Alzheimer's Disease (AD) is a chronic neurodegenerative disease that usually takes many years from preclinical phase to prodromal phase characterized by mild symptoms before the onset of dementia. Once diagnosed with AD, the brain is already severely damaged and the disease will process quickly to the most severe stages since there is no medications that reverse the neuronal injuries in the brain. Thus, simple, inexpensive, and widely available methods for detecting potential AD patients during their preclinical phases are urgently needed. In such case, olfactory testing may offer a chance for early diagnosis of AD. However, there are limitations in these olfactory tests due to the complexity of the brain areas it extends to and the frequently olfactory fatigue occurred in the behavioral olfactory tests. Great efforts have been done epidemiologically to investigate the correlation between olfactory functions and possibility of developing AD. Different patterns of olfactory dysfunction have been found in AD at early stages and even mild cognitive impairment (MIC), but the cause of the dysfunction remained unclear. Various kinds of AD animal models have been used in the field to clarify the existence of olfactory dysfunctions and thus study the underling mechanism of the dysfunction. In this review we discuss (1) the function of Tau physiologically and pathologically; (2) the genetic background and biological characteristics of the most commonly used Tau transgenic mice; (3) the structural and molecule basis of olfaction; (4) the possible relationship between Tau pathology and olfactory dysfunction. Finally, we suggest that the tau transgenic mouse models may be helpful in studying the possible mechanisms of the dysfunction.
Alzheimer Disease ; physiopathology ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Olfaction Disorders ; physiopathology ; tau Proteins

Objective To evaluate the clinical value of bedside index for severity in acute pancreatitis (BISAP) and APACHEⅡ score in predicting the severity and organ failure of acute pancreatitis (AP).Methods One hundred eighty-five patients of AP admitted to Department of Gastroenterology of First affiliated Hospital of Soochow University from January 2012 to December 2014 were studied retrospectively.According to BISAP score, patients who were ≥3 points were considered as high risk group, while ＜3 points were considered as low risk group.According to APACHEⅡ score, patients who were ≥ 8 points were considered as high risk group, while ＜ 8 points were considered as low risk group.According to the criteria of Pancreatic Diseases Group of Chinese Society of Gastroenterology of Chinese Medical Association, the patients were diagnosed as mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP), and severe acute pancreatitis (SAP).The BISAP, APACHEⅡ scores were calculated and compared between MAP group and MSAP + SAP group, respectively.The incidence of MSAP + SAP between high risk group and low risk group was also compared.The area of ROC curve (AUC) was used to evaluate the ability of BISAP and APACHEⅡ scoring system for predicting the severity of AP and the multiple organ dysfunction syndromes (MODS).Results Among 185 patients, MAP was identified in 101 patients, MSAP in 76 patients and SAP in 8 patients.Twenty-five MSAP patients developed organ dysfunction, and all the 8 SAP patients developed organ dysfunction.The BISAP scores of MSAP + SAP group and MAP group were (1.43 ± 0.89), (0.38 ± 0.61),andAPACHⅡ scores were (2.45± 1.36), (0.87± 0.62), the scores of MSAP+ SAP group were significantly higher than those in MAP group (P ＜0.01).In the 137 patients of low risk BISAP group, there were 47 MSAP + SAP patients (34.3％), while in the 48 patients of high risk BISAP group, there were 37 MSAP + SAP patients (77.0％);in the 153 patients of low risk APACHEⅡ group, there were 56 MSAP + SAP patients (36.6％), while in the 32 patients of high risk APACHEⅡ group, there were 28 MSAP + SAP patients (87.5％);the incidence of MSAP + SAP patients was significantly higher in high risk group than that in low risk group (P＜0.01).The AUC of BISAP, APACHEⅡ for MSAP+ MAP was 0.804 (95％ CI 0.738 ～ 0.870), 0.794 (95％ CI 0.725 ～ 0.863), and the AUC for organ dysfunction was 0.758 (95％ CI 0.686 ～0.830), 0.781 (95％ CI 0.710 ～0.852) , and the difference between BISAP and APACHE Ⅱ was not statistically significant (P ＞ 0.05).Conclusions The BISAP has the prediction ability for AP severity and prognosis similar to APACHEⅡ , and it consists of only 5 parameters and can be completed in the first 24 h of admission, therefore it is worth of clinical application.

