Light and Shadow of Na-Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Points for Improvement Based on Our Clinical Experience.

We analyzed the effect of Na-glucose cotransporter 2 inhibitors (SGLT2-I) in diabetic patients visiting our hospital. The study included 236 patients treated with SGLT2-I alone or with codiabetic drugs for at least two years. We analyzed overtime changes in glycosylated hemoglobin A1c (HbA1c) in the patients by repeated analyses of variance (ANOVA) and evaluated the therapeutic effect. HbA1c levels decreased significantly in the first six months after treatment. Afterward, they leveled off and increased slightly over the next two years. Six months after treatment, the mean (SD) of HbA1c was 8.19 (1.46) %; the mean difference dropped by 0.91%, and HbA1c in mild DM2 did not drop by below 8.0%. Overall, there was only a slight improvement. We performed multivariate logistic regression analysis using a model with or without improvement as the objective variable and several explanatory variables. Na and Hct were significant factors. They increased considerably over six months and then leveled off. eGFR significantly reduced in the hyperfiltration group six months after treatment. The annual decline rate in eGFR was also faster, even in the nonhyperfiltration group than in the healthy subjects, which may be a characteristic of renal clearance in SGLT2-I treatment. In conclusion, SGLT2-I is an excellent antidiabetic, nephroprotective agent to eliminate hyperfiltration, but unfortunately, SGLT2-I alone does not have enough power to reduce blood glucose levels. SGLT2-I, with insulin or insulin secretagogues, enhances insulin resistance, induces hyperinsulinemia, and exacerbates type 2 DM. In contrast, SGLT2-I, with noninsulin antidiabetic agents and a low-carbohydrate diet, may bring better results.

S100A8 and S100A9 are associated with endometrial shedding during menstruation.

Matrix metalloproteinases (MMPs) and their major source, endometrial stromal cells (ESCs), play important roles in menstruation. However, other mechanisms in endometrial shedding may be unexplored. This study focused on four proteins: S100A8 and S100A9 (alarmins) are binding partners and induce MMPs, MMP-3 cycle-dependently plays a key role in the proteolytic cascade, and CD147, which has S100A9 as its ligand, induces MMPs. Immunostaining for these proteins was performed on 118 resected specimens. The percentage and location of each positive reaction in ESCs were measured and compared using Image J. The influence of leukocytes on S100A8 or S100A9 immunopositivity was also examined. From the premenstrual phase, S100A8 and MMP-3 began to have overlapping expressions in ESCs of the superficial layer, and ESC detachment was found within these sites. S100A9 was expressed from the late secretory phase and CD147 already from earlier. Later, the expression sites of S100A9 and CD147 included those of S100A8. Before menstruation, S100A8 or S100A9 expression was not affected by leukocytes. These results suggest that the local formation of S100A8/S100A9 complex, which occurs specifically in ESCs upon progesterone withdrawal, induces the local expression of MMP-3 and serves as a switch to the lysis phase.

Development of the ultra-weak chemiluminescence method based on luminol reaction for use in the detection of ultra-trace levels of blood.

In this study, we focused on ultra-weak chemiluminescence (uwCL) measurements and aimed to develop a blood detection method at trace levels, that are difficult to observe using a conventional luminol reaction method (visual observation). Furthermore, we investigated sampling methods that could detect trace bloodstains from the field in our laboratory settings. To achieve these highly sensitive detection levels in the uwCL measurements, the optimal measurement conditions were established as follows: the luminol reaction solution chosen was a mixture of 6.0 × 10-3% luminol/1.5 × 10-2% sodium hydroxide solution and 1.5 × 10-2% hydrogen peroxide water (6:1); the temperature in the sample chamber was set to 20 °C; the sample chamber was filled with an oxygen displacement atmosphere; the sample chamber was filled with 3 mL of 0.01% sodium hydroxide solution prior to the experiment, and the measurement wavelength was set to 460 nm. Using the developed method, blood diluted to 12.5 million-fold (8.0 ng equivalent of the absolute weight of whole blood) was detectable, and high linearity (r = 0.9986) between uwCL intensity and whole blood equivalent was observed in the range of 8.0-100 ng. In contrast, the detection limit of the conventional method was 1.0 µg of the whole blood equivalent. Thus, the uwCL method was approximately 125 times more sensitive than the conventional method. In addition, we demonstrated that the sampling method of wiping with a melamine sponge soaked in a 10% sodium dodecyl sulfate solution is effective for sampling evidence materials at an appraisal site suspected of having traces of adhered blood.

