Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

Objective:

To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS) among patients with type 2 diabetic kidney disease.

Data Sources:

We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use of monotherapy, without applying any language restrictions. Keywords for the searches included “diabetic nephropathy,” “chronic kidney disease,” “chronic renal insufficiency,” “diabetes mellitus,” “dual therapy,” “combined therapy,” “dual blockade,” “renin-angiotensin system,” “angiotensin-converting enzyme inhibitor,” “angiotensin-receptor blocker,” “aldosterone blockade,” “selective aldosterone blockade,” “renin inhibitor,” “direct renin inhibitor,” “mineralocorticoid receptor blocker,” etc.

Study Selection:

The selected articles were carefully reviewed. We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus.

Results:

Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin II receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension. However, existing literature has presented mixed results, in particular, related to patient safety. In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons.

Conclusions:

Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility. Further trials are warranted to study the combination therapy as an evidence-based practice.     

Isoflavones and Prostate Cancer: A Review of Some Critical Issues

Objective:

The purpose of this review is to discuss some critical issues of isoflavones protective against the development of prostate cancer (PCa).

Data Sources:

Data cited in this review were obtained primarily from PubMed and Embase from 1975 to 2015.

Study Selection:

Articles were selected with the search terms “isoflavone”, “Phytoestrogen”, “soy”, “genistin”, and “PCa”.

Results:

Isoflavones do not play an important role on prostate-specific antigen levels reduction in PCa patients or healthy men. The effect of isoflavones on sex hormone levels and PCa risk may be determined by equol converting bacteria in the intestine, specific polymorphic variation and concentrations of isoflavones. The intake of various types of phytoestrogens with lower concentrations in the daily diet may produce synergistic effects against PCa. Moreover, prostate tissue may concentrate isoflavones to potentially anti-carcinogenic levels. In addition, it is noteworthy that isoflavones may act as an agonist in PCa.

Conclusions:

Isoflavones play a protective role against the development of PCa. However, careful consideration should be given when isoflavones are used in the prevention and treatment of PCa.     

Autophagy in 5-Fluorouracil Therapy in Gastrointestinal Cancer: Trends and Challenges

Objective:

5-Fluorouracil (5-FU)-based combination therapies are standard treatments for gastrointestinal cancer, where the modulation of autophagy is becoming increasingly important in offering effective treatment for patients in clinical practice. This review focuses on the role of autophagy in 5-FU-induced tumor suppression and cancer therapy in the digestive system.

Data Sources:

All articles published in English from 1996 to date those assess the synergistic effect of autophagy and 5-FU in gastrointestinal cancer therapy were identified through a systematic online search by use of PubMed. The search terms were “autophagy” and “5-FU” and (“colorectal cancer” or “hepatocellular carcinoma” or “pancreatic adenocarcinoma” or “esophageal cancer” or “gallbladder carcinoma” or “gastric cancer”).

Study Selection:

Critical reviews on relevant aspects and original articles reporting in vitro and/or in vivo results regarding the efficiency of autophagy and 5-FU in gastrointestinal cancer therapy were reviewed, analyzed, and summarized. The exclusion criteria for the articles were as follows: (1) new materials (e.g., nanomaterial)-induced autophagy; (2) clinical and experimental studies on diagnostic and/or prognostic biomarkers in digestive system cancers; and (3) immunogenic cell death for anticancer chemotherapy.

Results:

Most cell and animal experiments showed inhibition of autophagy by either pharmacological approaches or via genetic silencing of autophagy regulatory gene, resulting in a promotion of 5-FU-induced cancer cells death. Meanwhile, autophagy also plays a pro-death role and may mediate cell death in certain cancer cells where apoptosis is defective or difficult to induce. The dual role of autophagy complicates the use of autophagy inhibitor or inducer in cancer chemotherapy and generates inconsistency to an extent in clinic trials.

Conclusion:

Autophagy might be a therapeutic target that sensitizes the 5-FU treatment in gastrointestinal cancer.     

Evaluation of Three Small Molecular Drugs for Targeted Therapy to Treat Nonsmall Cell Lung Cancer

Objective:

To guide the optimal selection among first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in clinical practice. This review attempted to provide a thorough comparison among three first-generation EGFR-TKIs, namely icotinib, erlotinib, and gefitinib, with regard to their molecular structure, pharmacokinetic parameters, clinical data, adverse reactions, and contraindications.