Objective To explore the incidence and associated factors of aortic artery calcification (AAC) by lateral lumbar X-ray score in maintenance hemodialysis (MHD) patients.Mehtods A total of 155 MHD patients with complete clinical data in our hospital were enrolled in the study.Lateral lumbar X-ray score of the abdominal aorta was used to determine AAC in MHD patients.Results Aortic calcification was most severe in front of the fourth lumbar segment and ameliorated in higher lumbar levels.63.63％ of MHD patients presented visible calcification in the abdominal aorta,and 28.39％ had severe calcification with more than three segments.Age (OR=1.094,P＜0.01),dialysis vintage (OR=1.013,P=0.022),triglyceride (OR=1.261,P=0.030) and phosphate level (OR=1.324,P=0.023) were risk factors of abdominal aorta calcification,however serum albumin level (OR =0.239,P=0.013) was protect factor of aortic calcification.Conclusions Incidence of AAC is quite high in MHD patients and associated with increasing of age,duration of hemodialysis,serum triglyceride,phosphate level and plasma albumin.The semi-quantitative X-ray method of determining vascular calcification is less expensive and may be widely available clinically.

BACKGROUNDAdaptor proteins containing PH domain, PTB domain, and leucine zipper motif 1 and 2 (APPL1/2) play a key role in cell proliferation in many tissues. APPL1 or APPL2 as an adaptor for adiponectin receptors mediates the signaling pathway of adiponectin which acts as an anti-atherosclerotic adipokine. This study aimed to investigate whether genetic variations in the APPL1/2 genes affect the risk of coronary artery disease (CAD) in Chinese patients with type 2 diabetes mellitus (T2DM).

METHODSSeven haplotype-tagging single nucleotide polymorphisms (tag-SNPs) were selected from CHB HapMap database (Phase II) and total 203 CAD-positive cases and 106 CAD-negative controls with T2DM were genotyped for the 7 tag-SNPs by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.

RESULTSThe minor allele G of rs4640525 at APPL1 locus was protective from CAD in patients with T2DM, with the carriers of genotype CC at higher risk of CAD compared with non-carriers (OR = 2.830, 95%CI 1.285 - 6.230, P = 0.010; OR' = 4.992, 95%CI = 1.758 - 14.173, P' = 0.003, after adjustment for the other known CAD risk factors); the homozygotes of AA at rs11112412 in APPL2 gene had higher risk of CAD compared with those of GG (adjusted OR' = 5.697, 95%CI 1.006 - 32.257, P' = 0.049).

CONCLUSIONGenetic variation(s) in APPL1/2 may be associated with CAD risk in T2DM in Chinese population.

Adaptor Proteins, Signal Transducing ; genetics ; Aged ; Asian Continental Ancestry Group ; Coronary Artery Disease ; genetics ; Diabetes Mellitus, Type 2 ; genetics ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide

BACKGROUNDObstructive sleep apnea hypopnea syndrome, characterized by chronic intermittent hypoxia (CIH), is closely correlated with genioglossus dysfunction. CIH has been identified to mediate mitochondrial damage in genioglossus. It has been reported that endoplasmic reticulum stress (ERS) could be induced by mitochondrial dysfunction. This study aimed to investigate the role of ERS in CIH-induced genioglossus injury, as well as the possible intervention effect of adiponectin (Ad) supplement in rats.

METHODSForty-five male Wistar rats were randomly divided into three groups and submitted to room air (group A, n=15) as a control or CIH (groups B and C, n=15, respectively). Throughout the exposure period, intravenous Ad was given in group C; while intravenous normal saline was simultaneously given in groups A and B. After 35-day exposure, genioglossus samples were obtained from the pentobarbital-anaesthetized rats via surgical dissection, following blood sampling. Western blotting was applied to detect expressions of ERS signals and associated apoptotic pathways in genioglossus. Serum adiponectin levels were assessed via enzyme-linked immunosorbent assay (ELISA).