In-Hospital Prescription Checking System for Hospitalized Patients with Decreased Glomerular Filtration Rate.

Background: Clinical decision support systems (CDSS) are reported to be useful in preventing dosage errors in renally excreted drugs by alerting hospital pharmacists to inadequate dosages for hospitalized patients with decreased GFR. However, it is unclear whether CDSS can reduce dosage errors in renally excreted drugs in hospitalized patients. To prevent dosage errors in renally excreted drugs, we introduced a prescription checking system (PCS) for in-hospital prescriptions. This retrospective study aimed to evaluate whether a prescription audit by hospital pharmacists using the PCS reduced the rate of dosage errors in renally excreted drugs. Methods: The target drugs were allopurinol, cibenzoline, famotidine, and pilsicainide. Interrupted time series analysis was used to evaluate trends in the 4-weekly dosage error rates over 52 weeks before PCS implementation and 52 weeks after PCS implementation. Results: Before and after PCS implementation, 474 and 331 prescriptions containing one of the targeted drugs, respectively, were generated. The estimated baseline level of the 4-weekly dosage error rates was 34%. The trend before the PCS implementation was stable with no observable trend. The estimated level change from the last point in the pre-PCS implementation to the first point in the PCS implementation was -20% (P<0.001). There was no change in the trend after PCS implementation. Conclusions: We demonstrated that a prescription audit by hospital pharmacists using the PCS reduced the rate of dosage errors in the target renally excreted drugs in hospitalized patients. Although further studies are needed to confirm whether our results can be generalized to other health facilities, our findings highlight the need for a PCS to prevent the overdose of renally excreted drugs.

Prediction Accuracy of Area under the Concentration-Time Curve of Vancomycin by Bayesian Approach Using Creatinine-Based Equations of Estimated Kidney Function in Bedridden Elderly Japanese Patients.

An administration plan for vancomycin (VCM) in bedridden elderly patients has not been established. This retrospective study aimed to evaluate the prediction accuracy of the area under the concentration-time curve (AUC) of VCM by the Bayesian approach using creatinine-based equations of estimated kidney function in such patients. Kidney function was estimated using the Japanese equation of estimated glomerular filtration rate (eGFR) and the Cockcroft-Gault equation of estimated creatinine clearance (eCCr). eCCr (serum creatinine (SCr) + 0.2) was calculated by substituting the SCr level +0.2 mg/dL into the Cockcroft-Gault equation. For eGFR/0.789, eGFR, eCCr, and eCCr (SCr + 0.2), the AUC values were calculated by the Bayesian approach using the therapeutic drug monitoring (TDM) software, BMs-Pod (ver 8.06) and denoted as AUCeGFR/0.789, AUCeGFR, AUCeCCr, and AUCeCCr (SCr + 0.2) respectively. The reference AUC (AUCREF) was calculated by applying VCM's peak and trough steady-state concentrations to first-order pharmacokinetic equations. The medians (range) of AUCeGFR/0.789/AUCREF, AUCeGFR/AUCREF, AUCeCCr/AUCREF, and AUCeCCr (SCr + 0.2)/AUCREF were 0.88 (0.74-0.93), 0.90 (0.79-1.04), 0.92 (0.81-1.07), and 1.00 (0.88-1.11), respectively. Moreover, the percentage of patients within 10% of the AUCREF, defined as |Bayesian-estimated AUC - AUCREF| < AUCREF × 0.1, was the highest (86%) in AUCeCCr (SCr + 0.2). These results suggest that the Bayesian approach using eCCr (SCr + 0.2) has the highest prediction accuracy for the AUCREF in bedridden elderly patients. Although further studies are required with more accurate determination methods of the CCr and AUC, our findings highlight the potential of eCCr (SCr + 0.2) for estimating VCM's AUC by the Bayesian approach in such patients.

A Case of Colonic Micropapillary Carcinoma with a High Frequency of Apoptosis.