Data Sources:

An electronic literature search of the PubMed database and Google Scholar for all the available articles regarding gefitinib, icotinib, and erlotinib in the English language from January 2005 to December 2014 was used.

Study Selection:

The search terms or keywords included but not limited to “lung cancer”, “nonsmall cell lung cancer (NSCLC)”, “epidemiology”, “EGFR”, “TKIs”, and “optimal selection”.

Results:

As suggested by this review, even though the three first-generation EGFR-TKIs share the quinazoline structure, erlotinib had the strongest apoptosis induction activity because of its use of a different side-chain. The pharmacokinetic parameters indicated that both erlotinib and icotinib are affected by food. The therapeutic window of erlotinib is narrow, and the recommended dosage is close to the maximum tolerable dosage. Icotinib enjoys a wider therapeutic window, and its concentration in the blood is within a safe dosage range even if it is administered with food. Based on multiple large-scale clinical trials, erlotinib is universally applied as the first-line treatment. In marked contrast, icotinib is available only in China as the second- or third-line therapeutic approach for treating advanced lung cancer. In addition, it exhibits a similar efficacy but better safety profile than gefitinib.

Conclusions:

Although there is a paucity of literature regarding whether icotinib is superior to erlotinib, its superior toxicity profile, noninferior efficacy, and lower cost indicate that it is a better alternative for Chinese patients living with advanced NSCLC.     

Sex-determining Region of Y Chromosome-related High-mobility-group Box 2 in Malignant Tumors: Current Opinions and Anticancer Therapy

Objective:To gain insight into the mechanism by which sex-determining region of Y chromosome (SRY)-related high-mobility-group box 2 (SOX2) involved in carcinogenesis and cancer stem cells (CSCs).Data ...     

Role of Circulating Fibrocytes in Cardiac Fibrosis

Objective:

It is revealed that circulating fibrocytes are elevated in patients/animals with cardiac fibrosis, and this review aims to provide an introduction to circulating fibrocytes and their role in cardiac fibrosis.

Data Sources:

This review is based on the data from 1994 to present obtained from PubMed. The search terms were “circulating fibrocytes” and “cardiac fibrosis”.

Study Selection:

Articles and critical reviews, which are related to circulating fibrocytes and cardiac fibrosis, were selected.

Results:

Circulating fibrocytes, which are derived from hematopoietic stem cells, represent a subset of peripheral blood mononuclear cells exhibiting mixed morphological and molecular characteristics of hematopoietic and mesenchymal cells (CD34⁺/CD45⁺/collagen I⁺). They can produce extracellular matrix and many cytokines. It is shown that circulating fibrocytes participate in many fibrotic diseases, including cardiac fibrosis. Evidence accumulated in recent years shows that aging individuals and patients with hypertension, heart failure, coronary heart disease, and atrial fibrillation have more circulating fibrocytes in peripheral blood and/or heart tissue, and this elevation of circulating fibrocytes is correlated with the degree of fibrosis in the hearts.

Conclusions:

Circulating fibrocytes are effector cells in cardiac fibrosis.     

Insulin Neuroprotection and the Mechanisms

Objective:

To analyze the mechanism of neuroprotection of insulin and which blood glucose range was benefit for insulin exerting neuroprotective action.

Data Sources:

The study is based on the data from PubMed.

Study Selection:

Articles were selected with the search terms “insulin”, “blood glucose”, “neuroprotection”, “brain”, “glycogen”, “cerebral ischemia”, “neuronal necrosis”, “glutamate”, “γ-aminobutyric acid”.

Results:

Insulin has neuroprotection. The mechanisms include the regulation of neurotransmitter, promoting glycogen synthesis, and inhibition of neuronal necrosis and apoptosis. Insulin could play its role in neuroprotection by avoiding hypoglycemia and hyperglycemia.

Conclusions:

Intermittent and long-term infusion insulin may be a benefit for patients with ischemic brain damage at blood glucose 6–9 mmol/L.     

Intestinal Microbiota Metabolism and Atherosclerosis

Objective:

This review aimed to summarize the relationship between intestinal microbiota metabolism and cardiovascular disease (CVD) and to propose a novel CVD therapeutic target.