RESULTSSignificant hypoadiponectinemia was revealed in group B only (P < 0.05). Compared to those in groups A and C, expressions of markers involved in ERS, such as glucose regulated protein 78 (GRP78), p-PERK, phosphorylated eukaryotic initiation factor 2a (p-eIF2a), phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1a (p-IRE1a), spliced X-Box binding protein 1 (XBP1s) and activating transcription factor 6 (ATF6), were significantly enhanced in group B (all P < 0.01); while no significant difference was shown between groups A and C (all P > 0.05). ERSassociated apoptotic pathways were remarkably activated in group B. The involved markers detected as the expression of CCAAT/enhancer binding protein homologous protein (CHOP), B-cell lymphoma/leukemia associatied X protein (BAX) and caspase-12 were significantly elevated (all P < 0.01). Transvenous adiponectin supplement improved the above CIHinduced pathological changes in group C.

CONCLUSIONBeyond hypoadiponectinemia, CIH could enhance ERS and induce activation of ERS-associated apoptotic pathways in genioglossus, which could be significantly improved by adiponectin supplement.

Adiponectin ; administration & dosage ; therapeutic use ; Animals ; Endoplasmic Reticulum Stress ; drug effects ; Hypoxia ; drug therapy ; physiopathology ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Sleep Apnea, Obstructive ; drug therapy

To study the difference of changes on apoptosis, necrosis and respiratory burst of the polymorphonuclear neutrophils (PMN) in endotoxemia rat model. LPS (O(55)B(5), 5 mg/kg) was injected into abdominal cavity of 20 random normal Wistar rat. 2, 4, 8 and 12 hours after injection, the changes of apoptosis, necrosis and respiratory burst of the rats between PMN from the peripheral blood and from the bronchoalveolar lavage fluid were observed using the flow cytometer. At the same time, 5 uninjected rats were taken as control. The results demonstrated that the quantity proportions of apoptosis of PMN between the peripheral blood PMN and the bronchoalveolar lavage fluid PMN in rat's endotoxemia were similar. However, comparison with the uninjected LPS rat, the necrosis of peripheral blood PMN obviously increased and the respiratory burst capacity was clearly inhibited. Contrarily, the necrosis of bronchoalveolar lavage fluid PMN obviously decreased and the respiratory burst obviously increased in the injecting LPS rat. It was concluded that the necrosis and apoptosis displayed differently between the pulmonary and peripheral blood PMNs in endotoxemia. Under state of inflammation, the surviving PMN in tissue increased and kept the activated state due to tissue injury.
Animals ; Apoptosis ; Bronchoalveolar Lavage Fluid ; cytology ; Endotoxemia ; blood ; Necrosis ; Neutrophils ; physiology ; Pulmonary Alveoli ; pathology ; Rats ; Rats, Wistar ; Respiratory Burst

OBJECTIVETo evaluate the efficacy and safety of bevacizumab plus capecitabine in treating metastatic colorectal cancer(mCRC).

METHODSEleven patients with mCRC (6 females and 5 males) were enrolled in this study. Bevacizumab was given with 5 mg/kg every two weeks in five patients, 10 mg/kg every two weeks in four patients and 15 mg/kg every three weeks in two patients. All patients received capecitabine 2000 mg/m2 per day for 14 days.

RESULTSFive of 11 patients had partial response and five patients had stable disease and two patients had progressive disease. The disease control rate was 90.9%. The progress-free survival were 4 months and the median overall survival time were 15 months. The adverse events related to bevacizumab were grade 2 hypertension in 3 patients (27.3%) and grade 1 or 2 proteinuria in 4 patients (36.4%). Other adverse events such as mucositis, fatigue, subcutaneous haemorrhage were also observed. No thromboembolism or severe haemorrhage happened. No other grade 3 or 4 adverse events were observed.The adverse events in the combined therapy were hand-foot-syndrome (54.6%), diarrhea (27.3%), and neutropenia (18.2%), mainly due to capecitabine.

CONCLUSIONSThe combination of bevacizumab plus capecitabine has definite benefit in patients with mCRC. However,these benefits can not be maintained after the withdrawal of bevacizumab. The adverse drug reactions are well tolerated.

Aged ; Antibodies, Monoclonal, Humanized ; administration & dosage ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Bevacizumab ; Capecitabine ; Colorectal Neoplasms ; drug therapy ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; Female ; Fluorouracil ; administration & dosage ; analogs & derivatives ; Humans ; Male ; Middle Aged ; Treatment Outcome

BACKGROUNDbevacizumab is a humanized recombinant vascular endothelial growth factor (VEGF) monoclonal antibody, which specifically binds to VEGF and inhibits tumor cell growth, proliferation and metastasis. We aimed to investigate the safety and pharmacokinetics of bevacizumab in Chinese patients with advanced cancer.