Colorectal micropapillary carcinoma (MPC) exhibits aggressive biological characteristics, with empty spaces and reversed polarity, similar to the poorly differentiated clusters (PDCs) formed from detached cancer cells. Epithelial-mesenchymal transition, which is involved in the cancer cell acquisition of apoptosis resistance, is closely linked with histological findings of MPC, PDCs, and tumor buds (TBs), with MPC and TBs considered as apoptosis-resistant features. However, we encountered a case of colonic MPC with frequent apoptosis. We examined the case using immunohistochemistry. In many of the tumor glands (TGs) of the MPC, empty spaces and tumor cell detachment toward the gland interior were observed. Moreover, TG ruptures were scattered, with PDCs adjacent to them. Apoptosis occurred mainly at the TG and PDC peripheries in the middle and deep tumor layers, and transforming growth factor beta 1 (TGF-ß1) positivity was evident in those tumor cells. Cells positive for apoptosis-related M30 were distributed mainly in the deep layer with a significant PDC and TB presence. However, apoptosis and M30 positivity were low in the TBs. Non-tumorous bud components, especially those in the deep layer, had poor ability to promptly acquire apoptosis resistance. No nuclear ß-catenin positivity was found in any of the tumor cells. Apoptosis has the potential to reciprocally produce MPC, PDCs, and TBs, with TGF-ß1 involvement.

Membranous S100A10 involvement in the tumor budding of colorectal cancer during oncogenesis: report of two cases with immunohistochemical analysis.

BACKGROUND: Tumor budding (TB) and poorly differentiated clusters (PDCs) are a sequence of histologic findings that predict worse prognosis and node metastasis in colorectal cancer (CRC). TB and PDC (TB/PDC) are caused by cancer cell detachment and are distinguished by the number of cancer cells that constitute a cell cluster. In short, PDC is regarded as the previous step of TB. TB/PDC and epithelial-mesenchymal transition (EMT) are closely linked, but its pathogenic mechanisms are still unclear. S100A10, a member of the S100 protein family, forms a heterocomplex with annexin A2 (ANX A2) and then translocates to cell membrane from the cytoplasm and plays various roles in cell dynamics, including plasminogen activation. S100A10 is the activation modulator of the heterocomplex and promotes cell invasion. S100A10 is involved in the remodeling of both actin and extracellular matrix (ECM), which is also associated with EMT. CASE PRESENTATION: In two representative cases of conventional advanced CRC, we immunohistochemically examined S100A10 and ANX A2 expressions in which both TB and PDC were prominent. Both CRCs metastasized to multiple regional lymph nodes. In both cases, a membranous positivity for S100A10 was diffusely found in both tumor buds and PDCs and was observed in the tumor cells protruding toward the stroma, giving rise to TB/PDC. However, even in tumor glands with TB/PDC, the tumor cells with a smooth border around the stroma showed either cytoplasmic fine-granular expression or no positivity. The immunoreactivity for ANX A2 was almost the same as that for S100A10. In the main tumor components without TB/PDC, no distinct positivity was detected at their smooth borders. CONCLUSIONS: During oncogenesis, membranous S100A10 has the potential to be related to TB of CRC. This may be due to plasminogen activation, actin remodeling, and interaction with an altered ECM. However, further study is required to confirm this hypothesis.

Rational Design of Monodispersed Mutants of Proteins by Identifying Aggregation Contact Sites Using Solubilizing Agents.

Suppression of protein aggregation is a subject of growing importance in the treatment of protein aggregation diseases, an urgent worldwide human health problem, and the production of therapeutic proteins, such as antibody drugs. We previously reported a method to identify compounds that suppress aggregation, based on screening using multiple terminal deletion mutants. We now present a method to determine the aggregation contact sites of proteins, using such solubilizing compounds, to design monodispersed mutants. We applied this strategy to the chemokine receptor-binding domain (CRBD) of FROUNT, which binds to the membrane-proximal C-terminal intracellular region of CCR2. Initially, the backbone NMR signals were assigned to a certain extent by available methods, and the putative locations of five α-helices were identified. Based on NMR chemical shift perturbations upon varying the protein concentrations, the first and third helices were found to contain the aggregation contact sites. The two helices are amphiphilic, and based on an NMR titration with 1,6-hexanediol, a CRBD solubilizing compound, the contact sites were identified as the hydrophobic patches located on the hydrophilic sides of the two helices. Subsequently, we designed multiple mutants targeting amino acid residues on the contact sites. Based on their NMR spectra, a doubly mutated CRBD (L538E/P612S) was selected from the designed mutants, and its monodispersed nature was confirmed by other biophysical methods. We then assessed the CCR2-binding activities of the mutants. Our method is useful for the protein structural analyses, the treatment of protein aggregation diseases, and the improvement of therapeutic proteins.