Data Sources:

This study was based on data obtained from PubMed and EMBASE up to June 30, 2015. Articles were selected using the following search terms: “Intestinal microbiota”, “trimethylamine N-oxide (TMAO)”, “trimethylamine (TMA)”, “cardiovascular”, and “atherosclerosis”.

Study Selection:

Studies were eligible if they present information on intestinal microbiota metabolism and atherosclerosis. Studies on TMA-containing nutrients were also included.

Results:

A new CVD risk factor, TMAO, was recently identified. It has been observed that several TMA-containing compounds may be catabolized by specific intestinal microbiota, resulting in TMA release. TMA is subsequently converted to TMAO in the liver. Several preliminary studies have linked TMAO to CVD, particularly atherosclerosis; however, the details of this relationship remain unclear.

Conclusions:

Intestinal microbiota metabolism is associated with atherosclerosis and may represent a promising therapeutic target with respect to CVD management.     

Study of Individual Characteristic Abdominal Wall Thickness Based on Magnetic Anchored Surgical Instruments

Background:Magnetic anchored surgical instruments (MASI),relying on magnetic force,can break through the limitations of the single port approach in dexterity.Individual characteristic abdominal wall th...     

Current and Future Clinical Applications of Zinc Transporter-8 in Type 1 Diabetes Mellitus

Objective:

To evaluate the utility of zinc transporter-8 (ZnT8) in the improvement of type 1 diabetes mellitus (T1DM) diagnosis and prediction, and to explore whether ZnT8 is a potential therapeutic target in T1DM.

Data Sources:

A search was conducted within the medical database PubMed for relevant articles published from 2001 to 2015. The search terms are as follows: “ZnT8,” “type 1 diabetes,” “latent autoimmune diabetes in adults,” “type 2 diabetes,” “islet autoantibodies,” “zinc supplement,” “T cells,” “β cell,” “immune therapy.” We also searched the reference lists of selected articles.

Study Selection:

English-language original articles and critical reviews concerning ZnT8 and the clinical applications of islet autoantibodies in diabetes were reviewed.

Results:

The basic function of ZnT8 is maintaining intracellular zinc homeostasis, which modulates the process of insulin biosynthesis, storage, and secretion. Autoantibodies against ZnT8 (ZnT8A) and ZnT8-specific T cells are the reliable biomarkers for the identification, stratification, and characterization of T1DM. Additionally, the results from the animal models and clinical trials have shown that ZnT8 is a diabetogenic antigen, suggesting the possibility of ZnT8-specific immunotherapy as an alternative for T1DM therapy.

Conclusions:

ZnT8 is a novel islet autoantigen with a widely potential for clinical applications in T1DM. However, before the large-scale clinical applications, there are still many problems to be solved.     

J Wave Syndromes: A Decade of Progress

Objective:

The objective was to provide a brief history of J wave syndromes and to summarize our current understanding of their molecular, ionic, cellular mechanisms, and clinical features. We will also discuss the existing debates and further direction in basic and clinical research for J wave syndromes.

Data Sources:

The publications on key words of “J wave syndromes”, “early repolarization syndrome (ERS)”, “Brugada syndrome (BrS)” and “ST-segment elevation myocardial infarction (STEMI)” were comprehensively reviewed through search of the PubMed literatures without restriction on the publication date.

Study Selection:

Original articles, reviews and other literatures concerning J wave syndromes, ERS, BrS and STEMI were selected.

Results:

J wave syndromes were firstly defined by Yan et al. in a Chinese journal a decade ago, which represent a spectrum of variable phenotypes characterized by appearance of prominent electrocardiographic J wave including ERS, BrS and ventricular fibrillation (VF) associated with hypothermia and acute STEMI. J wave syndromes can be inherited or acquired and are mechanistically linked to amplification of the transient outward current (I_to)-mediated J waves that can lead to phase 2 reentry capable of initiating VF.

Conclusions:

J wave syndromes are a group of newly highlighted clinical entities that share similar molecular, ionic and cellular mechanism and marked by amplified J wave on the electrocardiogram and a risk of VF. The clinical challenge ahead is to identify the patients with J wave syndromes who are at risk for sudden cardiac death and determine the alternative therapeutic strategies to reduce mortality.     