METHODSThirty-nine Chinese patients with metastatic or relapsed cancers who failed prior therapy were enrolled in this phase I study of bevacizumab. Bevacizumab was infused by a calculated pump at doses from 5 mg/kg to 15 mg/kg in 90 minutes. Patients underwent serial pharmacokinetic evaluations. Patients that received at least one infusion of bevacizumab were included in the safety study.

RESULTSThirty-five patients finished all 5 infusions following protocol. One patient withdrew after 3 infusions due to grade 3 proteinuria. Common adverse events possibly related to the study drug were proteinuria (17/39, 43.6%), hypertension (13/39, 33.3%), gingival bleeding (7/39, 17.9%), epistaxis (6/39, 15.4%), pharyngeal inflammation (6/39, 15.4%), fatigue (6/39, 15.4%) and stomatitis (4/39, 10.3%). Bevacizumab pharmacokinetics was linear within the range of 5 mg/kg q2w--10 mg/kg q2w and 15 mg/kg q3w. CL (clearance), Vd (volume of distribution at elimination) and Vss (volume of distribution at steady state) were similar after single and multiple doses at 5, 10 and 15 mg/kg.

CONCLUSIONSBevacizumab is well tolerated in Chinese patients. No unexpected adverse events were observed. There is no racial difference in the pharmacokinetics.

Adult ; Aged ; Angiogenesis Inhibitors ; adverse effects ; pharmacokinetics ; therapeutic use ; Antibodies, Monoclonal ; adverse effects ; pharmacokinetics ; therapeutic use ; Antibodies, Monoclonal, Humanized ; Asian Continental Ancestry Group ; Bevacizumab ; Female ; Humans ; Male ; Middle Aged ; Neoplasms ; drug therapy

OBJECTIVEAccurate and reliable assessment of renal function is important in the management of children with chronic kidney disease (CKD). Glomerular filtration rate (GFR) is the best index of assessing kidney function. For assessment of GFR, both gold standard tests and prediction equations have been used. The well-known 24-hour endogenous creatinine clearance (Ccr), the Schwartz formula and the Filler formula are increasingly used in daily clinical practice. However, there are few studies on the applicability of these prediction equations for estimating GFR in Chinese children with CKD. The aim of this study was to compare these prediction equations estimating GFR with an isotope clearance method [isotope glomerular filtration rate (rGFR)] in such patients.

METHODChildren aged 1-16 years who underwent isotope (99m)Tc-diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) GFR testing (Gates' method) between the year of 2002 and 2005 were studied retrospectively. GFR was estimated using: (1) 24-hour Ccr, which was calculated using the standard formula: [urine creatinine (milligrammes per millilitre) × 24-hour urine volume/serum creatinine (milligrammes per millilitre) × 1440] × [1.73 (m(2))/body surface area (m(2))]; (2) the Schwartz formula, which is: eGFR (ml/min per 1.73 m(2)) = k × height (centimetres)/serum creatinine (micromoles per litre), where k is 62 in males at 13 years of age and older, 40 in infants, and 49 in all other children; and (3) the Filler formula, which is: logGFR = 1.962 + [1.123 × log(1/Cys C)], where cystatin C is measured in milligrammes per litre. Serum and urinary creatinine levels were detected by alkaline kinetic method. Serum cystatin C was analysed by particle-enhanced immunoturbidimetric assay. Bias and precision were evaluated.

RESULTThirty subjects (18 males and 12 females; mean age 9.4 years) fulfilling both inclusion criteria and exclusion criteria were included in this study. The mean (SD) rGFR was 81.57 (36.92) ml/min per 1.73 m(2); 18 subjects were in CKD stage I, 8 in CKD stage II, 8 in CKD stage III, and 1 in CKD stage IV. Only the mean 24 h Ccr-eGFR was slightly higher than rGFR (0.4 ml/min per 1.73 m(2) higher). Within 95% limits of agreement, the maximum absolute value of bias was about 50 ml/min per 1.73 m(2). Accuracy (estimated GFR values within ± 30% of rGFR) for all formulae was poor, ranging from 23.3% to 43.3%. All formulae overestimate or underestimate rGFR in different CKD stages.