Involvement of Annexin A2 Expression and Apoptosis in Reverse Polarization of Invasive Micropapillary Carcinoma of the Breast.

Invasive micropapillary carcinoma (IMPC) is characterized by pseudopapillary tumor-cell clusters with a reverse polarity (RP) floating in lacunar spaces, with aggressive biological characteristics. The RP prevention is considered to inhibit IMPC, but its pathogenic mechanisms remain unclear. Annexin A2 (ANX A2), a cell-polarity protein, is known to be involved in lumenogenesis. ANX A2 expression is immunohistochemically examined, as well as both epithelial membrane antigen (EMA) and mucin-1 glycoprotein (MUC-1), the gold-standard markers for luminal differentiation, in the background tumor components of a case of IMPC. The following findings were noticed: (1) Apoptosis was scattered with peripheral apoptotic vacuolar change; (2) EMA and MUC-1 expressions were found, rimming the peripheral apoptotic vacuoles (including the contact surface with neighboring tumor cells), and these positions corresponded to the ones with a distinct ANX A2 positivity; and (3) partially detached tumor cells showed distinct positivity of three proteins at the stroma-facing surface, which is consistent with a RP. Taken together, frequent apoptosis in tumor cells with membranous accumulation of ANX A2 is considered to be indispensable for the reverse polarization of IMPC, and that secondary necrosis following apoptosis induces the cell-polarity disorder and creates detached tumor cells with a RP.

Annexin A2 Expression in the Aerogenous Spread of Pulmonary Invasive Mucinous Adenocarcinoma with Gastric Lineage.

Spread through air spaces (STAS) is a unique form of lung cancer progression associated with a worse prognosis. However, the mechanisms underlying STAS and the associated proteins remain unclear. Annexin A2 (ANX A2), which is a membrane-binding protein involved in cell adhesion, is known to promote cancer invasion. In this report, we describe the immunohistochemical analysis of ANX A2 expression in an invasive mucinous adenocarcinoma (IMAC) resected from a 63-year-old man in whom the tumor cells had detached from the alveolar wall and exhibited STAS. At the detachment site, we observed cytoplasmic ANX A2 positivity on the basal side and in the exfoliative gap, as well as reduced collagen IV positivity expression. This biomarker pattern suggested an IMAC with gastric lineage. We hypothesize that ANX A2 is secreted from the basal sides of tumor cells and induces tumor cell detachment by degrading the basement membrane. A further comparison of this case with an IMAC with nongastric lineage suggested the following probabilities: (1) ANX A2 likely contributes to STAS in a manner that is dependent on its subcellular localization. (2) Both the subcellular localization of ANX A2 and the detachment site depend on tumor cell characteristics, including the biomarker immunophenotype.

Membranous overexpression of S100A10 is associated with a high-grade cellular status of breast carcinoma.

S100A10 promotes tumor invasion in various cancers. Although genetic studies on S100A10 in breast carcinoma (BC) have been used for molecular biological classification, immunohistochemical studies are lacking. We aimed to identify the correlation between S100A10 expression in BC and various pathological parameters, including morphological features to determine histological grade (HG). Immunostained serial paraffin-embedded tissue sections from 176 cases of resected BC or normal mammary ducts (controls) were assessed for the membrane expression of S100A10. Of the 176 cases, 125 conventional infiltrating ductal carcinomas were chosen, comprising 67 (53.6%) S100A10-positive tumors, whereas normal mammary ducts were S100A10-negative. S100A10 immunoreactivity in ductal carcinoma in situ (n = 51) was similar to that of invasive carcinoma. The distinct membrane-immunopositivity was correlated with high HG, severe nuclear pleomorphism, frequent mitotic counts, high Ki-67 labeling index, HER2/neu overexpression, and low estrogen receptor status (P < 0.05), but not with tubular formation, pT categories, node metastasis, vessel permeation, and pStage. Membrane overexpression of S100A10 in BC correlates with the high-grade morphological and molecular status of the carcinoma cell rather than stromal invasion and architectural deviation. Evidence points to the use of S100A10 as a biomarker representing a high-grade cellular status of BC.