Role of Quantitative Magnetic Resonance Imaging Parameters in the Evaluation of Treatment Response in Malignant Tumors

Objective:

To elaborate the role of quantitative magnetic resonance imaging (MRI) parameters in the evaluation of treatment response in malignant tumors.

Data Sources:

Data cited in this review were obtained mainly from PubMed in English from 1999 to 2014, with keywords “dynamic contrast-enhanced (DCE)-MRI,” “diffusion-weighted imaging (DWI),” “microcirculation,” “apparent diffusion coefficient (ADC),” “treatment response” and “oncology.”

Study Selection:

Articles regarding principles of DCE-MRI, principles of DWI, clinical applications as well as opportunity and aspiration were identified, retrieved and reviewed.

Results:

A significant correlation between ADC values and treatment response was reported in most DWI studies. Most quantitative DCE-MRI studies showed a significant correlation between K^trans values and treatment response. However, in different tumors and studies, both high and low pretreatment ADC or K^trans values were found to be associated with response rate. Both DCE-MRI and DWI demonstrated changes in their parameters hours to days after treatment, showing a decrease in K^trans or an increase in ADC associated with response in most cases.

Conclusions:

Combinations of quantitative MRI play an important role in the evaluation of treatment response of malignant tumors and hold promise for use as a cancer treatment response biomarker. However, validation is hampered by the lack of reproducibility and standardization. MRI acquisition protocols and quantitative image analysis approaches should be properly addressed prior to further testing the clinical use of quantitative MRI parameters in the assessment of treatments.     

Use of Platelet Indices for Determining Illness Severity and Predicting Prognosis in Critically Ⅲ Patients

Background:Decreased platelet (PLT) count is one of the independent risk factors for mortality in intensive care unit (ICU) patients.This study was to investigate the relationship between PLT indices a...     

Effects of Immunosuppressants on Immune Response to Vaccine in Inflammatory Bowel Disease

Objective:

To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants).

Data Sources:

We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators). The following terms were used: “inflammatory bowel disease (IBD)” OR “Crohn''s disease” OR “ulcerative colitis” AND (“vaccination” OR “vaccine”) AND (“corticosteroids” OR “mercaptopurine” OR “azathioprine” OR “methotrexate [MTX]”) AND “immunomodulators.”

Study Selection:

The inclusion criteria of articles were that the studies: (1) Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical, radiographic, endoscopic, and histologic criteria); (2) exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping, 15 mg or more MTX per week or within 3 months of stopping; (3) exposed patients received nonimmunomodulators (no therapy, antibiotics only, mesalazine only, biological agent only such as infliximab, adalimumab, certolizumab or natalizumab or within 3 months of stopping one of these agents). The exclusion criteria of articles were that the studies: (1) History of hepatitis B virus (HBV), influenza or streptococcus pneumoniae infection; (2) patients who had previously been vaccinated against HBV, influenza or streptococcus pneumoniae; (3) any medical condition known to cause immunosuppression (e.g. chronic renal failure and human immunodeficiency virus infection); (4) individuals with positive hepatitis markers or liver cirrhosis; (5) patients with a known allergy to eggs or other components of the vaccines and (6) pregnancy.

Results:

Patients treated with immunomodulators were associated with lower response rates to vaccination.

Conclusions:

Immunomodulators may impair the immune response to vaccination in patients with IBD. Vaccination should be made at the time of diagnosis or before starting immunosuppressed therapy.     

Why do primary care doctors undertake postgraduate diploma studies in a mixed private/public Asian setting?

Objective

The aim of this study was to examine the reasons why primary care doctors undertake postgraduate diploma studies in a mixed private/public Asian setting.

Methods

Twenty four past or current postgraduate diploma students of the family medicine unit (FMU) of the University of Hong Kong participated in three focus group interviews. A structured questionnaire was constructed based on the qualitative data collected and was sent to 328 former applicants of postgraduate diploma studies at FMU.

Results

“Upgrading medical knowledge and skills” and “improving quality of practice” were two of the factors that most of the respondents considered to be significant in motivating them to undertake postgraduate diploma studies. “Time constraint” and “workload in practice” were however the most significant demotivating factors. Financial issues were more seriously considered by the junior than the senior doctors. To be able to “expand patient base and/or number” was considered to be a significant factor by the private doctors who were also keen to “improve communication and relationship with patients”.