CONCLUSIONIn Chinese children with CKD, there was a significant difference between measured GFR and estimated GFR using 24h Ccr, Schwartz formula and Filler formula. More suitable GFR predictive equations to assess glomerular function of such patients should be developed.

Adolescent ; Child ; Child, Preschool ; Female ; Glomerular Filtration Rate ; Humans ; Infant ; Kidney Failure, Chronic ; physiopathology ; Kidney Function Tests ; Male ; Renal Insufficiency, Chronic ; physiopathology

BACKGROUNDThere are few studies to assess whether the effect-site concentration of propofol can predict anesthetic depth during the target-controlled infusion (TCI) induction in elderly patients. This study aimed to evaluate the relationship between effect-site concentration of propofol and depth of anesthesia during the TCI induction in elderly patients.

METHODSNinety patients (60 - 80 years) with an American Society of Anesthesiologists (ASA) physical status of 1 - 3, undergoing scheduled abdominal and thoracic surgery under general anesthesia were randomly allocated into one of three groups, Group S1, S2 and S3 (30 patients in each group). The patients in Group S1 received propofol with a target plasma concentration of 4.0 microg/ml; patients in Group S2 received propofol with an initial target plasma concentrations of 2.0 microg/ml that was raised to 4.0 microg/ml 3 minutes later; patients in Group S3 received an infused scheme of 3 steps; starting from a target plasma concentration of 2.0 microg/ml that was increased stepwised by 1 microg/ml until a target plasma concentration of 4.0 microg/ml was achieved, the interval between the two steps was 3 minutes. When an Observer's Assessment of Alertness/Sedation (OAA/S) score of 1 was achieved, remifentanil (effect-site concentration (Ce) of 4.0 ng/ml) and rocuronium 0.9 mg/kg were administered. Tracheal intubation was started 2 minutes after rocuronium injection. Changes of propofol Ce, blood pressure (BP), heart rate (HR), and bispectral index (BIS) were recorded.

RESULTSWhen an OAA/S score of 1 was achieved, Ce of propofol were (1.7 +/- 0.4) microg/ml, (1.9 +/- 0.3) microg/ml, (1.9 +/- 0.4) microg/ml and the BIS values were 64 +/- 5, 65 +/- 8, and 62 +/- 8 in Groups S1, S2 and S3. Before intubation, Ce of propofol was (2.8 +/- 0.2) microg/ml, (2.8 +/- 0.3) microg/ml, (2.7 +/- 0.3) microg/ml, and the BIS values were 48 +/- 7, 51 +/- 7, and 47 +/- 5 in Groups S1, S2 and S3. By linear regression analysis, a significant correlation between Ce of propofol and BIS values was found (r = -0.580, P < 0.01). Systolic blood pressure (SBP) before intubation was significantly lower in Group S1 than in Groups S2 and S3. SBP and HR after intubation in the three groups were significantly increased when compared with pre-intubation values, but they did not exceed baseline values.

CONCLUSIONSDuring the TCI induction, Ce of propofol with (1.9 +/- 0.3) microg/ml may make the elderly patients unconscious. When remifentanil with a Ce of 4.0 ng/ml is added a Ce of propofol with (2.8 +/- 0.3) microg/ml is suitable for intubation. The Ce of propofol has a close correlation with the BIS values. Also, a two-step TCI technique seems to be a more suitable method of anesthesia induction in elderly patients compared with the no-stepwise TCI technique and three-step TCI technique.

Aged ; Aged, 80 and over ; Androstanols ; therapeutic use ; Anesthesia, General ; methods ; Anesthesia, Intravenous ; methods ; Anesthetics, Intravenous ; administration & dosage ; pharmacokinetics ; therapeutic use ; Awareness ; physiology ; Female ; Humans ; Infusions, Intravenous ; methods ; Intubation, Intratracheal ; Linear Models ; Male ; Middle Aged ; Neuromuscular Nondepolarizing Agents ; therapeutic use ; Piperidines ; therapeutic use ; Propofol ; administration & dosage ; pharmacokinetics ; therapeutic use