.Administration of fasudil resulted in a significant decrease of m PAP and RV/(LV+S).In the HM group and LM group,m PAP and RV/(LV+S)were significantly lower than the model group.Compared with the control group,the contents of HIF-1α,VEGF,PRA,ANG-Ⅱand ALD in the model group were significantly increased.The administration of fasudil and high-dose MXXTM significantly reduced the contents of HIF-1α,VEGF,PRA,ANG-II and ALD.Compared with the control group,the expression of Rho A,ROCKⅠand ROCKⅡin the right ventricle of the model group were significantly increased.The administration of fasudil and high-dose MXXTM significantly reduced the expression of Rho A and RockⅡproteins.Our results indicated that high-dose of MXXTM had similar effects on reducing pulmonary artery pressure and improving right ventricular remodeling to fasudil.However,MXXTM was unable to restore parameters above to control levels.CONCLUSIONS:MXXTM attenuates hypoxia pulmonary arterial hypertension to improve right ventricular hypertrophy by inhibiting the Rho-kinase signaling pathway.

Effect of Early Intervention with Extract of Huannao Yicong Decoction(还脑益聪方) on the Pathologic Picture of Hippocampus and Neurocyte Apoptosis in APP Transgenic Mice Model of Dementia

Objective：To observe the effect of early intervention using extract of Huannao Yicong Decoction （还脑益聪方,HYD） on the pathological picture of hippocampus,neurocyte apoptosis,and associated regulatory genes inβ-amyloid precursor protein（APP） transgenic mice model of dementia.Methods：Sixty APP695^（V7171） transgenic mice were randomly divided into four groups of 15.The model group was treated with distilled water, the positive control group was treated with donepezil（0.65 mg/kg）,and the two HYD groups were treated with high dose（2.8 g/kg） and low dose（1.4 g/kg） HYD,respectively.All testing drugs were administered through gastrogavage by dissolving in equal volume of distilled water,once a day for six successive months.In addition, a normal control group with 15 healthy C57BL/6J mice of the same age and genetic background was set up with distilled water treatment.The pathologic picture of brain tissue was observed by microscopy with HE stain;the amount of apoptosis cells in the hippocampal CA1 area was detected by TUNEL;and expressions of associated genes,Bcl-2,and Bax were determined by immunohistochemical method.Results：Pathologic pictures of hippocampus showed that in the model group,cells messily arranged,neurons markedly decreased, and the surrounding tissue of some cells was loosened with edema,necrosis,and widened gap with glia cells proliferation.Compared with those in the normal group,the amount of apoptosis cells in the CA1 area was increased,Bcl-2 expression decreased,and Bax expression increased significantly,with markedly reduced Bcl-2/Bax ratio in the model group.Compared to the model group,the pathological changes were significantly milder in the HYD-treated groups,showing rather regularly arranged cells,significantly increased neurons, only few denatured necrotic cells with milder edema,less proliferation of glia cells,and obviously reduced cell apoptosis in CA1 area（P0.05 or P0.01）.Besides,Bcl-2 expression was up-regulated and Bax expression down-regulated,and Bcl-2/Bax ratio significantly increased in the two HYD groups（P0.05 or P0.01）. Conclusion：Early intervention with HYD could improve the abnormal pathologic picture of hippocampus and regulate the expressions of associated genes to suppress cell apoptosis,which might be its mechanism of action in alleviating cognitive functional disorder.

Comment on:simultaneous versus delayed resection for initially resectable synchronous colorectal cancer liver metastases

We read with great interest the recently published article of Boudjema and collaborators(1).The authors evaluated the safety and efficacy of delayed resection(DR)versus simultaneous resection(SR)for patients with initially resectable synchronous colorectal cancer liver metastases(CRC-SLM).The aforementioned study(METASYNC)was the first randomized controlled trial comparing two resection strategies for CRC-SLM.In the literature,large retrospective studies didn’t seem to favor one type of treatment,particularly when comparisons are based on a propensity match score(2).

A positive feedback inhibition of isocitrate dehydrogenase 3βon paired-box gene 6 promotes Alzheimer-like pathology

Impaired brain glucose metabolism is an early indicator of Alzheimer’s disease(AD);however,the fundamental mechanism is unknown.In this study,we found a substantial decline in isocitrate dehydrogenase 3β(IDH3β)levels,a critical tricarboxylic acid cycle enzyme,in AD patients and AD-transgenic mice’s brains.Further investigations demonstrated that the knockdown of IDH3βinduced oxidation-phosphorylation uncoupling,leading to reduced energy metabolism and lactate accumulation.The resulting increased lactate,a source of lactyl,was found to promote histone lactylation,thereby enhancing the expression of paired-box gene 6(PAX6).As an inhibitory transcription factor of IDH3β,the elevated PAX6 in turn inhibited the expression of IDH3β,leading to tau hyperphosphorylation,synapse impairment,and learning and memory deficits resembling those seen in AD.In AD-transgenic mice,upregulating IDH3βand downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies.Collectively,our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β.Breaking this loop by upregulating IDH3βor downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.