1H, 13C and 15N resonance assignments for a chemokine receptor-binding domain of FROUNT, a cytoplasmic regulator of chemotaxis.

FROUNT is a cytoplasmic protein that interacts with the membrane-proximal C-terminal regions (Pro-Cs) of the CCR2 and CCR5 chemokine receptors. The interactions between FROUNT and the chemokine receptors play an important role in the migration of inflammatory immune cells. Therefore, FROUNT is a potential drug target for inflammatory diseases. However, the structural basis of the interactions between FROUNT and the chemokine receptors remains to be elucidated. We previously identified the C-terminal region (residues 532-656) of FROUNT as the structural domain responsible for the Pro-C binding, referred to as the chemokine receptor-binding domain (CRBD), and then constructed its mutant, bearing L538E/P612S mutations, with improved NMR spectral quality, referred to as CRBD_LEPS. We now report the main-chain and side-chain 1H, 13C, and 15N resonance assignments of CRBD_LEPS. The NMR signals of CRBD_LEPS were well dispersed and their intensities were uniform on the 1H-15N HSQC spectrum, and thus almost all of the main-chain and side-chain resonances were assigned. This assignment information provides the foundation for NMR studies of the three-dimensional structure of CRBD_LEPS in solution and its interactions with chemokine receptors.

Efficient identification of compounds suppressing protein precipitation via solvent screening using serial deletion mutants of the target protein.

The control of protein solubility is a subject of broad interest. Although several solvent screening methods are available to search for compounds that enhance protein solubilization, their performance is influenced by the intrinsic solubility of the tested protein. We now present a method for screening solubilizing compounds, using an array of N- or C-terminal deletion mutants of the protein. A key behind this approach is that such terminal deletions of the protein affect its aggregation propensity. The solubilization activities of trial solvents are individually assessed, based on the number of solubilized mutants. The solubilizing compounds are then identified from the screened solvents. In this study, the C-terminal chemokine receptor-binding region of the cytoplasmic protein, FROUNT (FNT-C), which mediates intracellular signals leading to leukocyte migration, was subjected to the multicomponent screening. In total, 192 solution conditions were tested, using eight terminal deletion mutants of FNT-C. We identified five solvent conditions that solubilized four or five mutants of FNT-C, and the compounds in the screened solvents were then, respectively, assessed in terms of their solubilization ability. The best compound for solubilizing FNT-C was 1,6-hexanediol. Indeed, 1,6-hexanediol bound to FNT-C and suppressed its precipitation, as showed by NMR and dynamic light scattering analyses.

Identification and Preparation of a Novel Chemokine Receptor-Binding Domain in the Cytoplasmic Regulator FROUNT.

FROUNT is a cytoplasmic protein that binds to the membrane-proximal C-terminal regions (Pro-Cs) of chemokine receptors, CCR2 and CCR5. The FROUNT-chemokine receptor interactions play a pivotal role in the migration of inflammatory immune cells, indicating the potential of FROUNT as a drug target for inflammatory diseases. To provide the foundation for drug development, structural information of the Pro-C binding region of FROUNT is desired. Here, we defined the novel structural domain (FNT-CB), which mediates the interaction with the chemokine receptors. A recombinant GST-tag-fused FNT-CB protein expression system was constructed. The protein was purified by affinity chromatography and then subjected to in-gel protease digestion of the GST-tag. The released FNT-CB was further purified by anion-exchange and size-exclusion chromatography. Purified FNT-CB adopts a helical structure, as indicated by CD. NMR line-broadening indicated that weak aggregation occurred at sub-millimolar concentrations, but the line-broadening was mitigated by using a deuterated sample in concert with transverse relaxation-optimized spectroscopy. The specific binding of FNT-CB to CCR2 Pro-C was confirmed by the fluorescence-based assay. The improved NMR spectral quality and the retained functional activity of FNT-CB support the feasibility of further structural and functional studies targeted at the anti-inflammatory drug development.