Conclusion

These findings suggest that there are mixed reasons for primary care doctors to undertake postgraduate diploma studies. Course organisers should take into consideration these various reasons in planning their programmes.     

Role of MicroRNAs in Malignant Glioma

Objective:

This overview seeked to bring together the microRNA (miRNA) researches on biogenesis and bio-function in these areas of clinical diagnosis and therapy for malignant glioma.

Data Sources:

Using the keyword terms “glioma” and “miRNA,” we performed the literature search in PubMed, Ovid, and web.metstr.com databases from their inception to October 2014.

Study Selection:

In screening out the quality of the articles, factors such as clinical setting of the study, the size of clinical samples were taken into consideration. Animal studied for verification and reviews article were also included in our data collection.

Results:

Despite many advance in miRNA for malignant glioma, further studies were still required to focus on the following aspects: (i) Improving the understanding about biogenesis of miRNA and up-down regulation; (ii) utilizing high-throughput miRNA expression analysis to screen out the core miRNA for glioma; (iii) Focusing related miRNAs on the signal transduction pathways that regulate the proliferation and growth of glioma.

Conclusions:

We discussed the most promising miRNA, correlative signaling pathway and their relation with gliomas in the way of prompting miRNA target into being a clinical therapeutic strategy.     

Audit of an urban paediatric emergency department visits

Background:

This study aimed to highlight the health seeking behavior of children in an Emergency Department (ED).

Materials and Methods:

Retrospective files review of ED was done for the month of July, 2008. Data about the children ≤12 years of age was gathered.

Results:

In one month period a total 21000 patients visited our ED, out of them 6120 (29%) were children. Males, Saudis and children of (1-6 years) were more frequent, i.e., 3540 (57.8%), 5760 (94.1%) and 3180 (52%), respectively. Majority of patients visited in shift “2”, i.e., 15:30 hours to 23:30 hours. Among the patients “diseases of respiratory system” were found more frequent 4170 (68.1%) and main diagnosis was “acute upper respiratory tract infection” 3300 (53.9%). Non-urgent cases were 2020 (33%) while 244 (4%) were admitted.

Conclusion:

Young children as well as non-urgent cases were predominant. Evening shift was the busiest one.     

Asthma and Obstructive Sleep Apnea

Objective:

To get a comprehensive understanding about the relationship between obstructive sleep apnea (OSA) and asthma by reviewing the epidemiology, pathophysiology, and clinical manifestation and then summarizing the latest progress on diagnosis and treatment.

Data Sources:

Articles referred in this review were mainly collected from a comprehensive search of the PubMed published in English from 1990 to 2015 with the terms “OSA” and “asthma” as the main keywords. Highly regarded older publications were also included.

Study Selection:

Information about the features of the two diseases in common, the pathophysiologic association between them and their current treatments from the literature search were identified, retrieved, and summarized.

Results:

Both OSA and asthma are very prevalent conditions. The incidences of them have kept on rising in recent years. Asthma is often accompanied by snoring and apnea, and OSA often combines with asthma, as well. They have many predisposing and aggravating factors in common. Possible shared direct mechanistic links between them include mechanical effects, intermittent hypoxia, nerve reflex, inflammation, leptin, etc. Indirect mechanistic links include medication, nose diseases, smoking, obesity, and gastroesophageal reflux disease. Since OSA presents many similar features with nocturnal asthma, some scholars termed them as a sole syndrome – “alternative overlap syndrome,” and proved that asthma symptoms in those patients could be improved through the treatment of continuous positive airway pressure.

Conclusions:

OSA and asthma are closely associated in pathogenesis, symptoms, and therapies. With the growing awareness of the relationship between them, we should raise our vigilance on the coexistence of OSA in those difficult-to-control asthmatic patients. Further studies are still needed to guide the clinical works.     

New Delhi Metallo-β-Lactamase-Mediated Carbapenem Resistance: Origin,Diagnosis, Treatment and Public Health Concern

Objective:To review the origin,diagnosis,treatment and public health concern of New Delhi metallo-β-lactamase (NDM)-producing bacteria.Data Sources:We searched database for studies published in English...