Predictive factors for effectiveness and safety of enoxaparin for total knee arthroplasty in aged Japanese patients: a retrospective review.

BACKGROUND: The aims of this study were to investigate predictive factors involved in effectiveness and safety of enoxaparin for prevention of postoperative venous thromboembolism in aged Japanese total knee arthroplasty (TKA) patients. METHODS: Japanese patients over 65 years old who were administered enoxaparin for TKA were enrolled in this study. Their medical records were retrospectively reviewed. Data were corrected at the Izumi Regional Medical Center, from September 2009 to March 2014. Patients were stratified into groups according to whether enoxaparin was effective (no deep vein thrombosis event up to postoperative day 7) or not, and whether they had an adverse drug event (ADE) or not. RESULTS: A total of 128 patients were included in this study. One hundred five (82.0%) patients were in the effective group and 20 (15.6%) in the adverse drug event (ADE) group. Anemia (13 patients), abnormalities in liver function tests (4 patients), clinically relevant non-major bleeding (4 patients) and urticaria (1 patient) were observed as ADEs. Multivariate logistic regression analysis showed that the serum total protein level at postoperative day 1 (POD1, before enoxaparin administration), was associated with effectiveness of enoxaparin, while the serum total protein and hemoglobin level at POD1 were involved in ADE caused by enoxaparin. CONCLUSIONS: Although further large scale studies will be warranted, our results suggest that serum total protein level just before enoxaparin treatment for TKA relates to the effectiveness and safety of enoxaparin in a Japanese aged population. In addition, the results indicate that the development of anemia should be carefully monitored during enoxaparin treatment for TKA, particularly in patients with lower levels of serum hemoglobin before treatment.

[How to Apply Bayesian Theorem to the Evaluation of Myocardial Injury by Measuring High Sensitive Cardiac Troponins in the Patients with Suspected Acute Myocardial Infarction].

118 consecutive patients of suspected acute myocardial infarction with acute chest pain and shortness of breath visiting our emergency room were subjected for this clinical study. Based on final diagnosis of acute myocardial infarction (AMI) comprehensively determined by medical record, physical examination, ECG, echocardiography, cardiac catheterization, etc., except for cardiac biomarkers, the patients were classified into two groups, with AMI group (1) and without AMI group (0) and then ROC curve analysis was performed between without AMI group (1) and with AMI group (0). As a result of ROC curve analysis, AUC, cutoff value, sensitivity, specificity and likelihood ratio (LR) were calculated as shown in Fig. 4 (1-7) and Table 2 (1-7). Based on calculating equation led from Bayesian rules, post-test odds were calculated as product of pre-test odds and LR at the cutoff value in each biomarker such as hsCTnT, hsCTnI, h-FABP CK, CKMB activity and CKMB mass. As a result, post-test probability was improved from predictive pre-test probability 30% to post-test probability 89% and 86% in hsCTnT and hsTnI, respectively but less improved from 30% to 68% in h-FABP and unexpectedly improved from 30% to 82% in CKMB mass compared with hsCTnT and hsTnI. Based on Bayesian rule, it is very valuable to predict post-test probability from predictive pre-test probability 30% by calculation in particular, when post-test probability is over 85-90%. In conclusion, we believe that prediction of post-test probability by Bayesian rule can be surely used to evaluate clinical quality of biomarkers which are not depend on at least, specialty and experience of physicians.

Peripheral Vitamin C Levels in Alzheimer's Disease: A Cross-Sectional Study.

We previously reported lower lymphocyte vitamin C levels in individuals with type 2 diabetes mellitus and in individuals with severe Parkinson's disease. Oxidative stress has been proposed to play a key role in the progression of Alzheimer's disease. Thus, the objective of this study was to investigate the association between peripheral levels of vitamin C and the progression of cognitive dysfunction in Alzheimer's disease. Fifty individuals with Alzheimer's disease being treated at Shizuoka General Hospital were consecutively enrolled in this study from December 2009 to March 2015 (76.0±9.7 y of age [mean±SD]; 32 men and 18 women; Mini-Mental State Examination Japanese version (MMSE-J) score range, 8-27). Plasma and lymphocyte vitamin C levels in fasting blood samples were measured. The association between the MMSE-J scores and vitamin C levels was estimated using Spearman's rank correlation coefficient (ρ) and the criteria defined by Swinscow. Spearman's ρ for the relationship between peripheral vitamin C levels and the MMSE-J score was ρ=0.17 for plasma vitamin C and ρ=0.26 for lymphocyte vitamin C. Thus, the associations were relatively weak based on the criteria. In contrast with type 2 diabetes mellitus and Parkinson's disease, lymphocyte vitamin C levels in the peripheral blood may not directly reflect the progression of cognitive dysfunction in Alzheimer's disease. Additional longitudinal studies are needed to evaluate the clinical importance of changes of peripheral vitamin C status in Alzheimer's disease.

Factors affecting serum albumin in the perioperative period of colorectal surgery: a retrospective study.

BACKGROUND: Albumin is considered a negative acute-phase protein because its concentration decreases during injury and sepsis. Hypoalbuminemia is a risk factor for mortality, postoperative complications, and prolonged hospital stay. The magnitude of the systemic inflammatory response during the perioperative period, as indicated by the acute-phase proteins-C-reactive protein (CRP) in particular-, may help identify the risk of postoperative infectious complication. The correlation between serum albumin and CRP with gastrointestinal cancer has been reported. However, it is unclear whether antecedent CRP could be utilized to predict future hypoalbuminemia in the perioperative period in colorectal surgery. The primary endpoint of this study was to reveal that antecedent CRP could be utilized to predict future hypoalbuminemia in the perioperative period of colorectal surgery. METHODS: Thirty-seven patients who underwent elective open colorectal surgery were included in this study. Correlations between preoperative CRP and serum albumin on postoperative day (POD) 3, between preoperative CRP and serum albumin on POD 7 and between CRP on POD 3 and serum albumin on POD 7 were examined. Relationships between preoperative CRP and hypoalbuminemia on POD 3, between preoperative CRP and hypoalbuminemia on POD 7 and between CRP on POD 3 and hypoalbuminemia on POD 7 were examined by receiver operating characteristic analysis. RESULTS: Three-quarters of patients were older than 65 years of age. Significant correlations were observed between preoperative CRP and serum albumin on POD 3 (p = 0.023), between preoperative CRP and serum albumin on POD 7 (p = 0.023) and between CRP on POD 3 and serum albumin on POD 7 (p < 0.001). The area under the receiver operating characteristic curve of CRP on POD 3 to development of hypoalbuminemia on POD 7 was 0.833 (95 % CI 0.679-0.987) with an optimal threshold of 12.43 mg/dL, sensitivity 75 % and specificity 80 %. CONCLUSIONS: The present study revealed that antecedent CRP was associated with future serum albumin. Additionally, CRP on POD 3 could be useful in predicting the development of hypoalbuminemia on POD 7. This result suggests that CRP on POD 3 may be a valuable indicator for early nutritional intervention.

Serum cystatin C as a better marker of vancomycin clearance than serum creatinine in elderly patients.

OBJECTIVES: The purpose of this study is to assess the usefulness of the concentration of cystatin C (Cys-C) in serum for predicting the clearance of vancomycin (CLvcm) compared with the serum concentration of creatinine (SCr) in the elderly. METHODS: Thirty-nine serum samples were obtained from 24 elderly patients (65 years and older). Creatinine clearance (CLcr) and the glomerular filtration rate calculated from the concentration of Cys-C (GFRcys-c) were estimated using Cockcroft & Gault's formula and Larsson's formula, respectively. RESULTS: The correlation constant for CLvcm and the reciprocal of Cys-C (p=0.883) was significantly higher than that for CLvcm and the reciprocal of SCr (p=0.575, p<0.005). GFRcys-c was strongly correlated with CLvcm (p=0.883) and the constant was significantly higher than that for the correlation between CLvcm and CLcr (p=0.684, p<0.05). These results suggest that the serum concentration of Cys-C is a more reliable marker for predicting CLvcm than is SCr in elderly patients.